A Multimodal Phantom for Visualization and Assessment of Histotripsy Treatments on Ultrasound and X-Ray Imaging.

OBJECTIVE: Histotripsy is an emerging non-invasive, non-ionizing and non-thermal focal tumor therapy. Although histotripsy targeting is currently based on ultrasound (US), other imaging modalities such as cone-beam computed tomography (CBCT) have recently been proposed to enable the treatment of tumors not visible on ultrasound. The objective of this study was to develop and evaluate a multi-modality phantom to facilitate the assessment of histotripsy treatment zones on both US and CBCT imaging. METHODS: Fifteen red blood cell phantoms composed of alternating layers with and without barium were manufactured. Spherical 25-mm histotripsy treatments were performed, and treatment zone size and location were measured on CBCT and ultrasound. Sound speed, impedance and attenuation were measured for each layer type. RESULTS: The average ± standard deviation signed difference between measured treatment diameters was 0.29 ± 1.25 mm. The Euclidean distance between measured treatment centers was 1.68 ± 0.63 mm. The sound speed in the different layers ranged from 1491 to 1514 m/s and was within typically reported soft tissue ranges (1480-1560 m/s). In all phantoms, histotripsy resulted in sharply delineated treatment zones, allowing segmentation in both modalities. CONCLUSION: These phantoms will aid in the development and validation of X-ray-based histotripsy targeting techniques, which promise to expand the scope of treatable lesions beyond only those visible on ultrasound.

Initial Assessment of Boiling Histotripsy for Mechanical Ablation of Ex Vivo Human Prostate Tissue.

Boiling histotripsy (BH) is a focused ultrasound technology that uses millisecond-long pulses with shock fronts to induce mechanical tissue ablation. The pulsing scheme and mechanisms of BH differ from those of cavitation cloud histotripsy, which was previously developed for benign prostatic hyperplasia. The goal of the work described here was to evaluate the feasibility of using BH to ablate fresh ex vivo human prostate tissue as a proof of principle for developing BH for prostate applications. Fresh human prostate samples (N = 24) were obtained via rapid autopsy (<24 h after death, institutional review board exempt). Samples were analyzed using shear wave elastography to ensure that mechanical properties of autopsy tissue were clinically representative. Samples were exposed to BH using 10- or 1-ms pulses with 1% duty cycle under real-time B-mode and Doppler imaging. Volumetric lesions were created by sonicating 1-4 rectangular planes spaced 1 mm apart, containing a grid of foci spaced 1-2 mm apart. Tissue then was evaluated grossly and histologically, and the lesion content was analyzed using transmission electron microscopy and scanning electron microscopy. Observed shear wave elastography characterization of ex vivo prostate tissue (37.9 ± 22.2 kPa) was within the typical range observed clinically. During BH, hyperechoic regions were visualized at the focus on B-mode, and BH-induced bubbles were also detected using power Doppler. As treatment progressed, hypoechoic regions of tissue appeared, suggesting successful tissue fractionation. BH treatment was twofold faster using shorter pulses (1 ms vs. 10 ms). Histological analysis revealed lesions containing completely homogenized cell debris, consistent with histotripsy-induced mechanical ablation. It was therefore determined that BH is feasible in fresh ex vivo human prostate tissue producing desired mechanical ablation. The study supports further work aimed at translating BH technology as a clinical option for prostate ablation.

Assessment of bubble activity generated by histotripsy combined with echogenic liposomes.

