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Hugon, Gaëlle, Sébastien Goutal, Ambre Dauba, Louise Breuil, Benoit Larrat, Alexandra Winkeler, Anthony Novell, and Nicolas Tournier. "[18F]2-Fluoro-2-deoxy-sorbitol PET Imaging for Quantitative Monitoring of Enhanced Blood-Brain Barrier Permeability Induced by Focused Ultrasound." Pharmaceutics 13, no. 11 (October 20, 2021): 1752. http://dx.doi.org/10.3390/pharmaceutics13111752.
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Focused ultrasound in combination with microbubbles (FUS) provides an effective means to locally enhance the delivery of therapeutics to the brain. Translational and quantitative imaging techniques are needed to noninvasively monitor and optimize the impact of FUS on blood-brain barrier (BBB) permeability in vivo. Positron-emission tomography (PET) imaging using [18F]2-fluoro-2-deoxy-sorbitol ([18F]FDS) was evaluated as a small-molecule (paracellular) marker of blood-brain barrier (BBB) integrity. [18F]FDS was straightforwardly produced from chemical reduction of commercial [18F]2-deoxy-2-fluoro-D-glucose. [18F]FDS and the invasive BBB integrity marker Evan’s blue (EB) were i.v. injected in mice after an optimized FUS protocol designed to generate controlled hemispheric BBB disruption. Quantitative determination of the impact of FUS on the BBB permeability was determined using kinetic modeling. A 2.2 ± 0.5-fold higher PET signal (n = 5; p < 0.01) was obtained in the sonicated hemisphere and colocalized with EB staining observed post mortem. FUS significantly increased the blood-to-brain distribution of [18F]FDS by 2.4 ± 0.8-fold (VT; p < 0.01). Low variability (=10.1%) of VT values in the sonicated hemisphere suggests reproducibility of the estimation of BBB permeability and FUS method. [18F]FDS PET provides a readily available, sensitive and reproducible marker of BBB permeability to noninvasively monitor the extent of BBB disruption induced by FUS in vivo.
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Bastiancich, Chiara, Samantha Fernandez, Florian Correard, Anthony Novell, Benoit Larrat, Benjamin Guillet, and Marie-Anne Estève. "Molecular Imaging of Ultrasound-Mediated Blood-Brain Barrier Disruption in a Mouse Orthotopic Glioblastoma Model." Pharmaceutics 14, no. 10 (October 19, 2022): 2227. http://dx.doi.org/10.3390/pharmaceutics14102227.
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Glioblastoma (GBM) is an aggressive and malignant primary brain tumor. The blood-brain barrier (BBB) limits the therapeutic options available to tackle this incurable tumor. Transient disruption of the BBB by focused ultrasound (FUS) is a promising and safe approach to increase the brain and tumor concentration of drugs administered systemically. Non-invasive, sensitive, and reliable imaging approaches are required to better understand the impact of FUS on the BBB and brain microenvironment. In this study, nuclear imaging (SPECT/CT and PET/CT) was used to quantify neuroinflammation 48 h post-FUS and estimate the influence of FUS on BBB opening and tumor growth in vivo. BBB disruptions were performed on healthy and GBM-bearing mice (U-87 MG xenograft orthotopic model). The BBB recovery kinetics were followed and quantified by [99mTc]Tc-DTPA SPECT/CT imaging at 0.5 h, 3 h and 24 h post-FUS. The absence of neuroinflammation was confirmed by [18F]FDG PET/CT imaging 48 h post-FUS. The presence of the tumor and its growth were evaluated by [68Ga]Ga-RGD2 PET/CT imaging and post-mortem histological analysis, showing that tumor growth was not influenced by FUS. In conclusion, molecular imaging can be used to evaluate the time frame for systemic treatment combined with transient BBB opening and to test its efficacy over time.
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Xu, Zhouyang, Samuel Pichardo, and Bingbing Cheng. "Enhancement of brain hyperthermia via transcranial magnetic resonance imaging-guided focused ultrasound and microbubbles—Heating mechanism investigation using COMSOL." Journal of the Acoustical Society of America 154, no. 4_supplement (October 1, 2023): A279. http://dx.doi.org/10.1121/10.0023523.
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Noninvasive methods for enhancing the brain drug delivery has been pursued for years. Previously we developed a new MR-guided focused ultrasound (FUS)-based technique, which can achieve targeted brain hyperthermia for heat-triggered drug release and simultaneously open the blood–brain barrier safely for drug penetration. However, the underline mechanisms were unclear. This study aimed to explore the mechanisms for the enhanced FUS brain tissue hyperthermia with microbubbles via numerical modeling in COMSOL. The acoustic wave equation was employed to describe the FUS propagation. A bubble dynamics equation was adopted for calculating the stable bubble oscillations under FUS exposures. A modified bioheat transfer equation was utilized to compute the heating, with various heating sources including FUS, microbubble acoustic emission (MAE), and viscous dissipation (VD). The microbubbles were randomly distributed within the focal region. The sonication time was 6s with an initial temperature of 41°C. The average temperature in the focal region were 41.65°C, 42.24°C, 42.98°C, and 43.59°C for FUS alone, FUS + MAE, FUS + VD, and FUS + MAE + VD, respectively. Compared with the FUS alone, both MAE and VD made significant contributions to the heating with additional temperature increases of 47.6% and 67.2%, respectively.
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Xu, Lu, Yan Gong, Chih-Yen Chien, and Hong Chen. "Shaveless focused-ultrasound-induced blood-brain barrier opening in mice." Journal of the Acoustical Society of America 153, no. 3_supplement (March 1, 2023): A140. http://dx.doi.org/10.1121/10.0018435.
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To demonstrate that focused ultrasound-induced blood-brain barrier opening (FUS-BBBO) in mice can be achieved without shaving hairs. We performed FUS-BBBO in mice by using oil as the coupling medium without shaving hairs. The hydrophobic nature of oil leads to a higher affinity to hair than water-based ultrasound gel. FUS-BBBO outcome was compared under three conditions: “oil + hairs,” “gel + hairs,” and “gel + no hairs.” T2-weighted, T1-weighted MRI, and fluorescence imaging of the ex vivo brain slices were performed to measure the quality of coupling and outcome of FUS-BBBO. Results showed that “oil + hairs” consistently achieved high-quality acoustic coupling without trapping air bubbles (Figures A & B). FUS-BBBO outcome was not significantly different between the “oil + hairs” group and the “gel + no hairs” group based on T1-weighted MRI (Figures C & D) and ex vivo fluorescence imaging (Figure E). The FUS-BBBO efficiencies for both the “oil + hairs” and “gel + no hairs” groups were significantly higher than the “gel + hairs” group. This study demonstrated that FUS-BBBO in mice could be achieved without shaving hairs. Oil provides a simple solution for achieving effective acoustic coupling for transcranial FUS procedures.
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Wang, Tony R., Aaron E. Bond, Robert F. Dallapiazza, Aaron Blanke, David Tilden, Thomas E. Huerta, Shayan Moosa, Francesco U. Prada, and W. Jeffrey Elias. "Transcranial magnetic resonance imaging–guided focused ultrasound thalamotomy for tremor: technical note." Neurosurgical Focus 44, no. 2 (February 2018): E3. http://dx.doi.org/10.3171/2017.10.focus17609.
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Although the use of focused ultrasound (FUS) in neurosurgery dates to the 1950s, its clinical utility was limited by the need for a craniotomy to create an acoustic window. Recent technological advances have enabled efficient transcranial delivery of US. Moreover, US is now coupled with MRI to ensure precise energy delivery and monitoring. Thus, MRI-guided transcranial FUS lesioning is now being investigated for myriad neurological and psychiatric disorders. Among the first transcranial FUS treatments is thalamotomy for the treatment of various tremors. The authors provide a technical overview of FUS thalamotomy for tremor as well as important lessons learned during their experience with this emerging technology.
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Gagliardo, Cesare, Roberto Cannella, Costanza D’Angelo, Patrizia Toia, Giuseppe Salvaggio, Paola Feraco, Maurizio Marrale, et al. "Transcranial Magnetic Resonance Imaging-Guided Focused Ultrasound with a 1.5 Tesla Scanner: A Prospective Intraindividual Comparison Study of Intraoperative Imaging." Brain Sciences 11, no. 1 (January 4, 2021): 46. http://dx.doi.org/10.3390/brainsci11010046.
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Background: High-quality intraoperative imaging is needed for optimal monitoring of patients undergoing transcranial MR-guided Focused Ultrasound (tcMRgFUS) thalamotomy. In this paper, we compare the intraoperative imaging obtained with dedicated FUS-Head coil and standard body radiofrequency coil in tcMRgFUS thalamotomy using 1.5-T MR scanner. Methods: This prospective study included adult patients undergoing tcMRgFUS for treatment of essential tremor. Intraoperative T2-weighted FRFSE sequences were acquired after the last high-energy sonication using a dedicated two-channel FUS-Head (2ch-FUS) coil and body radiofrequency (body-RF) coil. Postoperative follow-ups were performed at 48 h using an eight-channel phased-array (8ch-HEAD) coil. Two readers independently assessed the signal-to-noise ratio (SNR) and evaluated the presence of concentric lesional zones (zone I, II and III). Intraindividual differences in SNR and lesional findings were compared using the Wilcoxon signed rank sum test and McNemar test. Results: Eight patients underwent tcMRgFUS thalamotomy. Intraoperative T2-weighted FRFSE images acquired using the 2ch-FUS coil demonstrated significantly higher SNR (R1 median SNR: 10.54; R2: 9.52) compared to the body-RF coil (R1: 2.96, p < 0.001; R2: 2.99, p < 0.001). The SNR was lower compared to the 48-h follow-up (p < 0.001 for both readers). Intraoperative zone I and zone II were more commonly visualized using the 2ch-FUS coil (R1, p = 0.031 and p = 0.008, R2, p = 0.016, p = 0.008), without significant differences with 48-h follow-up (p ≥ 0.063). The inter-reader agreement was almost perfect for both SNR (ICC: 0.85) and lesional findings (k: 0.82–0.91). Conclusions: In the study population, the dedicated 2ch-FUS coil significantly improved the SNR and visualization of lesional zones on intraoperative imaging during tcMRgFUS performed with a 1.5-T MR scanner.
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Soloukey, S., E. Collée, L. Verhoef, D. D. Satoer, C. M. F. Dirven, E. M. Bos, J. W. Schouten, et al. "P15.07.B FUNCTIONAL BRAIN MAPPING DURING AWAKE TUMOR RESECTIONS USING ESM-FMRI CO-REGISTERED FUNCTIONAL ULTRASOUND (FUS)-IMAGING." Neuro-Oncology 25, Supplement_2 (September 1, 2023): ii110—ii111. http://dx.doi.org/10.1093/neuonc/noad137.371.
