Airy-beam holographic sonogenetics for advancing neuromodulation precision and flexibility.

Advancing our understanding of brain function and developing treatments for neurological diseases hinge on the ability to modulate neuronal groups in specific brain areas without invasive techniques. Here, we introduce Airy-beam holographic sonogenetics (AhSonogenetics) as an implant-free, cell type-specific, spatially precise, and flexible neuromodulation approach in freely moving mice. AhSonogenetics utilizes wearable ultrasound devices manufactured using 3D-printed Airy-beam holographic metasurfaces. These devices are designed to manipulate neurons genetically engineered to express ultrasound-sensitive ion channels, enabling precise modulation of specific neuronal populations. By dynamically steering the focus of Airy beams through ultrasound frequency tuning, AhSonogenetics is capable of modulating neuronal populations within specific subregions of the striatum. One notable feature of AhSonogenetics is its ability to flexibly stimulate either the left or right striatum in a single mouse. This flexibility is achieved by simply switching the acoustic metasurface in the wearable ultrasound device, eliminating the need for multiple implants or interventions. AhSonogentocs also integrates seamlessly with in vivo calcium recording via fiber photometry, showcasing its compatibility with optical modalities without cross talk. Moreover, AhSonogenetics can generate double foci for bilateral stimulation and alleviate motor deficits in Parkinson's disease mice. This advancement is significant since many neurological disorders, including Parkinson's disease, involve dysfunction in multiple brain regions. By enabling precise and flexible cell type-specific neuromodulation without invasive procedures, AhSonogenetics provides a powerful tool for investigating intact neural circuits and offers promising interventions for neurological disorders.

Remote control of mechanochemical reactions under physiological conditions using biocompatible focused ultrasound.

External control of chemical reactions in biological settings with spatial and temporal precision is a grand challenge for noninvasive diagnostic and therapeutic applications. While light is a conventional stimulus for remote chemical activation, its penetration is severely attenuated in tissues, which limits biological applicability. On the other hand, ultrasound is a biocompatible remote energy source that is highly penetrant and offers a wide range of functional tunability. Coupling ultrasound to the activation of specific chemical reactions under physiological conditions, however, remains a challenge. Here, we describe a synergistic platform that couples the selective mechanochemical activation of mechanophore-functionalized polymers with biocompatible focused ultrasound (FUS) by leveraging pressure-sensitive gas vesicles (GVs) as acousto-mechanical transducers. The power of this approach is illustrated through the mechanically triggered release of covalently bound fluorogenic and therapeutic cargo molecules from polymers containing a masked 2-furylcarbinol mechanophore. Molecular release occurs selectively in the presence of GVs upon exposure to FUS under physiological conditions. These results showcase the viability of this system for enabling remote control of specific mechanochemical reactions with spatiotemporal precision in biologically relevant settings and demonstrate the translational potential of polymer mechanochemistry.

Mechanically manipulating glymphatic transport by ultrasound combined with microbubbles.

The glymphatic system is a perivascular fluid transport system for waste clearance. Glymphatic transport is believed to be driven by the perivascular pumping effect created by the pulsation of the arterial wall caused by the cardiac cycle. Ultrasound sonication of circulating microbubbles (MBs) in the cerebral vasculature induces volumetric expansion and contraction of MBs that push and pull on the vessel wall to generate a MB pumping effect. The objective of this study was to evaluate whether glymphatic transport can be mechanically manipulated by focused ultrasound (FUS) sonication of MBs. The glymphatic pathway in intact mouse brains was studied using intranasal administration of fluorescently labeled albumin as fluid tracers, followed by FUS sonication at a deep brain target (thalamus) in the presence of intravenously injected MBs. Intracisternal magna injection, the conventional technique used in studying glymphatic transport, was employed to provide a comparative reference. Three-dimensional confocal microscopy imaging of optically cleared brain tissue revealed that FUS sonication enhanced the transport of fluorescently labeled albumin tracer in the perivascular space (PVS) along microvessels, primarily the arterioles. We also obtained evidence of FUS-enhanced penetration of the albumin tracer from the PVS into the interstitial space. This study revealed that ultrasound combined with circulating MBs could mechanically enhance glymphatic transport in the brain.