Objective.Histotripsy is a form of focused ultrasound therapy that uses the mechanical activity of bubbles to ablate tissue. While histotripsy alone degrades the cellular content of tissue, recent studies have demonstrated it effectively disrupts the extracellular structure of pathologic conditions such as venous thrombosis when combined with a thrombolytic drug. Rather than relying on standard administration methods, associating thrombolytic drugs with an ultrasound-triggered echogenic liposome vesicle will enable targeted, systemic drug delivery. To date, histotripsy has primarily relied on nano-nuclei inherent to the medium for bubble cloud generation, and microbubbles associated with echogenic liposomes may alter the histotripsy bubble dynamics. The objective of this work was to investigate the interaction of histotripsy pulse with echogenic liposomes.Approach.Bubble clouds were generated using a focused source in anin vitromodel of venous flow. Acoustic emissions generated during the insonation were passively acquired to assess the mechanical activity of the bubble cloud. High frame rate, pulse inversion imaging was used to track the change in echogenicity of the liposomes following histotripsy exposure.Main results.For peak negative pressures less than 20 MPa, acoustic emissions indicative of stable and inertial bubble activity were observed. As the peak negative pressure of the histotripsy excitation increased, harmonics of the excitation were observed in OFP t-ELIP solutions and plasma alone. Additional observations with high frame rate imaging indicated a transition of bubble behavior as the pulse pressure transitioned to shock wave formation.Significance.These observations suggest that a complex interaction between histotripsy pulses and echogenic liposomes that may be exploited for combination treatment approaches.

Quantitative Assessment of Boiling Histotripsy Progression Based on Color Doppler Measurements.

Boiling histotripsy (BH) is a mechanical tissue liquefaction method that uses sequences of millisecond-long high intensity focused ultrasound (HIFU) pulses with shock fronts. The BH treatment generates bubbles that move within the sonicated volume due to acoustic radiation force. Since the velocity of the bubbles and tissue debris is expected to depend on the lesion size and liquefaction completeness, it could provide a quantitative metric of the treatment progression. In this study, the motion of bubble remnants and tissue debris immediately following BH pulses was investigated using high-pulse repetition frequency (PRF) plane-wave color Doppler ultrasound in ex vivo myocardium tissue. A 256-element 1.5 MHz spiral HIFU array with a coaxially integrated ultrasound imaging probe (ATL P4-2) produced 10 ms BH pulses to form volumetric lesions with electronic beam steering. Prior to performing volumetric BH treatments, the motion of intact myocardium tissue and anticoagulated bovine blood following isolated BH pulses was assessed as two limiting cases. In the liquid blood the velocity of BH-induced streaming at the focus reached over 200 cm/s, whereas the intact tissue was observed to move toward the HIFU array consistent with elastic rebound of tissue. Over the course of volumetric BH treatments tissue motion at the focus locations was dependent on the axial size of the forming lesion relative to the corresponding size of the HIFU focal area. For axially small lesions, the maximum velocity after the BH pulse was directed toward the HIFU transducer and monotonically increased over time from about 20-100 cm/s as liquefaction progressed, then saturated when tissue was fully liquefied. For larger lesions obtained by merging multiple smaller lesions in the axial direction, the high-speed streaming away from the HIFU transducer was observed at the point of full liquefaction. Based on these observations, the maximum directional velocity and its location along the HIFU propagation axis were proposed and evaluated as candidate metrics of BH treatment completeness.

Parameter estimation in high-intensity focused ultrasound therapy.

Hyperthermia using High-Intensity Focused Ultrasound (HIFU) is an acoustic therapy for cancer treatment. This technique consists of an increase in the temperature field of the tumor to achieve coagulative necrosis and immediate cell death. Therefore, for having a successful treatment, the physical problem requires to know several properties due to the high variability from individual to individual, or even for the same individual under different physiological conditions. This article presents a numerical simulation of hyperthermia therapy for cancer treatment using HIFU, as well as the estimation of parameters that influence the physical problem. Two mathematical models were considered to solve the forward problem. The acoustic model based on acoustic pressure performs a frequency-domain study, and the bioheat transfer model a time-dependent study. These models were solved using Comsol Multiphysics® software in a 2D-axisymmetric rectangular domain to determine the temperature field. Parameter estimation was coded in Matlab Mathworks® environment using a Bayesian approach. The Markov Chain Monte Carlo method by the Metropolis-Hastings algorithm was implemented, and the simulated temperature measurements were considered. Results suggest that specific HIFU therapy can be performed for each patient by estimating appropriate parameters for cancer treatment and provides the possibility to define procedures before and during the treatment.

A robotic magnetic resonance-guided high-intensity focused ultrasound platform for neonatal neurosurgery: Assessment of targeting accuracy and precision in a brain phantom.

