Focused Ultrasound Research Articles

Characterization of the Targeting Accuracy of a Neuronavigation-Guided Transcranial FUS System In Vitro, In Vivo, and In Silico.

Focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) is an emerging technique for the noninvasive and spatiotemporally controlled diagnosis of brain cancer by inducing blood-brain barrier (BBB) disruption to release brain tumor-specific biomarkers into the blood circulation. The feasibility, safety, and efficacy of sonobiopsy were demonstrated in both small and large animal models using magnetic resonance-guided FUS devices. However, the high cost and complex operation of magnetic resonance-guided FUS devices limit the future broad application of sonobiopsy in the clinic. In this study, a neuronavigation-guided sonobiopsy device is developed and its targeting accuracy is characterized in vitro, in vivo, and in silico. The sonobiopsy device integrated a commercially available neuronavigation system (BrainSight) with a nimble, lightweight FUS transducer. Its targeting accuracy was characterized in vitro in a water tank using a hydrophone. The performance of the device in BBB disruption was verified in vivo using a pig model, and the targeting accuracy was quantified by measuring the offset between the target and the actual locations of BBB opening. The feasibility of the FUS device in targeting glioblastoma (GBM) tumors was evaluated in silico using numerical simulation by the k-Wave toolbox in glioblastoma patients. It was found that the targeting accuracy of the neuronavigation-guided sonobiopsy device was 1.7 ± 0.8 mm as measured in the water tank. The neuronavigation-guided FUS device successfully induced BBB disruption in pigs with a targeting accuracy of 3.3 ± 1.4 mm. The targeting accuracy of the FUS transducer at the GBM tumor was 5.5 ± 4.9 mm. Age, sex, and incident locations were found to be not correlated with the targeting accuracy in GBM patients. This study demonstrated that the developed neuronavigation-guided FUS device could target the brain with a high spatial targeting accuracy, paving the foundation for its application in the clinic.

Evaluating immunological outcomes associated with histotripsy treatment in canine osteosarcoma: a comparative human oncology model

Abstract Osteosarcoma (OS), the most commonly occurring primary bone tumor in dogs and humans, has deficient treatment options and dismal survival outcomes. Spontaneously occurring OS in dogs shares numerous similarities with humans and has greater prevalence, allowing the dog to serve as an informative comparative oncology model. The objective of this study was to investigate the non-thermal focused ultrasound technique histotripsy as an innovative treatment option for OS. Histotripsy has the potential to both ablate the primary tumor and stimulate an antitumor immune response to mitigate metastatic disease, the leading cause of death in OS. To investigate the immunological outcomes associated with histotripsy and OS, we delivered histotripsy to client-owned canine OS patients (n=29) and utilized an in-vitro model for cross species comparisons between human, dog, and mouse. Histotripsy ablation led to a significantly greater expression of activation markers CD80 and CD62L on circulating monocytes, at 1- and 5-days post histotripsy (DPH), respectively. We observed a significantly greater production of TGFβ in circulating monocytes at 3 DPH compared to baseline. On an independent patient basis, we observed a greater population of CD5 +CD4 +and CD5 +CD8 +cells within the treated region of the tumor compared to untreated region and changes in genetic signature also indicated immune activation. Across species in-vitro we observed macrophage activation (CD80, CD62L, and CD86), and upregulation of genes associated with immune cell chemotaxis and pro-inflammatory response. Our results indicate that histotripsy ablation leads to immune activation and has strong potential to target both primary OS and metastatic disease. NIH (1R21 EB030182-01), Focused Ultrasound Foundation (PLL7GBVK and FUSF-RAP-823R1), and American Kennel Club (Canine Health Foundation No. 02773)

Investigating the immunomodulatory effects of histotripsy ablation for osteosarcoma

