Effects of contrast-enhanced ultrasound treatment on neoadjuvant chemotherapy in breast cancer.

Purpose: 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. Methods: 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). Results: 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. Conclusion: 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.

Perfusion-related changes in intestinal diffusion detected by NMR-MOUSE® monitoring in minipigs.

OBJECTIVE: The aim was to investigate perfusion-related changes in the intestinal diffusion assessed by NMR-MOUSE monitoring in minipigs. This was a follow-up study of previous experiments on landrace pigs demonstrating the feasibility of NMR-MOUSE monitoring in large animals. METHODS: 5 mature female minipigs (mean body weight 50 ±â€¯2 kg) underwent laparotomy with exposition of several small intestinal loops and their feeding vessels. The loops were examined consecutively using NMR-MOUSE monitoring for assessment of intestinal proton diffusion (fast diffusion component [FC] and slow diffusion component [SC]) and oxygen to see monitoring (O2C, LEA Medizintechnik GmbH, Giessen, Germany) for microcirculatory evaluation. Following a baseline measurement on each loop under physiological perfusion, measurements were continued as one of the following main treatments were performed per loop: method 1 - ischemia; method 2 - flow reduction; method 3 - intraluminal glucose followed by ischemia; method 4 - intraluminal glucose followed by flow reduction. Perioperative monitoring was supplemented by blood gas analyses and histopathological assessment of H.E. stained intestinal biopsies. RESULTS: The NMR-MOUSE measurement showed a significant difference in the change to baseline values in the FC during flow reduction compared to the other treatments according to the unadjusted (pM2 vs. M1 < 0.0001, pM2 vs. M3 = 0.0005, pM2 vs. M4 = 0.0005) and the adjusted p-values (pM2 vs. M1 < 0.0001, pM2 vs. M3 = 0.0030, pM2 vs. M4 = 0.0030). In the SC, the difference between ischemia and flow reduction was significant according to the unadjusted p-values (pM2 vs. M1 = 0.0397). Whereas the FC showed a trend towards ongoing increase during ischemia but towards ongoing decrease during flow reduction, the SC showed contrary trends. These effects seemed to be attenuated by prior glucose application. According to the results of O2C monitoring, ischemia as well as flow reduction caused a significant decrease of microcirculatory oxygen saturation (inner probe: methods 1-4 and outer probe methods 1, 2: p < 0.0001; outer probe: pM2 = 0.0001), velocity (inner probe: pM1 < 0.0001, pM2 = 0.0155, pM3 = 0.0027; outer probe: pM1 < 0.0001, pM2 = 0.0045, pM3 = 0.0047, pM4 = 0.0037) and serosal flow (outer probe, methods 1 and 2: p < 0.0001; pM3 = 0.0009, pM4 = 0.0008). The histopathological analysis showed a significant association with time (p = 0.003) but not with the experimental method (p = 0.1386). CONCLUSIONS: Intestinal diffusion is affected significantly by perfusion changes in mature minipigs. As shown by NMR-MOUSE monitoring, ischemia and flow reduction have contrary effects on intestinal diffusion and, additionally, the fast and slow diffusion components show opposite trends during each of those pathological perfusion states. Prior intraluminal glucose application seems to attenuate the effects of malperfusion on intestinal diffusion.