Detection Threshold and Reproducibility of 68Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer
Detection Threshold and Reproducibility of 68Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer
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DOI：
10.2967/jnumed.118.207704
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发表时间：
2018-09-01
影响因子：
9.3
通讯作者：
Fendler, Wolfgang P.
中科院分区：
文献类型：
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作者：
Luckerath, Katharina;Stuparu, Andreea D.;Fendler, Wolfgang P.
为了改进前列腺特异性膜抗原（PSMA）靶向治疗诊断方法，需要强大的前列腺癌小鼠模型。然而，临床前 PSMA 成像的重要特征，即成像信号的再现性以及定量细胞表面 PSMA 表达与小动物 PET/CT 病变可检测性之间的关系尚未确定。方法：在第 0 天将表达不同水平的人 PSMA 的鼠前列腺癌 RM1 亚系（C57BL/6 前列腺来源的 ras myc 转化细胞）注射到 C57BL/6 小鼠的肩部。在第 7 天和第 8 天进行 Ga-68-PSMA11 PET/CT，并由 2 位蒙面读数器进行判读，以确定日间和读数器间的再现性。在第 7 天和第 8 天通过细针抽吸肿瘤活检样本的流式细胞术对 PSMA 表达进行定量。细胞表面 PSMA 表达与 PET 信号相关。 PET 阳性阈值基于临床前列腺癌分子影像标准化评估 (PROMISE) 标准。结果：每克组织注射的 Ga-68-PSMA11 活性的最大百分比和平均百分比 (% IA/g) 几乎完全相关，由 2 位独立读者在 2 个不同的天确定（组内相关系数分别为 1.00/0.89 和 0.95/0.88）。每个细胞的 PSMA 分子数量从 RM1-黄色荧光蛋白亚系（PSMA(-)；2,000/细胞）增加到 RM1-低亚系（PSMA1；17,000/细胞）、RM1-中亚系（PSMA(++)；22,000/细胞）和 RM1-PGLS 亚系（PSMA 阳性、绿色荧光蛋白阳性、和 荧光素酶阳性； PSMA（+++）； 45,000/细胞）。表达水平与 Ga-68-PSMA11 PET 的视觉阳性率和 PSMA PET % IA/g 相关。 PET 阳性的 PSMA 阈值约为每个细胞 20,000。信号相关性在较低 PSMA 水平（RM1-低至 RM1-中；10-23 % IA/g）时接近，但在较高 PSMA 水平（RM1-中至 RM1-PGLS；23-27 % IA/g）时消失。结论：在前列腺癌小鼠模型中，Ga-68-PSMA11 PET/CT 与 PSMA 表达水平之间的体内关系对于较低的细胞表面 PSMA 表达水平而言是稳健的（
To improve prostate-specific membrane antigen (PSMA)-targeted theranostic approaches, robust murine models of prostate cancer are needed. However, important characteristics of preclinical PSMA imaging-that is, the reproducibility of the imaging signal and the relationship between quantitative cell surface PSMA expression and lesion detectability with small-animal PET/CT-have not been defined yet. Methods: Murine prostate cancer RM1 sublines (ras myc transformed cells of C57BL/6 prostate origin) expressing varying levels of human PSMA were injected into the shoulder of C57BL/6 mice on day 0. Ga-68-PSMA11 PET/CT was performed on days 7 and 8 and interpreted by 2 masked readers to determine interday and interreader reproducibility. PSMA expression was quantified on days 7 and 8 by flow cytometry of fine-needle aspiration tumor biopsy samples. Cell surface PSMA expression was correlated with PET signal. The threshold for PET positivity was based on the clinical Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. Results: The maximum and average percentages of injected Ga-68-PSMA11 activity per gram of tissue (% IA/g) correlated nearly perfectly as determined by 2 independent readers and on 2 separate days (intraclass correlation coefficient, 1.00/0.89 and 0.95/0.88, respectively). The number of PSMA molecules per cell increased from the RM1-yellow fluorescent protein subline (PSMA(-); 2,000/cell) to the RM1-low subline (PSMA1; 17,000/cell), the RM1-medium subline (PSMA(++); 22,000/cell), and the RM1-PGLS subline (PSMA-positive, green fluorescent protein-positive, and luciferase-positive; PSMA(+++); 45,000/cell). Expression levels correlated with the visual positivity rate on Ga-68-PSMA11 PET and with the PSMA PET % IA/g. The PSMA threshold for PET positivity was approximately 20,000 per cell. Signal correlation was close at lower PSMA levels (RM1-low to RM1-medium; 10-23 % IA/g) but was lost at higher PSMA levels (RM1-medium to RM1-PGLS; 23-27 % IA/g). Conclusion: The in vivo relationship between Ga-68-PSMA11 PET/CT and PSMA expression level in a murine model of prostate cancer was robust for lower cell surface PSMA expression levels (