Abstract Osteosarcoma (OS) is the most common primary bone cancer in humans and dogs. Canine OS shares many biological similarities with human OS and is a valuable comparative oncology research model. In both species, metastasis remains a major hurdle against improved survival, thus warranting a novel therapeutic approach such as histotripsy, a non-thermal, non-invasive, focused ultrasound ablation modality. Histotripsy can mechanically disintegrate gross tumor and potentially induces an anti-tumor immune response to inhibit metastatic development. The objectiveof this in vitro study was to investigate the immunomodulatory effects of histotripsy ablation of canine OS. We hypothesizedthat histotripsy ablation of OS promotes a pro-inflammatory immune signature in primary monocytes and macrophages. We isolated CD14+ primary monocytes using positive selection immunomagnetic cell separation from peripheral blood mononuclear cells of healthy dogs, and differentiated primary macrophages by culturing primary monocytes with canine GM-CSF for 72 hours. We co-cultured primary monocytes and macrophages with histotripsy-ablated canine D17 OS cells for 24 hours, then characterized their cell surface markers using flow cytometry and performed multiplex supernatant cytokine analysis. We observed upregulation of CD80 and CD62L on primary monocytes and a downregulation of CD206 on macrophages exposed to histotripsy-ablated D17 cells compared to controls, suggesting immune activation. We observed decreased levels of the pro-tumor cytokine, TGF-β, from primary monocytes exposed to histotripsy-ablated D17s compared to controls. Our results indicate that histotripsy ablation of OS can induce a pro-inflammatory immune signature. This work is supported by grants from the American Kennel Club Canine Health Foundation, the Focused Ultrasound Foundation.

Design of a 1-MHz therapeutic ultrasound array for small volume blood-brain barrier opening at cortical targets in macaques.

Focused ultrasound (FUS) can temporarily open the blood brain barrier (BBB) and increase the delivery of chemotherapeutics, viral vectors, and other agents to the brain parenchyma. To limit FUS BBB opening to a single brain region, the transcranial acoustic focus of the ultrasound transducer must not be larger than the region targeted. In this work, we design and characterize a therapeutic array optimized for BBB opening at the frontal eye field in macaques. We used 115 transcranial simulations in four macaques varying f-number and frequency to optimize the design for focus size, transmission, and small device footprint. The design leverages inward steering for focus tightening, a 1 MHz transmit frequency, and can focus to a simulation predicted 2.5 ± 0.3 mm lateral and 9.5 ± 1.0 mm axial full-width at half maximum spot size at the frontal eye field without aberration correction. The array is capable of steering axially 35 mm outward, 26 mm inward, and laterally 13 mm with > 50% the geometric focus pressure. The simulated design was fabricated, and we characterized the performance of the array using hydrophone beam maps in a water tank and through an ex vivo skull cap to compare measurements with simulation predictions, achieving a 1.8 mm lateral and 9.5 mm axial spot size with a transmission of 37 % (transcranial, phase corrected). The transducer produced by this design process is optimized for BBB opening at the frontal eye field in macaques.

Numerical simulation study of firing threshold of STN neuron stimulated by focused ultrasound.

Electroencephalography (EEG) is one of the functional brain imaging techniques to effectively measure neuronal activity, but its low spatial resolution makes it difficult to localize evoked excitatory neurons or areas of abnormal firing. Multimodal imaging techniques are expected to combine the high spatial resolution (mm level) of focused ultrasound (FUS) with the high temporal resolution (ms level) of EEG. The technique must be performed under the premise that ultrasound stimulation does not affect neuronal firing, and there is an urgent need to determine the threshold of this ultrasound stimulation parameter. In this paper, the subthalamic nucleus neuronal firing model and the bilayer sonophore model are combined to numerically simulate the neuronal firing rhythm under the conditions of different stimulation parameters. The correlation and frequency differences of neuronal firing rhythms with and without ultrasound stimulation were compared and used as an index to evaluate the degree of change, and the final range of effective threshold parameters for ultrasound stimulation of neurons but not inducing neuronal firing was obtained. The results showed that the correlation of neuronal firing rhythms in both conditions with and without stimulation decreased and the frequency difference increased with increasing ultrasound parameters such as duty cycle, intensity, center frequency and pulse repetition frequency. An effective range of stimulation threshold parameters can be obtained based on the correlation coefficients and frequency difference matrices under different parameter combinations. The threshold can further promote the safe and effective application of FUS for multimodal electrophysiological imaging.

SPatiotemporal-ENcoded acoustic radiation force imaging of focused ultrasound.