BACKGROUND: Intraventricular hemorrhage (IVH) is one of the most serious neurovascular complications resulting from premature birth. It can result in clotting of blood within the ventricles, which causes a buildup of cerebrospinal fluid that can lead to posthemorrhagic ventricular dilation and posthemorrhagic hydrocephalus. Currently, there are no direct treatments for these blood clots as the standard of care is invasive surgery to insert a shunt. Magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) has been investigated as a noninvasive treatment to lyse blood clots. However, current MRgHIFU systems are not suitable in the context of treating IVH in neonates. PURPOSE: We have developed a robotic MRgHIFU neurosurgical platform designed to treat the neonatal brain. This platform facilitates ergonomic patient positioning and directs treatment through their open anterior fontanelle while providing a larger treatment volume. The platform is based on an MR-compatible robot developed by our group. Further development of the platform has warranted investigation of its targeting ability to assess its feasibility in the neonatal brain. This study aimed to quantify the platform's targeting accuracy, precision, and repeatability using a brain phantom and clinical MRI system. METHODS: A thermosensitive brain-mimicking phantom was developed to test the platform's targeting accuracy. Rectangular grid patterns were created with HIFU thermal energy "lesions" in the phantoms by targeting specific coordinate points. The intended target locations were demarcated by inserting carbon fiber rods through a targeting assessment template. Coordinates for the intended and actual targets were derived from T2-weighted MRI scans, and the centroid distance between them was measured. Subsequently, the platform's targeting accuracy was quantified according to equations derived from ISO Standard 9283:1998. RESULTS: HIFU ablation resulted in distinct thermal lesions within the thermosensitive phantoms, which appeared as discrete hypointense regions in T2-weighted MR scans. A total of 127 target points were included in the data analysis, which yielded a targeting accuracy of 0.6 mm and targeting precision of 1.2 mm. CONCLUSIONS: The robotic MRgHIFU platform was shown to have a high degree of accuracy, precision, and repeatability. The results demonstrate the platform's functionality when targeting through simulated brain matter. These results serve as an initial verification of the platform targeting ability and showed promise toward the final application in a neonatal brain.

A time-driven activity-based costing approach of magnetic resonance-guided high-intensity focused ultrasound for cancer-induced bone pain.

OBJECTIVE: To determine resource consumption and total costs for providing magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) treatment to a patient with cancer-induced bone pain (CIBP). METHODS: We conducted a time-driven activity-based costing (TD-ABC) of MR-HIFU treatments for CIBP from a hospital perspective. A European care-pathway (including a macro-, meso-, and micro-level) was designed to incorporate the care-delivery value chain. Time estimates were obtained from medical records and from prospective direct observations. To calculate the capacity cost rate, data from the controlling department of a German university hospital were allocated to the modules of the care pathway. Best- and worst-case scenarios were calculated by applying lower and upper bounds of time measurements. RESULTS: The macro-level care pathway consisted of eight modules (i.e., outpatient consultations, pretreatment imaging, preparation, optimization, sonication, post-treatment, recovery, and anesthesia). The total cost of an MR-HIFU treatment amounted to €5147 per patient. Best- and worst-case scenarios yielded a total cost of €4092 and to €5876. According to cost categories, costs due to equipment accounted for 41% of total costs, followed by costs with personnel (32%), overhead (16%) and materials (11%). CONCLUSION: MR-HIFU is an emerging noninvasive treatment for alleviating CIBP, with increasing evidence on treatment efficacy. This costing study can support MR-HIFU reimbursement negotiations and facilitate the adoption of MR-HIFU as first-line treatment for CIBP. The present TD-ABC model creates the opportunity of benchmarking the provision of MR-HIFU to bone tumor.Key pointsMagnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is an emerging noninvasive treatment modality for alleviating cancer-induced bone pain (CIBP).From a hospital perspective, the total cost of MR-HIFU amounted to €5147 per treatment.This time-driven activity-based costing model creates the opportunity of benchmarking the provision of MR-HIFU to bone tumor.

Role of contrast-enhanced ultrasonography in MR-guided focused ultrasound ablation on uterus fibroids: lesion selection and assessment of ablative effects.

