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Introduction: The non-perfused volume divided by total fibroid load (NPV/TFL) is a predictive outcome parameter for MRI-guided high-intensity focused ultrasound (MR-HIFU) treatments of uterine fibroids, which is related to long-term symptom relief. In current clinical practice, the MR-HIFU outcome parameters are typically determined by visual inspection, so an automated computer-aided method could facilitate objective outcome quantification. The objective of this study was to develop and evaluate a deep learning-based segmentation algorithm for volume measurements of the uterus, uterine fibroids, and NPVs in MRI in order to automatically quantify the NPV/TFL., Materials and Methods: A segmentation pipeline was developed and evaluated using expert manual segmentations of MRI scans of 115 uterine fibroid patients, screened for and/or undergoing MR-HIFU treatment. The pipeline contained three separate neural networks, one per target structure. The first step in the pipeline was uterus segmentation from contrast-enhanced (CE)-T1w scans. This segmentation was subsequently used to remove non-uterus background tissue for NPV and fibroid segmentation. In the following step, NPVs were segmented from uterus-only CE-T1w scans. Finally, fibroids were segmented from uterus-only T2w scans. The segmentations were used to calculate the volume for each structure. Reliability and agreement between manual and automatic segmentations, volumes, and NPV/TFLs were assessed., Results: For treatment scans, the Dice similarity coefficients (DSC) between the manually and automatically obtained segmentations were 0.90 (uterus), 0.84 (NPV) and 0.74 (fibroid). Intraclass correlation coefficients (ICC) were 1.00 [0.99, 1.00] (uterus), 0.99 [0.98, 1.00] (NPV) and 0.98 [0.95, 0.99] (fibroid) between manually and automatically derived volumes. For manually and automatically derived NPV/TFLs, the mean difference was 5% [-41%, 51%] (ICC: 0.66 [0.32, 0.85])., Conclusion: The algorithm presented in this study automatically calculates uterus volume, fibroid load, and NPVs, which could lead to more objective outcome quantification after MR-HIFU treatments of uterine fibroids in comparison to visual inspection. When robustness has been ascertained in a future study, this tool may eventually be employed in clinical practice to automatically measure the NPV/TFL after MR-HIFU procedures of uterine fibroids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract: Invasive open surgery used to be compulsory to access tumor mass to perform excision or resection. Development of minimally invasive laparoscopic procedures followed, as well as catheter-based approaches, such as stenting, endovascular surgery, chemoembolization, brachytherapy, which minimize side effects and reduce the risks to patients. Completely noninvasive procedures bring further benefits in terms of reducing risk, procedure time, recovery time, potential of infection, or other side effects. Focusing ultrasound waves from the outside of the body specifically at the disease site has proven to be a safe noninvasive approach to localized ablative hyperthermia, mechanical ablation, and targeted drug delivery. Focused ultrasound as a medical intervention was proposed decades ago, but it only became feasible to plan, guide, monitor, and control the treatment procedures with advanced radiological imaging capabilities. The purpose of this review is to describe the imaging capabilities and approaches to perform these tasks, with the emphasis on magnetic resonance imaging and ultrasound. Some procedures already are in clinical practice, with more at the clinical trial stage. Imaging is fully integrated in the workflow and includes the following: (1) planning, with definition of the target regions and adjacent organs at risk; (2) real-time treatment monitoring via thermometry imaging, cavitation feedback, and motion control, to assure targeting and safety to adjacent normal tissues; and (3) evaluation of treatment efficacy, via assessment of ablation and physiological parameters, such as blood supply. This review also focuses on sonosensitive microparticles and nanoparticles, such as microbubbles injected in the bloodstream. They enable ultrasound energy deposition down to the microvascular level, induce vascular inflammation and shutdown, accelerate clot dissolution, and perform targeted drug delivery interventions, including focal gene delivery. Especially exciting is the ability to perform noninvasive drug delivery via opening of the blood-brain barrier at the desired areas within the brain. Overall, focused ultrasound under image guidance is rapidly developing, to become a choice noninvasive interventional radiology tool to treat disease and cure patients., Competing Interests: Conflicts of interest and sources of funding: A.L.K. was supported in part via NIH R01 EB023055, a research grant for his UVA Laboratory from Virginia Catalyst Program, via SoundPipe Therapeutics (Charlottesville, VA), and a grant from Focused Ultrasound Foundation via FUS/Immunotherapy Center at UVA., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: A method for periprocedural contrast agent-free visualization of uterine fibroid perfusion could potentially shorten magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) treatment times and improve outcomes. Our goal was to test feasibility of perfusion fraction mapping by intravoxel incoherent motion (IVIM) modeling using diffusion-weighted MRI as method for visual evaluation of MR-HIFU treatment progression., Methods: Conventional and T2-corrected IVIM-derived perfusion fraction maps were retrospectively calculated by applying two fitting methods to diffusion-weighted MRI data ( b  = 0, 50, 100, 200, 400, 600 and 800 s/mm 2 at 1.5 T) from forty-four premenopausal women who underwent MR-HIFU ablation treatment of uterine fibroids. Contrast in perfusion fraction maps between areas with low perfusion fraction and surrounding tissue in the target uterine fibroid immediately following MR-HIFU treatment was evaluated. Additionally, the Dice similarity coefficient (DSC) was calculated between delineated areas with low IVIM-derived perfusion fraction and hypoperfusion based on CE-T1w., Results: Average perfusion fraction ranged between 0.068 and 0.083 in areas with low perfusion fraction based on visual assessment, and between 0.256 and 0.335 in surrounding tissues (all p  < 0.001). DSCs ranged from 0.714 to 0.734 between areas with low perfusion fraction and the CE-T1w derived non-perfused areas, with excellent intraobserver reliability of the delineated areas (ICC 0.97)., Conclusion: The MR-HIFU treatment effect in uterine fibroids can be visualized using IVIM perfusion fraction mapping, in moderate concordance with contrast enhanced MRI. IVIM perfusion fraction mapping has therefore the potential to serve as a contrast agent-free imaging method to visualize the MR-HIFU treatment progression in uterine fibroids.

To investigate the feasibility and tolerability of ultrasound and microbubbles (USMB)-enhanced chemotherapy delivery for head and neck cancer, we performed a veterinary trial in feline companion animals with oral squamous cell carcinomas. Six cats were treated with a combination of bleomycin and USMB therapy three times, using the Pulse Wave Doppler mode on a clinical ultrasound system and EMA/FDA approved microbubbles. They were evaluated for adverse events, quality of life, tumour response and survival. Furthermore, tumour perfusion was monitored before and after USMB therapy using contrast-enhanced ultrasound (CEUS). USMB treatments were feasible and well tolerated. Among 5 cats treated with optimized US settings, 3 had stable disease at first, but showed disease progression 5 or 11 weeks after first treatment. One cat had progressive disease one week after the first treatment session, maintaining a stable disease thereafter. Eventually, all cats except one showed progressive disease, but each survived longer than the median overall survival time of 44 days reported in literature. CEUS performed immediately before and after USMB therapy suggested an increase in tumour perfusion based on an increase in median area under the curve (AUC) in 6 out of 12 evaluated treatment sessions. In this small hypothesis-generating study, USMB plus chemotherapy was feasible and well-tolerated in a feline companion animal model and showed potential for enhancing tumour perfusion in order to increase drug delivery. This could be a forward step toward clinical translation of USMB therapy to human patients with a clinical need for locally enhanced treatment.

