skip to main content

Title: Non-contrast power Doppler ultrasound imaging for early assessment of trans-arterial chemoembolization of liver tumors

Trans-arterial chemoembolization (TACE) is an important yet variably effective treatment for management of hepatic malignancies. Lack of response can be in part due to inability to assess treatment adequacy in real-time. Gold-standard contrast enhanced computed tomography and magnetic resonance imaging, although effective, suffer from treatment-induced artifacts that prevent early treatment evaluation. Non-contrast ultrasound is a potential solution but has historically been ineffective at detecting treatment response. Here, we propose non-contrast ultrasound with recent perfusion-focused advancements as a tool for immediate evaluation of TACE. We demonstrate initial feasibility in an 11-subject pilot study. Treatment-induced changes in tumor perfusion are detected best when combining adaptive demodulation (AD) and singular value decomposition (SVD) techniques. Using a 0.5 s (300-sample) ensemble size, AD + SVD resulted in a 7.42 dB median decrease in tumor power after TACE compared to only a 0.06 dB median decrease with conventional methods.

; ; ; ;
Award ID(s):
Publication Date:
Journal Name:
Scientific Reports
Nature Publishing Group
Sponsoring Org:
National Science Foundation
More Like this
  1. (Early Access) Effective tissue clutter filtering is critical for non-contrast ultrasound imaging of slow blood flow in small vessels. Independent component analysis (ICA) has been considered by other groups for ultrasound clutter filtering in the past and was shown to be superior to principal component analysis (PCA)-based methods. However, it has not been considered specifically for slow flow applications or revisited since the onset of other slow flow-focused advancements in beamforming and tissue filtering, namely angled plane wave beamforming and full spatiotemporal singular value decomposition (SVD) (i.e., PCA-based) tissue filtering. In this work, we aim to develop a full spatiotemporal ICA-based tissue filtering technique facilitated by plane wave applications and compare it to SVD filtering. We compare ICA and SVD filtering in terms of optimal image quality in simulations and phantoms as well as in terms of optimal correlation to ground truth blood signal in simulations. Additionally, we propose an adaptive blood independent component sorting and selection method. We show that optimal and adaptive ICA can consistently separate blood from tissue better than principal component analysis (PCA)-based methods using simulations and phantoms. Additionally we demonstrate initial in vivo feasibility in ultrasound data of a liver tumor.
  2. Abstract Background

    Alzheimer’s disease (AD) is a progressive neurodegenerative disease that impacts nearly 400 million people worldwide. The accumulation of amyloid beta (Aβ) in the brain has historically been associated with AD, and recent evidence suggests that neuroinflammation plays a central role in its origin and progression. These observations have given rise to the theory that Aβ is the primary trigger of AD, and induces proinflammatory activation of immune brain cells (i.e., microglia), which culminates in neuronal damage and cognitive decline. To test this hypothesis, many in vitro systems have been established to study Aβ-mediated activation of innate immune cells. Nevertheless, the transcriptional resemblance of these models to the microglia in the AD brain has never been comprehensively studied on a genome-wide scale.


    We used bulk RNA-seq to assess the transcriptional differences between in vitro cell types used to model neuroinflammation in AD, including several established, primary and iPSC-derived immune cell lines (macrophages, microglia and astrocytes) and their similarities to primary cells in the AD brain. We then analyzed the transcriptional response of these innate immune cells to synthetic Aβ or LPS and INFγ.


    We found that human induced pluripotent stem cell (hIPSC)-derived microglia (IMGL) are the in vitro cell modelmore »that best resembles primary microglia. Surprisingly, synthetic Aβ does not trigger a robust transcriptional response in any of the cellular models analyzed, despite testing a wide variety of Aβ formulations, concentrations, and treatment conditions. Finally, we found that bacterial LPS and INFγ activate microglia and induce transcriptional changes that resemble many, but not all, aspects of the transcriptomic profiles of disease associated microglia (DAM) present in the AD brain.


    These results suggest that synthetic Aβ treatment of innate immune cell cultures does not recapitulate transcriptional profiles observed in microglia from AD brains. In contrast, treating IMGL with LPS and INFγ induces transcriptional changes similar to those observed in microglia detected in AD brains.