OBJECTIVES: To determine whether contrast-enhanced ultrasonography (CEUS) can be used for selecting lesions and assessing the ablative effects of MRgFUS ablation on uterus fibroids, compared with MR imaging. METHODS: This retrospective study was approved by the institutional review board of our hospital. From April 2018 to November 2019, a total of 44 symptomatic fibroids in 38 patients who underwent MRgFUS ablation were included. The association between pre-ablation characteristics on CEUS/MR imaging and the non-perfusion volume (NPV) after ablation was analyzed using multivariable linear regression analysis. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve values was compared between the CEUS and MR imaging regression models. NPV after ablation was compared between CEUS and enhanced MR imaging. RESULTS: On CEUS, entangled branch vessels, fast-in, and fast-out patterns were significantly associated with NPV, with an AUC of 0.95 (95% CI; 0.88, 1.00). On MR imaging, hyper-intensity on T2-weighted images (T2WI), hyper-intense ring-like signal on T2WI images, and hyper-enhancement on contrast-enhanced T1WI images were correlated with NPV, with an AUC of 0.86 (95% CI; 0.70, 1.00). After ablation, no differences in NPV were noted between contrast-enhanced T1WI (84.13 ± 75.42 cm3) and CEUS (80.22 ± 76.49 cm3). CONCLUSIONS: Some pre-ablation characteristics of uterine fibroids on CEUS were associated with NPV after MRgFUS. CEUS may contribute to the evaluation of ablative outcomes and patient selection, similar to MR imaging. KEY POINTS: • Contrast-enhanced ultrasonography (CEUS) is effective for selecting the appropriate uterine fibroids before MR-guided focused ultrasound (MRgFUS) ablation and evaluating non-perfusion volumes (NPV) after ablation, as a potential alternative to MR imaging. • Before ablation, entangled branch vessels, fast-in, and fast-out patterns on CEUS were significantly associated with NPV after MRgFUS. • No significant differences in NPV were detected between contrast-enhanced T1WI and CEUS after ablation.

A standard test phantom for the performance assessment of magnetic resonance guided high intensity focused ultrasound (MRgHIFU) thermal therapy devices.

Purpose: Test objects for High Intensity Focused Ultrasound (HIFU) are required for the standardization and definition of treatment, Quality Assurance (QA), comparison of results between centers and calibration of devices. This study describes a HIFU test object which provides temperature measurement as a function of time, in a reference material compatible with Magnetic Resonance (MR) and ultrasound.Materials and methods: T-Type fine wire thermocouples were used as sensors and 5 correction methods for viscous heating artifacts were assessed. The phantom was tested in a MR-HIFU Philips Sonalleve device over a period of 12 months, demonstrating stability and validity to evaluate the performance of the device.Results: The study furnished useful information regarding the MR-HIFU sessions and highlighted potential limitations of the existing QA and monitoring methods. The importance of temperature monitoring along the whole acoustic path was demonstrated as MR Thermometry readings differed in the three MR plane views (coronal, sagittal, transverse), in particular when the focus was near a soft-tissue/bone interface, where there can be an MR signal loss with significant temperature and thermal dose underestimation (138% variation between the three plane views).Conclusions: The test object was easy to use and has potential as a valid tool for training, QA, research and development for MR guided HIFU and potentially ultrasound guided devices.

Histology to 3D in vivo MR registration for volumetric evaluation of MRgFUS treatment assessment biomarkers.

Advances in imaging and early cancer detection have increased interest in magnetic resonance (MR) guided focused ultrasound (MRgFUS) technologies for cancer treatment. MRgFUS ablation treatments could reduce surgical risks, preserve organ tissue and function, and improve patient quality of life. However, surgical resection and histological analysis remain the gold standard to assess cancer treatment response. For non-invasive ablation therapies such as MRgFUS, the treatment response must be determined through MR imaging biomarkers. However, current MR biomarkers are inconclusive and have not been rigorously evaluated against histology via accurate registration. Existing registration methods rely on anatomical features to directly register in vivo MR and histology. For MRgFUS applications in anatomies such as liver, kidney, or breast, anatomical features that are not caused by the treatment are often insufficient to drive direct registration. We present a novel MR to histology registration workflow that utilizes intermediate imaging and does not rely on anatomical MR features being visible in histology. The presented workflow yields an overall registration accuracy of 1.00 ± 0.13 mm. The developed registration pipeline is used to evaluate a common MRgFUS treatment assessment biomarker against histology. Evaluating MR biomarkers against histology using this registration pipeline will facilitate validating novel MRgFUS biomarkers to improve treatment assessment without surgical intervention. While the presented registration technique has been evaluated in a MRgFUS ablation treatment model, this technique could be potentially applied in any tissue to evaluate a variety of therapeutic options.

