Azam Aleena, Kurbegovic Sorel, Carlsen Esben Andreas, Andersen Thomas Lund, Larsen Vibeke André, Law Ian, Skjøth-Rasmussen Jane, Kjaer Andreas
Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital - Rigshospitalet, Blegdamsvej 9, Copenhagen, DK- 2100, Denmark.
Cluster for Molecular Imaging, Department of Biomedical Sciences, Copenhagen University Hospital - Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
EJNMMI Res. 2024 Oct 29;14(1):100. doi: 10.1186/s13550-024-01164-9.
Treatment of patients with low-grade and high-grade gliomas is highly variable due to the large difference in survival expectancy. New non-invasive tools are needed for risk stratification prior to treatment. The urokinase plasminogen activator receptor (uPAR) is expressed in several cancers, associated with poor prognosis and may be non-invasively imaged using uPAR-PET. We aimed to investigate the uptake of the uPAR-PET tracer [Ga]Ga-NOTA-AE105 in primary gliomas and establish its prognostic value regarding overall survival (OS), and progression-free survival (PFS). Additionally, we analyzed the proportion of uPAR-PET positive tumors to estimate the potential number of candidates for future uPAR-PRRT.
In a prospective phase II clinical trial, 24 patients suspected of primary glioma underwent a dynamic 60-min PET/MRI following the administration of approximately 200 MBq (range: 83-222 MBq) [Ga]Ga-NOTA-AE105. Lesions were considered uPAR positive if the tumor-to-background ratio, calculated as the ratio of TumorSUVmax-to-Normal-BrainSUVmean tumor-SUVmax-to-background-SUVmean, was ≥ 2.0. The patients were followed over time to assess OS and PFS and stratified into high and low uPAR expression groups based on TumorSUVmax.
Of the 24 patients, 16 (67%) were diagnosed with WHO grade 4 gliomas, 6 (25%) with grade 3, and 2 (8%) with grade 2. Two-thirds of all patients (67%) presented with uPAR positive lesions and 94% grade 4 gliomas. At median follow up of 18.8 (2.1-45.6) months, 19 patients had disease progression and 14 had died. uPAR expression dichotomized into high and low, revealed significant worse prognosis for the high uPAR group for OS and PFS with HR of 14.3 (95% CI, 1.8-112.3; P = 0.011), and HR of 26.5 (95% CI, 3.3-214.0; P = 0.0021), respectively. uPAR expression as a continuous variable was associated with worse prognosis for OS and PFS with HR of 2.7 (95% CI, 1.5-4.8; P = 0.0012), and HR of 2.5 (95% CI, 1.5-4.2; P = 0.00073), respectively.
The majority of glioma patients and almost all with grade 4 gliomas displayed uPAR positive lesions underlining the feasibility of Ga-NOTA-AE105 PET/MRI in gliomas. High uPAR expression is significantly correlated with worse survival outcomes for patients. Additionally, the high proportion of uPAR positive gliomas underscores the potential of uPAR-targeted radionuclide therapy in these patients.
EudraCT No: 2016-002417-21; the Scientific Ethics Committee: H-16,035,303; the Danish Data Protection Agency: 2012-58-0004; clinical trials registry: NCT02945826, 26Oct2016, URL: https://classic.
gov/ct2/show/NCT02945826 .
由于低级别和高级别胶质瘤患者的生存预期差异很大，其治疗方式高度可变。在治疗前需要新的非侵入性工具进行风险分层。尿激酶型纤溶酶原激活物受体（uPAR）在多种癌症中表达，与预后不良相关，并且可以使用uPAR-PET进行非侵入性成像。我们旨在研究uPAR-PET示踪剂[镓]Ga-NOTA-AE105在原发性胶质瘤中的摄取情况，并确定其对总生存期（OS）和无进展生存期（PFS）的预后价值。此外，我们分析了uPAR-PET阳性肿瘤的比例，以估计未来uPAR-PRRT候选者的潜在数量。
在一项前瞻性II期临床试验中，24例疑似原发性胶质瘤患者在静脉注射约200MBq（范围：83-222MBq）[镓]Ga-NOTA-AE105后接受了60分钟的动态PET/MRI检查。如果肿瘤与背景比值（计算为肿瘤SUVmax与正常脑SUVmean之比，即肿瘤SUVmax与背景SUVmean之比）≥2.0，则病变被认为是uPAR阳性。对患者进行随访以评估OS和PFS，并根据肿瘤SUVmax将其分为uPAR高表达组和低表达组。
24例患者中，16例（67%）被诊断为WHO 4级胶质瘤，6例（25%）为3级，2例（8%）为2级。所有患者中有三分之二（67%）出现uPAR阳性病变，4级胶质瘤患者中这一比例为94%。在中位随访18.8（2.1-45.6）个月时，19例患者出现疾病进展，14例死亡。将uPAR表达分为高表达和低表达，结果显示高uPAR组的OS和PFS预后明显更差，HR分别为14.3（95%CI，1.8-112.3；P=0.011）和26.5（95%CI，3.3-214.0；P=0.0021）。uPAR表达作为连续变量与OS和PFS的预后较差相关，HR分别为2.7（95%CI，1.5-4.8；P=0.0012）和2.5（95%CI，1.5-4.2；P=0.00073）。
大多数胶质瘤患者以及几乎所有4级胶质瘤患者均表现为uPAR阳性病变，这突出了Ga-NOTA-AE105 PET/MRI在胶质瘤中的可行性。高uPAR表达与患者较差的生存结果显著相关。此外，高比例的uPAR阳性胶质瘤强调了uPAR靶向放射性核素治疗在这些患者中的潜力。
EudraCT编号：2016-002417-21；科学伦理委员会：H-16,035,303；丹麦数据保护局：2012-58-0004；临床试验注册：NCT02945826，2016年10月26日，网址：https://classic.
gov/ct2/show/NCT02945826 。
