Ultrasound (US) contrast agents can be used to generate super resolution (SR) images of the vasculature by accumulating the localizations of separable contrast signatures over tens of thousands of frames. This research presents a SR imaging method that localizes the activation signals of octafluoropropane (OFP, C3F8, -37 deg. C boiling point) phase-change contrast agents (PCCAs, or droplets), rather than microbubble signals. The unique activation signature of low-boiling point PCCAs was separated from the tissue background by frequency filtering alone. Plane-wave imaging was used to both activate droplets and image the activation signals. A low-frequency bandwidth (BW) to receive the activation signals and a high-frequency transmit BW enabled the collection of high contrast-to-tissue ratio (CTR) images which were then processed for SR. We demonstrate the application of this technique by localizing activations within a crossed microtube setup in a tissue- mimicking agar phantom kept at 37 deg. C.
Abstract The purpose of this study was to evaluate a new in vivo approach for rapidly measuring tumor volumes in rodent models for glioblastoma (GBM). GBM is the most common primary brain tumor with <5% of patients surviving >5 years post diagnosis. These poor outcomes underscore the importance of researching new treatment options, and murine models play a vital role in this. Noninvasive measurements of murine GBM tumors are commonly performed using CT and MRI but these tools are costly and time-consuming to use. BLI can quickly detect the presence of GBM cells in vivo, but image data can be challenging to correlate to tumor volume. In this study we demonstrate the feasibility of imaging GBM in vivo through the intact mouse skull using a benchtop robotic ultrasound scanner. This approach could offer researchers a means to quickly size tumors in the murine brain noninvasively. To test feasibility of this approach, a female athymic nude mouse aged 16 weeks was implanted with 2e5 U87 GBM cells in the brain. The tumor was given 25 days to develop prior to ultrasound imaging. After imaging, the brain was harvested for ex vivo validation of tumor presence and volume. Imaging was performed using a Vega ultrasound system (Revvity, Waltham, MA, USA) with the mouse in supine position and fur removed from head with depilatory cream. In vivo imaging consisted of a contrast-enhanced acoustic angiography (AA) scan to assess tumor perfusion. An ex vivo B-mode scan of the brain was collected after sacrificing the animal to validate the location and size of the tumor without interference from the skull. The tumor volumes were measured in each image and compared. 3D segmentations in the ex vivo and in vivo images yielded volumes of 43.1 mm3 and 44.6 mm3, respectively, a 3.5% variance. In the in vivo AA image, the borders of the tumor were adequately well-defined for volume estimation, despite some shadowing from the sagittal suture of the skull. In the B-mode image of the excised brain, the tumor appeared hyperechoic compared to the contralateral hemisphere. Images were acquired in < 2 min. This pilot study demonstrates a potential alternative to CT and MRI for monitoring of GBM volumes in vivo. Citation Format: Thomas M. Kierski, Juan D. Rojas, Morrent Thang, Shawn D. Hingtgen, Phillip G. Durham, Paul A. Dayton, Tomek J. Czernuszewicz, Ryan C. Gessner. Noninvasive measurement of murine glioblastoma in vivo with a benchtop ultrasound instrument [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4159.
Abstract Background: Functional and molecular changes often precede gross anatomical changes in cancer, so early assessment of a tumor’s functional and molecular response to therapy can help reduce a patient’s exposure to the side effects of ineffective chemotherapeutics or other treatment strategies. Clear-cell renal cell carcinoma (ccRCC) is an aggressive and hyper-vascular form of renal cancer that is often treated with anti-angiogenic and Notch Inhibition therapies, which target the vasculature feeding the disease. The purpose of this work is to show that ultrasound microvascular imaging can provide indications of response to antiangiogenic and Notch Inhibition therapies prior to measurable changes in tumor size. Methods: Mice bearing 786-O ccRCC xenograft tumors were treated with SU (Sunitnib malate, Selleckchem, TX), an antiangiogenic drug, and a combination of SU and the Notch inhibitor GSI (Gamma secretase inhibitor, PF-03084014, Pfizer, New York, NY) therapies (n=8). A 3D ultrasound system (SonoVol Inc., Research Triangle Park, NC), in addition to microbubble ultrasound contrast agents, was used to obtain a measurement of microvascular density over time and assess the response of the tumors to the therapies. CD31 immunohistochemistry was performed to serve as a gold standard for comparison against imaging results. Statistical tests included: Spearman correlation to compare imaging and histology; Kruskal-Wallis analysis with Tukey multiple comparison post-test to determine if the vessel density or tumor volume were significantly different between the treatment groups; and receiver operating characteristic (ROC) curve analysis to determine sensitivity/specificity for separating treated/untreated groups. Results: Data indicated that ultrasound-derived microvascular density can detect response to antiangiogenic and Notch inhibition therapies a week prior to changes in tumor volume. Furthermore, the imaging measurements of vasculature are strongly correlated with physiological characteristics of the tumors as measured by histology (p=0.75). Moreover, data demonstrated that ultrasound measurements of vascular density can determine response to therapy and classify between-treatment groups 1 week after the start of treatment with a high sensitivity and specificity of 94% and 86%, respectively. Conclusion: This work shows vascular density measurements that are strongly correlated with histology can be obtained using ultrasound, and that imaging-derived vessel density metrics may be a better tool for assessing the response of ccRCC to antiangiogenic and Notch inhibition therapies than anatomical size measurements. Note: This abstract was not presented at the meeting. Citation Format: Juan D. Rojas, Virginie Papadopoulou, Tomasz Czernuszewicz, Rajalekha Rajamahendiran, Anna Chytil, Yun-Chen Chiang, Diana Chong, Victoria L. Bautch, Wendy K. Rathmell, Stephen Aylward, Ryan Gessner, Paul Dayton. Early treatment response detected in a murine clear cell renal cell carcinoma model in response to combination therapy with antiangiogenic and notch inhibition therapy using a non-invasive imaging tool [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1958.