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Abstract BACKGROUND Neurosurgical resection of brain tumors resembles a balancing act between maximing extent of tumor resection (efficacy) and minimizing the risk of post-operative neurological deficits (safety). Given the difficulty of this trade-off, it is surprising how limited the neurosurgeon’s intra-operative tools are. To this day, neurosurgeons still resect brain tumors without any form of real-time volumetric functional imaging. Functional Ultrasound (fUS) shows great potential as a next-generation intra-operative functional imaging technique, combining submillimeter-subsecond spatiotemporal resolution, high-depth penetration and large fields of view. In previous work we have successfully shown fUS’ ability to map out hemodynamics-based functional brain activity during language and motor tasks during awake tumor resections. However, there has been no study comparing fUS-acquired functional maps and its gold standard counterpart of BOLD-fMRI imaging or Electrocortical Stimulation Mapping (ESM). Here we present our first results of concomitant ESM-, fMRI- and fUS-imaging in the same human subjects. MATERIAL AND METHODS In N = 3 patients undergoing awake surgery for tumor removal, we performed paired functional testing with pre-operative fMRI and intra-operative fUS and ESM. Using conventional linear ultrasound arrays (GE L8-18I-D (7.8 MHz) and GE 9L-D Logiq 9 (5.3 MHz)) interfaced with our experimental system (Vantage-256, Verasonics), we could acquire fUS-images up to 8 cm in depth with a PRF up to 800 Hz. Building on clinically available neuro-navigation software with optical tracking (Brainlab), we co-registered our intra-operative fUS-maps and ESM-hotspots to pre-operative MRI/CT-data in real-time to study spatiotemporal overlap. RESULTS In motor, language and visual tasks, we were able to demonstrate consistent spatial overlap between the fUS-based and ESM- and fMRI-based functional regions. Our fUS functional maps presented with unprecedented mesoscopic-scale precision (400 µm), even at depths of over > 5 cm. In contrast to fMRI and ESM, fUS was also able to concomitantly visualize the in-vivo microvascular morphology underlying the functional hemodynamics. The current results were only obtainable after we developed a powerful study pipeline including pre-operative fMRI-imaging and ROI-planning, intra-operative integration of experimental Doppler-data and co-registered functional analyses. CONCLUSION The work presented here is the first-ever, in-human comparison between ESM-, fMRI- and fUS-based functional data, serving as a significant milestone towards further clinical maturity of fUS as a new intra-operative tool to improve the safety and efficacy of neurosurgical brain tumor resections. Disclosure: This work was supported by the NWO-Groot grant of The Dutch Organization for Scientific Research (NWO) (Grant no. 108845).
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Sheybani, Natasha, Soumen Paul, Katelyenn McCauley, Victoria Breza, Stuart Berr, G. Wilson Miller, Kiel Neumann, and Richard Price. "472 ImmunoPET-informed sequence for focused ultrasound-targeted mCD47 blockade controls glioma." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A502—A503. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0472.
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BackgroundThe natural disease course for glioblastoma (GB) entails invariably grim outcomes for patients. Phagocytic immunotherapies, such as CD47 blockade (e.g. mCD47), have recently demonstrated promise for GB therapy. However, their efficacy is challenged by presence of the blood brain and tumor barriers (BBB/BTB). Transient disruption of the BBB/BTB via focused ultrasound (FUS) and circulating microbubbles (MB) holds promise for improving therapeutic outcomes in the context of mCD47. However, critical questions regarding the optimal protocol for therapeutic antibody delivery with FUS remain. We herein leverage immuno-PET imaging to spatiotemporally map [89Zr]-mCD47 delivery across the BBB/BTB with FUS in an orthotopic GB model. We then use these insights to design a combinatorial paradigm for mCD47 delivery with repeat FUS BBB/BTB-D.MethodsMRI-guided FUS BBB/BTB-D was performed in the presence of systemically circulating MBs in mice with orthotopically implanted GL261 tumors. Mice received i.v. [89Zr]-mCD47 either without FUS, immediately prior to FUS [FUSPRE] or following FUS [FUSPOST]. Subsequently, mice underwent serial static PET/CT imaging followed by terminal ex vivo assessment of antibody biodistribution. A therapeutic paradigm was then executed, wherein GL261-bearing mice received i.v. mCD47 (8 mg/kg) either as monotherapy or in combination with FUS BBB/BTB-D over three sessions spaced three days apart. Overall survival was monitored and tumor outgrowth was tracked via serial contrast-enhanced MRI.ResultsContrast-enhanced MRI confirmed BBB/BTB-D in GL261 tumors (figure 1A). However, PET/CT imaging revealed a lack of tumor-preferential [89Zr]-mCD47 uptake with or without FUSPRE, suggesting that neither condition improved antibody penetrance over that in naïve brain (figure 1B-C). Remarkably, FUSPOST conferred superlative [89Zr]-mCD47 uptake at the site of BBB/BTB-D, boasting between 4.3- to 6.7-fold more uptake relative to other groups (figure 1C). This elevation in uptake was sustained over the time points assessed (0–72 hours post-FUS) (figure 1C-D). Using these insights, we evaluated a rational paradigm (figure 2A) combining mCD47 with repeat FUSPOST BBB/BTB-D (figure 2B-C) for glioma therapy. FUS-mediated delivery of mCD47 across the BBB/BTB significantly constrained tumor outgrowth (figure 2D-E) and enhanced survival (figure 2F) in GL261-bearing mice.Abstract 472 Figure 1Immuno-PET monitoring of [89Zr]-mCD47 delivery(A) Representative contrast-enhanced T1-weighted MR images of GL261 tumor-bearing brain pre- and post-FUS. Enhancement in the right cerebral hemisphere on pre-FUS imaging indicates baseline barrier disruption induced by the presence of a brain tumor. Expansion of the enhanced region on post-FUS imaging reflects effective FUS-mediated BBB/BTB disruption. (B) Representative axial decay-corrected PET/CT images for each experimental group on Day 14. White arrows denote region of visibly elevated radioactivity at the tumor site targeted with FUS. (C) Whole brain standardized [89Zr]-mCD47 uptake values (SUVs) extracted from serial static PET/CT images obtained between days 14 and 16 post-implantation (0 to 2 days post-[89Zr]-mCD47 injection).%ID/mL =% injected dose per mL. **p<0.01, ****p<0.0001 vs. group(s) indicated. Significance assessed by RM mixed effects model implementing restricted maximum likelihood method, followed by Tukey multiple comparison correction. (D) Tumor-drug exposure for [89Zr]-mCD47 in naïve brain or GL261 tumors, based on integration of SUVs from decay-corrected PET/CT images collected between 0 and 48 hours after BBB/BTB-D and/or [89Zr]-mCD47 injection. Significance assessed by one-way ANOVA followed by Tukey multiple comparison correction. ****p<0.0001 vs. all other groupsAbstract 472 Figure 2Therapeutic impact of FUS-mediated mCD47 delivery(A) Overview of experimental design for evaluating mCD47 delivery to orthotopically implanted GL261 tumors in the context of repeat BBB/BTB-D with FUS. Mice received i.v. mCD47 (8 mg/kg) either alone (FUS-) or following BBB/BTB-D at 0.4 MPa (FUS+). (B) Axial contrast-enhanced T1-weighted MR images of murine GL261-tumors pre- and post-FUS. (C) Mean greyscale intensity (MGI) of contrast enhancement pre- and post-FUS over three separate BBB/BTB-D sessions conducted every three days. Calculated as fold change over contralateral brain. Mean ± SD. **p=0.0023. Significance assessed by RM 2-way ANOVA followed by Sidak’s multiple comparison test. (D) Contrast-enhanced T1-weighted MR images of GL261 tumors on days 14, 17 and 20 post-implantation. ? = image excluded due to poor quality. (E) GL261 tumor outgrowth quantified based on serial MR imaging. Mean ± SD. *p=0.0010. Significance assessed by RM mixed-effects model implementing restricted maximum likelihood method, followed by Sidak’s multiple comparison test. (F) Kaplan-Meier curve depicting overall survival of GL261-bearing mice. n=5–6 mice per group. *p=0.0008. Significance assessed by log-rank (Mantel-Cox) testConclusionsTaken together, our findings suggest that mCD47 delivery with FUS BBB/BTB-D is a promising therapeutic strategy for GB. For myriad ongoing pre-clinical and clinical evaluations of FUS-mediated immunotherapy delivery, these findings generate timely and compelling insights regarding impact of injection timing on antibody penetrance in brain tumors. This study underscores the outstanding potential role of immuno-PET imaging for rational design and monitoring of response to FUS immunotherapy approaches.AcknowledgementsThis study was supported by NIH R01CA197111, R01EB020147, R21NS118278 and the Schiff Foundation (R.J.P.). Additional support from NCI F99/K00 Predoctoral to Postdoctoral Fellow Transition Award (F99CA234954), NSF Graduate Research Fellowship and the Robert R. Wagner Fellowship (N.D.S.).Ethics ApprovalThis study was prospectively reviewed and approved by the University of Virginia Animal Care and Use Committee.ConsentN/A
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Thanou, M., and W. Gedroyc. "MRI-Guided Focused Ultrasound as a New Method of Drug Delivery." Journal of Drug Delivery 2013 (May 12, 2013): 1–12. http://dx.doi.org/10.1155/2013/616197.
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Ultrasound-mediated drug delivery under the guidance of an imaging modality can improve drug disposition and achieve site-specific drug delivery. The term focal drug delivery has been introduced to describe the focal targeting of drugs in tissues with the help of imaging and focused ultrasound. Focal drug delivery aims to improve the therapeutic profile of drugs by improving their specificity and their permeation in defined areas. Focused-ultrasound- (FUS-) mediated drug delivery has been applied with various molecules to improve their local distribution in tissues. FUS is applied with the aid of microbubbles to enhance the permeability of bioactive molecules across BBB and improve drug distribution in the brain. Recently, FUS has been utilised in combination with MRI-labelled liposomes that respond to temperature increase. This strategy aims to “activate” nanoparticles to release their cargo locally when triggered by hyperthermia induced by FUS. MRI-guided FUS drug delivery provides the opportunity to improve drug bioavailability locally and therefore improve the therapeutic profiles of drugs. This drug delivery strategy can be directly translated to clinic as MRg FUS is a promising clinically therapeutic approach. However, more basic research is required to understand the physiological mechanism of FUS-enhanced drug delivery.
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Zhang, Junhang, Chen Gong, Zihan Yang, Fan Wei, Xin Sun, Jie Ji, Yushun Zeng, et al. "Ultrasound Flow Imaging Study on Rat Brain with Ultrasound and Light Stimulations." Bioengineering 11, no. 2 (February 10, 2024): 174. http://dx.doi.org/10.3390/bioengineering11020174.
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Functional ultrasound (fUS) flow imaging provides a non-invasive method for the in vivo study of cerebral blood flow and neural activity. This study used functional flow imaging to investigate rat brain’s response to ultrasound and colored-light stimuli. Male Long-Evan rats were exposed to direct full-field strobe flashes light and ultrasound stimulation to their retinas, while brain activity was measured using high-frequency ultrasound imaging. Our study found that light stimuli, particularly blue light, elicited strong responses in the visual cortex and lateral geniculate nucleus (LGN), as evidenced by changes in cerebral blood volume (CBV). In contrast, ultrasound stimulation elicited responses undetectable with fUS flow imaging, although these were observable when directly measuring the brain’s electrical signals. These findings suggest that fUS flow imaging can effectively differentiate neural responses to visual stimuli, with potential applications in understanding visual processing and developing new diagnostic tools.
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Fadera, Siaka, Chinwendu Chukwu, Andrew H. Stark, Yimei Yue, Jinyun Yuan, Chih-Yen Chien, Lu Xu, Mohammad Albuhssin, and Hong Chen. "DDEL-11. FOCUSED ULTRASOUND-MEDIATED DELIVERY OF ANTI-PROGRAMMED CELL DEATH-LIGAND 1 ANTIBODY TO THE BRAIN OF A PORCINE MODEL." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v103. http://dx.doi.org/10.1093/neuonc/noad179.0390.