Assessment of Collaborative Robot (Cobot)-Assisted Histotripsy for Venous Clot Ablation.

OBJECTIVE: The application of bubble-based ablation with the focus ultrasound therapy histotripsy is gaining traction for the treatment of venous thrombosis, among other pathologies. For extensive clot burden, the histotripsy source must be translated to ensure uniform bubble activity throughout the vascular obstruction. The purpose of this study was to evaluate the targeting accuracy of a histotripsy system comprised of a focused source, ultrasound image guidance, and a collaborative robot (cobot) positioner. The system was designed with a primary emphasis for treating deep vein thrombosis. METHODS: Studies to test treatment planning and targeting bubble activity with the histotripsy-cobot system were conducted in an in vitro clot model. A tissue-mimicking phantom was also targeted with the system, and the predicted and actual areas of liquefaction were compared to gauge the spatial accuracy of ablation. RESULTS: The system provided submillimeter accuracy for both tracking along an intended path (within 0.6 mm of a model vessel) and targeting bubble activity within the venous clot model (0.7 mm from the center of the clot). Good correlation was observed between the planned and actual liquefaction locations in the tissue phantom, with an average Dice similarity coefficient of 77.8%, and average Hausdorff distance of 1.6 mm. CONCLUSION: Cobots provide an effective means to apply histotripsy pulses over a treatment volume, with the ablation precision contingent on the quality of image guidance. SIGNIFICANCE: Overall, these results demonstrate cobots can be used to guide histotripsy ablation for targets that extend beyond the natural focus of the transducer.

Innovations in the Neurosurgical Management of Epilepsy.

Technical limitations and clinical challenges have historically limited the diagnostic tools and treatment methods available for surgical approaches to the management of epilepsy. By contrast, recent technological innovations in several areas hold significant promise in improving outcomes and decreasing morbidity. We review innovations in the neurosurgical management of epilepsy in several areas, including wireless recording and stimulation systems (particularly responsive neurostimulation [NeuroPace]), conformal electrodes for high-resolution electrocorticography, robot-assisted stereotactic surgery, optogenetics and optical imaging methods, novel positron emission tomography ligands, and new applications of focused ultrasonography. Investigation into genetic causes of and susceptibilities to epilepsy has introduced a new era of precision medicine, enabling the understanding of cell signaling mechanisms underlying epileptic activity as well as patient-specific molecularly targeted treatment options. We discuss the emerging path to individualized treatment plans, predicted outcomes, and improved selection of effective interventions, on the basis of these developments.

Efficacy and safety assessment of an ultrasound-based thermal treatment of varicose veins in a sheep model.

Purpose: Varicose veins are a common pathology that can be treated by endovenous thermal procedures like radiofrequency ablation (RFA). Such catheter-based techniques consist in raising the temperature of the vein wall to 70 to 120 °C to induce vein wall coagulation. Although effective, this treatment option is not suited for all types of veins and can be technically challenging.Materials and methods: In this study, we used High-Intensity Focused Ultrasound (HIFU) as a non-invasive thermal ablation procedure to treat varicose veins and we assessed the long-term efficacy and safety of the procedure in a sheep model. In vivo experiments were first conducted on two saphenous veins to measure the temperature rise induced at the vein wall during HIFU ablation and were compared with reported RFA-induced thermal rise. Thermocouples were inserted in situ to perform 20 measurements during 8-s ultrasound pulses at 3 MHz. Eighteen saphenous veins of nine anesthetized sheep (2-2.5 % Isoflurane) were then exposed to similar pulses (85 W acoustic, 8 s). After treatments, animals recovered from anesthesia and were followed up 30, 60 and 90 days post-treatment (n = 3 animals per group). At the end of the follow-up, vein segments and perivenous tissues were harvested and histologically examined.Results: Temperatures induced by HIFU pulses were found to be comparable to reported RFA treatments. Likewise, histological findings were similar to the ones reported after RFA and laser-based coagulation necrosis of the vein wall, thrombotic occlusions and vein wall fibrosis.Conclusion: These results support strongly the effectiveness and safety of HIFU for ablating non-invasively veins.