    « less
  3. Abstract Background Immunotherapy in colorectal cancer (CRC) regulates specific immune checkpoints and, when used in combination with chemotherapy, can improve patient prognosis. One specific immune checkpoint is the recruitment of circulating monocytes that differentiate into tumor-associated macrophages (TAMs) and promote tumor angiogenesis. Changes in vascularization can be non-invasively assessed via diffuse reflectance spectroscopy using hemoglobin concentrations and oxygenation in a localized tumor volume. In this study, we examine whether blockade of monocyte recruitment via CCL2 (macrophage chemoattractant protein-1) leads to enhanced sensitivity of 5-fluorouracil (5-FU) in a CT26-Balb/c mouse model of CRC. It was hypothesized that the blockade of TAMs will alter tumor perfusion, increasing chemotherapy response. A subcutaneous tumor model using Balb/c mice injected with CT26 colon carcinoma cells received either a saline or isotype control, anti-CCL2, 5-FU, or a combination of anti-CCL2 and 5-FU. Results Findings show that 12 days post-treatment, monocyte recruitment was significantly reduced by approximately 61% in the combination group. This shows that the addition of anti-CCL2 to 5-FU slowed the fold-change (change from the original measurement to the final measurement) in tumor volume from Day 0 to Day 12 (~ 5 fold). Modest improvements in oxygen saturation (~ 30%) were observed in the combination group. Conclusion Themore »findings in this work suggest that the blockade of CCL2 is sufficient in the reduction of TAMs that are recruited into the tumor microenvironment and has the ability to modestly alter tumor perfusion during early-tumor response to treatment even though the overall benefit is relatively modest.« less
  4. Abstract

    Ultrasound allows imaging at a much greater depth than optical methods, but existing genetically encoded acoustic reporters for in vivo cellular imaging have been limited by poor sensitivity, specificity and in vivo expression. Here we describe two acoustic reporter genes (ARGs)—one for use in bacteria and one for use in mammalian cells—identified through a phylogenetic screen of candidate gas vesicle gene clusters from diverse bacteria and archaea that provide stronger ultrasound contrast, produce non-linear signals distinguishable from background tissue and have stable long-term expression. Compared to their first-generation counterparts, these improved bacterial and mammalian ARGs produce 9-fold and 38-fold stronger non-linear contrast, respectively. Using these new ARGs, we non-invasively imaged in situ tumor colonization and gene expression in tumor-homing therapeutic bacteria, tracked the progression of tumor gene expression and growth in a mouse model of breast cancer, and performed gene-expression-guided needle biopsies of a genetically mosaic tumor, demonstrating non-invasive access to dynamic biological processes at centimeter depth.

  5. Abstract

    Spatial Frequency Domain Imaging (SFDI) can provide longitudinal, label-free, and widefield hemodynamic and scattering measurements of murine tumors in vivo. Our previous work has shown that the reduced scattering coefficient (μ′s) at 800 nm, as well as the wavelength dependence of scattering, both have prognostic value in tracking apoptosis and proliferation during treatment with anti-cancer therapies. However, there is limited work in validating these optical biomarkers in clinically relevant tumor models that manifest specific treatment resistance mechanisms that mimic the clinical setting. It was recently demonstrated that metronomic dosing of cyclophosphamide induces a strong anti-tumor immune response and tumor volume reduction in the E0771 murine breast cancer model. This immune activation mechanism can be blocked with an IFNAR-1 antibody, leading to treatment resistance. Here we present a longitudinal study utilizing SFDI to monitor this paired responsive-resistant model for up to 30 days of drug treatment. Mice receiving the immune modulatory metronomic cyclophosphamide schedule had a significant increase in tumor optical scattering compared to mice receiving cyclophosphamide in combination with the IFNAR-1 antibody (9% increase vs 10% decrease on day 5 of treatment, p < 0.001). The magnitude of these differences increased throughout the duration of treatment. Additionally, scattering changes on day 4 of treatmentmore »could discriminate responsive versus resistant tumors with an accuracy of 78%, while tumor volume had an accuracy of only 52%. These results validate optical scattering as a promising prognostic biomarker that can discriminate between treatment responsive and resistant tumor models.

    « less