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Abstract Focused ultrasound-combined with microbubble-mediated blood-brain barrier opening (FUS-BBBO) has been established as a promising brain drug delivery technology for the treatment of brain tumors. Immune checkpoint inhibitor therapy is a form of cancer immunotherapy that has revolutionized the treatment of cancer and shown remarkable efficacy in a range of cancers. Previous studies reported successful delivery of a checkpoint inhibitor anti-PD-L1 antibody (aPD-L1) by FUS-BBBO in the mouse brain. The objective of this study was to evaluate the feasibility and safety of FUS-BBBO in the delivery of aDP-L1 to the brain of a large animal model. Pigs (4 weeks old, male, n=3) were used as the large animal model. A FUS transducer (frequency of 650 kHz, aperture of 65 mm, and a focal length of 65 mm) was used to sonicate three different brain regions in the presence of systemically injected microbubbles (Definity) for every pig. Near-infrared fluorescent dye-labeled aPD-L1 was injected intravenously to the pig after FUS sonication. Contrast-enhanced MRI was conducted to evaluate the BBB permeability. Pig brains were then harvested and imaged by the Licor Pear imaging system. Successful BBBO was confirmed by in vivo T1-weighted MR imaging. The average MR contrast enhancement volume in the FUS-targeted regions was 4.8× of that in the contralateral non-targeted regions. Ex vivo fluorescence imaging found that FUS sonication enhanced aPD-L1 delivery by 2.1× compared with the non-targeted regions. Histological analysis by hematoxylin and eosin (H&E) staining did not find evidence for tissue damage. These findings suggest that FUS-BBBO can achieve noninvasive, localized, and safe delivery of aPD-L1 to the brain of large animals, providing strong preclinical data to support the clinical translation of this promising technique for brain cancer immunotherapy.
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Soloukey, S., L. Verhoef, F. Mastik, B. S. Generowicz, E. M. Bos, B. S. Harhangi, K. E. Collée, et al. "P09.03 Fully integrating functional Ultrasound (fUS) into the onco-neurosurgical operating room: Towards a new real-time, high-resolution image-guided resection tool with multimodal potential." Neuro-Oncology 23, Supplement_2 (September 1, 2021): ii26—ii27. http://dx.doi.org/10.1093/neuonc/noab180.091.
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Abstract BACKGROUND Onco-neurosurgical practice still relies heavily on pre-operatively acquired images to guide intra-operative decision-making for safe tumor removal, a practice with inherent pitfalls such as registration inaccuracy due to brain shift, and lack of real-time (functional) feedback. Exploiting the opportunity for real-time imaging of the exposed brain can improve intra-operative decision-making, neurosurgical safety and patient outcomes. Previously, we described functional Ultrasound (fUS) as a high-resolution, depth-resolved imaging technique able to detect functional regions and vascular morphology during awake resections. Here, we present for the first time fUS as a fully integrated, MRI/CT-registered imaging modality in the OR. MATERIAL AND METHODS fUS relies on high-frame-rate (HFR) ultrasound, making the technique sensitive for very small motions caused by vascular dynamics (µDoppler) and allowing measurements of changes in cerebral blood volume (CBV) with micrometer-millisecond precision. This opens up the possibility to 1) detect functional response, as CBV-changes reflect changes in metabolism of activated neurons through neurovascular coupling and 2) visualize in-vivo vascular morphology of tumor and healthy tissue. During a range of anesthetized and awake onco-neurosurgical procedures we acquired images of brain and spinal cord using conventional linear ultrasound probes connected to an experimental acquisition unit. Building on Brainlab’s ‘Cranial Navigation’ and ‘Intra-Operative Ultrasound’ modules, we could co-register our intra-operative Power Doppler Images (PDIs) to patient-registered MRI/CT-data. Using the ‘IGTLink’ research interface, we could access and store real-time tracking data for informed volume reconstructions in post-processing. RESULTS Intra-operative fUS could be registered to MRI/CT-images in real-time, showing overlays of PDIs at imaging depths of >5 centimeters. During meningioma resections, these co-registered PDIs revealed fUS’ ability to visualize the tumor’s feeding vessels and surrounding healthy vasculature prior to durotomy, with a level of detail unprecedented by conventional MRI-sequences. Comparing post-operatively reconstructed 3D-vascular maps of pre- and post-durotomy acquisitions, further confirmed the dural dependency of the vascular network feeding the tumor. During awake resections, fUS revealed distinct functional areas as activated during motor and language tasks. CONCLUSION fUS is a new real-time, high-resolution and depth-resolved imaging technique, combining characteristics uniquely beneficial for a potential image-guided resection tool. The successful integration of fUS in the onco-neurosurgical OR demonstrated by our team, is an essential step towards clinical integration of fUS, as well as the technique’s validation against modalities such as MRI and CT.
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Maslova, Stefanyda, Zehra Demir, Thomas Sherlock, Beyzanur Ak, Serge Yaacoub, Dalia Haydar, and Natasha Sheybani. "MDB-108. MRI-GUIDED FOCUSED ULTRASOUND BLOOD BRAIN/TUMOR BARRIER DISRUPTION FOR AUGMENTATION OF ANTIBODY DELIVERY TO HIGH-RISK MEDULLOBLASTOMAS." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.556.
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Abstract BACKGROUND Medulloblastoma is the most common pediatric brain cancer, and among its four molecular subgroups, group 3 (G3MB) harbors the worst prognosis (5-year survival rate <50%). Effective treatment of G3MB remains difficult due to disease complexity, its challenging niche within the immunologically- and pharmacologically-privileged central nervous system, and significant risk of long-term developmental deficits due to treatment toxicities. MRI-guided focused ultrasound (MRgFUS) holds the potential to revolutionize care as a non-invasive, non-ionizing approach for spatially precise intervention in G3MBs. Given that the utility of FUS in MBs remains unknown, we implemented FUS-mediated blood brain/tumor barrier disruption (BBB/BTB-D) in a high-fidelity model of G3MB and evaluated its impact on localized antibody delivery – with an eye toward future applications in immuno-oncology. METHODS An orthotopic syngeneic model was established via stereotactic implantation of G3MB cells (Gfi1/c-MYC driven) into the cerebellum. G3MB growth kinetics were validated via serial MRI. Multiple protocols for naive cerebellum or G3MB BBB/BTB-D were established with a 1.15 MHz FUS system under 9.4T MRI guidance. Across both settings, mice were sonicated with concomitant intravenous administration of microbubbles and fluorescently-labeled IgG. Safety was confirmed by acoustic emissions monitoring, susceptibility-weighted imaging, histology, and acute activity monitoring. Antibody delivery was evaluated via ex vivo epifluorescence imaging. RESULTS Post-contrast T1w-MRI depicted clear evidence of localized BBB/BTB-D in naive and G3MB mice. No damage was noted by imaging or histopathologic analysis, and mice displayed normal cardiorespiratory and motor functions following FUS. FUS conferred significantly increased epifluorescence signal in targeted cerebellum (1.3x) and G3MBs (1.5x) relative to controls, indicating improved antibody access. CONCLUSIONS Our findings support the safety and feasibility of FUS BBB/BTB-D in naive and G3MB-bearing cerebellum. We demonstrate that FUS markedly improves antibody penetrance within G3MBs. Ongoing studies are evaluating FUS in combination with novel immunotherapeutic antibodies for G3MB therapy.
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Nayak, Rohit, Jeyeon Lee, Setayesh Sotoudehnia, Su-Youne Chang, Mostafa Fatemi, and Azra Alizad. "Mapping Pharmacologically Evoked Neurovascular Activation and Its Suppression in a Rat Model of Tremor Using Functional Ultrasound: A Feasibility Study." Sensors 23, no. 15 (August 3, 2023): 6902. http://dx.doi.org/10.3390/s23156902.
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Functional ultrasound (fUS), an emerging hemodynamic-based functional neuroimaging technique, is especially suited to probe brain activity and primarily used in animal models. Increasing use of pharmacological models for essential tremor extends new research to the utilization of fUS imaging in such models. Harmaline-induced tremor is an easily provoked model for the development of new therapies for essential tremor (ET). Furthermore, harmaline-induced tremor can be suppressed by the same classic medications used for essential tremor, which leads to the utilization of this model for preclinical testing. However, changes in local cerebral activities under the effect of tremorgenic doses of harmaline have not been completely investigated. In this study, we explored the feasibility of fUS imaging for visualization of cerebral activation and deactivation associated with harmaline-induced tremor and tremor-suppressing effects of propranolol. The spatial resolution of fUS using a high frame rate imaging enabled us to visualize time-locked and site-specific changes in cerebral blood flow associated with harmaline-evoked tremor. Intraperitoneal administration of harmaline generated significant neural activity changes in the primary motor cortex and ventrolateral thalamus (VL Thal) regions during tremor and then gradually returned to baseline level as tremor subsided with time. To the best of our knowledge, this is the first functional ultrasound study to show the neurovascular activation of harmaline-induced tremor and the therapeutic suppression in a rat model. Thus, fUS can be considered a noninvasive imaging method for studying neuronal activities involved in the ET model and its treatment.
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Chu, Po-Chun, Wen-Yen Chai, Han-Yi Hsieh, Jiun-Jie Wang, Shiaw-Pyng Wey, Chiung-Yin Huang, Kuo-Chen Wei, and Hao-Li Liu. "Pharmacodynamic Analysis of Magnetic Resonance Imaging-Monitored Focused Ultrasound-Induced Blood-Brain Barrier Opening for Drug Delivery to Brain Tumors." BioMed Research International 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/627496.
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Microbubble-enhanced focused ultrasound (FUS) can enhance the delivery of therapeutic agents into the brain for brain tumor treatment. The purpose of this study was to investigate the influence of brain tumor conditions on the distribution and dynamics of small molecule leakage into targeted regions of the brain after FUS-BBB opening. A total of 34 animals were used, and the process was monitored by 7T-MRI. Evans blue (EB) dye as well as Gd-DTPA served as small molecule substitutes for evaluation of drug behavior. EB was quantified spectrophotometrically. Spin-spin (R1) relaxometry and area under curve (AUC) were measured by MRI to quantify Gd-DTPA. We found that FUS-BBB opening provided a more significant increase in permeability with small tumors. In contrast, accumulation was much higher in large tumors, independent of FUS. The AUC values of Gd-DTPA were well correlated with EB delivery, suggesting that Gd-DTPA was a good indicator of total small-molecule accumulation in the target region. The peripheral regions of large tumors exhibited similar dynamics of small-molecule leakage after FUS-BBB opening as small tumors, suggesting that FUS-BBB opening may have the most significant permeability-enhancing effect on tumor peripheral. This study provides useful information toward designing an optimized FUS-BBB opening strategy to deliver small-molecule therapeutic agents into brain tumors.
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Edelman, Bradley J., Dominique Siegenthaler, Paulina Wanken, Bethan Jenkins, Bianca Schmid, Andrea Ressle, Nadine Gogolla, Thomas Frank, and Emilie Macé. "The COMBO window: A chronic cranial implant for multiscale circuit interrogation in mice." PLOS Biology 22, no. 6 (June 3, 2024): e3002664. http://dx.doi.org/10.1371/journal.pbio.3002664.
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Neuroscientists studying the neural correlates of mouse behavior often lack access to the brain-wide activity patterns elicited during a specific task of interest. Fortunately, large-scale imaging is becoming increasingly accessible thanks to modalities such as Ca2+ imaging and functional ultrasound (fUS). However, these and other techniques often involve challenging cranial window procedures and are difficult to combine with other neuroscience tools. We address this need with an open-source 3D-printable cranial implant—the COMBO (ChrOnic Multimodal imaging and Behavioral Observation) window. The COMBO window enables chronic imaging of large portions of the brain in head-fixed mice while preserving orofacial movements. We validate the COMBO window stability using both brain-wide fUS and multisite two-photon imaging. Moreover, we demonstrate how the COMBO window facilitates the combination of optogenetics, fUS, and electrophysiology in the same animals to study the effects of circuit perturbations at both the brain-wide and single-neuron level. Overall, the COMBO window provides a versatile solution for performing multimodal brain recordings in head-fixed mice.