Objectives: Visualization of the bone distribution is an important prerequisite for MRI-guided high-intensity focused ultrasound (MRI-HIFU) treatment planning of bone metastases. In this context, we evaluated MRI-based synthetic CT (sCT) imaging for the visualization of cortical bone., Methods: MR and CT images of nine patients with pelvic and femoral metastases were retrospectively analyzed in this study. The metastatic lesions were osteolytic, osteoblastic or mixed. sCT were generated from pre-treatment or treatment MR images using a UNet-like neural network. sCT was qualitatively and quantitatively compared to CT in the bone (pelvis or femur) containing the metastasis and in a region of interest placed on the metastasis itself, through mean absolute difference (MAD), mean difference (MD), Dice similarity coefficient (DSC), and root mean square surface distance (RMSD)., Results: The dataset consisted of 3 osteolytic, 4 osteoblastic and 2 mixed metastases. For most patients, the general morphology of the bone was well represented in the sCT images and osteolytic, osteoblastic and mixed lesions could be discriminated. Despite an average timespan between MR and CT acquisitions of 61 days, in bone, the average (± standard deviation) MAD was 116 ± 26 HU, MD - 14 ± 66 HU, DSC 0.85 ± 0.05, and RMSD 2.05 ± 0.48 mm and, in the lesion, MAD was 132 ± 62 HU, MD - 31 ± 106 HU, DSC 0.75 ± 0.2, and RMSD 2.73 ± 2.28 mm., Conclusions: Synthetic CT images adequately depicted the cancellous and cortical bone distribution in the different lesion types, which shows its potential for MRI-HIFU treatment planning., Key Points: • Synthetic computed tomography was able to depict bone distribution in metastatic lesions. • Synthetic computed tomography images intrinsically aligned with treatment MR images may have the potential to facilitate MR-HIFU treatment planning of bone metastases, by combining visualization of soft tissues and cancellous and cortical bone., (© 2022. The Author(s).)

Background: Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly heterogeneous in different tumor types and patients, we propose ultrasound-directed enzyme-prodrug therapy (UDEPT) as a means to increase enzyme access and availability for prodrug activation locally. Methods: We synthesized β-glucuronidase-sensitive self-immolative doxorubicin prodrugs with different spacer lengths between the active drug moiety and the capping group. We evaluated drug conversion, uptake and cytotoxicity in the presence and absence of the activating enzyme β-glucuronidase. To trigger the cell release of β-glucuronidase, we used high-intensity focused ultrasound to aid in the conversion of the prodrugs into their active counterparts. Results: More efficient enzymatic activation was observed for self-immolative prodrugs with more than one aromatic unit in the spacer. In the absence of β-glucuronidase, the prodrugs showed significantly reduced cellular uptake and cytotoxicity compared to the parent drug. High-intensity focused ultrasound-induced mechanical destruction of cancer cells resulted in release of intact β-glucuronidase, which activated the prodrugs, restored their cytotoxicity and induced immunogenic cell death. Conclusion: These findings shed new light on prodrug design and activation, and they contribute to novel UDEPT-based mechanochemical combination therapies for the treatment of cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: To demonstrate that interleaved MR thermometry can monitor temperature in water and fat with adequate temporal resolution. This is relevant for high intensity focused uUltrasounds (HIFU) treatment of bone lesions, which are often found near aqueous tissues, as muscle, or embedded in adipose tissues, as subcutaneous fat and bone marrow., Methods: Proton resonance frequency shift (PRFS)-based thermometry scans and T 1 -based 2D variable flip angle (2D-VFA) thermometry scans were acquired alternatingly over time. Temperature in water was monitored using PRFS thermometry, and in fat by 2D-VFA thermometry with slice profile effect correction. The feasibility of interleaved water/fat temperature monitoring was studied ex vivo in porcine bone during MR-HIFU sonication. Precision and stability of measurements in vivo were evaluated in a healthy volunteer under non-heating conditions., Results: The method allowed observing temperature change over time in muscle and fat, including bone marrow, during MR-HIFU sonication, with a temporal resolution of 6.1 s. In vivo, the apparent temperature change was stable on the time scale of the experiment: In 7 min the systematic drift was <0.042°C/min in muscle (PRFS after drift correction) and <0.096°C/min in bone marrow (2D-VFA). The SD of the temperature change averaged over time was 0.98°C (PRFS) and 2.7°C (2D-VFA)., Conclusions: Interleaved MR thermometry allows temperature measurements in water and fat with a temporal resolution high enough for monitoring HIFU ablation. Specifically, combined fat and water thermometry provides uninterrupted information on temperature changes in tissue close to the bone cortex., (© The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Chemotherapy efficacy is often reduced by insufficient drug uptake in tumor cells. The combination of ultrasound and microbubbles (USMB) has been shown to improve drug delivery and to enhance the efficacy of several drugs in vitro and in vivo , through effects collectively known as sonopermeation. However, clinical translation of USMB therapy is hampered by the large variety of (non-clinical) US set-ups and US parameters that are used in these studies, which are not easily translated to clinical practice. In order to facilitate clinical translation, the aim of this study was to prove that USMB therapy using a clinical ultrasound system (Philips iU22) in combination with clinically approved microbubbles (SonoVue) leads to efficient in vitro sonopermeation. To this end, we measured the efficacy of USMB therapy for different US probes (S5-1, C5-1 and C9-4) and US parameters in FaDu cells. The US probe with the lowest central frequency (i.e. 1.6 MHz for S5-1) showed the highest USMB-induced intracellular uptake of the fluorescent dye SYTOX™ Green (SG). These SG uptake levels were comparable to or even higher than those obtained with a custom-built US system with optimized US parameters. Moreover, USMB therapy with both the clinical and the custom-built US system increased the cytotoxicity of the hydrophilic drug bleomycin. Our results demonstrate that a clinical US system can be used to perform USMB therapy as efficiently as a single-element transducer set-up with optimized US parameters. Therefore, future trials could be based on these clinical US systems, including validated US parameters, in order to accelerate successful translation of USMB therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Maar, Rousou, van Elburg, Vos, Lajoinie, Bos, Moonen and Deckers.)