Focused ultrasound-mediated brain genome editing.

Gene editing in the brain has been challenging because of the restricted transport imposed by the blood-brain barrier (BBB). Current approaches mainly rely on local injection to bypass the BBB. However, such administration is highly invasive and not amenable to treating certain delicate regions of the brain. We demonstrate a safe and effective gene editing technique by using focused ultrasound (FUS) to transiently open the BBB for the transport of intravenously delivered CRISPR/Cas9 machinery to the brain.

The mechanosensitive ion channel Piezo1 contributes to ultrasound neuromodulation.

Transcranial low-intensity ultrasound is a promising neuromodulation modality, with the advantages of noninvasiveness, deep penetration, and high spatiotemporal accuracy. However, the underlying biological mechanism of ultrasonic neuromodulation remains unclear, hindering the development of efficacious treatments. Here, the well-known Piezo1 was studied through a conditional knockout mouse model as a major mediator for ultrasound neuromodulation ex vivo and in vivo. We showed that Piezo1 knockout (P1KO) in the right motor cortex of mice significantly reduced ultrasound-induced neuronal calcium responses, limb movement, and muscle electromyogram (EMG) responses. We also detected higher Piezo1 expression in the central amygdala (CEA), which was found to be more sensitive to ultrasound stimulation than the cortex was. Knocking out the Piezo1 in CEA neurons showed a significant reduction of response under ultrasound stimulation, while knocking out astrocytic Piezo1 showed no-obvious changes in neuronal responses. Additionally, we excluded an auditory confound by monitoring auditory cortical activation and using smooth waveform ultrasound with randomized parameters to stimulate P1KO ipsilateral and contralateral regions of the same brain and recording evoked movement in the corresponding limb. Thus, we demonstrate that Piezo1 is functionally expressed in different brain regions and that it is an important mediator of ultrasound neuromodulation in the brain, laying the ground for further mechanistic studies of ultrasound.

Low-Intensity Focused Ultrasound to the Human Dorsal Anterior Cingulate Attenuates Acute Pain Perception and Autonomic Responses.

The dorsal anterior cingulate cortex (dACC) is a critical brain area for pain and autonomic processing, making it a promising noninvasive therapeutic target. We leverage the high spatial resolution and deep focal lengths of low-intensity focused ultrasound (LIFU) to noninvasively modulate the dACC for effects on behavioral and cardiac autonomic responses using transient heat pain stimuli. A N = 16 healthy human volunteers (6 M/10 F) received transient contact heat pain during either LIFU to the dACC or Sham stimulation. Continuous electroencephalogram (EEG), electrocardiogram (ECG), and electrodermal response (EDR) were recorded. Outcome measures included pain ratings, heart rate variability, EDR response, blood pressure, and the amplitude of the contact heat-evoked potential (CHEP).LIFU reduced pain ratings by 1.09 ± 0.20 points relative to Sham. LIFU increased heart rate variability indexed by the standard deviation of normal sinus beats (SDNN), low-frequency (LF) power, and the low-frequency/high-frequency (LF/HF) ratio. There were no effects on the blood pressure or EDR. LIFU resulted in a 38.1% reduction in the P2 CHEP amplitude. Results demonstrate LIFU to the dACC reduces pain and alters autonomic responses to acute heat pain stimuli. This has implications for the causal understanding of human pain and autonomic processing in the dACC and potential future therapeutic options for pain relief and modulation of homeostatic signals.

Histotripsy: A Method for Mechanical Tissue Ablation with Ultrasound.