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Blaize, Kévin, Fabrice Arcizet, Marc Gesnik, Harry Ahnine, Ulisse Ferrari, Thomas Deffieux, Pierre Pouget, et al. "Functional ultrasound imaging of deep visual cortex in awake nonhuman primates." Proceedings of the National Academy of Sciences 117, no. 25 (June 8, 2020): 14453–63. http://dx.doi.org/10.1073/pnas.1916787117.
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Deep regions of the brain are not easily accessible to investigation at the mesoscale level in awake animals or humans. We have recently developed a functional ultrasound (fUS) technique that enables imaging hemodynamic responses to visual tasks. Using fUS imaging on two awake nonhuman primates performing a passive fixation task, we constructed retinotopic maps at depth in the visual cortex (V1, V2, and V3) in the calcarine and lunate sulci. The maps could be acquired in a single-hour session with relatively few presentations of the stimuli. The spatial resolution of the technology is illustrated by mapping patterns similar to ocular dominance (OD) columns within superficial and deep layers of the primary visual cortex. These acquisitions using fUS suggested that OD selectivity is mostly present in layer IV but with extensions into layers II/III and V. This imaging technology provides a new mesoscale approach to the mapping of brain activity at high spatiotemporal resolution in awake subjects within the whole depth of the cortex.
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Montaldo, Gabriel, Alan Urban, and Emilie Macé. "Functional Ultrasound Neuroimaging." Annual Review of Neuroscience 45, no. 1 (July 8, 2022): 491–513. http://dx.doi.org/10.1146/annurev-neuro-111020-100706.
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Functional ultrasound (fUS) is a neuroimaging method that uses ultrasound to track changes in cerebral blood volume as an indirect readout of neuronal activity at high spatiotemporal resolution. fUS is capable of imaging head-fixed or freely behaving rodents and of producing volumetric images of the entire mouse brain. It has been applied to many species, including primates and humans. Now that fUS is reaching maturity, it is being adopted by the neuroscience community. However, the nature of the fUS signal and the different implementations of fUS are not necessarily accessible to nonspecialists. This review aims to introduce these ultrasound concepts to all neuroscientists. We explain the physical basis of the fUS signal and the principles of the method, present the state of the art of its hardware implementation, and give concrete examples of current applications in neuroscience. Finally, we suggest areas for improvement during the next few years.
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Zhang, Xinrui, Mariana Bobeica, Michael Unger, Anastasia Bednarz, Bjoern Gerold, Ina Patties, Andreas Melzer, and Lisa Landgraf. "Focused ultrasound radiosensitizes human cancer cells by enhancement of DNA damage." Strahlentherapie und Onkologie 197, no. 8 (April 22, 2021): 730–43. http://dx.doi.org/10.1007/s00066-021-01774-5.
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Abstract Purpose High-intensity focused ultrasound (HIFU/FUS) has expanded as a noninvasive quantifiable option for hyperthermia (HT). HT in a temperature range of 40–47 °C (thermal dose CEM43 ≥ 25) could work as a sensitizer to radiation therapy (RT). Here, we attempted to understand the tumor radiosensitization effect at the cellular level after a combination treatment of FUS+RT. Methods An in vitro FUS system was developed to induce HT at frequencies of 1.147 and 1.467 MHz. Human head and neck cancer (FaDU), glioblastoma (T98G), and prostate cancer (PC-3) cells were exposed to FUS in ultrasound-penetrable 96-well plates followed by single-dose X‑ray irradiation (10 Gy). Radiosensitizing effects of FUS were investigated by cell metabolic activity (WST‑1 assay), apoptosis (annexin V assay, sub-G1 assay), cell cycle phases (propidium iodide staining), and DNA double-strand breaks (γH2A.X assay). Results The FUS intensities of 213 (1.147 MHz) and 225 W/cm2 (1.467 MHz) induced HT for 30 min at mean temperatures of 45.20 ± 2.29 °C (CEM43 = 436 ± 88) and 45.59 ± 1.65 °C (CEM43 = 447 ± 79), respectively. FUS improves the effect of RT significantly by reducing metabolic activity in T98G cells 48 h (RT: 96.47 ± 8.29%; FUS+RT: 79.38 ± 14.93%; p = 0.012) and in PC-3 cells 72 h (54.20 ± 10.85%; 41.01 ± 11.17%; p = 0.016) after therapy, but not in FaDu cells. Mechanistically, FUS+RT leads to increased apoptosis and enhancement of DNA double-strand breaks compared to RT alone in T98G and PC-3 cells. Conclusion Our in vitro findings demonstrate that FUS has good potential to sensitize glioblastoma and prostate cancer cells to RT by mainly enhancing DNA damage.
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Hoque, Nazia, Choudhury Hasan, Md Rana, Amrit Varsha, Md Sohrab, and Khondaker Rahman. "Fusaproliferin, a Fungal Mycotoxin, Shows Cytotoxicity against Pancreatic Cancer Cell Lines." Molecules 23, no. 12 (December 11, 2018): 3288. http://dx.doi.org/10.3390/molecules23123288.
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As a part of our ongoing research on endophytic fungi, we have isolated a sesterterpene mycotoxin, fusaproliferin (FUS), from a Fusarium solani strain, which is associated with the plant Aglaonema hookerianum Schott. FUS showed rapid and sub-micromolar IC50 against pancreatic cancer cell lines. Time-dependent survival analysis and microscopy imaging showed rapid morphological changes in cancer cell lines 4 h after incubation with FUS. This provides a new chemical scaffold that can be further developed to obtain more potent synthetic agents against pancreatic cancer.
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Sharma, Deepa, Farah Hussein, Niki Law, Golnaz Farhat, Christine Tarapacki, Lakshmanan Sannachi, Anoja Giles, and Gregory J. Czarnota. "Focused Ultrasound Stimulation of Microbubbles in Combination With Radiotherapy for Acute Damage of Breast Cancer Xenograft Model." Technology in Cancer Research & Treatment 21 (January 2022): 153303382211329. http://dx.doi.org/10.1177/15330338221132925.
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Objective: Several studies have focused on the use of ultrasound-stimulated microbubbles (USMB) to induce vascular damage in order to enhance tumor response to radiation. Methods: In this study, power Doppler imaging was used along with immunohistochemistry to investigate the effects of combining radiation therapy (XRT) and USMB using an ultrasound-guided focused ultrasound (FUS) therapy system in a breast cancer xenograft model. Specifically, MDA-MB-231 breast cancer xenograft tumors were induced in severe combined immuno-deficient female mice. The mice were treated with FUS alone, ultrasound and microbubbles (FUS + MB) alone, 8 Gy XRT alone, or a combined treatment consisting of ultrasound, microbubbles, and XRT (FUS + MB + XRT). Power Doppler imaging was conducted before and 24 h after treatment, at which time mice were sacrificed and tumors assessed histologically. The immunohistochemical analysis included terminal deoxynucleotidyl transferase dUTP nick end labeling, hematoxylin and eosin, cluster of differentiation-31 (CD31), Ki-67, carbonic anhydrase (CA-9), and ceramide labeling. Results: Tumors receiving treatment of FUS + MB combined with XRT demonstrated significant increase in cell death (p = 0.0006) compared to control group. Furthermore, CD31 and Power Doppler analysis revealed reduced tumor vascularization with combined treatment indicating ( P < .0001) and ( P = .0001), respectively compared to the control group. Additionally, lesser number of proliferating cells with enhanced tumor hypoxia, and ceramide content were also reported in group receiving a treatment of FUS + MB + XRT. Conclusion: The study results demonstrate that the combination of USMB with XRT enhances treatment outcomes.
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Ishigaki, Shinsuke, Yuichi Riku, Yusuke Fujioka, Kuniyuki Endo, Nobuyuki Iwade, Kaori Kawai, Minaka Ishibashi, et al. "Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases." Brain 143, no. 8 (August 1, 2020): 2398–405. http://dx.doi.org/10.1093/brain/awaa196.
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Abstract Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer’s disease, or Pick’s disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer’s disease or Pick’s disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.
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Tazhibi, Masih, Nicholas McQuillan, Hong-Jian Wei, Antonios Pouliopoulos, Ethan Bendau, Zachary Englander, Andrea Webster, et al. "RADT-17. FOCUSED ULTRASOUND MEDIATED BLOOD–BRAIN BARRIER OPENING IS SAFE AND FEASIBLE CONCURRENT WITH AND ADJUVANT TO A CLINICAL RADIATION SCHEME FOR BRAINSTEM DMG." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi44—vi45. http://dx.doi.org/10.1093/neuonc/noab196.175.
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Abstract Diffuse midline gliomas (DMG) are pediatric tumors with dismal prognosis. When these tumors emerge in the brainstem, there exists no feasible method of surgical resection or systemic intervention, making ionizing radiation the sole therapeutic avenue to date. However, radiotherapy (RT) provides only marginal survival benefit as the topographically diffuse and highly infiltrative tumors spread in areas in which the blood-brain barrier (BBB) is relatively intact. Focused ultrasound (FUS) with intravenous microbubbles provides a compelling solution, transiently and non-invasively opening the BBB to allow drug delivery across the cerebrovasculature. Nonetheless, it remains unclear whether FUS can be safely administered at the brainstem in patients receiving RT. Therefore, the goal of this study was to assess the safety and feasibility of FUS administered concurrent with and adjuvant to a clinical hypofractionated radiation scheme for brainstem DMG. Non-tumor bearing B6 albino mice were randomly assorted into control, RT, FUS, and RT+FUS groups. Mice designated RT+FUS received 39Gy/13fx (hypofractionated RT scheme) to the brainstem with two sessions of FUS approximately 1 week apart. A single-element, spherical-segment FUS transducer driven by a function generator through a power amplifier was used with concomitant microbubble injection to sonicate the brainstem. Magnetic resonance imaging (MRI) was used to confirm BBB opening and cardiopulmonary measures were recorded throughout sonication. Vitals were assessed daily, and all treatment animals underwent Kondziela inverted screen testing and sequential weight lifting to assess brainstem-related strength and motor coordination deficits. In both FUS and RT+FUS mice, MRI confirmed brainstem BBB opening and subsequent closure within 96 hours. Mouse weights were stable, with slight drops (mean=5.5%) following FUS that resolved within three days. No attenuation in cardiorespiratory, strength, and motor coordination measurements was observed from FUS. FUS is a safe and feasible technique for brainstem BBB opening concurrent with and adjuvant to clinical hypofractionated RT.
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Fadera, Siaka, Lu Xu, Chih-Yen Chien, Yimei Yue, Dezhuang Ye, Chinwendu Chukwu, and Hong Chen. "Feasibility of MRI-guided focused ultrasound-mediated intranasal delivery in a large animal model." Journal of the Acoustical Society of America 153, no. 3_supplement (March 1, 2023): A139. http://dx.doi.org/10.1121/10.0018430.
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Intranasal delivery provides non-invasive delivery of drugs from the nose to the brain bypassing the blood-brain barrier (BBB). We previously reported the focused ultrasound (FUS)-mediated intranasal delivery (FUSIN) of various agents in mice using FUS. However, no study has investigated the feasibility of FUSIN in large animals. The objective of this study was to investigate the feasibility of MR-guided FUS-mediated intranasal delivery in a large animal model. Pigs were used as the large animal model due to their clinical relevance to humans. Fluorescence-labeled albumin was mixed with an MRI contrast agent and administrated intranasally to the pig using a catheter. Followed by intravenous injection of microbubbles, FUS sonication was performed at two brain regions, the cortex and brainstem. T1-weighted MR images showed enhancement of MRI contrast agent at the olfactory region of the pig nose. Fluorescence imaging displayed enhanced fluorescence intensity at the FUS-targeted brain regions. These findings suggest that MR-guided FUS can achieve noninvasive and localized delivery of intranasally administered agents to the brain in large animals.