Neuromodulation technology has provided novel therapeutic approaches for diseases caused by neural circuit dysfunction. Transcranial focused ultrasound (FU) is an emerging neuromodulation approach that combines noninvasiveness with relatively sharp focus, even in deep brain regions. It has numerous advantages such as high precision and good safety in neuromodulation, allowing for modulation of both peripheral and central nervous systems. To ensure accurate treatment targeting in FU neuromodulation, a magnetic resonance acoustic radiation force imaging (MR-ARFI) sequence is crucial for the visualization of the focal point. Currently, the commonly used 2D Spin Echo ARFI (2D SE-ARFI) sequence suffers from the long acquisition time, while the echo planar imaging ARFI (EPI-ARFI) sequence with a shorter acquisition time is vulnerable to the magnetic field inhomogeneities. To address these problems, we proposed a spatiotemporal-encoded acoustic radiation force imaging sequence (i.e., SE-SPEN-ARFI, shortened to SPEN-ARFI) in this study. The displacement at the focal spot obtained was highly consistent with that of the SE-ARFI sequence. Our research shows that SPEN-ARFI allows for rapid image acquisition and has less image distortions even under great field inhomogeneities. Therefore, a SPEN-ARFI sequence is a practical alternative for the treatment planning in ultrasound neuromodulation.

Focused ultrasound-mediated small-molecule delivery to potentiate immune checkpoint blockade in solid tumors.

In the last decade, immune checkpoint blockade (ICB) has revolutionized the standard of treatment for solid tumors. Despite success in several immunogenic tumor types evidenced by improved survival, ICB remains largely unresponsive, especially in "cold tumors" with poor lymphocyte infiltration. In addition, side effects such as immune-related adverse events (irAEs) are also obstacles for the clinical translation of ICB. Recent studies have shown that focused ultrasound (FUS), a non-invasive technology proven to be effective and safe for tumor treatment in clinical settings, could boost the therapeutic effect of ICB while alleviating the potential side effects. Most importantly, the application of FUS to ultrasound-sensitive small particles, such as microbubbles (MBs) or nanoparticles (NPs), allows for precise delivery and release of genetic materials, catalysts and chemotherapeutic agents to tumor sites, thus enhancing the anti-tumor effects of ICB while minimizing toxicity. In this review, we provide an updated overview of the progress made in recent years concerning ICB therapy assisted by FUS-controlled small-molecule delivery systems. We highlight the value of different FUS-augmented small-molecules delivery systems to ICB and describe the synergetic effects and underlying mechanisms of these combination strategies. Furthermore, we discuss the limitations of the current strategies and the possible ways that FUS-mediated small-molecule delivery systems could boost novel personalized ICB treatments for solid tumors.

Clinical and Physiological Effects of Single Day Accelerated Theta Burst Transcranial Focused Ultrasound in Parkinson’s Disease (P4-11.008)

<h3>Objective:</h3> To evaluate the tolerability and efficacy of an accelerated schedule of theta burst focused ultrasound stimulation (tbTUS) delivered to the primary motor cortex in Parkinson’s disease (PD) patients assessed by transcranial magnetic stimulation (TMS) and United Parkinson’s Disease Rating Scale (UPDRS)-Part III. <h3>Background:</h3> Low intensity transcranial focused ultrasound stimulation (TUS) is an emerging technology for non-invasive brain stimulation (NIBS) that can penetrate deeper in the brain with more focal stimulation compared to currently used forms of NIBS. TUS delivered in a theta burst pattern (tbTUS) for 80s induces sustained increases in motor cortex excitability lasting at least 30 minutes and is a promising NIBS protocol for treatment of neurological disorders. Accelerated stimulation schedules with several treatments per day can shorten treatment duration and improve accessibility. <h3>Design/Methods:</h3> Three sets of tbTUS were delivered in consecutive order to the right and left primary motor cortices at 30-minute intervals. 10 PD patients attended one visit each for real and sham treatments in random order. Before and after interventions, TMS measures of motor-evoked potentials (MEP), short-interval intracortical inhibition (SICI), short-interval intracortical excitation (SICF), and UPDRS-Part III scores were collected. Patients and UPDRS raters were blinded to the stimulation condition. <h3>Results:</h3> Real but not sham tbTUS treatment led to increased MEP amplitude and SICF. While both conditions led to similar changes in UPDRS-III scores, rigidity subscores were reduced only with real treatment. There were no adverse effects. <h3>Conclusions:</h3> The study is ongoing, and more patients are being recruited. Preliminary findings show that accelerated tbTUS is a safe and tolerable treatment schedule for PD patients. Improvements in rigidity suggests that tbTUS could be further studied as a non-invasive treatment for PD. Future research may investigate the optimal time between sonications with a longer treatment duration and a larger number of patients. <b>Disclosure:</b> Yi Rong Ding has nothing to disclose. Dr. Samuel has nothing to disclose. Dr. Grippe has nothing to disclose. Dr. SARICA has nothing to disclose. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Insightec. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston Scientific. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medtronic. Dr. Lozano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Functional Neuromodulation. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merz. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Paladin Labs. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Chen has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Canadian Journal of Neurological Sciences. Dr. Chen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Movement Disorders. The institution of Dr. Chen has received research support from Canadian Institutes of Health Research. The institution of Dr. Chen has received research support from NIH. The institution of Dr. Chen has received research support from Natural Science and Engineering Research Council of Canada. Dr. Chen has received research support from Parkinson Foundation. The institution of Dr. Chen has received research support from National Organization for Rare Disease. The institution of Dr. Chen has received research support from Merz.