Aggressive, desmoplastic tumors are notoriously difficult to treat because of their extensive stroma, high interstitial pressure, and resistant tumor microenvironment.We have developed a combination therapy that can significantly slow the growth of large, stroma-rich tumors by causing massive apoptosis in the tumor center while simultaneously increasing nanoparticle uptake through a treatment-induced increase in the accumulation and retention of nanoparticles in the tumor.The vascular disrupting agent Combretastatin A-4 Phosphate (CA4P) is able to increase the accumulation of radiation-containing nanoparticles for internal radiation therapy, and the retention of these delivered radioisotopes is maintained over several days.We use ultrasound to measure the effect of CA4P in live tumor-bearing mice, and we encapsulate the radio-theranostic isotope 177 Lutetium as a therapeutic agent as well as a means to measure nanoparticle accumulation and retention in the tumor.This combination therapy induces prolonged apoptosis in the tumor, decreasing both the fibroblast and total cell density and allowing further tumor growth inhibition using a cisplatin-containing nanoparticle.
A feature of French geothermal engineering is the development of industrial projects in normal gradient, non-convective areas. The Economic feasibility of exploiting highly productive wells (between 150 and 350 m³/h at temperatures from 55° to 85°C and depths of 1,500 to 2,000 m) for direct heat production in sedimentary basins with normal gradient, has been proved by the 50 plants mounted during the last few years which provide heat for over 500,000 people. This opens new possibilities for geothermal energy development over the world, in particular for areas where heat consumption is higher than 2,500 Toe/year in a few km². The recent and rapid development of geothermal projects in France, in particular in the Paris Basin has provided much more information on the characteristics of the Jurassic "Dogger", which is the unit tapped by most geothermal doublets (one production and one injection wells). Detailed study of the Dogger reservoir in the Paris Basin is one of the main objectives of the IMRG research and development program drawn up in 1983. The preliminary results presented here are oriented towards, (i) improved knowledge of the potential geothermal resources, and (ii) analysis of optimum exploitation conditions. Uma característica da engenharia geotérmica francesa é o desenvolvimento de projetos industriais em áreas não-convectivas de gradiente normal. Foi comprovada a factibilidade econômica de exploração de poços altamente produtivos (entre 150 e 350 m³/h, temperaturas entre 55° e 85°C e profundidades de 1500 a 2000 m) para a produção direta de calor, em bacias sedimentares com gradiente normal, através de 50 plantas instaladas durante os últimos anos, as quais proporcionam calor para mais de 500.000 pessoas. Isto abre novas possibilidades para o desenvolvimento de energia geotermal a nível mundial, em particular, nas áreas onde o consumo de calor é maior que 2.500 Toe/ano em poucos km². O desenvolvimento rápido e recente de projetos geotermais na França, particularmente na Bacia de Paris, proporcionou muita informação sobre as características do "Dogger" jurássico, que é a unidade perfurada pela maioria dos poços geotermais (um de produção e o outro de injeção). Estudo detalhado do reservatório "Dogger" na Bacia de Paris, é um dos principais objetivos do programa de desenvolvimento e pesquisa do IMRG, preparado em 1983. Os resultados preliminares apresentados neste trabalho têm as seguintes finalidades: i) melhorar o conhecimento das fontes potenciais de calor e ii) analisar as condições ótimas de exploração.
We will give an overview of the technology, and present results showing the robotic ultrasound system's use in a variety of use cases, including dual-imaging aligned with bioluminescence data for oncology studies, therapeutic ultrasound delivery, and multi-modality ultrasound imaging for liver disease.
