Heid Irina, Trajkovic-Arsic Marija, Lohöfer Fabian, Kaissis Georgios, Harder Felix N, Mayer Moritz, Topping Geoffrey J, Jungmann Friderike, Crone Barbara, Wildgruber Moritz, Karst Uwe, Liotta Lucia, Algül Hana, Yen Hsi-Yu, Steiger Katja, Weichert Wilko, Siveke Jens T, Makowski Marcus R, Braren Rickmer F
School of Medicine, Institute of Diagnostic and Interventional Radiology, Technical University of Munich, Munich, Germany.
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany.
Eur J Nucl Med Mol Imaging. 2022 Dec;50(1):115-129. doi: 10.1007/s00259-022-05930-6. Epub 2022 Sep 8.
Pancreatic ductal adenocarcinoma (PDAC) is a molecularly heterogeneous tumor entity with no clinically established imaging biomarkers. We hypothesize that tumor morphology and physiology, including vascularity and perfusion, show variations that can be detected by differences in contrast agent (CA) accumulation measured non-invasively. This work seeks to establish imaging biomarkers for tumor stratification and therapy response monitoring in PDAC, based on this hypothesis.
Regional CA accumulation in PDAC was correlated with tumor vascularization, stroma content, and tumor cellularity in murine and human subjects. Changes in CA distribution in response to gemcitabine (GEM) were monitored longitudinally with computed tomography (CT) Hounsfield Units ratio (HUr) of tumor to the aorta or with magnetic resonance imaging (MRI) ΔR area under the curve at 60 s tumor-to-muscle ratio (AUC60r). Tissue analyses were performed on co-registered samples, including endothelial cell proliferation and cisplatin tissue deposition as a surrogate of chemotherapy delivery.
Tumor cell poor, stroma-rich regions exhibited high CA accumulation both in human (meanHUr 0.64 vs. 0.34, p < 0.001) and mouse PDAC (meanAUC60r 2.0 vs. 1.1, p < 0.001). Compared to the baseline, in vivo CA accumulation decreased specifically in response to GEM treatment in a subset of human (HUr -18%) and mouse (AUC60r -36%) tumors. Ex vivo analyses of mPDAC showed reduced cisplatin delivery (GEM: 0.92 ± 0.5 mg/g, vs. vehicle: 3.1 ± 1.5 mg/g, p = 0.004) and diminished endothelial cell proliferation (GEM: 22.3% vs. vehicle: 30.9%, p = 0.002) upon GEM administration.
In PDAC, CA accumulation, which is related to tumor vascularization and perfusion, inversely correlates with tumor cellularity. The standard of care GEM treatment results in decreased CA accumulation, which impedes drug delivery. Further investigation is warranted into potentially detrimental effects of GEM in combinatorial therapy regimens.
胰腺导管腺癌（PDAC）是一种分子异质性肿瘤实体，尚无临床公认的影像学生物标志物。我们假设肿瘤形态和生理学，包括血管生成和灌注，会表现出可通过非侵入性测量的造影剂（CA）蓄积差异检测到的变化。基于这一假设，本研究旨在建立用于PDAC肿瘤分层和治疗反应监测的影像学生物标志物。
在小鼠和人类受试者中，将PDAC中的局部CA蓄积与肿瘤血管生成、基质含量和肿瘤细胞密度相关联。通过计算机断层扫描（CT）肿瘤与主动脉的亨氏单位比值（HUr）或磁共振成像（MRI）60秒时肿瘤与肌肉的曲线下面积比值（AUC60r）纵向监测吉西他滨（GEM）治疗后CA分布的变化。对配准后的样本进行组织分析，包括内皮细胞增殖和顺铂组织沉积，作为化疗给药的替代指标。
在人类（平均HUr 0.64对0.34，p < 0.001）和小鼠PDAC（平均AUC60r 2.0对1.1，p < 0.001）中，肿瘤细胞少、基质丰富的区域均表现出较高的CA蓄积。与基线相比，在一部分人类（HUr -18%）和小鼠（AUC60r -36%）肿瘤中，体内CA蓄积在GEM治疗后特异性降低。对小鼠PDAC的离体分析显示，给予GEM后顺铂递送减少（GEM组：0.92 ± 0.5 mg/g，对照组：3.1 ± 1.5 mg/g，p = 0.004），内皮细胞增殖减少（GEM组：22.3%，对照组：30.9%，p = 0.002）。
在PDAC中，与肿瘤血管生成和灌注相关的CA蓄积与肿瘤细胞密度呈负相关。标准治疗方案GEM治疗导致CA蓄积减少，这会阻碍药物递送。有必要进一步研究GEM在联合治疗方案中的潜在有害作用。