Natural aging and Alzheimer’s disease pathology increase susceptibility to focused ultrasound-induced blood–brain barrier opening

Focused Ultrasound (FUS) paired with systemically-injected microbubbles (μB) is capable of transiently opening the blood–brain barrier (BBBO) for noninvasive and targeted drug delivery to the brain. FUS-BBBO is also capable of modulating the neuroimmune system, further qualifying its therapeutic potential for neurodegenerative diseases like Alzheimer’s disease (AD). Natural aging and AD impose significant strain on the brain and particularly the BBB, modifying its structure and subsequently, its functionality. The emerging focus on treating neurodegenerative diseases with FUS-BBBO necessitates an investigation into the extent that age and AD affect the BBB’s response to FUS. FUS-BBBO was performed with a 1.5-MHz, geometrically focused transducer operated at 450 kPa and paired with a bolus microbubble injection of 8 × 108 μB/mL. Here we quantify the BBBO, BBB closing (BBBC) timeline, and BBB permeability (BBBP) following FUS-BBBO in male mice with and without AD pathology, aged 10 weeks, one year, or two years. The data presented herein indicates that natural aging and AD pathology may increase initial BBBO volume by up to 34.4% and 40.7% respectively, extend BBBC timeline by up to 1.3 and 1.5 days respectively, and increase BBBP as measured by average Ktrans values up to 80% and 86.1% respectively in male mice. This characterization of the BBB response to FUS-BBBO with age and AD further clarifies the nature and extent of the functional impact of these factors and may offer new considerations for planning FUS-BBBO interventions in aged and AD populations.

Ultrasound-induced cavitation renders prostate cancer cells susceptible to hyperthermia: Analysis of potential cellular and molecular mechanisms.

Background: Focused ultrasound (FUS) has become an important non-invasive therapy for prostate tumor ablation via thermal effects in the clinic. The cavitation effect induced by FUS is applied for histotripsy, support drug delivery, and the induction of blood vessel destruction for cancer therapy. Numerous studies report that cavitation-induced sonoporation could provoke multiple anti-proliferative effects on cancer cells. Therefore, cavitation alone or in combination with thermal treatment is of great interest but research in this field is inadequate. Methods: Human prostate cancer cells (LNCap and PC-3) were exposed to 40s cavitation using a FUS system, followed by water bath hyperthermia (HT). The clonogenic assay, WST-1 assay, and Transwell® invasion assay, respectively, were used to assess cancer cell clonogenic survival, metabolic activity, and invasion potential. Fluorescence microscopy using propidium iodide (PI) as a probe of cell membrane integrity was used to identify sonoporation. The H2A.X assay and Nicoletti test were conducted in the mechanism investigation to detect DNA double-strand breaks (DSBs) and cell cycle arrest. Immunofluorescence microscopy and flow cytometry were performed to determine the distribution and expression of 5α-reductase (SRD5A). Results: Short FUS shots with cavitation (FUS-Cav) in combination with HT resulted in, respectively, a 2.2, 2.3, and 2.8-fold decrease (LNCap) and a 2.0, 1.5, and 1.6-fold decrease (PC-3) in the clonogenic survival, cell invasiveness and metabolic activity of prostate cancer cells when compared to HT alone. FUS-Cav immediately induced sonoporation in 61.7% of LNCap cells, and the combination treatment led to a 1.4 (LNCap) and 1.6-fold (PC-3) increase in the number of DSBs compared to HT alone. Meanwhile, the combination therapy resulted in 26.68% of LNCap and 31.70% of PC-3 with cell cycle arrest in the Sub-G1 phase and 35.37% of PC-3 with cell cycle arrest in the G2/M phase. Additionally, the treatment of FUS-Cav combined with HT block the androgen receptor (AR) signal pathway by reducing the relative Type I 5α-reductase (SRD5A1) level to 38.28 ± 3.76% in LNCap cells, and decreasing the relative Type III 5α-reductase 3 (SRD5A3) level to 22.87 ± 4.88% in PC-3 cells, in contrast, the relative SRD5A level in untreated groups was set to 100%. Conclusion: FUS-induced cavitation increases the effects of HT by interrupting cancer cell membranes, inducing the DSBs and cell cycle arrest, and blocking the AR signal pathway of the prostate cancer cells, with the potential to be a promising adjuvant therapy in prostate cancer treatment.

