Institute for Experimental Molecular Imaging, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Chair for Medical Engineering, Department of Electrical Engineering and Information Technology, Ruhr University Bochum, Bochum, Germany.
Theranostics. 2021 Sep 21;11(19):9557-9570. doi: 10.7150/thno.64767. eCollection 2021.
Preclinical and clinical data indicate that contrast-enhanced ultrasound can enhance tumor perfusion and vessel permeability, thus, improving chemotherapy accumulation and therapeutic outcome. Therefore, we investigated the effects of high mechanical index (MI) contrast-enhanced Doppler ultrasound (CDUS) on tumor perfusion in breast cancer. In this prospective study, breast cancer patients were randomly assigned to receive either 18 minutes of high MI CDUS during chemotherapy infusion (n = 6) or chemotherapy alone (n = 5). Tumor perfusion was measured before and after at least six chemotherapy cycles using motion-model ultrasound localization microscopy. Additionally, acute effects of CDUS on vessel perfusion and chemotherapy distribution were evaluated in mice bearing triple-negative breast cancer (TNBC). Morphological and functional vascular characteristics of breast cancer in patients were not significantly influenced by high MI CDUS. However, complete clinical tumor response after neoadjuvant chemotherapy was lower in high MI CDUS-treated (1/6) compared to untreated patients (4/5) and size reduction of high MI CDUS treated tumors tended to be delayed at early chemotherapy cycles. In mice with TNBC high MI CDUS decreased the perfused tumor vessel fraction (p < 0.01) without affecting carboplatin accumulation or distribution. Higher vascular immaturity and lower stromal stabilization may explain the stronger vascular response in murine than human tumors. High MI CDUS had no detectable effect on breast cancer vascularization in patients. In mice, the same high MI CDUS setting did not affect chemotherapy accumulation although strong effects on the tumor vasculature were detected histologically. Thus, sonopermeabilization in human breast cancers might not be effective using high MI CDUS protocols and future applications may rather focus on low MI approaches triggering microbubble oscillations instead of destruction. Furthermore, our results show that there are profound differences in the response of mouse and human tumor vasculature to high MI CDUS, which need to be further explored and considered in clinical translation.
临床前和临床数据表明，对比增强超声可以增强肿瘤灌注和血管通透性，从而提高化疗药物的积累和治疗效果。因此，我们研究了高机械指数（MI）对比增强多普勒超声（CDUS）对乳腺癌肿瘤灌注的影响。
在这项前瞻性研究中，乳腺癌患者被随机分为化疗输注时接受 18 分钟高 MI CDUS（n=6）或单独化疗（n=5）。使用运动模型超声定位显微镜，在至少六个化疗周期前后测量肿瘤灌注。此外，在携带三阴性乳腺癌（TNBC）的小鼠中评估了 CDUS 对血管灌注和化疗分布的急性影响。
高 MI CDUS 对患者乳腺癌的形态和功能血管特征没有显著影响。然而，与未治疗患者（4/5）相比，接受高 MI CDUS 治疗的患者在新辅助化疗后完全临床肿瘤反应较低（1/6），并且高 MI CDUS 治疗肿瘤的大小缩小在早期化疗周期中趋于延迟。在 TNBC 小鼠中，高 MI CDUS 降低了灌注肿瘤血管分数（p<0.01），而不影响卡铂的积累或分布。更高的血管不成熟和更低的基质稳定可能解释了在小鼠肿瘤中比在人类肿瘤中更强的血管反应。
高 MI CDUS 对患者乳腺癌血管生成没有可检测的影响。在小鼠中，相同的高 MI CDUS 设置不会影响化疗药物的积累，尽管在组织学上检测到对肿瘤血管的强烈影响。因此，使用高 MI CDUS 方案在人类乳腺癌中可能不会有效实现声孔化，未来的应用可能更多地集中在触发微泡振荡而不是破坏的低 MI 方法上。此外，我们的结果表明，小鼠和人类肿瘤血管对高 MI CDUS 的反应存在深刻差异，需要进一步探索和考虑在临床转化中。
