Abstract

Purpose

DOTA-D-Phe¹-Tyr³-octreotide with gallium-68 ([⁶⁸Ga]Ga-DOTA-TOC) is one of the PET tracers that forms the basis for peptide receptor radionuclide therapy based on somatostatin receptor subtype 2 (SSTR2) expression in meningiomas. Yet, the quantitative relationship between [⁶⁸Ga]Ga-DOTA-TOC accumulation and SSTR2 is unknown. We conducted a correlative analysis of a range of [⁶⁸Ga]Ga-DOTA-TOC PET metric(s) as imaging surrogate(s) of the receptor binding in meningiomas by correlating the PET results with SSTR2 expression from surgical specimens. We additionally investigated possible influences of secondary biological factors such as vascularization, inflammation and proliferation.

Methods

Fifteen patients with MRI-presumed or recurrent meningiomas underwent a 60-min dynamic [⁶⁸Ga]Ga-DOTA-TOC PET/CT before surgery. The PET data comprised maximum and mean standardized uptake values (SUV_max, SUV_mean) with and without normalization to reference regions, and quantitative measurements derived from kinetic modelling using a reversible two-tissue compartment model with the fractional blood volume (V_B). Expressions of SSTR2 and proliferation (Ki-67, phosphohistone-H3, proliferating cell nuclear antigen) were determined by immunohistochemistry and/or quantitative polymerase chain reaction (qPCR), while biomarkers of vascularization (vascular endothelial growth factor A (VEGFA), endothelial marker CD34) and inflammation (cytokine interleukin-18, microglia/macrophage-specific marker CD68) by qPCR.

Results

Histopathology revealed 12 World Health Organization (WHO) grade I and three WHO grade II meningiomas showing no link to SSTR2. The majority of [⁶⁸Ga]Ga-DOTA-TOC PET metrics showed significant associations with SSTR2 protein, while all PET metrics were positively correlated with SSTR2 mRNA with the best results for mean tumour-to-blood ratio (TBR_mean) (r = 0.757, P = 0.001) and SUV_mean (r = 0.714, P = 0.003). Significant positive correlations were also found between [⁶⁸Ga]Ga-DOTA-TOC PET metrics, and VEGFA and V_B. SSTR2 mRNA was moderately correlated with VEGFA (r = 0.539, P = 0.038). Neither [⁶⁸Ga]Ga-DOTA-TOC PET metrics nor SSTR2 were correlated with proliferation or inflammation.

Conclusion

[⁶⁸Ga]Ga-DOTA-TOC accumulation in meningiomas is associated with SSTR2 binding and vascularization with TBR_mean being the best PET metric for assessing SSTR2.

中文翻译：

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[68Ga] Ga-DOTA-TOC PET在脑膜瘤中的药代动力学分析，用于评估体内生长抑素受体亚型2。

摘要

目的

含镓68（[ ⁶⁸ Ga] Ga-DOTA-TOC）的DOTA-D-Phe ¹ -Tyr ^3-奥曲肽是PET示踪剂之一，构成了基于生长抑素受体亚型2（SSTR2）的肽受体放射性核素治疗的基础脑膜瘤中的表达。然而，[ ⁶⁸ Ga] Ga-DOTA-TOC积累与SSTR2之间的定量关系是未知的。我们通过将PET结果与手术标本中的SSTR2表达相关联，对一系列[ ⁶⁸ Ga] Ga-DOTA-TOC PET度量进行了相关分析，作为脑膜瘤中受体结合的成像替代物。我们还研究了诸如血管生成，炎症和增殖等次生生物学因素的可能影响。

方法

15名MRI推测或复发性脑膜瘤患者在手术前进行了60分钟动态[ ⁶⁸ Ga] Ga-DOTA-TOC PET / CT检查。PET数据包括最大和平均标准化摄入值（SUV_最大，SUV_平均值），对参考区域进行归一化和不对归一化，以及通过使用可逆两组织隔室模型（分数血容量为V _B）进行动力学建模得出的定量测量结果）。通过免疫组织化学和/或定量聚合酶链反应（qPCR）确定SSTR2的表达和增殖（Ki-67，磷酸化组蛋白H3，增殖性细胞核抗原），而血管生成的生物标记物（血管内皮生长因子A（VEGFA），内皮标记物CD34）和炎症（细胞因子白介素18，小胶质细胞/巨噬细胞特异性标记CD68）。

结果

组织病理学检查发现，有12个世界卫生组织（WHO）的I级脑膜瘤和3个WHO的II级脑膜瘤与SSTR2无关联。[ ⁶⁸ Ga] Ga-DOTA-TOC的大多数PET指标显示与SSTR2蛋白显着相关，而所有PET指标均与SSTR2 mRNA正相关，以平均肿瘤血比（TBR_平均值）为最佳结果（r  = 0.757，P  = 0.001）和SUV_平均值（r  = 0.714，P  = 0.003）。在[ ⁶⁸ Ga] Ga-DOTA-TOC PET指标与VEGFA和V _B之间也发现了显着的正相关。SSTR2 mRNA与VEGFA（r = 0.539，P  = 0.038）。[ ⁶⁸ Ga] Ga-DOTA-TOC PET指标和SSTR2均与增殖或炎症无关。

结论

[ ⁶⁸ Ga] Ga-DOTA-TOC在脑膜瘤中的蓄积与SSTR2结合和血管形成有关，TBR_平均值是评估SSTR2的最佳PET指标。