Focused ultrasound for the remote modulation of nitric oxide release from injectable PEG-fibrinogen hydrogels for tendon repair

Introduction: Tendon disorders such as tendinosis, the degradation of collagen in tendon, or tendonitis, inflammation of tendon tissue, contribute to 30% of musculoskeletal complaints. To address the limitations of currently available treatments for tendon repair, an injectable polyethylene glycol (PEG)-fibrinogen hydrogel encompassing nitric oxide (NO) releasing µ-particles was generated. The release of nitric oxide, a therapeutic molecule that modulates many wound healing processes, from the hydrogel can be modified with thermal and mechanical stimulus. To achieve remote control over NO release from hydrogels after deployment, focused ultrasound (FUS) was explored as it provides highly controlled thermal and mechanical stimulus non-invasively.Methods: In this work, the ability of FUS to remotely elicit on-demand NO generation from acoustically active composite hydrogels via thermal and/or mechanical stimulus was explored. Specifically, the temperature and time-dependent release of NO was simulated and characterized when applying FUS to composite hydrogels.Results: Results from acoustic simulations as well as thermocouple heating studies indicated that high spatial and temporal control over hydrogel warming could be achieved non-invasively with a 3.5 MHz FUS transducer. FUS was also able to remotely control NO release from hydrogels with various thermal magnitudes and durations. Additionally, no apparent changes in the mechanical properties of hydrogels were observed with FUS treatment.Discussion: Utilizing FUS thermal and mechanical stimulus provides a potential method of remotely controlling NO release from hydrogels at a wound site to aid in tendon repair.

Changes in cervical cytokine profiles following focused ultrasound treatment for high-risk human papillomavirus infection-related low-grade cervical lesions.

To evaluate the changes of cervical soluble immune markers after focused ultrasound (FU) treatment to explore the underlying local immune effects of FU in the treatment of high-risk human papillomavirus (HR-HPV) infection-related low-grade squamous intraepithelial lesion (LSIL). A total of 35 patients diagnosed with HR-HPV infection-related histological LSIL who met the inclusion criteria were enrolled in this prospective study and treated with FU. The authors used cytometric bead array to measure T-helper type 1 (Th1) cytokine (interleukin [IL] 2, tumor necrosis factor, and interferon γ) and Th2 cytokine (IL-4, IL-5, IL-6, and IL-10) levels in the cervicovaginal lavage of patients before and 3 months after FU treatment. After FU treatment, the concentrations of Th2 cytokines IL-5 and IL-6 were significantly lower than those before FU treatment (P = 0.044 and P = 0.028, respectively). HR-HPV infection was cleared in 27 patients, with a clearance rate of 77.1% (27 of 35). The concentration of IL-4 in patients with HR-HPV clearance after FU treatment was significantly lower than that in patients without HR-HPV clearance (P = 0.045). FU can inhibit the production of certain Th2 cytokines and may improve the local immune status of the cervix, thereby eliminating HR-HPV infection.

An Efficient and Multi-Focal Focused Ultrasound Technique for Harmonic Motion Imaging.