Histotripsy is a relatively new therapeutic ultrasound technology to mechanically liquefy tissue into subcellular debris using high-amplitude focused ultrasound pulses. In contrast to conventional high-intensity focused ultrasound thermal therapy, histotripsy has specific clinical advantages: the capacity for real-time monitoring using ultrasound imaging, diminished heat sink effects resulting in lesions with sharp margins, effective removal of the treated tissue, a tissue-selective feature to preserve crucial structures, and immunostimulation. The technology is being evaluated in small and large animal models for treating cancer, thrombosis, hematomas, abscesses, and biofilms; enhancing tumor-specific immune response; and neurological applications. Histotripsy has been recently approved by the US Food and Drug Administration to treat liver tumors, with clinical trials undertaken for benign prostatic hyperplasia and renal tumors. This review outlines the physical principles of various types of histotripsy; presents major parameters of the technology and corresponding hardware and software, imaging methods, and bioeffects; and discusses the most promising preclinical and clinical applications.

A tool for monitoring cell type-specific focused ultrasound neuromodulation and control of chronic epilepsy.

Focused ultrasound (FUS) is a powerful tool for noninvasive modulation of deep brain activity with promising therapeutic potential for refractory epilepsy; however, tools for examining FUS effects on specific cell types within the deep brain do not yet exist. Consequently, how cell types within heterogeneous networks can be modulated and whether parameters can be identified to bias these networks in the context of complex behaviors remains unknown. To address this, we developed a fiber Photometry Coupled focused Ultrasound System (PhoCUS) for simultaneously monitoring FUS effects on neural activity of subcortical genetically targeted cell types in freely behaving animals. We identified a parameter set that selectively increases activity of parvalbumin interneurons while suppressing excitatory neurons in the hippocampus. A net inhibitory effect localized to the hippocampus was further confirmed through whole brain metabolic imaging. Finally, these inhibitory selective parameters achieved significant spike suppression in the kainate model of chronic temporal lobe epilepsy, opening the door for future noninvasive therapies.

Progress in Noninvasive Low-Intensity Focused Ultrasound Neuromodulation.

Low-intensity focused ultrasound represents groundbreaking medical advancements, characterized by its noninvasive feature, safety, precision, and broad neuromodulatory capabilities. This technology operates through mechanisms, for example, acoustic radiation force, cavitation, and thermal effects. Notably, with the evolution of medical technology, ultrasound neuromodulation has been gradually applied in treating central nervous system diseases, especially stroke. Furthermore, burgeoning research areas such as sonogenetics and nanotechnology show promising potential. Despite the benefit of low-intensity focused ultrasound the precise biophysical mechanism of ultrasound neuromodulation still need further exploration. This review discusses the recent and ongoing developments of low-intensity focused ultrasound for neurological regulation, covering the underlying rationale to current utility and the challenges that impede its further development and broader adoption of this promising alternative to noninvasive therapy.

Noninvasive focused ultrasound-mediated delivery of rAAV9-EGFP vectors for neuronal targeting in rats.