Purpose: To perform dynamic T 1 mapping using a 2D variable flip angle (VFA) method, a correction for the slice profile effect is needed. In this work we investigated the impact of flip angle selection and excitation RF pulse profile on the performance of slice profile correction when applied to T 1 mapping over a range of T 1 values., Methods: A correction of the slice profile effect is proposed, based on Bloch simulation of steady-state signals. With this correction, Monte Carlo simulations were performed to assess the accuracy and precision of 2D VFA T 1 mapping in the presence of noise, for RF pulses with time-bandwidth products of 2, 3 and 10 and with flip angle pairs in the range [1°-90°]. To evaluate its performance over a wide range of T 1 , maximum errors were calculated for six T 1 values between 50 ms and 1250 ms. The method was demonstrated using in vitro and in vivo experiments., Results: Without corrections, 2D VFA severely underestimates T 1 . Slice profile errors were effectively reduced with the correction based on simulations, both in vitro and in vivo. The precision and accuracy of the method depend on the nominal T 1 values, the FA pair, and the RF pulse shape. FA pairs leading to <5% errors in T 1 can be identified for the common RF shapes, for T 1 values between 50 ms and 1250 ms., Conclusions: 2D VFA T 1 mapping with Bloch-simulation-based correction can deliver T 1 estimates that are accurate and precise to within 5% over a wide T 1 range., (© 2021 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: Cancer induced bone pain (CIBP) strongly interferes with patient's quality of life. Currently, the standard of care includes external beam radiotherapy (EBRT), resulting in pain relief in approximately 60% of patients. Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU) is a promising treatment modality for CIBP., Methods: A single arm, R-IDEAL stage I/IIa study was conducted. Patients presenting at the department of radiation oncology with symptomatic bone metastases in the appendicular skeleton, as well as in the sacrum and sternum were eligible for inclusion. All participants underwent EBRT, followed by MR-HIFU within 4 days. Safety and feasibility were assessed, and pain scores were monitored for 4 weeks after completing the combined treatment., Results: Six patients were enrolled. Median age was 67 years, median lesion diameter was 56,5 mm. In all patients it was logistically possible to plan and perform the MR-HIFU treatment within 4 days after EBRT. All patients tolerated the combined procedure well. Pain response was reported by 5 out of 6 patients at 7 days after completion of the combined treatment, and stabilized on 60% at 4 weeks follow up. No treatment related serious adverse events occurred., Conclusion: This is the first study to combine EBRT with MR-HIFU. Our results show that combined EBRT and MR-HIFU in first-line treatment of CIBP is safe and feasible, and is well tolerated by patients. Superiority over standard EBRT, in terms of (time to) pain relief and quality of life need to be evaluated in comparative (randomized) study., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors declare receiving a Horizon 2020 Grant for the conduct of the submitted research. Dr. Verkooijen reports grants from Elekta, outside the submitted work., (© 2021 The Author(s).)

Real-time MR-imaging has been clinically adapted for monitoring thermal therapies since it can provide on-the-fly temperature maps simultaneously with anatomical information. However, proton resonance frequency based thermometry of moving targets remains challenging since temperature artifacts are induced by the respiratory as well as physiological motion. If left uncorrected, these artifacts lead to severe errors in temperature estimates and impair therapy guidance. In this study, we evaluated deep learning for on-line correction of motion related errors in abdominal MR-thermometry. For this, a convolutional neural network (CNN) was designed to learn the apparent temperature perturbation from images acquired during a preparative learning stage prior to hyperthermia. The input of the designed CNN is the most recent magnitude image and no surrogate of motion is needed. During the subsequent hyperthermia procedure, the recent magnitude image is used as an input for the CNN-model in order to generate an on-line correction for the current temperature map. The method's artifact suppression performance was evaluated on 12 free breathing volunteers and was found robust and artifact-free in all examined cases. Furthermore, thermometric precision and accuracy was assessed for in vivo ablation using high intensity focused ultrasound. All calculations involved at the different stages of the proposed workflow were designed to be compatible with the clinical time constraints of a therapeutic procedure., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: In breast cancer, local tumour control is thought to be optimised by administering higher local levels of cytotoxic chemotherapy, in particular doxorubicin. However, systemic administration of higher dosages of doxorubicin is hampered by its toxic side effects. In this study, we aim to increase doxorubicin deposition in the primary breast tumour without changing systemic doxorubicin concentration and thus without interfering with systemic efficacy and toxicity. This is to be achieved by combining Lyso-Thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox, Celsion Corporation, Lawrenceville, NJ, USA) with mild local hyperthermia, induced by Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU). When heated above 39.5°C, LTLD releases a high concentration of doxorubicin intravascularly within seconds. In the absence of hyperthermia, LTLD leads to a similar biodistribution and antitumour efficacy compared with conventional doxorubicin., Methods and Analysis: This is a single-arm phase I study in 12 chemotherapy-naïve patients with de novo stage IV HER2-negative breast cancer. Previous endocrine treatment is allowed. Study treatment consists of up to six cycles of LTLD at 21-day intervals, administered during MR-HIFU-induced hyperthermia to the primary tumour. We will aim for 60 min of hyperthermia at 40°C-42°C using a dedicated MR-HIFU breast system (Profound Medical, Mississauga, Canada). Afterwards, intravenous cyclophosphamide will be administered. Primary endpoints are safety, tolerability and feasibility. The secondary endpoint is efficacy, assessed by radiological response.This approach could lead to optimal loco-regional control with less extensive or even no surgery, in de novo stage IV patients and in stage II/III patients allocated to receive neoadjuvant chemotherapy., Ethics and Dissemination: This study has obtained ethical approval by the Medical Research Ethics Committee Utrecht (Protocol NL67422.041.18, METC number 18-702). Informed consent will be obtained from all patients before study participation. Results will be published in an academic peer-reviewed journal., Trial Registration Numbers: NCT03749850, EudraCT 2015-005582-23., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although the biological characteristics of uterine fibroids (UF) have implications for therapy choice and effectiveness, there is limited MRI data about these characteristics. Currently, the Funaki classification and Scaled Signal Intensity (SSI) are used to predict treatment outcome but both screening-tools appear to be suboptimal. Therefore, multiparametric and quantitative MRI was studied to evaluate various biological characteristics of UF., Methods: 87 patients with UF underwent an MRI-examination. Differences between UF tissues and myometrium were investigated using T2-mapping, Apparent Diffusion Coefficient (ADC) maps with different b-value combinations, contrast-enhanced T1-weighted and T2-weighted imaging. Additionally, the Funaki classification and SSI were calculated., Results: Significant differences between myometrium and UF tissue in T2-mapping (p = 0.001), long-TE ADC low b-values (p = 0.002), ADC all b-values (p < 0.001) and high b-values (p < 0.001) were found. Significant differences between Funaki type 3 versus type 1 and 2 were observed in SSI (p < 0.001) and T2-values (p < 0.001). Significant correlations were found between SSI and T2-mapping (p < 0.001; ρ s  = 0.82), ADC all b-values (p = 0.004; ρ s  = 0.31), ADC high b-values (p < 0.001; ρ s  = 0.44) and long-TE ADC low b-values (p = 0.004; ρ s  = 0.31)., Conclusions: Quantitative MR-data allowed us to distinguish UF tissue from myometrium and to discriminate different UF tissue types and may, therefore, be a useful tool to predict treatment outcome/determine optimal treatment modality.