Harmonic motion imaging (HMI) is an ultrasound-based elasticity imaging technique that utilizes oscillatory acoustic radiation force to estimate the mechanical properties of tissues, as well as monitor high-intensity focused ultrasound (HIFU) treatment. Conventionally, in HMI, a focused ultrasound (FUS) transducer generates oscillatory tissue displacements, and an imaging transducer acquires channel data for displacement estimation, with each transducer being driven with a separate system. The fixed position of the FUS focal spot requires mechanical translation of the transducers, which can be a time-consuming and challenging procedure. In this study, we developed and characterized a new HMI system with a multi-element FUS transducer with the capability of electronic focal steering of ±5 mm and ±2 mm from the geometric focus in the axial and lateral directions, respectively. A pulse sequence was developed to drive both the FUS and imaging transducers using a single ultrasound data acquisition (DAQ) system. The setup was validated on a tissue-mimicking phantom with embedded inclusions. Integrating beam steering with the mechanical translation of the transducers resulted in a consistent high contrast-to-noise ratio (CNR) for the inclusions with Young's moduli of 22 and 44 kPa within a 5-kPa background while the data acquisition speed is increased by 4.5-5.2-fold compared to the case when only mechanical movements were applied. The feasibility of simultaneous generation of multiple foci and tracking the induced displacements is demonstrated in phantoms for applications where imaging or treatment of a larger region is needed. Moreover, preliminary feasibility is shown in a human subject with a breast tumor, where the mean HMI displacement within the tumor was about 4 times lower than that within perilesional tissues. The proposed HMI system facilitates data acquisition in terms of flexibility and speed and can be potentially used in the clinic for breast cancer imaging and treatment.

A numerical investigation of passive acoustic mapping for monitoring bubble-mediated focused ultrasound treatment of the spinal cord.

Focused ultrasound (FUS) combined with intravenous microbubbles (MBs) has been shown to increase drug delivery to the spinal cord in animal models. Eventual clinical translation of such a technique in the sensitive spinal cord requires robust treatment monitoring to ensure efficacy, localization, safety, and provide key intraprocedural feedback. Here, the use of passive acoustic mapping (PAM) of MB emissions with a spine-specific detector array in the context of transvertebral FUS sonications is investigated in silico. Using computed tomography-derived human vertebral geometry, transvertebral detection of MBs is evaluated over varying source locations with and without phase and amplitude corrections (PACs). The impact of prefocal cavitation is studied by simulating concurrent cavitation events in the canal and pre-laminar region. Spatially sensitive application of phase and amplitude is used to balance signal strengths emanating from different axial depths in combination with multiple dynamic ranges to elicit multisource viewing. Collectively, the results of this study encourage the use of PAM in transvertebral FUS applications with PACs to not only localize sources originating in the spinal canal but also multiple sources of innate amplitude mismatches when corrective methods are applied.

MP73-13 MRI ANALYSIS OF PROSTATE MORPHOMETRY AND PERIPROSTATIC ANATOMICAL RELATIONSHIPS BEFORE AND AFTER PARTIAL HIGH-INTENSITY FOCUSED ULTRASOUND TREATMENT OF LOCALIZED PROSTATE CANCER.