Non-contrast enhanced MRI for assessment of uterine fibroids' early response to ultrasound-guided high-intensity focused ultrasound thermal ablation.

PURPOSE: To examine non-contrast enhanced MRI value to evaluate necrotic area and ablation rate of uterine fibroids after high-intensity focused ultrasound (HIFU) thermal ablation. METHOD: In total, 508 patients with 598 fibroids who underwent HIFU treatment were enrolled. Contrast-enhanced MRI (CE-MRI) with diffusion-weighted imaging (DWI)were performed before treatment and within two days post-treatment. DWI signal performance of post-operative fibroids was observed; apparent diffusion coefficient (ADC) and DWI signal values pre- and post-operation were measured. The volume of post-operative DWI signal change area and post-contrast enhanced fibroid necrosis area were compared. RESULTS: Average ADC and DWI signal values before HIFU treatment were higher than those post-operation; the difference was statistically significant before and after ablation (P < 0.05). After HIFU, 78.09 % (467 / 598) of DWI showed complete regular or irregular high-signal rings and 21.91 % (131 / 598) showed incomplete high-signal rings. No significant difference was noted between the complete high-signal ring volume on DWI and the non-enhanced volume (P > 0.05); however, this difference was statistically significant compared with the incomplete high-signal ring volume on DWI (P < 0.05). Two doctors had good agreements on evaluating the morphology of high-signal rings (κ > 0.75, P < 0.05). CONCLUSIONS: Combined with pre-operative T2WI and post-operative DWI, non-contrast enhanced MRI can effectively evaluate ablation rate for most patients with uterine fibroids.

Feasibility and safety assessment of magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-mediated mild hyperthermia in pelvic targets evaluated using an in vivo porcine model.

Purpose: To evaluate the feasibility and assess safety parameters of magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-mediated hyperthermia (HT; heating to 40-45 °C) in various pelvic targets in a porcine model in vivo.Methods: Thirteen HT treatments were performed in six pigs with a commercial MRgHIFU system (Sonalleve V2, Profound Medical Inc., Mississauga, Canada) to muscle adjacent to the ventral/dorsal bladder wall and uterus to administer 42 °C (±1°) for 30 min (±5%) using an 18-mm target diameter and 100 W power. Feasibility was assessed using accuracy, uniformity, and MR-thermometry performance-based metrics. Safety parameters were assessed for tissues in the targets and beam-path by contrast-enhanced MRI, gross-pathology and histopathology.Results: Across all HT sessions, the mean difference between average temperature (Tavg) and the target temperature within the target region-of-interest (tROI, the cross-section of the heated volume at focal depth) was 0.51 ± 0.33 °C. Within the tROI, the temperature standard deviation averaged 1.55 ± 0.31 °C, the average 30-min Tavg variation was 0.80 ± 0.17 °C, and the maximum difference between Tavg and the 10th- or 90th-percentile temperature averaged 2.01 ± 0.44 °C. The average time to reach ≥41 °C and cool to ≤40 °C within the tROI at the beginning and end of treatment was 47.25 ± 27.47 s and 66.37 ± 62.68 s, respectively. Compared to unheated controls, no abnormally-perfused tissue or permanent damage was evident in the MR images, gross pathology or histological analysis.Conclusions: MRgHIFU-mediated HT is feasible and safety assessment is satisfactory for treating an array of clinically-mimicking pelvic geometries in a porcine model in vivo, implying the technique may have utility in treating pelvic targets in human patients.

Longitudinal Functional Assessment of Brain Injury Induced by High-Intensity Ultrasound Pulse Sequences.