OBJECTIVE: To evaluate the synergistic potential of Focused Ultrasound (FUS) in conjunction with microbubbles (MB) and recombinant adeno-associated virus serotype 9 (rAAV9) vectors for targeted gene delivery to neuronal cells in rats, optimizing gene expression conditions and assessing any adverse effects. METHODS: The parameters for permeability enhancement of the rat's blood-brain barrier (BBB) were established using FUS+MB, with MRI scans and Evans Blue (EB) dye assisting in the evaluation. Rats underwent FUS-mediated transfection using rAAV9-Syn-EGFP vectors produced via a triple-transfection in HEK293T cells. Following this, the uptake and expression of GFP in targeted brain regions were evaluated using confocal fluorescence microscopy at various time intervals. Inflammatory responses post-FUS treatment were tracked by observing levels of GFAP, a marker for astrocytic activation, and TNF-α, a pro-inflammatory cytokine. Motor behavior effects post-intervention were gauged using the Rotarod test across multiple groups over a span of four weeks. RESULTS: FUS+MB affected BBB permeability, with optimal results at 4 W for 200 s showing 85 % permeability and evident Gd-DTPA leakage. Settings beyond these resulted in tissue damage. Control groups exhibited a basal GFP expression of 2 % ± 0.5 %, whereas FUS+MB with rAAV-EGFP injections substantially increased GFP expression to about 67 % ± 6 % in targeted neurons. This GFP expression peaked at three weeks post-treatment and remained evident six months later. Following FUS treatment, both GFAP and TNF-α levels underwent fluctuations before eventually nearing their baseline values. The Rotarod test revealed no significant behavioral differences post-treatments among the groups. CONCLUSIONS: Combining FUS+MB with rAAV offers an innovative approach to enhance therapeutic delivery to the central nervous system (CNS) by transiently adjusting BBB permeability.

Displacement and functional ultrasound (fUS) imaging of displacement-guided focused ultrasound (FUS) neuromodulation in mice.

Focused ultrasound (FUS) stimulation is a promising neuromodulation technique with the merits of non-invasiveness, high spatial resolution, and deep penetration depth. However, simultaneous imaging of FUS-induced brain tissue displacement and the subsequent effect of FUS stimulation on brain hemodynamics has proven challenging thus far. In addition, earlier studies lack in situ confirmation of targeting except for the magnetic resonance imaging-guided FUS system-based studies. The purpose of this study is 1) to introduce a fully ultrasonic approach to in situ target, modulate neuronal activity, and monitor the resultant neuromodulation effect by respectively leveraging displacement imaging, FUS, and functional ultrasound (fUS) imaging, and 2) to investigate FUS-evoked cerebral blood volume (CBV) response and the relationship between CBV and displacement. We performed displacement imaging on craniotomized mice to confirm the in situ targeting for neuromodulation site. We recorded hemodynamic responses evoked by FUS while fUS imaging revealed an ipsilateral CBV increase that peaks at 4 s post-FUS. We report a stronger hemodynamic activation in the subcortical region than cortical, showing good agreement with a brain elasticity map that can also be obtained using a similar methodology. We observed dose-dependent CBV responses with peak CBV, activated area, and correlation coefficient increasing with the ultrasonic dose. Furthermore, by mapping displacement and hemodynamic activation, we found that displacement colocalized and linearly correlated with CBV increase. The findings presented herein demonstrated that FUS evokes ipsilateral hemodynamic activation in cortical and subcortical depths while the evoked hemodynamic responses colocalize and correlate with FUS-induced displacement. We anticipate that our findings will help consolidate accurate targeting as well as shedding light on one of the mechanisms behind FUS modulation, i.e., how FUS mechanically displaces brain tissue affecting cerebral hemodynamics and thereby its associated connectivity.

Prostate cancer focal therapy: surgeon experience influences oncological results.