You have accessJournal of UrologyCME1 Apr 2023MP73-13 MRI ANALYSIS OF PROSTATE MORPHOMETRY AND PERIPROSTATIC ANATOMICAL RELATIONSHIPS BEFORE AND AFTER PARTIAL HIGH-INTENSITY FOCUSED ULTRASOUND TREATMENT OF LOCALIZED PROSTATE CANCER. Denis Seguier, Srinath Kotarmarti, Zoe Michael, Rajan Gupta, Cary Robertson, Thomas Polascik, Jonathan Olivier, and Arnauld Villers Denis SeguierDenis Seguier More articles by this author , Srinath KotarmartiSrinath Kotarmarti More articles by this author , Zoe MichaelZoe Michael More articles by this author , Rajan GuptaRajan Gupta More articles by this author , Cary RobertsonCary Robertson More articles by this author , Thomas PolascikThomas Polascik More articles by this author , Jonathan OlivierJonathan Olivier More articles by this author , and Arnauld VillersArnauld Villers More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003341.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Little is known regarding anatomical changes to peri-prostatic tissues after focal high intensity focused ultrasound (fHIFU) for localized prostate cancer. We sought to provide a novel approach to assess prostato-pelvic anatomical morphometric magnetic resonance imaging (MRI) changes post- fHIFU. METHODS: 38 patients (Pts) over two institutions (Lille University Hospital and Duke University Hospital) undergoing fHIFU with pre-and post-treatment (Pre-/Post-Tx) (≥6 months) MRI were included. Pre- and post-TX. MRIs were assessed for prostate and treated region volume. Distances to pubic bone and rectum were measured to account for the post-Tx periprostatic changes. Two subgroups were also identified, those with recurrence (positive biopsy and/or subsequent whole gland Tx) and those recurrence-free. Specific MRI features were also described within those two groups. RESULTS: The median treated-lobe volume was of 16.8 ml (IQR 10.6-21.5) on pre-Tx MRI and of 10.2 ml on post-Tx MRI (IQR 7.2-14.8). Comparison on pre-Tx MRI vs. post-Tx MRI showed a significant difference (p<0.01). The median percentage reduction of treated lobe volume for the entire cohort was 28.5% (IQR: 17-47). No significant difference was identified between the non-recurring group and the recurring group for prostate volume and treated lobe-volume both at pre- and post-Tx. Analysis of prostato-rectal measurements was conducted in 17 Pts. The mean value of the median prostato-rectal distance was 2 mm (SD 1) in pre-Tx and 1.97 mm (SD 1.1) in post-Tx. We noted no significant difference in either the pre-Tx or post-Tx configuration (p=0.78 and p=0.1 respectively) between the groups of recurring vs. non-recurring Pts. 13 Pts were qualitatively classified as presenting an aspect of loss of symmetry in the prostato-rectal space on post-Tx MRI. No significative difference existed between the recurring and non-recurring group for this parameter. CONCLUSIONS: With this study, we described a novel standardized method of morphometric alteration post-fHIFU. This preliminary work incite further studies to assess the clinical significance and implications of these results in a larger prospective cohort. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1040 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Denis Seguier More articles by this author Srinath Kotarmarti More articles by this author Zoe Michael More articles by this author Rajan Gupta More articles by this author Cary Robertson More articles by this author Thomas Polascik More articles by this author Jonathan Olivier More articles by this author Arnauld Villers More articles by this author Expand All Advertisement PDF downloadLoading ...

Perspective: Focused-Ultrasound Guided Neuropeptide Delivery as a Novel Therapeutic Approach in Psychiatry

Although drugs are a critical component of mental healthcare, most have modest benefits and significant side effects. One way to develop a superior intervention would be to administer drugs with the spatial and temporal precision that better replicates natural diversity within neurotransmitter systems. A technology called focused-ultrasound (FU) may be able to safely and transiently disrupt the blood-brain barrier with spatial precision, permitting the site-specific delivery of molecules that do not conventionally cross the blood-brain barrier. If this method is proven to be safe and effective in larger human trials, it may trigger a paradigm shift in biopsychology research where the level of precision with which neurotransmitter systems can be influenced is massively increased. In this article, we use the example of oxytocin in the treatment of Autism. We propose that intranasal administration is not highly effective because it leads to oxytocin’s wide dispersion throughout the brain, failing to specifically stimulate oxytocin’s prosocial effects in specific regions. Consequently, we hypothesize that site-specific delivery of oxytocin, particularly in brain regions such as the Nucleus Accumbens and Ventral Tegmental Area, would lead to more consistent benefits.

Focused ultrasound restrains the growth of orthotopic colon cancer via promoting pyroptosis.