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Fadera, Siaka. "Focused ultrasound-mediated delivery of anti-programmed cell death-ligand 1 antibody to the brain of a porcine model." Journal of the Acoustical Society of America 154, no. 4_supplement (October 1, 2023): A224. http://dx.doi.org/10.1121/10.0023352.
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Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment by leveraging the body's immune system to combat cancer cells. However, its effectiveness in brain cancer is hindered by the blood-brain barrier (BBB), impeding the delivery of ICIs to brain tumor cells. This study aimed to assess the safety and feasibility of using focused ultrasound combined with microbubbles-mediated BBB opening (FUS-BBBO) to facilitate trans-BBB delivery of an ICI, anti-programmed cell death-ligand 1 antibody (aPD-L1), to the brain of a large animal model. In a porcine model, FUS sonication of targeted brain regions was performed after intravenous microbubble injection, which was followed by intravenous administration of aPD-L1 labeled with a near-infrared fluorescent dye. The permeability of the BBB was evaluated using contrast-enhanced MRI, while fluorescence imaging and histological analysis were conducted on ex vivo pig brains. Results showed a significant 4.8-fold increase in MR contrast enhancement volume in FUS-targeted regions compared to non-targeted regions. FUS sonication enhanced aPD-L1 delivery by an average of 2.1-fold, according to fluorescence imaging. In vivo MRI and ex vivo staining found the procedure did not cause significant acute tissue damage. These findings demonstrate that FUS-BBBO offers a noninvasive, localized, and safe delivery approach for ICIs in a large animal model, showcasing its potential for clinical translation.
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Fadera, Siaka, Chinwendu Chukwu, Andrew H. Stark, Yimei Yue, Lu Xu, Chih-Yen Chien, Jinyun Yuan, and Hong Chen. "Focused Ultrasound-Mediated Delivery of Anti-Programmed Cell Death-Ligand 1 Antibody to the Brain of a Porcine Model." Pharmaceutics 15, no. 10 (October 17, 2023): 2479. http://dx.doi.org/10.3390/pharmaceutics15102479.
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Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment by leveraging the body’s immune system to combat cancer cells. However, its effectiveness in brain cancer is hindered by the blood-brain barrier (BBB), impeding the delivery of ICIs to brain tumor cells. This study aimed to assess the safety and feasibility of using focused ultrasound combined with microbubble-mediated BBB opening (FUS-BBBO) to facilitate trans-BBB delivery of an ICI, anti-programmed cell death-ligand 1 antibody (aPD-L1) to the brain of a large animal model. In a porcine model, FUS sonication of targeted brain regions was performed after intravenous microbubble injection, which was followed by intravenous administration of aPD-L1 labeled with a near-infrared fluorescent dye. The permeability of the BBB was evaluated using contrast-enhanced MRI in vivo, while fluorescence imaging and histological analysis were conducted on ex vivo pig brains. Results showed a significant 4.8-fold increase in MRI contrast-enhancement volume in FUS-targeted regions compared to nontargeted regions. FUS sonication enhanced aPD-L1 delivery by an average of 2.1-fold, according to fluorescence imaging. In vivo MRI and ex vivo staining revealed that the procedure did not cause significant acute tissue damage. These findings demonstrate that FUS-BBBO offers a noninvasive, localized, and safe delivery approach for ICI delivery in a large animal model, showcasing its potential for clinical translation.
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Chen, Mark, Eric S. Xu, Nathan H. Leisenring, Diana M. Cardona, Lixia Luo, Yan Ma, Andrea Ventura, and David G. Kirsch. "The Fusion Oncogene FUS-CHOP Drives Sarcomagenesis of High-Grade Spindle Cell Sarcomas in Mice." Sarcoma 2019 (July 25, 2019): 1–14. http://dx.doi.org/10.1155/2019/1340261.
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Myxoid liposarcoma is a malignant soft tissue sarcoma characterized by a pathognomonic t(12;16)(q13;p11) translocation that produces a fusion oncoprotein, FUS-CHOP. This cancer is remarkably sensitive to radiotherapy and exhibits a unique pattern of extrapulmonary metastasis. Here, we report the generation and characterization of a spatially and temporally restricted mouse model of sarcoma driven by FUS-CHOP. Using different Cre drivers in the adipocyte lineage, we initiated in vivo tumorigenesis by expressing FUS-CHOP in Prrx1+ mesenchymal progenitor cells. In contrast, expression of FUS-CHOP in more differentiated cells does not form tumors in vivo, and early expression of the oncoprotein during embryogenesis is lethal. We also employ in vivo electroporation and CRISPR technology to rapidly generate spatially and temporally restricted mouse models of high-grade FUS-CHOP-driven sarcomas for preclinical studies.
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Lipsman, Nir. "Focused ultrasound in the human brain: Current and emerging applications." Journal of the Acoustical Society of America 153, no. 3_supplement (March 1, 2023): A100. http://dx.doi.org/10.1121/10.0018301.
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MR-guided Focused ultrasound (MRgFUS) is a disruptive medical technology, and its implementation in the clinic represents the culmination of decades of research. Lying at the convergence of physics, engineering, imaging, biology and neuroscience, FUS offers the ability to non-invasively and precisely intervene in key circuits that drive common and challenging brain conditions. The actions of FUS in the brain take many forms, ranging from transient blood-brain barrier opening to permanent thermoablation, among other mechanisms. The last decade has seen a dramatic expansion of indications for and experience with FUS in humans, with a resultant exponential increase in academic and public interest in the technology. Applications now span the clinical spectrum in neurological and psychiatric diseases, with insights still emerging from preclinical models and human trials. This presentation provides an overview of clinical trials at various stages of developing using FUS and describes the potential impact, and future directions, of FUS on the landscape of brain therapies.
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Sheybani, Natasha D. "Emerging applications of image-guided therapeutic ultrasound for brain tumor-directed immunomodulation and immunotherapy." Journal of the Acoustical Society of America 152, no. 4 (October 2022): A154. http://dx.doi.org/10.1121/10.0015866.
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Immunotherapy has been established as a disruptive pillar of cancer treatment. However, the impact of immunotherapy has yet to be fully realized in neuro-oncology owing to the unique physical barriers (i.e., blood brain/tumor barriers [BBB/BTB]) and distinct immune microenvironment within brain tumors. These obstacles may be overcome through the alliance of image-guided interventions, such as therapeutic ultrasound, with immunotherapies. Specifically, transient disruption of the BBB/BTB via focused ultrasound (FUS) and circulating microbubbles is a promising strategy for potentiating immunotherapy through both immuno-modulation and drug delivery – notably, in a non-invasive, non-ionizing, and precisely targeted manner. We have demonstrated that FUS BBB/BTB disruption invokes mild, transient shifts in the immune milieu of brain tumor-bearing mice. Additionally, we have leveraged immuno-PET imaging to rationally deploy a therapeutic approach combining innate immune checkpoint inhibitor delivery with FUS. We show that this immunoPET-informed paradigm achieves superlative targeted antibody delivery and improved therapeutic outcomes in murine glioblastomas, with markedly reduced systemic antibody dose. Our ongoing investigations seek to advance the nexus of FUS, molecular imaging, and biomarker discovery with the goal of enabling non-invasive, precision immunotherapy paradigms for brain tumors.
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Le, Binh Thanh, and R. N. Taylor. "Ground response to tunnelling incorporating soil reinforcement system." Canadian Geotechnical Journal 56, no. 11 (November 2019): 1719–28. http://dx.doi.org/10.1139/cgj-2018-0075.
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The forepole umbrella system (FUS) uses steel pipes installed from within a tunnel to provide a canopy above the tunnel heading that both increases stability and reduces tunnelling-induced ground movements. Although the system is known to be beneficial and has been used in a number of projects, there is little information on how key parameters including length and forepole stiffness combine to produce effective support. To investigate this, centrifuge tests incorporating the three-dimensional (3D) geometry of a tunnel heading in clay and the model FUS have been undertaken. The tunnel heading was supported by a pressurized rubber bag lining with excavation being simulated by a reduction in air support pressure. Image analysis was used to obtain subsurface ground movements and a newly developed 3D imaging system was used to measure the soil surface deformations accurately. The performance of the FUS and the influences of key FUS parameters were quantified via the settlement reduction factor. The results showed that the FUS, arranged in various settings, reduced the maximum surface settlement by 35%–75%. The effects of the FUS parameters on the reinforcing effectiveness are dependent on the ratio of cover depth to tunnel diameter. An optimum design arrangement of the FUS is suggested.
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Soloukey, Sadaf, Arnaud J. P. E. Vincent, Djaina D. Satoer, Frits Mastik, Marion Smits, Clemens M. F. Dirven, Christos Strydis, et al. "NIMG-19. USING FUNCTIONAL ULTRASOUND (FUS) TO MAP BRAIN FUNCTIONALITY AND TUMOR VASCULATURE WITH MICROMETER-MILLISECOND PRECISION." Neuro-Oncology 22, Supplement_2 (November 2020): ii151. http://dx.doi.org/10.1093/neuonc/noaa215.632.
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Abstract OBJECTIVE In the early 20th century, Dr. Cushing first demonstrated the use of electrical stimulation mapping (ESM) to define motor and sensory cortices during neurosurgical procedures. Essentially, little has changed in what guides a neurosurgeon’s intra-operative decision-making since. Inherent limitations of ESM such as limited depth penetration and risk of seizure elicitation, warrant the development of new image-guided resection tools. Here, we present functional Ultrasound (fUS)-imaging as a new, high-resolution tool to guide intra-operative decision-making during awake tumor removal. METHODS fUS relies on high-frame-rate ultrasound, which offers images at thousands of frames-per-second. As such, fUS is sensitive to very small motions caused by vascular dynamics (µDoppler), allowing measurements of changes in cerebral blood volume (CBV). This facilitates the possibility to 1) detect functional response, as CBV-changes reflect changes in metabolism of activated neurons through neurovascular coupling and 2) visualize high-resolution vascular morphology of tumor and healthy tissue. During conventional awake craniotomy surgery, n= 10 patients were asked to perform 60s functional tasks to elicit cortical responses. Simultaneously, a conventional 5 MHz ultrasound probe connected to an experimental acquisition system, was placed over ESM-defined functional areas. After image acquisition, correlation analyses with the corresponding tasks revealed functional and non-functional areas. In addition, 3D vascular maps were reconstructed from subsequent 2D-Power Doppler Images (PDIs). RESULTS fUS was able to detect functional areas as activated using conventional motor tasks, as well as complex language-related tasks. In addition, both 2D-PDIs and 3D-reconstructions revealed the ability of fUS to detect unique high-resolution onco-vascular characteristics in high- and low-grade malignancies. In all cases, images were acquired with micrometer-millisecond (300 µm, 1.5-2.0 msec) precision at imaging depths > 5 cm. CONCLUSIONS Applying fUS-imaging successfully in this awake craniotomy series serves as a clear demonstration of the technique’s revolutionary potential for maximizing safe tumor removal.