INTRODUCTION: Characterization of the index lesion of prostate cancer (PCa) has facilitated the development of focal therapy to reduce complications caused by radical treatments. In the present study, we sought to identify factors associated with the oncological results of focal therapy for PCa. METHODS: Between April 2017 and February 2020, 123 PCa patients received focal therapy performed with high-intensity focused ultrasound (HIFU). The patients presented unilateral localized disease, PSA < 20 ng/dl, clinical stage T1-T2, ISUP grade 1-3, and more than 10 years of life expectancy. Five certified surgeons with different levels of experience performed the procedures and were divided into groups #1 and #2 (>30 HIFUs performed) and #3 (10-15 HIFUs performed each). All patients were prospectively followed and underwent surveillance biopsy 1 year post-treatment. The primary endpoint was radical treatment, and secondary endpoints included focal therapy failure and in-field recurrence. Univariate and multivariate logistic regression were used to detect associations between clinical and procedure variables and the endpoints. RESULTS: The median follow-up was 54.3 months, with a mean age of 64.4 years. The mean PSA was 6.6 ng/dl; 59.3% of patients had intermediate-risk disease, and the remaining had low-risk. During follow-up, 29 (23.6%) patients required radical treatment (external beam radiation therapy), 37 (30.1%) experienced treatment failure, and 26 (21.1%) had an in-field recurrence with an ISUP grade of ≥2. Radical treatment in the follow-up was associated with patients treated by surgeons in group #3 and with elevated post-HIFU PSA concentrations. Baseline PSA concentrations, group #3 surgeons, and post-HIFU PSA concentrations were associated with treatment failure. In-field positive biopsies were associated with baseline and post-HIFU PSA concentrations. Furthermore, patients treated by surgeons in group #3 were independently associated with radical treatment and focal therapy failure. CONCLUSION: Focal therapy with HIFU has acceptable oncological outcomes in the medium term, and the surgeon's experience and technique are independently associated with the need for subsequent radical treatment and focal therapy failure.

Closed-Loop Control of Macrophage Engineering Enabled by Focused-Ultrasound Responsive Mechanoluminescence Nanoplatform for Precise Cancer Immunotherapy.

Macrophage engineering has emerged as a promising approach for modulating the anti-tumor immune response in cancer therapy. However, the spatiotemporal control and real-time feedback of macrophage regulatory process is still challenging, leading to off-targeting effect and delayed efficacy monitoring therefore raising risk of immune overactivation and serious side effects. Herein, a focused ultrasound responsive immunomodulator-loaded optical nanoplatform (FUSION) is designed to achieve spatiotemporal control and status reporting of macrophage engineering in vivo. Under the stimulation of focused ultrasound (FUS), the immune agonist encapsulated in FUSION can be released to induce selective macrophage M1 phenotype differentiation at tumor site and the near-infrared mechanoluminescence of FUSION is generated simultaneously to indicate the initiation of immune activation. Meanwhile, the persistent luminescence of FUSION is enhanced due to hydroxyl radical generation in the pro-inflammatory M1 macrophages, which can report the effectiveness of macrophage regulation. Then, macrophages labeled with FUSION as a living immunotherapeutic agent (FUSION-M) are utilized for tumor targeting and focused ultrasound activated, immune cell-based cancer therapy. By combining the on-demand activation and feedback to form a closed loop, the nanoplatform in this work holds promise in advancing the controllability of macrophage engineering and cancer immunotherapy for precision medicine.

Focused ultrasound-mediated blood-brain barrier opening is safe and feasible with moderately hypofractionated radiotherapy for brainstem diffuse midline glioma.

BACKGROUND: Diffuse midline glioma (DMG) is a pediatric tumor with dismal prognosis. Systemic strategies have been unsuccessful and radiotherapy (RT) remains the standard-of-care. A central impediment to treatment is the blood-brain barrier (BBB), which precludes drug delivery to the central nervous system (CNS). Focused ultrasound (FUS) with microbubbles can transiently and non-invasively disrupt the BBB to enhance drug delivery. This study aimed to determine the feasibility of brainstem FUS in combination with clinical doses of RT. We hypothesized that FUS-mediated BBB-opening (BBBO) is safe and feasible with 39 Gy RT. METHODS: To establish a safety timeline, we administered FUS to the brainstem of non-tumor bearing mice concurrent with or adjuvant to RT; our findings were validated in a syngeneic brainstem murine model of DMG receiving repeated sonication concurrent with RT. The brainstems of male B6 (Cg)-Tyrc-2J/J albino mice were intracranially injected with mouse DMG cells (PDGFB+, H3.3K27M, p53-/-). A clinical RT dose of 39 Gy in 13 fractions (39 Gy/13fx) was delivered using the Small Animal Radiation Research Platform (SARRP) or XRAD-320 irradiator. FUS was administered via a 0.5 MHz transducer, with BBBO and tumor volume monitored by magnetic resonance imaging (MRI). RESULTS: FUS-mediated BBBO did not affect cardiorespiratory rate, motor function, or tissue integrity in non-tumor bearing mice receiving RT. Tumor-bearing mice tolerated repeated brainstem BBBO concurrent with RT. 39 Gy/13fx offered local control, though disease progression occurred 3-4 weeks post-RT. CONCLUSION: Repeated FUS-mediated BBBO is safe and feasible concurrent with RT. In our syngeneic DMG murine model, progression occurs, serving as an ideal model for future combination testing with RT and FUS-mediated drug delivery.