Objectives: The clinical applicability of magnetic resonance image-guided high-intensity focused ultrasound (MR-HIFU) treatment of uterine fibroids is often limited due to inaccessible fibroids or bowel interference. The aim of this study was to implement a newly developed 3-step modified manipulation protocol and to evaluate its influence on the number of eligible women and treatment failure rate., Methods: From June 2016 to June 2018, 165 women underwent a screening MRI examination, 67 women of whom were consecutively treated with MR-HIFU at our institution. Group 1 (n = 20) was treated with the BRB manipulation protocol which consisted of sequential applications of urinary bladder filling, rectal filling, and urinary bladder emptying. Group 2 (n = 47) was treated using the 3-step modified manipulation protocol which included (1) the BRB maneuver with adjusted rectal filling by adding psyllium fibers to the solution; (2) Trendelenburg position combined with bowel massage; (3) the manual uterine manipulation (MUM) method for uterine repositioning. A comparison was made between the two manipulation protocols to evaluate differences in safety, the eligibility percentage, and treatment failure rate due to unsuccessful manipulation., Results: After implementing the 3-step modified manipulation protocol, our ineligibility rate due to bowel interference or inaccessible fibroids decreased from 18% (16/88) to 0% (0/77). Our treatment failure rate due to unsuccessful manipulation decreased from 20% (4/20) to 2% (1/47). There were no thermal complications to the bowel or uterus., Conclusions: Implementation of the 3-step modified manipulation protocol during MR-HIFU therapy of uterine fibroids improved the eligibility percentage and reduced the treatment failure rate., Trial Registration: Registry number NL56182.075.16 KEY POINTS: • A newly developed 3-step modified manipulation protocol was successfully implemented without the occurrence of thermal complication to the bowel or uterus. • The 3-step modified manipulation protocol increased our eligibility percentage for MR-HIFU treatment of uterine fibroids. • The 3-step modified manipulation protocol reduced our treatment failure rate for MR-HIFU treatment of uterine fibroids.

The poor pharmacokinetics and selectivity of low-molecular-weight anticancer drugs contribute to the relatively low effectiveness of chemotherapy treatments. To improve the pharmacokinetics and selectivity of these treatments, the combination of a doxorubicin-glucuronide prodrug (DOX-propGA3) nanogel formulation and the liberation of endogenous β-glucuronidase from cells exposed to high-intensity focused ultrasound (HIFU) were investigated in vitro. First, a DOX-propGA3-polymer was synthesized. Subsequently, DOX-propGA3-nanogels were formed from this polymer dissolved in water using inverse mini-emulsion photopolymerization. In the presence of bovine β-glucuronidase, the DOX-propGA3 in the nanogels was quantitatively converted into the chemotherapeutic drug doxorubicin. Exposure of cells to HIFU efficiently induced liberation of endogenous β-glucuronidase, which in turn converted the prodrug released from the DOX-propGA3-nanogels into doxorubicin. β-glucuronidase liberated from cells exposed to HIFU increased the cytotoxicity of DOX-propGA3-nanogels to a similar extend as bovine β-glucuronidase, whereas in the absence of either bovine β-glucuronidase or β-glucuronidase liberated from cells exposed to HIFU, the DOX-propGA3-nanogels hardly showed cytotoxicity. Overall, DOX-propGA3-nanogels systems might help to further improve the outcome of HIFU-related anticancer therapy.

Objectives: Since 2004, uterine fibroids have been treated with MR-HIFU, but there are persevering doubts on long-term efficacy to date. In the Focused Ultrasound Myoma Outcome Study (FUMOS), we evaluated long-term outcomes after MR-HIFU therapy, primarily to assess the reintervention rate., Methods: Data was retrospectively collected from 123 patients treated with MR-HIFU at our hospital from 2010 to 2017. Follow-up duration and baseline (MRI) characteristics were retrieved from medical records. Treatment failures, adverse events, and the nonperfused volume percentage (NPV%) were determined. Patients received a questionnaire about reinterventions, recovery time, satisfaction, and pregnancy outcomes. Restrictive treatment protocols were compared with unrestrictive (aiming for complete ablation) treatments. Subgroups were analyzed based on the achieved NPV < 50 or ≥ 50%., Results: Treatment failures occurred in 12.1% and the number of adverse events was 13.7%. Implementation of an unrestrictive treatment protocol significantly (p = 0.006) increased the mean NPV% from 37.4% [24.3-53.0] to 57.4% [33.5-76.5]. At 63.5 ± 29.0 months follow-up, the overall reintervention rate was 33.3% (n = 87). All reinterventions were performed within 34 months follow-up, but within 21 months in the unrestrictive group. The reintervention rate significantly (p = 0.002) decreased from 48.8% in the restrictive group (n = 43; follow-up 87.5 ± 7.3 months) to 18.2% in the unrestrictive group (n = 44; follow-up 40.0 ± 22.1 months). The median recovery time was 2.0 [1.0-7.0] days. Treatment satisfaction rate was 72.4% and 4/11 women completed family planning after MR-HIFU., Conclusions: The unrestrictive treatment protocol significantly increased the NPV%. Unrestrictive MR-HIFU treatments led to acceptable reintervention rates comparable to other reimbursed uterine-sparing treatments, and no reinterventions were reported beyond 21 months follow-up., Key Points: • All reinterventions were performed within 34 months follow-up, but in the unrestrictive treatment protocol group, no reinterventions were reported beyond 21 months follow-up. • The NPV% was negatively associated with the risk of reintervention; thus, operators should aim for complete ablation during MR-guided HIFU therapy of uterine fibroids. • Unrestrictive treatments have led to acceptable reintervention rates after MR-guided HIFU therapy compared to other reimbursed uterine-sparing treatments.

