The clinical course for patients with neuroendocrine neoplasms (NENs) ranges from indolent to highly aggressive. Noninvasive tools to improve prognostication and guide decisions on treatment are warranted. Expression of urokinase plasminogen activator receptor (uPAR) is present in many cancer types and associated with a poor outcome. Therefore, using an in-house–developed uPAR PET tracer [⁶⁸Ga]Ga-NOTA-Asp-Cha-Phe-D-Ser-D-Arg-Tyr-Leu-Trp-Ser-OH (⁶⁸Ga-NOTA-AE105), we aimed to assess uPAR expression in NENs. We hypothesized that uPAR expression was detectable in a significant proportion of patients and associated with a poorer outcome. In addition, as uPAR-targeted radionuclide therapy has previously proven effective in preclinical models, the study would also indicate the potential for uPAR-targeted radionuclide therapy in NEN patients. Methods: In a prospective clinical phase II trial, we included 116 patients with NENs of all grades, of whom 96 subsequently had uPAR PET/CT performed with evaluable lesions. PET/CT was performed 20 min after injection of approximately 200 MBq of ⁶⁸Ga-NOTA-AE105. uPAR target-to-liver ratio was used to define lesions as uPAR-positive when lesion SUV_max–to–liver SUV_mean ratio was at least 2. Patients were followed for at least 1 y to assess progression-free and overall survival. Results: Most patients had small intestinal NENs (n = 61) and metastatic disease (n = 86). uPAR-positive lesions were seen in 68% (n = 65) of all patients and in 75% (n = 18) of patients with high-grade (grade 3) NENs. During follow-up (median, 28 mo), 59 patients (62%) experienced progressive disease and 28 patients (30%) died. High uPAR expression, defined as a uPAR target-to-liver ratio above median, had a hazard ratio of 1.87 (95% CI, 1.11–3.17) and 2.64 (95% CI, 1.19–5.88) for progression-free and overall survival, respectively (P < 0.05 for both). Conclusion: When ⁶⁸Ga-NOTA-AE105 PET was used to image uPAR in patients with NENs, uPAR-positive lesions were seen in most patients, notably in patients with both low-grade and high-grade NENs. Furthermore, uPAR expression was associated with a worse prognosis. We suggest that uPAR PET is relevant for risk stratification and that uPAR may be a promising target for therapy in patients with NENs.

神经内分泌肿瘤 (NEN) 患者的临床病程从惰性到高度侵袭性不等。改善预后和指导治疗决策的无创工具是必要的。尿激酶纤溶酶原激活物受体 (uPAR) 的表达存在于许多癌症类型中，并且与不良结果相关。因此，使用内部开发的 uPAR PET 示踪剂 [ ⁶⁸ Ga]Ga-NOTA-Asp-Cha-Phe-D-Ser-D-Arg-Tyr-Leu-Trp-Ser-OH ( ⁶⁸Ga-NOTA-AE105)，我们旨在评估 NEN 中的 uPAR 表达。我们假设在很大一部分患者中可检测到 uPAR 表达，并且与较差的结果相关。此外，由于 uPAR 靶向放射性核素治疗先前已在临床前模型中证明有效，该研究还将表明 uPAR 靶向放射性核素治疗在 NEN 患者中的潜力。方法：在一项前瞻性临床 II 期试验中，我们纳入了 116 名所有级别的 NEN 患者，其中 96 名随后接受了 uPAR PET/CT 评估病灶。^{在注射大约 200 MBq 的68} Ga-NOTA-AE105后 20 分钟进行 PET/CT 。uPAR 靶肝比值用于将病变定义为 uPAR 阳性，当病变 SUV 达到肝脏 SUV 最大值_时平均比率至少为 2。随访患者至少 1 年以评估无进展生存期和总生存期。结果：大多数患者患有小肠 NEN（n = 61）和转移性疾病（n = 86）。uPAR 阳性病变见于 68% ( n = 65) 的所有患者和 75% ( n = 18) 的高级别（3 级）NEN 患者。在随访期间（中位时间，28 个月），59 名患者 (62%) 出现疾病进展，28 名患者 (30%) 死亡。高 uPAR 表达，定义为高于中位数的 uPAR 靶肝比，对于无进展生存和总生存的风险比分别为 1.87（95% CI，1.11-3.17）和 2.64（95% CI，1.19-5.88） ，分别（两者P < 0.05）。结论：当使用⁶⁸ Ga-NOTA-AE105 PET 对 NEN 患者的 uPAR 成像时，在大多数患者中可以看到 uPAR 阳性病变，特别是在低级别和高级 NEN 患者中。此外，uPAR 表达与较差的预后相关。我们建议 uPAR PET 与风险分层相关，并且 uPAR 可能是 NEN 患者治疗的有希望的目标。