Multimodal evaluation of the effects of low-intensity ultrasound on cerebral blood flow after traumatic brain injury in mice.

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide, and destruction of the cerebrovascular system is a major factor in the cascade of secondary injuries caused by TBI. Laser speckle imaging (LSCI)has high sensitivity in detecting cerebral blood flow. LSCI can visually show that transcranial focused ultrasound stimulation (tFUS) treatment stimulates angiogenesis and increases blood flow. To study the effect of tFUS on promoting angiogenesis in Controlled Cortical impact (CCI) model. tFUS was administered daily for 10 min and for 14 consecutive days after TBI. Cerebral blood flow was measured by LSCI at 1, 3, 7 and 14 days after trauma. Functional outcomes were assessed using LSCI and neurological severity score (NSS). After the last test, Nissl staining and vascular endothelial growth factor (VEGF) were used to assess neuropathology. TBI can cause the destruction of cerebrovascular system. Blood flow was significantly increased in TBI treated with tFUS. LSCI, behavioral and histological findings suggest that tFUS treatment can promote angiogenesis after TBI.

Evaluating the safety of high-intensity focused ultrasound treatment for rectal endometriosis: results from a French prospective multicentre study including 60 patients.

STUDY QUESTION: Is increasing the intensity of high-intensity focused ultrasound (HIFU) by 30% in the treatment of rectal endometriosis a safe procedure? SUMMARY ANSWER: This study demonstrates the safety of a 30% increase in the intensity of HIFU in the treatment of rectal endometriosis, with no Clavien-Dindo Grade III complications overall, and namely no rectovaginal fistulae. WHAT IS KNOWN ALREADY: A feasibility study including 20 patients with rectal endometriosis demonstrated, with no severe complications, a significant improvement in digestive disorders, dysmenorrhoea, dyspareunia, and health status, although the volume of the endometriosis nodule did not appear to be reduced. STUDY DESIGN, SIZE, DURATION: A prospective multicentre cohort study was conducted between 2020 and 2022 with 60 patients with symptomatic rectal endometriosis. Following the failure of medical treatment, HIFU treatment was offered as an alternative to surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS: As the main objective of this study was to examine safety, all adverse events observed during the 6 months of follow-up were analysed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and Clavien-Dindo classifications. Secondary objectives included evaluating the evolution of symptoms using validated questionnaires: gynaecological and digestive pain symptoms with a visual analogue scale, health status with the Medical Outcomes Study 36-item Short Form (SF-36) questionnaire, average post-operative daily pain level, and analgesic medication required in the 10 days following treatment. MRI was also performed at Day 1 to detect early complications. Finally, we performed a blinded MRI review of the evolution of the nodule at 6 months post-treatment. MAIN RESULTS AND THE ROLE OF CHANCE: The procedure was performed under spinal anaesthesia for 30% of the patients. The median duration of treatment was 32 min. Fifty-five patients left the hospital on Day 1. MRI scans performed on Day 1 did not highlight any early-onset post-operative complication. Using the Clavien-Dindo classification, we listed 56.7% Grade I events, 3.4% Grade II events, and no events Grade III or higher. At 1, 3, and 6 months, all gynaecologic, digestive and general symptoms, as well as health status, had significantly improved. The evolution of the nodule was also significant (P < 0.001) with a 28% decrease in volume. LIMITATIONS, REASONS FOR CAUTION: The main objective was safety and not effectiveness. The study was not randomized and there was no control group. WIDER IMPLICATIONS OF THE FINDINGS: HIFU treatment for rectal endometriosis results in an improvement of symptoms with low morbidity; as such, for selected patients, it could be a valuable alternative to surgical approaches following the failure of medical treatment. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the company EDAP TMS. Professors Dubernard and Rousset are consultants for EDAP TMS. Dubernard received travel support from EDAP-TMS. Dr F. Chavrier received industrial grants from EDAP-TMS. He has developed a device for generating focused ultrasonic waves with reduced treatment time. This device has been patented by EDAP-TMS. Dr Lafon received industrial grants from EDAP-TMS; he declares that EDAP-TMS provided funding directly to INSERM to support a young researcher chair in therapeutic ultrasound, which is unrelated to the current study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT04494568.

