From the Advanced Imaging Research Center.
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Charlestown.
Invest Radiol. 2021 Jul 1;56(7):450-457. doi: 10.1097/RLI.0000000000000760.
In the United States, prostate cancer (PCa) is the most common cancer in men. Multi-parametric magnetic resonance imaging (MRI) is increasingly being relied upon for the diagnosis and characterization of PCa, but differentiating malignancy from benign prostatic hyperplasia (BPH) in the transition zone using MRI can be challenging. The characteristically high levels of zinc in human prostate tissue and a close relationship between malignant proliferation and zinc homeostatic dysregulation create opportunities to visualize PCa with novel contrast media. In mouse models, glucose-stimulated zinc secretion (GSZS) can be preferentially observed in healthy prostate tissue compared with malignant tissue; in vivo, these differences can be captured with MRI by using Gdl1, a gadolinium-based zinc-responsive contrast agent. In this study, we examined whether this technology can be applied in a large animal model by imaging older dogs with clinically diagnosed BPH.
Four intact male dogs 6 years or older with enlarged prostates were imaged (T1-weighted turbo spin-echo, TE/TR, 12/400 milliseconds and T2-weighted, TE/TR, 112/5000 milliseconds) using a 3 T scanner before and at multiple time points after intravenous injection of 0.05 mmol/kg GdL1 plus either (a) 2 mL/kg of 50% dextrose in 1 session or (b) 2 mL/kg normal saline in another session. The two sessions were one week apart, and their order was randomly determined for each dog. During postprocessing, regions of interest were generated in prostate tissue and in paraspinal muscles to evaluate the contrast-to-noise ratio (CNR). The ratio of CNR at any postinjection time point compared with baseline CNR was defined as r-CNR. After the second imaging session, the dogs were euthanized, and their prostates were harvested for histopathological examination. Baseline and postintervention plasma and urine samples were analyzed for total zinc by inductively coupled plasma mass spectrometry.
The mean ± SD r-CNR values at 13 minutes postinjection in the dextrose versus saline imaging sessions were 134% ± 10% and 127% ± 7%, respectively (P < 0.01). The histopathologic evaluation of prostate tissues confirmed BPH in all dogs. Interestingly, prostatic intraepithelial neoplasia was detected in 1 animal, and a suspicious mass was found in the same region on T2-weighted scans. The r-CNR of the mass was calculated as 113% ± 4% and 111% ± 6% in the dextrose and saline groups, respectively, with no significant differences between the 2 interventions (P = 0.54), whereas there was a statistically significant difference between the r-CNR of the whole prostate in the dextrose (130% ±11%) and saline (125% ± 9%) interventions (P = 0.03). Inductively coupled plasma mass spectrometry analyses showed a significantly higher urinary zinc in the dextrose versus saline groups, but no differences were found in plasma zinc levels.
T1-weighted MRI of the enlarged canine prostate showed higher r-CNR after injection of GdL1 plus dextrose compared with GdL1 plus saline, consistent with GSZS from BPH tissues. One small region of neoplastic tissue was identified in a single dog on the basis of less GSZS from that region by MRI. These findings suggest a new method for the detection of PCa by MRI that could facilitate the differentiation of BPH from PCa in the transition zone.
在美国，前列腺癌（PCa）是男性中最常见的癌症。多参数磁共振成像（MRI）越来越多地用于 PCa 的诊断和特征描述，但在过渡区使用 MRI 区分恶性肿瘤和良性前列腺增生（BPH）可能具有挑战性。人类前列腺组织中锌含量高，以及恶性增殖与锌稳态失调之间的密切关系，为使用新型对比剂可视化 PCa 提供了机会。在小鼠模型中，与恶性组织相比，健康前列腺组织中可以优先观察到葡萄糖刺激的锌分泌（GSZS）；在体内，这些差异可以通过使用 Gdl1（一种基于钆的锌反应性对比剂）在 MRI 中捕获。在这项研究中，我们通过对患有临床诊断为 BPH 的老年犬进行成像，检查了这项技术是否可以应用于大型动物模型。
在 3 T 扫描仪上对 4 只年龄在 6 岁或以上、前列腺增大的完整雄性犬进行成像（T1 加权涡轮自旋回波，TE/TR，12/400 毫秒和 T2 加权，TE/TR，112/5000 毫秒），在静脉注射 0.05 mmol/kg GdL1 前后和之后的多个时间点进行成像，分别加入（a）2 mL/kg 50%葡萄糖溶液于 1 次，或（b）2 mL/kg 生理盐水于另一次。两次注射相隔一周，每次注射的顺序由每只狗随机确定。在图像处理过程中，在前列腺组织和脊柱旁肌肉中生成感兴趣区域，以评估对比噪声比（CNR）。定义任何注射后时间点的 CNR 与基线 CNR 的比值为 r-CNR。在第二次成像后，对狗进行安乐死，并采集其前列腺组织进行组织病理学检查。对基线和干预后的血浆和尿液样本进行电感耦合等离子体质谱分析，以测定总锌含量。
在葡萄糖与生理盐水成像组中，注射后 13 分钟时的平均 r-CNR 值分别为 134%±10%和 127%±7%（P＜0.01）。所有犬的前列腺组织的组织病理学评估均证实为 BPH。有趣的是，在 1 只犬中发现了前列腺上皮内瘤变，并且在 T2 加权扫描中同一区域发现了可疑肿块。肿块的 r-CNR 分别为葡萄糖组 113%±4%和生理盐水组 111%±6%，两种干预措施之间无显著差异（P=0.54），而葡萄糖组（130%±11%）和生理盐水组（125%±9%）前列腺整体的 r-CNR 之间存在统计学差异（P=0.03）。电感耦合等离子体质谱分析显示，葡萄糖组的尿锌水平明显高于生理盐水组，但血浆锌水平无差异。
在犬的增大前列腺上进行 T1 加权 MRI 显示，注射 GdL1 加葡萄糖后 r-CNR 高于 GdL1 加生理盐水，这与 BPH 组织中的 GSZS 一致。根据 MRI 对该区域的 GSZS 较少，在一只狗中识别出一个小的肿瘤组织区域。这些发现表明，MRI 检测 PCa 的新方法可以促进过渡区 BPH 与 PCa 的区分。