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Soloukey, Sadaf, Luuk Verhoef, Frits Mastik, Bastian Generowicz, Eelke Bos, Joost Schouten, Biswadjiet Harhangi, et al. "ITVT-10. Using functional Ultrasound (fUS) for real-time, depth-resolved functional and vascular delineation of brain tumors with micrometer-millisecond precision." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi230. http://dx.doi.org/10.1093/neuonc/noab196.921.
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Abstract BACKGROUND Neurosurgical practice still relies heavily on pre-operatively acquired images to guide tumor resections, a practice which comes with inherent pitfalls such as registration inaccuracy due to brain shift, and lack of real-time functional or morphological feedback. Here we describe functional Ultrasound (fUS) as a new high-resolution, depth-resolved, MRI/CT-registered imaging technique able to detect functional regions and vascular morphology during awake and anesthesized tumor resections. MATERIALS AND METHODS fUS relies on high-frame-rate (HFR) ultrasound, making the technique sensitive to very small motions caused by vascular dynamics (µDoppler) and allowing measurements of changes in cerebral blood volume (CBV) with micrometer-millisecond precision. This opens up the possibility to 1) detect functional response, as CBV-changes reflect changes in metabolism of activated neurons through neurovascular coupling, and 2) visualize in-vivo vascular morphology of pathological and healthy tissue with high resolution at unprecedented depths. During a range of anesthetized and awake neurosurgical procedures we acquired vascular and functional images of brain and spinal cord using conventional ultrasound probes connected to a research acquisition system. Building on Brainlab’s Intra-Operative Navigation modules, we co-registered our intra-operative Power Doppler Images (PDIs) to patient-registered MRI/CT-data in real-time. RESULTS During meningioma and glioma resections, our co-registered PDIs revealed fUS’ ability to visualize the tumor’s feeding vessels and vascular borders in real-time, with a level of detail unprecedented by conventional MRI-sequences. During awake resections, fUS was able to detect distinct, ESM-confirmed functional areas as activated during conventional motor and language tasks. In all cases, images were acquired with micrometer-millisecond (300 µm, 1.5–2.0 ms) precision at imaging depths exceeding 5 cm. CONCLUSION fUS is a new real-time, high-resolution and depth-resolved imaging technique, combining favorable imaging specifications with characteristics such as mobility and ease of use which are uniquely beneficial for a potential image-guided neurosurgical tool.
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Woldegerima, Ayda, Hong-Jian Wei, Chunchao Zhang, Sridevi Yadavillli, Roger Packer, Cheng-Chia Wu, and Javad Nazarian. "DIPG-73. FOCUSED ULTRASOUND FOR TREATMENT OF CHILDREN DIAGNOSED WITH DIFFUSE MIDLINE GLIOMAS." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.126.
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Abstract BACKGROUND Diffuse midline glioma (DMG) is a highly aggressive and fatal brain tumor that predominantly impacts children and young adults. The infiltrative pattern and rapid growth characteristics of DMG causes a significant challenge in finding an effective treatment. Additionally, the blood-brain barrier (BBB) poses a significant challenge by restricting the passage of therapeutic drugs to tumor bed. Currently the established standard of care is radiotherapy (RT), which is transitory. Thus there is a need for improved treatment options. OBJECTIVE Focused ultrasound (FUS) is an advancing non-invasive technology that has been used to open BBB and enhance drug delivery. We hypothesize that a combination therapy of FUS with pharmacological agents will be an effective and non-invasive treatment option for children diagnosed with DMG. METHOD Syngeneic DMG murine models were used to study the combination therapy of FUS with ONC201, FUS with anti-PD1 and FUS with RT. FUS mediated BBB opening was monitored with contrast-enhanced T1-weighted MRI. FUS-mediated drug delivery was validated with western blot, assessment of ROS, and optical label imaging. Kaplan Meier analysis was used to assess survival benefits. Single cell RNA-sequencing (scRNA-Seq) analysis is being done to assess the treatment effects of FUS and RT combination therapy. RESULTS/CONCLUSION We found that FUS and ONC201 combination therapy resulted in a decrease in NDUFA12 protein (a biomarker of ONC201 response) and an increase in ROS production compared to ONC201 monotherapy. For FUS and anti-PD1 combination therapy, an increased anti-PD1 delivery to the brainstem was detected. The overall survival of mice treated with FUS and anti-PD1 combination therapy increased when compared to anti-PD1 alone. Our preliminary scRNA-Seq analysis showed that combination therapy of FUS and RT induces innate immune response compared to the untreated group. Combination therapy with focused ultrasound shows a promising outcome by increasing the efficacy of therapeutic drugs and immunotherapy.
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Price, Richard J. "Promoting immunotherapy of cancer with focused ultrasound." Journal of the Acoustical Society of America 153, no. 3_supplement (March 1, 2023): A99. http://dx.doi.org/10.1121/10.0018300.
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Immunotherapy (ITx) has revolutionized cancer treatment. Nonetheless, for several indications, many patients do not respond to ITx due to poor immune cell infiltration and/or limited ITx penetration into solid tumors. Both thermally ablative (T) and mechanical (M) forms of focused ultrasound (FUS) may be capable of overcoming these challenges. For example, the pre-clinical application of T-FUS in combination with myeloreductive gemcitabine elicits immunological control of 4T1 breast tumors and metastases, results that inspired the Br54 clinical trial for early stage breast cancer patients at UVA. Meanwhile, our Br48 clinical trial, which combines αPD-1 ITx with T-FUS in Stage III/IV breast cancer patients, shows that the well-tolerated treatment yields reduced regulatory T cells and transcriptional alterations consistent with inflammasome activation, interferon gamma signaling and αβ T cell activation. Regarding M-FUS, in pre-clinical brain tumor studies, we have used ImmunoPET imaging to optimize the timing of ITx antibodies (i.e., αCD47) administration with M-FUS-mediated blood-tumor barrier opening. This readily translatable treatment controlled GL261 tumors and improved survival markedly over previous studies that required multi-fold more αCD47 administration to achieve an effect. Overall, our pre-clinical and clinical results support the use of both T-FUS and M-FUS in combination with ITx for multiple cancer indications.
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Morgan-Curtis, Fea, Lucas Ruge-Jones, Grace M. Wood, Lisa Berntsen, Jacob C. Elliott, Daniel Hayes, and Julianna C. Simon. "Ultrasound diagnosis and treatment of heterotopic ossification." Journal of the Acoustical Society of America 155, no. 3_Supplement (March 1, 2024): A326. http://dx.doi.org/10.1121/10.0027686.
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Heterotopic ossification (HO), or the presence of bone in soft tissues, can occur after musculoskeletal trauma, causing pain and reduced mobility. However, even the most sensitive diagnostic modality requires 2–3 weeks after initiation to detect HO, and the only treatment is surgical resection after HO matures (>2 years). Here, we evaluate the color Doppler ultrasound twinkling artifact for early diagnosis of HO and focused ultrasound (fUS) for treatment of early HO. We began by evaluating twinkling and fUS parameters in ossified cell culture. We then evaluated imaging and treatment parameters in mice with HO. Results show that twinkling correlated well with the presence of ossified cells; although the exact size/number of ossified cells required for twinkling was unclear. In mice, twinkling was found to detect HO in some mice as early as 3 days-post-injection, which is earlier than other imaging modalities. For treatment, fUS at 1.07-MHz and 0.2% duty-cycle with p + /p− = 17/7 MPa was found to be most successful at disrupting mineralizations with little damage to surrounding cells. Mice treated with fUS were found to have less advanced HO compared to sham mice. These results highlight the promise of ultrasound for the diagnosis and treatment of early HO. [Work supported by CDMRP PR201164].
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Yang, Andrew I., Hanane Chaibainou, Sumei Wang, Frederick L. Hitti, Brendan J. McShane, David Tilden, Matthew Korn, et al. "Focused Ultrasound Thalamotomy for Essential Tremor in the Setting of a Ventricular Shunt: Technical Report." Operative Neurosurgery 17, no. 4 (March 19, 2019): 376–81. http://dx.doi.org/10.1093/ons/opz013.
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Abstract BACKGROUND A recent randomized controlled trial of magnetic resonance imaging (MRI)-guided focused ultrasound (FUS) for essential tremor (ET) demonstrated safety and efficacy. Patients with ventricular shunts may be good candidates for FUS to minimize hardware-associated infections. OBJECTIVE To demonstrate feasibility of FUS in this subset of patients. METHODS A 74-yr-old male with medically refractory ET, and a right-sided ventricular shunt for normal pressure hydrocephalus, underwent FUS to the right ventro-intermedius (VIM) nucleus. The VIM nucleus was directly targeted using deterministic tractography. Clinical outcomes were measured using the Clinical Rating Scale for Tremor. RESULTS Shunt components required 6% of the total ultrasound transducer elements to be shut off. Eight therapeutic sonications were delivered (maximum temperature, 64°), leading to a 90% improvement in hand tremor and a 100% improvement in functional disability at the 3-mo follow-up. No complications were noted. CONCLUSION This is the first case of FUS thalamotomy in a patient with a shunt. Direct VIM targeting and achievement of therapeutic temperatures with acoustic energy is feasible in this subset of patients.
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Wei, Hong-Jian, Antonios Pouliopoulos, Nina Yoh, Masih Tazhibi, Nicholas McQuillan, Xu Zhang, Luca Szalontay, et al. "EPCT-23 PRE-CLINICAL STUDY OF FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING AND PANOBINOSTAT FOR DIFFUSE INTRINSIC PONTINE GLIOMA TREATMENT." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i52. http://dx.doi.org/10.1093/neuonc/noab090.209.
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Abstract Diffuse intrinsic pontine glioma (DIPG) is the lethal high-grade brain tumor in children with no effective treatment options to date. Despite excessive clinical trials, the prognosis remains poor, with a median overall survival (mOS) of less than 1 year. Genomic studies of DIPG tissue have identified highly recurrent mutations in genes encoding histone H3 resulting in the substitution of lysine to methionine at position 27 (K27M), which is found in approximately 80% of DIPG. Recent drug screening studies identified the histone deacetylase (HDAC) inhibitors panobinostat as a highly effective drug against DIPG in vitro. However, due to the poor Blood-Brain Barrier (BBB) penetration of systemic administration, to enhance the delivery of panobinostat to improve treatment efficacy is needed. Focused ultrasound (FUS) has been shown to be able to safely and non-invasively open BBB to enhance drug delivery. Hence, in this study, we hypothesize that FUS-mediated BBBO (BBBO) can enhance the delivery of panobinostat for a therapeutic benefit in DIPG. Herein we established the syngeneic DIPG model by intracranially injecting mouse DIPG cells (PDGFB+, H3.3K27M, p53−/−) and used FUS and microbubbles to open BBB and enhance the panobinostat delivery. Magnetic resonance (MR) imaging was utilized to evaluate BBBO and tumor progression. We first demonstrated that FUS-mediated BBB-opening is safe and feasible to mice with DIPG tumors by MR imaging and passive cavitation detection. Moreover, this DIPG cell line is very sensitive to panobinostat in in vitro cytotoxicity assay. The combined treatment of FUS-mediated BBBO and panobinostat showed benefits in both local control and overall survival. The current results demonstrated FUS could increase the treatment efficacy of panobinostat to DIPG animals may be due to the increase of targeted delivery of systemic panobinostat to DIPG tumors in brainstem.
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Elliott, Jacob C., Grace M. Wood, and Julianna C. Simon. "Real-time assessment of focused ultrasound-induced bioeffects in elastic tissues." Journal of the Acoustical Society of America 155, no. 3_Supplement (March 1, 2024): A50—A51. http://dx.doi.org/10.1121/10.0026763.