Purpose: To demonstrate that proton resonance frequency shift MR thermometry (PRFS-MRT) acquisition with nonselective free induction decay (FID), combined with coil sensitivity profiles, allows spatially resolved B 0 drift-corrected thermometry., Methods: Phantom experiments were performed at 1.5T and 3T. Acquisition of PRFS-MRT and FID were performed during MR-guided high-intensity focused ultrasound heating. The phase of the FIDs was used to estimate the change in angular frequency δω drift per coil element. Two correction methods were investigated: (1) using the average δω drift over all coil elements (0th-order) and (2) using coil sensitivity profiles for spatially resolved correction. Optical probes were used for independent temperature verification. In-vivo feasibility of the methods was evaluated in the leg of 1 healthy volunteer at 1.5T., Results: In 30 minutes, B 0 drift led to an apparent temperature change of up to -18°C and -98°C at 1.5T and 3T, respectively. In the sonicated area, both corrections had a median error of 0.19°C at 1.5T and -0.54°C at 3T. At 1.5T, the measured median error with respect to the optical probe was -1.28°C with the 0th-order correction and improved to 0.43°C with the spatially resolved correction. In vivo, without correction the spatiotemporal median of the apparent temperature was at -4.3°C and interquartile range (IQR) of 9.31°C. The 0th-order correction had a median of 0.75°C and IQR of 0.96°C. The spatially resolved method had the lowest median at 0.33°C and IQR of 0.80°C., Conclusion: FID phase information from individual receive coil elements allows spatially resolved B 0 drift correction in PRFS-based MRT., (© 2019 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Reevaluation of the effectiveness of Magnetic Resonance-High Intensity Focused Ultrasound (MR-HIFU) therapy for uterine fibroids by excluding studies with restrictive treatment protocols that are no longer used., Methods: The National Guideline Clearinghouse, Cochrane Library, TRIP, MEDLINE, EMBASE and WHO International Clinical Trials Registry Platform (ICTRP) databases were searched from inception until the 22nd of June 2018. Keywords included "MR-HIFU", "MRgFUS", and "Leiomyoma". Only studies about MR-HIFU treatment of uterine fibroids with at least three months of clinical follow-up were evaluated for inclusion. Treatments with ultrasound-guided HIFU devices or protocols not aiming for complete ablation were eliminated. The primary outcome was the improvement in fibroid-related symptoms. Technical outcomes included screening and treatment failures, treatment time, application of bowel-interference mitigation strategies and the Non-Perfused Volume (NPV) percentage. Other secondary outcomes were the quality of life, fibroid shrinkage, safety, re-interventions, reproductive outcomes, and costs. Meta-analysis was performed using a random-effects model (DerSimonian and Laird)., Results: A total of 18 articles (1323 treated patients) met the inclusion criteria. All selected studies were case series except for one cross-over trial. Overall, the quality of the evidence was poor to moderate. The mean NPV% directly post-treatment was 68.1%. The use of bowel-interference mitigation strategies may lead to increased NPV%. The mean symptom reduction at 12-months was 59.9% and fibroid shrinkage was 37.7%. The number of adverse events was low (8.7%), stratification showed a difference between HIFU systems. The re-intervention percentage at 3-33.6 months follow-up ranged from 0 to 21%. Longer follow-up was associated with a higher risk at re-interventions. Reproductive outcomes and costs couldn't be analyzed., Conclusions: Treatment guidelines aiming for complete ablation enhanced the effectiveness of MR-HIFU therapy. However, controlled trials should define the role of MR-HIFU in the management of uterine fibroids., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: The PLANET method was designed to simultaneously reconstruct maps of T 1 and T 2 , the off-resonance, the RF phase, and the banding free signal magnitude. The method requires a stationary B 0 field over the course of a phase-cycled balanced SSFP acquisition. In this work we investigated the influence of B 0 drift on the performance of the PLANET method for single-component and two-component signal models, and we propose a strategy for drift correction., Methods: The complex phase-cycled balanced SSFP signal was modeled with and without frequency drift. The behavior of the signal influenced by drift was mathematically interpreted as a sum of drift-dependent displacement of the data points along an ellipse and drift-dependent rotation around the origin. The influence of drift on parameter estimates was investigated experimentally on a phantom and on the brain of healthy volunteers and was verified by numerical simulations. A drift correction algorithm was proposed and tested on a phantom and in vivo., Results: Drift can be assumed to be linear over the typical duration of a PLANET acquisition. In a phantom (a single-component signal model), drift induced errors of 4% and 8% in the estimated T 1 and T 2 values. In the brain, where multiple components are present, drift only had a minor effect. For both single-component and two-component signal models, drift-induced errors were successfully corrected by applying the proposed drift correction algorithm., Conclusion: We have demonstrated theoretically and experimentally the sensitivity of the PLANET method to B 0 drift and have proposed a drift correction method., (© 2019 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Tumor drug distribution and concentration are important factors for effective tumor treatment. A promising method to enhance the distribution and the concentration of the drug in the tumor is to encapsulate the drug in a temperature sensitive liposome. The aim of this study was to investigate the tumor drug distribution after treatment with various injected doses of different liposomal formulations of doxorubicin, ThermoDox (temperature sensitive liposomes) and DOXIL (non-temperature sensitive liposomes), and free doxorubicin at macroscopic and microscopic levels. Only ThermoDox treatment was combined with hyperthermia. Experiments were performed in mice bearing a human fibrosarcoma. At low and intermediate doses, the largest growth delay was obtained with ThermoDox, and at the largest dose, the largest growth delay was obtained with DOXIL. On histology, tumor areas with increased doxorubicin concentration correlated with decreased cell proliferation, and substantial variations in doxorubicin heterogeneity were observed. ThermoDox treatment resulted in higher tissue drug levels than DOXIL and free doxorubicin for the same dose. A relation with the distance to the vasculature was shown, but vessel perfusion was not always sufficient to determine doxorubicin delivery. Our results indicate that tumor drug distribution is an important factor for effective tumor treatment and that its dependence on delivery formulation merits further systemic investigation.

In this work, we present a new method for visualization of fiducial markers (FMs) in the prostate for MRI-only radiotherapy with a positive contrast directly at the MR console. The method is based on high bandwidth phase-cycled balanced steady-state free precession (bSSFP) sequence, which is available on many clinical scanners, does not require any additional post-processing or software, and has a higher signal-to-noise (SNR) compared to conventional gradient-echo (GE) imaging. Complex phase-cycled bSSFP data is acquired with different RF phase increment settings such that the manifestation of the artifacts around FMs in the acquired complex images is different for each dynamic acquisition and depends on the RF phase increment used. First, we performed numerical simulations to investigate the complex-valued phase-cycled bSSFP signal in the presence of a gold FM, and to investigate the relation of the true physical location of the FM with the geometrical manifestation of the artifacts. Next, to validate the simulations, we performed phantoms and in vivo studies and compared the experimentally obtained artifacts with those predicted in simulations. The accuracy of the method was assessed by comparing the distances between the FM's centers and the center of mass of FMs system measured using phase-cycled bSSFP MR images and using reference CT (or MRI-only) images. The results show accurate (within 1 mm) matching of FMs localization between CT and MR images on five patients, proving the feasibility of in vivo FMs detection on MR images only. The FMs show a positive contrast with respect to the prostate background on real/imaginary phase-cycled bSSFP images, which was confirmed by simulations. The proposed method facilitates robust FMs visualization with positive contrast directly at the MR console, allowing RT technicians to obtain immediate feedback on the anticipated feasibility of accurate FMs localization while the patient is being scanned.