Exposure of the brain to high-intensity stress waves creates the potential for long-term functional deficits not related to thermal or cavitational damage. Possible sources of such exposure include overpressure from blast explosions or high-intensity focused ultrasound (HIFU). While current ultrasound clinical protocols do not normally produce long-term neurological deficits, the rapid expansion of potential therapeutic applications and ultrasound pulse-train protocols highlights the importance of establishing a safety envelope beyond which therapeutic ultrasound can cause neurological deficits not detectable by standard histological assessment for thermal and cavitational damage. In this study, we assessed the neuroinflammatory response, behavioral effects, and brain micro-electrocorticographic (µECoG) signals in mice following exposure to a train of transcranial pulses above normal clinical parameters. We found that the HIFU exposure induced a mild regional neuroinflammation not localized to the primary focal site, and impaired locomotor and exploratory behavior for up to 1 month post-exposure. In addition, low frequency (δ) and high frequency (ß, γ) oscillations recorded by ECoG were altered at acute and chronic time points following HIFU application. ECoG signal changes on the hemisphere ipsilateral to HIFU exposure are of greater magnitude than the contralateral hemisphere, and persist for up to three months. These results are useful for describing the upper limit of transcranial ultrasound protocols, and the neurological sequelae of injury induced by high-intensity stress waves.

Cost-utility analysis of focal high-intensity focussed ultrasound vs active surveillance for low- to intermediate-risk prostate cancer using a Markov multi-state model.

OBJECTIVES: To estimate the relative cost-effectiveness of focal high-intensity focussed ultrasound (F-HIFU) compared to active surveillance (AS) in patients with low- to intermediate-risk prostate cancer, in France. PATIENTS AND METHODS: A Markov multi-state model was elaborated for this purpose. Our analyses were conducted from the French National Health Insurance perspective, with a time horizon of 10 years and a 4% discount rate for cost and effectiveness. A secondary analysis used a 30-year time horizon. Costs are presented in 2016 Euros (€), and effectiveness is expressed as quality-adjusted life years (QALYs). Model parameters' value (probabilities for transitions between health states, and cost and utility of health states) is supported by systematic literature reviews (PubMed) and random effect meta-analyses. The cost of F-HIFU in our model was the temporary tariff attributed by the French Ministry of Health to the overall treatment of prostate cancer by HIFU (€6047). Our model was analysed using Microsoft Excel 2010 (Microsoft Corp., Redmond, WA, USA). Uncertainty about the value of the model parameters was handled through probabilistic analyses. RESULTS: The five health states of our model were as follows: initial state (AS or F-HIFU), radical prostatectomy, radiation therapy, metastasis, and death. Transition probabilities from the initial F-HIFU state relied on four articles eligible for our meta-analyses. All were non-comparative studies. Utilities relied on a single cohort in San Diego, CA, USA. For a fictive cohort of 1000 individuals followed for 10 years, F-HIFU would be €207 520 more costly and would yield 382 less QALYs than AS, which means that AS is cost-effective when compared to F-HIFU. For a threshold value varying from €0 to 100 000/QALY, the probability of AS being cost-effective compared to F-HIFU varied from 56.5% to 60%. This level of uncertainty was in the same range with a 30-year time horizon. CONCLUSION: Given existing published data, our results suggest that AS is cost-effective compared to F-HIFU in patients with low- and intermediate-risk prostate cancer, but with high uncertainty. This uncertainty must be scaled down by continuing to supply the model with new published data and ideally through a randomised clinical trial that includes cost-effectiveness analyses.

In vitro assessment of stiffness-dependent histotripsy bubble cloud activity in gel phantoms and blood clots.

