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Assessment of murine colorectal cancer by micro-ultrasound using three dimensional reconstruction and non-linear contrast imaging.

ABSTRACT: The relatively low success rates of current colorectal cancer (CRC) therapies have led investigators to search for more specific treatments. Vertebrate models of colorectal cancer are essential tools for the verification of new therapeutic avenues such as gene therapy. The evaluation of colorectal cancer in mouse models has been limited due to the lack of an accurate quantitative and longitudinal noninvasive method. This work introduces a method of three-dimensional micro-ultrasound reconstruction and microbubble administration for the comprehensive and longitudinal evaluation of CRC progression. This approach enabled quantification of both tumor volume and relative vascularity using a well-established inducible murine model of colon carcinogenesis. This inducible model recapitulated the adenocarcinoma sequence that occurs in human CRC allowing systematic in situ evaluation of the ultrasound technique. The administration of intravenous microbubbles facilitated enhancement of colon vascular contrast and quantification of relative vascularity of the mid and distal colon of the mouse in three dimensions. In addition, two-dimensional imaging in the sagittal orientation of the colon using Non-Linear Contrast Mode enabled calculation of relative blood volume and perfusion as the microbubbles entered the colon microvasculature. Quantitative results provided by the outlined protocol represent a noninvasive tool that can more accurately define CRC development and progression. This ultrasound technique will allow the practical and economical longitudinal study of murine CRC in both basic and preclinical studies.

SUBMITTER: Freeling JL

PROVIDER: S-EPMC5147881 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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Assessment of murine colorectal cancer by micro-ultrasound using three dimensional reconstruction and non-linear contrast imaging.

Freeling Jessica L JL Rezvani Khosrow K

Molecular therapy. Methods & clinical development 20161130

The relatively low success rates of current colorectal cancer (CRC) therapies have led investigators to search for more specific treatments. Vertebrate models of colorectal cancer are essential tools for the verification of new therapeutic avenues such as gene therapy. The evaluation of colorectal cancer in mouse models has been limited due to the lack of an accurate quantitative and longitudinal noninvasive method. This work introduces a method of three-dimensional micro-ultrasound reconstructi ...[more]

PMID: 28053998

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Project description:BackgroundCavitation of microbubble contrast agents with ultrasound produces shear-mediated vasodilation and an increase in tissue perfusion. We investigated the influence of the size of the cavitation volume by comparing flow augmentation produced by two-dimensional (2D) versus three-dimensional (3D) therapeutic ultrasound. We also hypothesized that cavitation could augment flow beyond the ultrasound field through release of vasodilators that are carried downstream.MethodsIn 11 rhesus macaques, cavitation of intravenously administered lipid-shelled microbubbles was performed in the proximal forearm flexor muscles unilaterally for 10 min. Ultrasound cavitation (1.3 MHz, 1.5 MPa peak negative pressure) was performed with 2D or 3D transmission with beam elevations of 5 and 25 mm, respectively, and pulsing intervals (PIs) sufficient to allow complete postdestruction refill (5 and 12 sec for 2D and 3D, respectively). Contrast ultrasound perfusion imaging was performed before and after cavitation, using multiplane assessment within and beyond the cavitation field in 1.5-cm increments. Cavitation in the hindlimb of mice using 2D ultrasound at a PI of 1 or 5 sec was performed to examine microvascular flow changes from cavitation in only arteries versus the microcirculation.ResultsIn primates, the degree of muscle flow augmentation in the center of the cavitation field was similar for 2D and 3D conditions (five- to sixfold increase for both, P < .01 vs baseline). The spatial extent of flow augmentation was only modestly greater for 3D cavitation because of an increase in perfusion with 2D transmission that was detected outside of the cavitation field. In mice, cavitation in the microvascular compartment (PI 5 sec) produced the greatest degree of flow augmentation, yet cavitation in the arterial compartment (PI 1 sec) still produced a three- to fourfold increase in flow (P < .001 vs control). The mechanism for flow augmentation beyond the cavitation zone was investigated by in vitro studies that demonstrated cavitation-related release of vasodilators, including adenosine triphosphate and nitric oxide, from erythrocytes and endothelial cells.ConclusionsCompared with 2D transmission, 3D cavitation of microbubbles generates a similar degree of muscle flow augmentation, possibly because of a trade-off between volume of cavitation and PI, and only modestly increases the spatial extent of flow augmentation because of the ability of cavitation to produce conducted effects beyond the ultrasound field.

Project description:BackgroundThough contrast-enhanced ultrasound (CEUS) perfusion parameters have been approved to be potential indicators for response to chemotherapy in solid tumors, their ability in assessment of colorectal liver metastasis (CRLM) to chemotherapy with bevacizumab (Bev) has rarely been investigated.MethodsFrom March 2021 to May 2022, 115 consecutive CRLM patients with CEUS pre- and post-2 months' chemotherapy with Bev were prospectively enrolled. One target lesion per patient underwent CEUS quantitative analysis with SonoLiver software. Rise time, time-to-peak, mean transit time, maximal intensity (IMAX), and area under the time-intensity curve (AUC) were assessed with region of interest (ROI) selected on whole lesion, lesion periphery, and internal lesion, respectively. The reduction and ratio of post- to pre-treatment in parameters were investigated in development cohort (n=89) and validated in internal validation cohort (n=26) according to the chronological order.ResultsWith modified Response Evaluation Criteria in Solid Tumor as reference, 48, 14 responders and 41, 12 non-responders were included in development and validation cohort, respectively. Significantly smaller values of IMAX and AUC on ROIwhole, ROIperipheral, and ROIinternal, were observed post-treatment in development cohort (all P<0.05). In predicting treatment response, the influence of ROI selection was observed when using ∆IMAX and ∆AUC, while no influence was observed using ratios. Areas under the receiver operating characteristic curve (AUROCs) for ∆IMAX and ∆AUC on ROIperipheral were 0.939 (0.867-0.979), 0.951 (0.883-0.985), and 0.917 (0.740-0.988), 0.923 (0.748-0.990) in development and validation cohort, respectively. For ratios of IMAX and AUC, AUROCs were 0.976 (0.919-0.997), 0.938 (0.865-0.978), and 0.899 (0.717-0.982), 0.982 (0.836-1.000) in development and validation cohort, respectively.ConclusionsIMAX and AUC showed significant reductions in responders, and different analyses ROIs influence the performance of ∆IMAX and ∆AUC in response assessment. Parameters derived from ROI peripheral exhibited the most promising results in predicting treatment response.

Dataset Information

Assessment of murine colorectal cancer by micro-ultrasound using three dimensional reconstruction and non-linear contrast imaging.

Publications

Assessment of murine colorectal cancer by micro-ultrasound using three dimensional reconstruction and non-linear contrast imaging.

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