Focused ultrasound (FUS) is a non-invasive tumor therapy technology emerging in recent years, which can treat various solid tumors. However, it is unclear whether FUS can affect the pyroptosis of colon cancer (CC) cells. Here, we analyzed the effect of FUS on pyroptosis in the orthotopic CC model. After an orthotopic CC mouse model was constructed by injecting CT26-Luc cells, BABL/C mice were allocated to the normal, tumor, FUS, and FUS + BAY11-7082 (pyroptosis inhibitor) groups. We monitored the tumor status of the mice through in vivo fluorescence image analysis. The histopathological injury of the intestinal tissue and the expression of IL-1β, IL-18, caspase-recruitment domain (ASC), cleaved caspase-1, gasdermin D (GSDMD), and NLRP3 of the CC tumors were examined utilizing hematoxylin and eosin staining, immunohistochemical assay, and Western blot. FUS restrained the fluorescence intensity of the tumors in orthotopic CC mice, while FUS-mediated suppression of the bioluminescent signal of the tumors was alleviated by BAY11-7082. FUS was found to relieve the injury of the intestinal tissues in CC mice as revealed by morphology. Furthermore, the expressions of IL-1β, IL-18, GSDMD, ASC, cleaved caspase-1, and NLRP3 of the CC tumors in the FUS group were higher than those in the tumor group, while BAY11-7082 addition partly reversed the FUS's effects on orthotopic CC model mice. Our results pointed out that FUS presented anti-tumor activity in experimental CC, and its mechanism was correlated with the promotion of pyroptosis.

Development of Cationic Lipid LAH4-L1 siRNA Complexes for Focused Ultrasound Enhanced Tumor Uptake.

RNAi has considerable potential as a cancer therapeutic approach, but effective and efficient delivery of short interfering RNA (siRNA) to tumors remains a major hurdle. It remains a challenge to prepare a functional siRNA complex, target enough dose to the tumor, and stimulate its internalization into tumor cells and its release to the cytoplasm. Here, we show how these key barriers to siRNA delivery can be overcome with a complex─comprising siRNA, cationic lipids, and pH-responsive peptides─that is suited to tumor uptake enhancement via focused ultrasound (FUS). The complex provides effective nucleic acid encapsulation, nuclease protection, and endosomal escape such that gene silencing in cells is substantially more effective than that obtained with either equivalent lipoplexes or commercial reagents. In mice bearing MDA-MB-231 breast cancer xenografts, both lipid and ternary, lipid:peptide:siRNA complexes, prepared with near-infrared fluorescently labeled siRNA, accumulate in tumors following FUS treatments. Therefore, combining a well-designed lipid:peptide:siRNA complex with FUS tumor treatments is a promising route to achieve robust in vivo gene delivery.

Nonspherical ultrasound microbubbles

Surface tension provides microbubbles (MB) with a perfect spherical shape. Here, we demonstrate that MB can be engineered to be nonspherical, endowing them with unique features for biomedical applications. Anisotropic MB were generated via one-dimensionally stretching spherical poly(butyl cyanoacrylate) MB above their glass transition temperature. Compared to their spherical counterparts, nonspherical polymeric MB displayed superior performance in multiple ways, including i) increased margination behavior in blood vessel-like flow chambers, ii) reduced macrophage uptake invitro, iii) prolonged circulation time invivo, and iv) enhanced blood-brain barrier(BBB) permeation invivo upon combination with transcranial focused ultrasound (FUS). Our studies identify shape as a design parameter in the MB landscape, and they provide a rational and robust framework for further exploring the application of anisotropic MB for ultrasound-enhanced drug delivery and imaging applications.

Transcranial focused ultrasound-mediated unbinding of phenytoin from plasma proteins for suppression of chronic temporal lobe epilepsy in a rodent model

The efficacy of many anti-epileptic drugs, including phenytoin (PHT), is reduced by plasma protein binding (PPB) that sequesters therapeutically active drug molecules within the bloodstream. An increase in systemic dose elevates the risk of drug side effects, which demands an alternative technique to increase the unbound concentration of PHT in a region-specific manner. We present a low-intensity focused ultrasound (FUS) technique that locally enhances the efficacy of PHT by transiently disrupting its binding to albumin. We first identified the acoustic parameters that yielded the highest PHT unbinding from albumin among evaluated parameter sets using equilibrium dialysis. Then, rats with chronic mesial temporal lobe epilepsy (mTLE) received four sessions of PHT injection, each followed by 30 min of FUS delivered to the ictal region, across 2 weeks. Two additional groups of mTLE rats underwent the same procedure, but without receiving PHT or FUS. Assessment of electrographic seizure activities revealed that FUS accompanying administration of PHT effectively reduced the number and mean duration of ictal events compared to other conditions, without damaging brain tissue or the blood–brain barrier. Our results demonstrated that the FUS technique enhanced the anti-epileptic efficacy of PHT in a chronic mTLE rodent model by region-specific PPB disruption.