Focal high-intensity focused ultrasound therapy for localized prostate cancer: An interim analysis of the multinational FASST study.

BACKGROUND: High-intensity focused ultrasound (HIFU) emerged as a novel approach for the treatment of localized prostate cancer (PCa). However, prospective studies on HIFU-related outcomes and predictors of treatment failure (TF) remain scarce. MATERIALS AND METHODS: We conducted a multinational prospective cohort study among patients undergoing HIFU therapy for localized, low- to intermediate-risk PCa. Follow-up data on serial prostate specific antigen (PSA), multi-parametric magnetic resonance imaging (mpMRI), targeted/systematic biopsies, adverse events and functional outcomes were collected. The primary endpoint was TF, defined as histologically confirmed PCa requiring whole-gland salvage treatment. Uni- and multi-variable adjusted hazard ratios (HRs) were calculated using Cox proportional hazard regression models. RESULTS: At baseline, mean (standard deviation) age was 64.14 (7.19) years, with the majority of patients showing T-stage 1 (73.9%) and International Society of Urological Pathology grading system Grade 2 (58.8%). PSA nadir (median, 1.70 ng/mL) was reached after 6 months. Of all patients recruited, 16% had clinically significant PCa, as confirmed by biopsy, of which 13.4% had TF. Notably, T-stage and number of positive cores at initial biopsy were independent predictors of TF during follow-up (HR [95% CI] 1.27 [1.02-1.59] and 5.02 [1.80-14.03], respectively). Adverse events were minimal (17% and 8% early and late adverse events, respectively), with stable or improved functional outcomes in the majority of patients. CONCLUSIONS: This interim analysis of a multinational study on HIFU therapy for the management of low-to-intermediate-risk PCa reveals good functional outcomes, minimal adverse events and low incidence of TF over the short-term. Data on long-term outcomes, specifically as it relates to oncological outcomes, are awaited eagerly.

Focused Ultrasound-Responsive Nanocomposite with Near-Infrared II Mechanoluminescence for Spatiotemporally Selective Immune Activation in Lymph Nodes.

The immune regulation of the lymphatic system, especially the lymph node (LN), is of great significance for the treatment of diseases and the inhibition of pathogenic organisms spreading in the body. However, achieving precise spatiotemporal control of immune cell activation in LN in vivo remains a challenge due to tissue depth and off-target effects. Furthermore, minimally invasive and real-time feedback methods to monitor the regulation of the immune system in LN are lacking. Here, focused ultrasound responsive immunomodulator loaded nanoplatform (FURIN) with near-infrared II (NIR-II) luminescence is designed to achieve spatiotemporally controllable immune activation in LN in vivo. The NIR-II persistent luminescence of FURIN can track its delivery in LN through bioimaging. Under focused ultrasound (FUS) stimulation, the immunomodulator encapsulated in FURIN can be released locally in the LN to activate immune cells such as dendritic cells and the NIR-II mechanoluminescence of FURIN provides real-time optical feedback signals for immune activation. This work points to a FUS mediated, spatiotemporal selective immune activation strategy in vivo with the feedback control of luminescence signals via ultrasound responsive nanocomposite, which is of great significance in improving the efficacy and reducing the side effect of immune regulation for the development of potential immunotherapeutic methods in the future.