Purpose: For free-breathing renal perfusion imaging using arterial spin labeling (ASL), retrospective image realignment has been found essential to reduce subtraction artifacts and, independently, background suppression has been demonstrated to reduce physiologic noise. However, negative results on ASL precision and accuracy have been reported for the combination of both. In this study, the effect of background suppression -level in combination with image registration on free-breathing renal ASL signal quality, with registration either on ASL-images themselves or guided by additionally acquired fat-images, was investigated. The results from free-breathing acquisitions were compared with the reference paced-breathing motion compensation strategy., Methods: Pseudocontinuous ASL (pCASL) data with additional fat-images were acquired from 10 subjects at 1.5T with varying background suppression levels during free-breathing and paced-breathing. Images were registered using the ASL-images themselves (ASLReg) or using their corresponding fat-images (FatReg). Temporal signal-to-noise ratio (tSNR) served to evaluate precision and perfusion weighted signal (PWS) to assess accuracy., Results: In combination with image registration, background suppression significantly improved tSNR by 50% (P < .05). For heavy suppression, ASLReg and FatReg showed similar performance in terms of tSNR and PWS. Background suppression with two inversion pulses induced a small, nonsignificant (P > .05) PWS reduction, but increased PWS accuracy. When applying heavy background suppression, free-breathing acquisitions resulted in similar ASL-quality to paced-breathing acquisitions., Conclusion: Background suppression was found beneficial for free-breathing renal pCASL precision without compromising accuracy, despite motion challenges. In combination with ASLReg or FatReg, background suppression enabled clinically viable free-breathing renal pCASL., (© 2019 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Hypoxia is a characteristic feature of solid tumors and an important cause of resistance to radiotherapy. Hypoxic cell radiosensitizers have been shown to increase radiotherapy efficacy, but dose-limiting side effects prevent their widespread use in the clinic. We propose the encapsulation of hypoxic cell radiosensitizers in temperature-sensitive liposomes (TSL) to target the radiosensitizers specifically to tumors and to avoid unwanted accumulation in healthy tissues. The main objective of the present study is to develop and characterize TSL loaded with the radiosensitizer pimonidazole (PMZ) and to evaluate the in vitro efficacy of free PMZ and PMZ encapsulated in TSL in combination with hyperthermia and radiotherapy. PMZ was actively loaded into TSL at different drug/lipid ratios, and the physicochemical characteristics and the stability of the resulting TSL-PMZ were evaluated. PMZ release was determined at 37 °C and 42 °C in HEPES buffer saline and fetal bovine serum. The concentration-dependent radiosensitizing effect of PMZ was investigated by exposing FaDu cells to different PMZ concentrations under hypoxic conditions followed by exposure to ionizing irradiation. The efficacy of TSL-PMZ in combination with hyperthermia and radiotherapy was determined in vitro, assessing cell survival and DNA damage by means of the clonogenic assay and histone H2AX phosphorylation, respectively. All TSL-PMZ formulations showed high encapsulation efficiencies and were stable for 30 d upon storage at 4 °C and 20 °C. Fast PMZ release was observed at 42 °C, regardless of the drug/lipid ratio. Increasing the PMZ concentration significantly enhanced the effect of ionizing irradiation. Pre-heated TSL-PMZ in combination with radiotherapy caused a 14.3-fold increase in cell death as compared to radiotherapy treatment alone. In conclusion, our results indicate that TSL-PMZ in combination with hyperthermia can assist in improving the efficacy of radiotherapy under hypoxic conditions.

Hybrid MR-linac systems enable intrafraction motion monitoring during radiation therapy. Since time-resolved 3D MRI is still challenging, various motion models have been developed that rely on time-resolved 2D imaging. Continuous validation of these models is important for accurate dose accumulation mapping. In this study we used 2D simultaneous multislice (SMS) imaging to improve the PCA-based motion modeling method developed previously (Stemkens et al 2016 Phys. Med. Biol. 61 5335-55). From the additional simultaneously acquired slices, several independent motion models could be generated, which allowed for an assessment of the sensitivity of the motion model to the location of the time-resolved 2D slices. Additionally, the best model could be chosen at every time-point, increasing the method's robustness. Imaging experiments were performed in six healthy volunteers using three simultaneous slices, which generated three independent models per volunteer. For each model the motion traces of the liver tip and both kidneys were estimated. We found that the location of the 2D slices influenced the model's error in five volunteers significantly with a p -value  <0.05, and that selecting the best model at every time-point can improve the method. This allows for more accurate and robust motion characterization in MR-guided radiotherapy.

The visualisation of the celiac plexus using respiratory- and cardiac-triggered three-dimensional (3D) sheath inked rapid acquisition with refocused echoes imaging (SHINKEI) was evaluated. After ethical approval and written informed consent, eight volunteers (age 27 ± 5 years, mean ± standard deviation) were scanned at 1.5 and 3 T. Displacement of the celiac ganglia due to aortic pulsatility was studied on axial single-slice breath-hold balanced turbo field-echo cine sequences in five volunteers and found to be 3.0 ± 0.5 mm (left) and 3.1 ± 0.4 mm (right). Respiratory- and cardiac-triggered 3D SHINKEI images were compared to respiratory- and cardiac-triggered fat-suppressed 3D T2-weighted turbo spin-echo and respiratory-triggered 3D SHINKEI in all volunteers. Visibility of the celiac ganglia was rated by three radiologists as visible or non-visible. On 3D SHINKEI with double-triggering at 1.5 T, the left and right ganglia were seen by all observers in 7/8 and 8/8 volunteers, respectively. At 3 T, this was the case for 6/8 and 7/8 volunteers, respectively. The nerve-to-muscle signal ratio increased from 1.9 ± 0.5 on fat-suppressed 3D T2-weighted turbo spin-echo to 4.7 ± 0.8 with 3D SHINKEI. Anatomical validation was performed in a human cadaver. An expert in anatomy confirmed that the hyperintense structure visible on ex vivo 3D SHINKEI scans was the celiac plexus. In conclusion, double-triggering allowed visualisation of the celiac plexus using 3D SHINKEI at both 1.5 T and 3 T.