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Highly elastic tissues have proven resistant to fractionation via focused ultrasound (fUS); however, our previous work in rat tendon has demonstrated a small window of parameters conducive to mild mechanical disruption. For therapeutic applications, there is a need to assess the extent of fUS-induced mechanical bioeffects in real time in order to avoid over- or under-treatment. Here, elastic collagen hydrogels (TeloCol®-10), as well as healthy and collagenase-soaked ex vivo bovine tendons, were exposed to fUS at 1.1–3.68 MHz (p + ≤ 127 MPa, p− ≤ 35 MPa) using 10-ms pulses repeated at 1 Hz. Cavitation signals were collected using simultaneous passive cavitation imaging (PCI) and passive cavitation detection (PCD) to monitor fUS treatment in real time. Preliminary data in polyacrylamide hydrogels and ex vivo bovine tendon show no consistent trends between simultaneous PCI and PCD signals; this is potentially due to different orientations of the receiving transducers, which we will further investigate. However, neither PCI nor PCD trends were consistently linked to a mechanical bioeffect. Therefore, we are exploring the addition of Doppler ultrasound to PCI/PCD to help link the fUS exposure to the desired bioeffect. [Work supported by NIHR01EB032860]
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Johnson, Sara L., Henrik Odeen, Allison Payne, and Harry Vine. "An MR-compatible fiber-optic probe for measuring focused ultrasound-induced temperature rises without viscous heating artifacts." Journal of the Acoustical Society of America 155, no. 3_Supplement (March 1, 2024): A323. http://dx.doi.org/10.1121/10.0027673.
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Focused ultrasound (FUS) beam interactions with thermocouples and fiber optic (FO) probes cause a “viscous heating artifact” (VHA), which prevent accurate temperature measurements during acoustic sonication. This work demonstrates a novel fiber-optic temperature probe which is insensitive to VHA, validated in an MR-guided FUS treatment setting. The FO probe (OSENSA Innovations; PRB-140, 0.14 mm diameter) was inserted with an 18G catheter into a tissue-mimicking gelatin phantom. The FO probe tip was located with high-resolution MR images (0.25 × 0.25 × 0.5 mm3) for targeting with FUS. Continuous-wave FUS sonications (50 W, 20 s) were delivered at a distance of ∼1.5 mm from the FO probe tip using a 256 phased-array transducer (Imasonic, France; 1 MHz, 2.1 × 2.3 × 9.8 FWHM spot size) and FUS-induced heating was measured with 3D MR temperature imaging (MRTI; 0.5 × 0.5 × 1 mm3 resolution, 3.9 s acquisition). The VHA effect was not observed in the PRB-140 FO probe measurement data. The FO probe heating and cooling curves closely matched those measured by MRTI, with a root mean-squared error (RMSE) of 0.61 °C. In contrast, the RMSE of VHA-sensitive FO probe was 6.00 °C for a similar acoustic power output. This ultrasound artifact-immune FO temperature probe is highly advantageous for MR temperature sequence development and precise temperature monitoring in FUS treatment applications.
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Dillon, Patrick Michael, Bethany J. Horton, Timothy Bullock, Christiana Brenin, and David R. Brenin. "Focused ultrasound therapy combined with pembrolizumab in metastatic breast cancer." Journal of Clinical Oncology 36, no. 5_suppl (February 10, 2018): TPS19. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.tps19.
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TPS19 Background: Focused ultrasound (FUS) is an ablative therapy which can heat tumors rapidly to cell damaging temperatures and simultaneously perturb the microenvironment, the microvasculature, and the lymphatics. At typical energy levels, FUS can induce controlled apoptotic cell death rather than liquefactive necrosis. FUS does not involve radiation. FUS is a partially ablative therapy using high energy ultrasound waves to induce heat shock proteins, cytokine release and cellular mediated mechanisms resulting in T cell activation and recognition of tumor antigens. FUS has been demonstrated to be an effective method for inducing tumor antigen exposure and presentation to dendritic cells, thus acting as an auto-vaccine. Pembrolizumab (PBZ) is a PD-1 targeted antibody used in multiple solid tumors to augment T cell activation. It is hypothesized that the combination of these two modalities will result in T cell infiltration into breast tumors as well as systemic immune responses. Methods: In this pilot study, we will examine PBZ therapy in combination with FUS to assess for immune stimulation and antitumor effects at local ablation sites, distant non-treated sites and in the blood. Biopsy before and after treatments will examine the tissue in the peripheral zone of ablation as well as at distant metastatic sites for CD8 and CD4 T cells, MDSC’s, T-regulatory cells and cytokine responses. Twelve patients will be randomized to receive either PBZ 14 days before or 7 days after a single time FUS partial tumor ablation on day 15. Biopsies will be on days 1, 22 and 64 and tumor imaging will be every 12 weeks. Patients must have metastatic or unresectable breast cancer, adequate organ function, and prior therapy in the metastatic setting. They must also have a tumor in the breast or axilla amenable to FUS and biopsy. Clinical trial information: NCT03237572.
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Wang, Shutao, Cheng-Chia Wu, Hairong Zhang, Maria Eleni Karakatsani, Yi-Fang Wang, Yang Han, Kunal R. Chaudhary, Cheng-Shie Wuu, Elisa Konofagou, and Simon K. Cheng. "Focused ultrasound induced-blood–brain barrier opening in mouse brain receiving radiosurgery dose of radiation enhances local delivery of systemic therapy." British Journal of Radiology 93, no. 1109 (May 1, 2020): 20190214. http://dx.doi.org/10.1259/bjr.20190214.
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Objective: Investigate the temporal effects of focused ultrasound (FUS)-induced blood–brain barrier (BBB) opening in post-radiotherapy mouse brains. Methods and materials: C57B6 mice without tumors were used to simulate the scenario after gross total resection (GTR) of brain tumor. Radiation dose of 6 Gy x 5 was delivered to one-hemisphere of the mouse brain. FUS-induced BBB-opening was delivered to the irradiated and non-irradiated brain and was confirmed with MRI. Dynamic MRI was performed to evaluate blood vessel permeability. Two time points were selected: acute (2 days after radiation) and chronic (31 days after radiation). Results: BBB opening was achieved after FUS in the irradiated field as compared to the contralateral non-irradiated brain without any decrease in permeability. In the acute group, a trend for higher gadolinium concentration was observed in radiated field. Conclusion: Localized BBB-opening can be successfully achieved without loss of efficacy by FUS as early as 2 days after radiotherapy. Advances in knowledge: Adjuvant radiation after GTR is commonly used for brain tumors. Focused ultrasound facilitated BBB-opening can be achieved without loss of efficacy in the post-irradiated brain as early as 2 days after radiation therapy. This allows for further studies on early application of FUS-mediated BBB-opening.
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Yang, Jack B., Lauren Powlovich, David Moore, Linda Martin, Braden Miller, Jill Nehrbas, Anant R. Tewari, and Jaime Mata. "Transcutaneous Ablation of Lung Tissue in a Porcine Model Using Magnetic-Resonance-Guided Focused Ultrasound (MRgFUS)." Tomography 10, no. 4 (April 6, 2024): 533–42. http://dx.doi.org/10.3390/tomography10040042.
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Focused ultrasound (FUS) is a minimally invasive treatment that utilizes high-energy ultrasound waves to thermally ablate tissue. Magnetic resonance imaging (MRI) guidance may be combined with FUS (MRgFUS) to increase its accuracy and has been proposed for lung tumor ablation/debulking. However, the lungs are predominantly filled with air, which attenuates the strength of the FUS beam. This investigation aimed to test the feasibility of a new approach using an intentional lung collapse to reduce the amount of air inside the lung and a controlled hydrothorax to create an acoustic window for transcutaneous MRgFUS lung ablation. Eleven pigs had one lung mechanically ventilated while the other lung underwent a controlled collapse and subsequent hydrothorax of that hemisphere. The MRgFUS lung ablations were then conducted via the intercostal space. All the animals recovered well and remained healthy in the week following the FUS treatment. The location and size of the ablations were confirmed one week post-treatment via MRI, necropsy, and histological analysis. The animals had almost no side effects and the skin burns were completely eliminated after the first two animal studies, following technique refinement. This study introduces a novel methodology of MRgFUS that can be used to treat deep lung parenchyma in a safe and viable manner.
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Rytkönen, Jussi, Kimmo Lehtimäki, Taina-Kaisa Stenius, Riikka Immonen, Ari Suhonen, and Artem Shatillo. "Abstract LB155: In vivo imaging of vascular pathology in mouse orthotopic glioma model using functional ultrasound." Cancer Research 83, no. 8_Supplement (April 14, 2023): LB155. http://dx.doi.org/10.1158/1538-7445.am2023-lb155.
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Abstract Neovascularization together with aberrant vasculature is a hallmark of glioblastomas. Understanding tumor vasculature can have a pivotal role in planning therapeutics approaches. The objective of this study was to investigate morphological, vasculature and blood flow changes induced by aggressive tumor growth, using in vivo imaging - magnetic resonance imaging (MRI) and functional ultrasound (fUS) imaging in a mouse model of orthotopic glioma. Female NMRI nude mice were xenografted orthotopically with U-87 MG, a human glioblastoma, cells (5 × 104) at the age of 8 weeks. Four weeks after implantation the mice we anesthetized with isoflurane and scanned with 11.7 T small animal MRI (Bruker) for tumor volumetry. Thereafter, the mice were imaged with Iconeus One imaging system (Iconeus, Paris, France) for structural information of brain vasculature and relative cerebral blood volume (rCBV) changes. High resolution vascular imaging was performed after intravenous injection of microbubble contrast agent (SonoVue, sulphur hexafluoride microbubbles). The average tumor size was 58.8 ± 27.6 mm3 (mean ± SD, n=7) four weeks after implantation. Aberrant vasculature could be visualized with structural fUS imaging as and the necrotic core of the tumor could be observed. A reduced rCBF was observed in ipsilateral hemisphere on the relative power doppler signal timeseries as a lower amplitude and faster decay compared to contralateral side. As a summary, in vivo fUS imaging is a noninvasive tool to visualize vascular changes induced by aggressive brain tumor growth which are not detectable with conventional imaging methods (CT, MRI, PET, SPECT) and can provide a novel readout for efficacy studies. Citation Format: Jussi Rytkönen, Kimmo Lehtimäki, Taina-Kaisa Stenius, Riikka Immonen, Ari Suhonen, Artem Shatillo. In vivo imaging of vascular pathology in mouse orthotopic glioma model using functional ultrasound [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB155.
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Sheybani, Natasha Diba, Alexandra R. Witter, Timothy N. Bullock, and Richard J. Price. "MR image-guided focused ultrasound immune modulation for glioma therapy." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 178.26. http://dx.doi.org/10.4049/jimmunol.200.supp.178.26.
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Abstract Glioblastoma (GB) is the most common and malignant brain tumor. Despite standard treatment with surgery, radiation and chemotherapy, its diffuse nature and proclivity for recurrence renders it largely intractable. Immunotherapy (ITx) approaches (e.g. anti-PD1) may hold promise for treating GB; however, the blood-brain (BBB) and blood-tumor (BTB) barriers hinder delivery of systemically administered ITx drugs. A potential approach to enhancing ITx delivery is MRI-guided focused ultrasound (FUS), a non-invasive technique that, when combined with concomitant systemic injection of microbubbles (MB), can transiently disrupt the BBB/BTB and mechanically perturb the tumor microenvironment. Here, we investigate whether localized BBB/BTB disruption with FUS+MB enhances anti-tumor immune responses and inhibits tumor growth, as a prelude to eventual combination with immune checkpoint blockade. One week after FUS+MB (peak negative acoustic pressure=0.6 MPa) treatment of a murine glioma model stably transfected with luciferase (GL261-luc2), CD86 mean fluorescence intensity on dendritic cells (DC) increased ~3-fold in deep cervical lymph nodes, intratumoral CD4+ T cells doubled, and intratumoral CD8+ T cells increased by ~17% (by flow cytometry). Serial bioluminescence imaging of tumors revealed significant reduction in total photon flux as early as 6 days following FUS+MB (p=0.0106), indicating tumor growth inhibition. We conclude that FUS+MB can promote DC maturity and potentially mediate adaptive immunity against glioma, independent of drug delivery. Ongoing studies entail combining FUS+MB with anti-PD-1 delivery to evaluate whether an allied treatment approach can promote an even more robust anti-glioma response.