As a bubble-based ablative therapy, the efficacy of histotripsy has been demonstrated in healthy or acutely diseased models. Chronic conditions associated with stiff tissues may require additional bubble activity prior to histotripsy liquefaction. In this study, histotripsy pulses were generated in agarose phantoms of Young's moduli ranging from 12.3 to 142 kPa, and in vitro clot models with mild and strong platelet-activated retraction. Bubble cloud emissions were tracked with passive cavitation imaging, and the threshold acoustic power associated with phantom liquefaction was extracted with receiver operator characteristic analysis. The power of histotripsy-generated emissions and the degree of liquefaction were tabulated for both clot models. For the agarose phantoms, the acoustic power associated with liquefaction increased with Young's modulus. When grouped based on agarose concentration, only two arms displayed a significant difference in the liquefaction threshold acoustic power (22.1 kPa versus 142 kPa Young's modulus). The bubble cloud dynamics tracked with passive cavitation imaging indicated no strong changes in the bubble dynamics based on the phantom stiffness. For identical histotripsy exposure, the power of acoustic emissions and degree of clot lysis did not vary based on the clot model. Overall, these results indicate that a fixed threshold acoustic power mapped with passive cavitation imaging can be utilized for predicting histotripsy liquefaction over a wide range of tissue stiffness.

Diffusion-Weighted Magnetic Resonance Imaging in Assessment of Primary Liver Cancer after HIFU Treatment.

OBJECTIVE: To determine the feasibility and role of diffusion-weighted magnetic resonance imaging (DWI) in the assessment of high-intensity focused ultrasound (HIFU) for the treatment of primary liver cancer. STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Department of Radiology, Renmin Hospital, Hubei University of Medicine, China, from July 2016 to March 2018. METHODOLOGY: Forty-eight patients with primary liver cancer underwent conventional magnetic resonance plain scans, dynamic contrast-enhanced scans, and DWI before and two weeks after HIFU treatment, to compare and analyse the changes in apparent diffusion coefficient (ADC) and signal intensity (SI) in four regions of interest (the centre and the surrounding of the lesion, liver tissues around the lesion, back muscles) before and after HIFU treatment. RESULTS: Before HIFU treatment, the lesion showed high signals on the original DWI image, and the ADC image showed cool colours. Two weeks after HIFU treatment, the lesion showed low signals on the original DWI image, and ADC image showed warm colours; the ADC values of the centre and the surrounding of the lesion were significantly higher than those before treatment (both p<0.001); SI values of centre and surrounding of the lesion were significantly lower than those before treatment (both p<0.001). One case (2.08%) each of residual tumor tissue and recurrence were observed and followed up for 3 months. CONCLUSION: DWI can make a relatively accurate judgment on the therapeutic effect of HIFU for the treatment of primary liver cancer. Increased ADC values and reduced SI values can be used as markers for the evaluation of coagulative necrosis of primary liver cancer after HIFU treatment. In addition, DWI combined with dynamic contrast-enhanced MRI can make up for their own shortcomings.

A propensity-matched analysis of clinical outcomes between open thyroid lobectomy and high-intensity focused ultrasound (HIFU) ablation of benign thyroid nodules.

BACKGROUND: High-intensity focused ultrasound is a promising, nonoperative treatment for benign thyroid nodules. Our study aimed to compare treatment outcomes of single-session high-intensity focused ultrasound ablation with open lobectomy after propensity score matching. METHODS: After propensity matching, we compared treatment-related morbidity, treatment time, duration of hospitalization, improvement in symptom score, cost, and acoustic parameters of consecutive patients who underwent high-intensity focused ultrasound ablation or lobectomy. All eligible patients completed the computerized, multidimensional voice program and Voice Handicap Index questionnaire before, and 3 and 6 months after treatment. RESULTS: The matched cohort comprised 154 patients (77 in each group). Although treatment-related morbidity was comparable between the two groups (P = .368), treatment time (P <.001), duration of hospitalization (P <.001), and medical cost (P <.001) were less in the high-intensity focused ultrasound group. After high-intensity focused ultrasound ablation, the 6-month nodule shrinkage (mean ± SD) was 64% ± 26% and the 6-month symptom improvement score was comparable with lobectomy (P = .283). At 6 months, none of the acoustic parameters were changed from the baseline in both groups (P >.05), and the Voice Handicap Index questionnaire did not differ between the two groups (P >.05). CONCLUSION: Despite having similar treatment-related morbidity and voice outcomes, there were possibly some advantages with high-intensity focused ultrasound during open lobectomy, including the avoidance of a neck scar, shorter treatment time and duration of hospitalization, and lower medical cost.