Purpose: In this work we demonstrate how sequence parameter settings influence the accuracy and precision in T 1 , T 2 , and off-resonance maps obtained with the PLANET method for a single-component signal model. In addition, the performance of the method for the particular case of a two-component relaxation model for white matter tissue was assessed., Methods: Numerical simulations were performed to investigate the influence of sequence parameter settings on the accuracy and precision in the estimated parameters for a single-component model, as well as for a two-component white matter model. Phantom and in vivo experiments were performed for validation. In addition, the effects of Gibbs ringing were investigated., Results: By making a proper choice for sequence parameter settings, accurate and precise parameter estimation can be achieved for a single-component signal model over a wide range of relaxation times at realistic SNR levels. Due to the presence of a second myelin-related signal component in white matter, an underestimation of approximately 30% in T 1 and T 2 was observed, predicted by simulations and confirmed by measurements. Gibbs ringing artifacts correction improved the precision and accuracy of the parameter estimates., Conclusion: For a single-component signal model there is a broad "sweet spot" of sequence parameter combinations for which a high accuracy and precision in the parameter estimates is achieved over a wide range of relaxation times. For a multicomponent signal model, the single-component PLANET reconstruction results in systematic errors in the parameter estimates as expected., (© 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Introduction: To increase the efficacy of chemoradiation and decrease its toxicity in normal tissue, a new concept is proposed, local radiosensitizer delivery, which combines triggered release of a radiosensitizer from thermosensitive liposomes with local hyperthermia and radiotherapy. Here, key aspects of this concept were investigated in vitro I) the effect of hyperthermia on the enhancement of radiotherapy by ThermoDox (thermosensitive liposome containing doxorubicin), II) the concentration dependence of the radiosensitizing effect of doxorubicin and III) the sequence of doxorubicin, hyperthermia and radiotherapy maximizing the radiosensitizing effect., Methods: Survival of HT1080 (human fibrosarcoma) cells was measured after exposure to ThermoDox or doxorubicin for 60 minutes, at 37 or 43°C, with or without irradiation. Furthermore, cell survival was measured for cells exposed to different doxorubicin concentrations and radiation doses. Finally, cell survival was measured after applying doxorubicin and/or hyperthermia before or after irradiation. Cell survival was measured by clonogenic assay. In addition, DNA damage was assessed by γH2AX staining., Results: Exposure of cells to doxorubicin at 37°C resulted in cell death, but exposure to ThermoDox at 37°C did not. In contrast, ThermoDox and doxorubicin at 43°C resulted in similar cytotoxicity, and in combination with irradiation caused a similar enhancement of cell kill due to radiation. Doxorubicin enhanced the radiation effect in a small, but significant, concentration-dependent manner. Hyperthermia showed the strongest enhancement of radiation effect when applied after irradiation. In contrast, doxorubicin enhanced radiation effect only when applied before irradiation. Concurrent doxorubicin and hyperthermia immediately before or after irradiation showed equal enhancement of radiation effect., Conclusion: In vitro, ThermoDox resulted in cytotoxicity and enhancement of irradiation effect only in combination with hyperthermia. Therefore hyperthermia-triggered radiosensitizer release from thermosensitive liposomes may ultimately serve to limit toxicities due to the radiosensitizer in unheated normal tissue and result in enhanced efficacy in the heated tumor., Competing Interests: The authors have declared that no competing interests exist

Hybrid MR-linac systems can use fast dynamic MR sequences for tumor tracking and adapt the radiation treatment in real-time. For this the imaging latency must be as short as possible. This work describes how different acquisition parameters influence this latency. First, the latency was measured for Cartesian readouts with phase encode orderings linear, reverse-linear, and high-low. Second, the latency was measured for radial readouts with linear and golden angle profile orderings. To reduce the latency, a spatio-temporal (k-t) filter that suppresses the k-space center of earlier acquired spokes was implemented for the golden angle sequence. For Cartesian readouts a high-low ordering achieved a three times lower latency compared to a linear ordering with our sampling parameters. For radial readouts the filter was able to reduce the acquisition latency from half the acquisition time to a quarter of the acquisition time. The filter did not compromise the signal-to-noise ratio and the artifact power.

Medical imaging is currently employed in the diagnosis, planning, delivery and response monitoring of cancer treatments. Due to physiological motion and/or treatment response, the shape and location of the pathology and organs-at-risk may change over time. Establishing their location within the acquired images is therefore paramount for an accurate treatment delivery and monitoring. A feasible solution for tracking anatomical changes during an image-guided cancer treatment is provided by image registration algorithms. Such methods are, however, often built upon elements originating from the computer vision/graphics domain. Since the original design of such elements did not take into consideration the material properties of particular biological tissues, the anatomical plausibility of the estimated deformations may not be guaranteed. In the current work we adapt two existing variational registration algorithms, namely Horn-Schunck and EVolution, to online soft tissue tracking. This is achieved by enforcing an incompressibility constraint on the estimated deformations during the registration process. The existing and the modified registration methods were comparatively tested against several quality assurance criteria on abdominal in vivo MR and CT data. These criteria included: the Dice similarity coefficient (DSC), the Jaccard index, the target registration error (TRE) and three additional criteria evaluating the anatomical plausibility of the estimated deformations. Results demonstrated that both the original and the modified registration methods have similar registration capabilities in high-contrast areas, with DSC and Jaccard index values predominantly in the 0.8-0.9 range and an average TRE of 1.6-2.0 mm. In contrast-devoid regions of the liver and kidneys, however, the three additional quality assurance criteria have indicated a considerable improvement of the anatomical plausibility of the deformations estimated by the incompressibility-constrained methods. Moreover, the proposed registration models maintain the potential of the original methods for online image-based guidance of cancer treatments.

Purpose: To demonstrate that fluid filling of the digestive tract improves the performance of respiratory motion-compensated proton resonance frequency shift (PRFS)-based magnetic resonance (MR) thermometry in the pancreas., Materials and Methods: In seven volunteers (without heating), we evaluated PRFS thermometry in the pancreas with and without filling of the surrounding digestive tract. All data acquisition was performed at 1.5T, then all datasets were analyzed and compared with three different PRFS respiratory motion-compensated thermometry methods: gating, multibaseline, and referenceless. The temperature precision of the different methods was evaluated by assessing temperature standard deviation over time, while a simulation experiment was used to study the accuracy of the methods., Results: Without fluid intake, errors in temperature precision in the pancreas up to 10°C were observed for all evaluated methods. After liquid intake, temperature precision improved to median values between 1.8 and 2.9°C. The simulations showed that gating had the lowest accuracy, with errors up to 7°C. Multibaseline and referenceless thermometry performed better, with a median error in the pancreas between -3 and +3°C after fluid intake, for all volunteers., Conclusion: Preparation of the digestive tract near the pancreas by filling it with fluid improved MR thermometry precision and accuracy for all common respiratory motion-compensated methods evaluated. These improvements are attributed to reducing field inhomogeneity in the pancreas., Level of Evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:692-701., (© 2017 International Society for Magnetic Resonance in Medicine.)