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Ye, Dezhuang, Xiaohui Zhang, Lihua Yang, Yimei Yue, Yuan-chuan Tai, Joshua B. Rubin, Yongjian Liu, and Hong Chen. "HGG-17. FOCUSED ULTRASOUND-ENHANCED DELIVERY OF RADIOLABELED AGENTS TO DIFFUSE INTRINSIC PONTINE GLIOMA." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i20—i21. http://dx.doi.org/10.1093/neuonc/noab090.083.
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Abstract Diffuse intrinsic pontine glioma (DIPG) arising in the brainstem is the deadliest pediatric brain cancer with nearly 100% fatality and a median survival of <1 year. The critical location in the brainstem and the often intact blood-brain barrier (BBB) pose significant challenges in the treatment of DIPG. The objective of this study was to demonstrate the potential for focused ultrasound-induced BBB disruption (FUS-BBBD) to improve DIPG treatment by enhancing the safe and efficient delivery of drugs. A genetically engineered mouse model of DIPG was generated using the RCAS (replication-competent avian sarcoma-leucosis virus long-terminal repeat with splice acceptor)/tumor virus A modeling system. A magnetic resonance-guided FUS (MRgFUS) system was used to induce BBB disruption in these mice with the FUS targeted at the center of the tumor. Two radiolabeled agents with different sizes were used to evaluate the delivery efficiency of the FUS-BBBD technique in DIPG mice: a small-molecular radiotracer, 68Ga-DOTA-ECL1i, and a radiolabeled nanoparticle, 64Cu-labeled copper nanoparticles (64Cu-CuNCs, ~ 5 nm in diameter). 68Ga-DOTA-ECL1i (half-life ~ 1 h) and 64Cu-CuNCs (half-life ~13 h) were intravenously injected into the mice after FUS sonication, and microPET/CT imaging was performed at 1 h and 24 h, respectively, to evaluate the spatial-temporal distribution of these two agents in the brain and quantify the delivery outcome. FUS treatment increased the uptake of 68Ga-DOTA-ECL1i and 64Cu-CuNCs to the DIPG tumor by 3.25 folds and 4.07 folds on average, respectively. These findings demonstrated, for the first time, that FUS can increase BBB permeability in a murine model of DIPG and significantly enhance the delivery of agents of different sizes into the DIPG tumor.
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Elias, W. Jeff, Mohamad Khaled, Justin D. Hilliard, Jean-Francois Aubry, Robert C. Frysinger, Jason P. Sheehan, Max Wintermark, and Maria Beatriz Lopes. "A magnetic resonance imaging, histological, and dose modeling comparison of focused ultrasound, radiofrequency, and Gamma Knife radiosurgery lesions in swine thalamus." Journal of Neurosurgery 119, no. 2 (August 2013): 307–17. http://dx.doi.org/10.3171/2013.5.jns122327.
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Object The purpose of this study was to use MRI and histology to compare stereotactic lesioning modalities in a large brain model of thalamotomy. Methods A unilateral thalamotomy was performed in piglets utilizing one of 3 stereotactic lesioning modalities: focused ultrasound (FUS), radiofrequency, and radiosurgery. Standard clinical lesioning parameters were used for each treatment; and clinical, MRI, and histological assessments were made at early (< 72 hours), subacute (1 week), and later (1–3 months) time intervals. Results Histological and MRI assessment showed similar development for FUS and radiofrequency lesions. T2-weighted MRI revealed 3 concentric lesional zones at 48 hours with resolution of perilesional edema by 1 week. Acute ischemic infarction with macrophage infiltration was most prominent at 72 hours, with subsequent resolution of the inflammatory reaction and coalescence of the necrotic zone. There was no apparent difference in ischemic penumbra or “sharpness” between FUS or radiofrequency lesions. The radiosurgery lesions presented differently, with latent effects, less circumscribed lesions at 3 months, and apparent histological changes seen in white matter beyond the thalamic target. Additionally, thermal and radiation lesioning gradients were compared with modeling by dose to examine the theoretical penumbra. Conclusions In swine thalamus, FUS and radiosurgery lesions evolve similarly as determined by MRI, histological examination, and theoretical modeling. Radiosurgery produces lesions with more delayed effects and seemed to result in changes in the white matter beyond the thalamic target.
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Song, Minho, Oleg A. Sapozhnikov, Yak-Nam Wang, Joo Ha Hwang, and Tatiana D. Khokhlova. "Passive and Doppler-based assessment of cavitation activity induced by pulsed focused ultrasound." Journal of the Acoustical Society of America 152, no. 4 (October 2022): A249—A250. http://dx.doi.org/10.1121/10.0016171.
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Pulsed focused ultrasound (pFUS) exposures utilizing short, nonlinearly distorted pulses at low duty cycle have been shown to enhance drug and gene delivery to targeted tissue through inertial cavitation activity. Passive cavitation detection (PCD) and mapping of broadband emissions are current conventional methods to monitor and quantify cavitation but provide limited spatial resolution. Here, plane-wave Doppler imaging was used with PCD to quantify pFUS-induced cavitation in ex vivo bovine tissues and in vivo surgically exposed porcine liver, kidney, and pancreas. A 1.5 MHz FUS transducer (aperture 75 mm, F-number 0.75) was used to deliver 60 pulses (duration 1 ms, 0.1% duty cycle, focal pressure p+ = 70i–110 MPa, p− = 13–20 MPa). A coaxially mounted ATL P7-4 ultrasound imaging probe was used for PCD during the FUS pulse, and Doppler and B-mode sequences. Disrupted tissue areas were collected for histology and compared to Doppler power images. Maximum Doppler power was found to correlate to broadband noise level for each FUS pulse. The Doppler power map integrated over the exposure was observed to correlate spatially with tissue disruption area from histology, which thus represents a promising real-time metric for quantifying cavitation activity induced by pFUS exposures. [Work supported by NIH R01CA154451, R01EB025187, and R01EB23910.]
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Hersh, Andrew M., Meghana Bhimreddy, Carly Weber-Levine, Kelly Jiang, Safwan Alomari, Nicholas Theodore, Amir Manbachi, and Betty M. Tyler. "Applications of Focused Ultrasound for the Treatment of Glioblastoma: A New Frontier." Cancers 14, no. 19 (October 8, 2022): 4920. http://dx.doi.org/10.3390/cancers14194920.
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Glioblastoma (GBM) is an aggressive primary astrocytoma associated with short overall survival. Treatment for GBM primarily consists of maximal safe surgical resection, radiation therapy, and chemotherapy using temozolomide. Nonetheless, recurrence and tumor progression is the norm, driven by tumor stem cell activity and a high mutational burden. Focused ultrasound (FUS) has shown promising results in preclinical and clinical trials for treatment of GBM and has received regulatory approval for the treatment of other neoplasms. Here, we review the range of applications for FUS in the treatment of GBM, which depend on parameters, including frequency, power, pulse duration, and duty cycle. Low-intensity FUS can be used to transiently open the blood–brain barrier (BBB), which restricts diffusion of most macromolecules and therapeutic agents into the brain. Under guidance from magnetic resonance imaging, the BBB can be targeted in a precise location to permit diffusion of molecules only at the vicinity of the tumor, preventing side effects to healthy tissue. BBB opening can also be used to improve detection of cell-free tumor DNA with liquid biopsies, allowing non-invasive diagnosis and identification of molecular mutations. High-intensity FUS can cause tumor ablation via a hyperthermic effect. Additionally, FUS can stimulate immunological attack of tumor cells, can activate sonosensitizers to exert cytotoxic effects on tumor tissue, and can sensitize tumors to radiation therapy. Finally, another mechanism under investigation, known as histotripsy, produces tumor ablation via acoustic cavitation rather than thermal effects.
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Zhang, Xue, Fengchao Wang, Yi Hu, Runze Chen, Dawei Meng, Liang Guo, Hailong Lv, Jisong Guan, and Yichang Jia. "In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model." Brain 143, no. 5 (May 1, 2020): 1350–67. http://dx.doi.org/10.1093/brain/awaa076.
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Abstract Many RNA-binding proteins, including TDP-43, FUS, and TIA1, are stress granule components, dysfunction of which causes amyotrophic lateral sclerosis (ALS). However, whether a mutant RNA-binding protein disrupts stress granule processing in vivo in pathogenesis is unknown. Here we establish a FUS ALS mutation, p.R521C, knock-in mouse model that carries impaired motor ability and late-onset motor neuron loss. In disease-susceptible neurons, stress induces mislocalization of mutant FUS into stress granules and upregulation of ubiquitin, two hallmarks of disease pathology. Additionally, stress aggravates motor performance decline in the mutant mouse. By using two-photon imaging in TIA1-EGFP transduced animals, we document more intensely TIA1-EGFP-positive granules formed hours but cleared weeks after stress challenge in neurons in the mutant cortex. Moreover, neurons with severe granule misprocessing die days after stress challenge. Therefore, we argue that stress granule misprocessing is pathogenic in ALS, and the model we provide here is sound for further disease mechanistic study.
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Sigona, Michelle K., Thomas J. Manuel, Huiwen Luo, Marshal A. Phipps, Pai-Feng Yang, Kianoush Banaie Boroujeni, Robert L. Treuting, et al. "Generating patient-specific acoustic simulations for transcranial focused ultrasound procedures based on optical tracking information." Journal of the Acoustical Society of America 152, no. 4 (October 2022): A155. http://dx.doi.org/10.1121/10.0015868.
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During transcranial focused ultrasound (FUS) procedures, accurate targeting is important and neuronavigation with optically tracked tools is used to estimate the free-field focal location on pre-acquired images. Offline neuronavigation systems do not typically incorporate aberrating effects of the skull known to displace and distort the focus. Here, we developed a pipeline that integrated patient-specific acoustic simulations informed by transformations from optically tracked FUS procedures as a tool to evaluate transcranial pressure fields and demonstrated its use in three FUS scenarios: magnetic resonance imaging-guided (MR-guided) phantom experiments, MR-guided non-human primate (NHP) experiments, an offline behaving NHP experiments. Distance vectors between the estimated focus from optical tracking and peak intracranial location from simulations were less than 1 mm for all groups (Phantom: 0.6 ± 0.3 mm, NHP: 0.7 ± 0.3 mm, Behaving NHP: 0.5 ± 0.2 mm). Comparisons of the target registration error of MR measurements with the optically tracked focus (TRETracked) and simulated focus (TRESimulated) suggest that focal location errors are dominated by optical tracking errors rather than aberration through the skull in the NHP (Phantom: TRETracked: 3.3 ± 1.4 mm, Phantom TRESimulated: 3.3 ± 1.9 mm, NHP TRETracked: 3.9 ± 1.9 mm, NHP TRESimulated: 4.1 ± 1.6 mm). Our software pipeline provides patient-specific estimates of the acoustic field during transcranial FUS procedures.