Focused ultrasound versus the loop electrosurgical excision procedure to treat women with cervical high-grade squamous intraepithelial lesions under 40: a retrospective study.

BACKGROUND: This study aimed to compare the efficacy of focused ultrasound (FUS) and the loop electrosurgical excision procedure (LEEP) for the treatment of cervical high-grade squamous intraepithelial lesions (HSILs) among women of reproductive age. METHODS: Case records of patients aged < 40 years who were treated for cervical HSILs using either FUS or LEEP from September 1, 2020 to May 31, 2022 were retrospectively reviewed. Patients were followed up for cure, recurrence, human papillomavirus (HPV) clearance, and complications within 1 year of treatment. Odds ratios and 95% confidence intervals were determined using univariate and multivariate logistic regression models to analyze the association between disease evidence or HPV clearance and treatment modalities or other covariates. RESULTS: Of the 1,054 women who underwent FUS or LEEP, 225 met our selection criteria. Among the selected women, 101 and 124 received FUS and LEEP, respectively. There was no significant difference between the FUS and LEEP groups in the cure rate during the 3-6 months of follow-up (89.11% vs. 94.35%, P = 0.085) and recurrence rate during the 6-12 months follow-up (2.22% vs. 1.71%, P = 0.790). Both groups exhibited enhanced cumulative HPV clearance rates; however, the rates were not significantly different between the FUS and LEEP groups (74.23% vs. 82.79%, P = 0.122 during the 3-6 months follow-up; 84.95% vs. 89.17%, P = 0.359 during the 6-12 months follow-up). Furthermore, the incidence of complications caused by the FUS and LEEP techniques was comparable (5.0% vs. 5.6%, P = 0.818). CONCLUSIONS: We found that FUS and LEEP have similar efficacy, safety, and reliability in treating women (aged < 40 years) with HSILs.

Outcomes of Focused Ultrasound Thalamotomy in Tremor Syndromes.

BACKGROUND: The current literature comparing outcomes after a unilateral magnetic resonance image-guided focused ultrasound (MRgFUS) thalamotomy between tremor syndromes is limited and remains a possible preoperative factor that could help predict the long-term outcomes. OBJECTIVE: The aim was to report on the outcomes between different tremor syndromes after a unilateral MRgFUS thalamotomy. METHODS: A total of 66 patients underwent a unilateral MRgFUS thalamotomy for tremor between November 2018 and May 2020 at St Vincent's Hospital Sydney. Each patient's tremor syndrome was classified prior to treatment. Clinical assessments, including the hand tremor score (HTS) and Quality of Life in Essential Tremor Questionnaire (QUEST), were performed at baseline and predefined intervals to 36 months. RESULTS: A total of 63 patients, comprising 30 essential tremor (ET), 24 dystonic tremor (DT), and 9 Parkinson's disease tremor (PDT) patients, returned for at least one follow-up. In the ET patients, at 24 months there was a 61% improvement in HTS and 50% improvement in QUEST compared to baseline. This is in comparison to PDT patients, where an initial benefit in HTS and QUEST was observed, which waned at each follow-up, remaining significant only up until 12 months. In the DT patients, similar results were observed to the ET patients: at 24 months there was a 61% improvement in HTS and 43% improvement in QUEST compared to baseline. CONCLUSION: These results support the use of unilateral MRgFUS thalamotomy for the treatment of DT, which appears to have a similar expected outcome to patients diagnosed with ET. Patients with PDT should be warned that there is a risk of treatment failure. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.