Purpose: To demonstrate the feasibility of a novel, ellipse fitting approach, named PLANET, for simultaneous estimation of relaxation times T 1 and T 2 from a single 3D phase-cycled balanced steady-state free precession (bSSFP) sequence., Methods: A method is presented in which the elliptical signal model is used to describe the phase-cycled bSSFP steady-state signal. The fitting of the model to the acquired data is reformulated into a linear convex problem, which is solved directly by a linear least squares method, specific to ellipses. Subsequently, the relaxation times T 1 and T 2 , the banding free magnitude, and the off-resonance are calculated from the fitting results., Results: Maps of T 1 and T 2 , as well as an off-resonance and a banding free magnitude can be simultaneously, quickly, and robustly estimated from a single 3D phase-cycled bSSFP sequence. The feasibility of the method was demonstrated in a phantom and in the brain of healthy volunteers on a clinical MR scanner. The results were in good agreement for the phantom, but a systematic underestimation of T 1 was observed in the brain., Conclusion: The presented method allows for accurate mapping of relaxation times and off-resonance, and for the reconstruction of banding free magnitude images at realistic signal-to-noise ratios. Magn Reson Med 79:711-722, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., (© 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Image-guided external beam radiotherapy (EBRT) allows radiation dose deposition with a high degree of accuracy and precision. Guidance is usually achieved by estimating the displacements, via image registration, between cone beam computed tomography (CBCT) and computed tomography (CT) images acquired at different stages of the therapy. The resulting displacements are then used to reposition the patient such that the location of the tumor at the time of treatment matches its position during planning. Moreover, ongoing research aims to use CBCT-CT image registration for online plan adaptation. However, CBCT images are usually acquired using a small number of x-ray projections and/or low beam intensities. This often leads to the images being subject to low contrast, low signal-to-noise ratio and artifacts, which ends-up hampering the image registration process. Previous studies addressed this by integrating additional image processing steps into the registration procedure. However, these steps are usually designed for particular image acquisition schemes, therefore limiting their use on a case-by-case basis. In the current study we address CT to CBCT and CBCT to CBCT registration by the means of the recently proposed EVolution registration algorithm. Contrary to previous approaches, EVolution does not require the integration of additional image processing steps in the registration scheme. Moreover, the algorithm requires a low number of input parameters, is easily parallelizable and provides an elastic deformation on a point-by-point basis. Results have shown that relative to a pure CT-based registration, the intrinsic artifacts present in typical CBCT images only have a sub-millimeter impact on the accuracy and precision of the estimated deformation. In addition, the algorithm has low computational requirements, which are compatible with online image-based guidance of EBRT treatments.

Background: During lengthy magnetic resonance-guided high intensity focused ultrasound (MRg-HIFU) thermal ablations in abdominal organs, the therapeutic work-flow is frequently hampered by various types of physiological motion occurring at different time-scales. If left un-addressed this can lead to an incomplete therapy and/or to tissue damage of organs-at-risk. While previous studies focus on correction schemes for displacements occurring at a particular time-scale within the work-flow of an MRg-HIFU therapy, in the current work we propose a motion correction strategy encompassing the entire work-flow., Methods: The proposed motion compensation framework consists of several linked components, each being adapted to motion occurring at a particular time-scale. While respiration was addressed through a fast correction scheme, long term organ drifts were compensated using a strategy operating on time-scales of several minutes. The framework relies on a periodic examination of the treated area via MR scans which are then registered to a reference scan acquired at the beginning of the therapy. The resulting displacements were used for both on-the-fly re-optimization of the interventional plan and to ensure the spatial fidelity between the different steps of the therapeutic work-flow. The approach was validated in three complementary studies: an experiment conducted on a phantom undergoing a known motion pattern, a study performed on the abdomen of 10 healthy volunteers and during 3 in-vivo MRg-HIFU ablations on porcine liver., Results: Results have shown that, during lengthy MRg-HIFU thermal therapies, the human liver and kidney can manifest displacements that exceed acceptable therapeutic margins. Also, it was demonstrated that the proposed framework is capable of providing motion estimates with sub-voxel precision and accuracy. Finally, the 3 successful animal studies demonstrate the compatibility of the proposed approach with the work-flow of an MRg-HIFU intervention under clinical conditions., Conclusions: In the current study we proposed an image-based motion compensation framework dedicated to MRg-HIFU thermal ablations in the abdomen, providing the possibility to re-optimize the therapy plan on-the-fly with the patient on the interventional table. Moreover, we have demonstrated that even under clinical conditions, the proposed approach is fully capable of continuously ensuring the spatial fidelity between the different phases of the therapeutic work-flow.

Biological motion is a problem for non- or mini-invasive interventions when conducted in mobile/deformable organs due to the targeted pathology moving/deforming with the organ. This may lead to high miss rates and/or incomplete treatment of the pathology. Therefore, real-time tracking of the target anatomy during the intervention would be beneficial for such applications. Since the aforementioned interventions are often conducted under B-mode ultrasound (US) guidance, target tracking can be achieved via image registration, by comparing the acquired US images to a separate image established as positional reference. However, such US images are intrinsically altered by speckle noise, introducing incoherent gray-level intensity variations. This may prove problematic for existing intensity-based registration methods. In the current study we address US-based target tracking by employing the recently proposed EVolution registration algorithm. The method is, by construction, robust to transient gray-level intensities. Instead of directly matching image intensities, EVolution aligns similar contrast patterns in the images. Moreover, the displacement is computed by evaluating a matching criterion for image sub-regions rather than on a point-by-point basis, which typically provides more robust motion estimates. However, unlike similar previously published approaches, which assume rigid displacements in the image sub-regions, the EVolution algorithm integrates the matching criterion in a global functional, allowing the estimation of an elastic dense deformation. The approach was validated for soft tissue tracking under free-breathing conditions on the abdomen of seven healthy volunteers. Contact echography was performed on all volunteers, while three of the volunteers also underwent standoff echography. Each of the two modalities is predominantly specific to a particular type of non- or mini-invasive clinical intervention. The method demonstrated on average an accuracy of  ∼1.5 mm and submillimeter precision. This, together with a computational performance of 20 images per second make the proposed method an attractive solution for real-time target tracking during US-guided clinical interventions.

Purpose: The combination of ultrasound and microbubbles can facilitate cellular uptake of (model) drugs via transient permeabilization of the cell membrane. By using fluorescent molecules, this process can be studied conveniently with confocal fluorescence microscopy. This study aimed to investigate the relation between cellular uptake and fluorescence intensity increase of intercalating model drugs., Procedures: SYTOX Green, an intercalating fluorescent dye that displays >500-fold fluorescence enhancement upon binding to nucleic acids, was used as a model drug for ultrasound-induced cellular uptake. SYTOX Green uptake was monitored in high spatiotemporal resolution to qualitatively assess the relation between uptake and fluorescence intensity in individual cells. In addition, the kinetics of fluorescence enhancement were studied as a function of experimental parameters, in particular, laser duty cycle (DC), SYTOX Green concentration and cell line., Results: Ultrasound-induced intracellular SYTOX Green uptake resulted in local fluorescence enhancement, spreading throughout the cell and ultimately accumulating in the nucleus during the 9-min acquisition. The temporal evolution of SYTOX Green fluorescence was substantially influenced by laser duty cycle: continuous laser (100 % DC) induced a 6.4-fold higher photobleaching compared to pulsed laser (3.3 % DC), thus overestimating the fluorescence kinetics. A positive correlation of fluorescence kinetics and SYTOX Green concentration was found, increasing from 0.6 × 10 -3 to 2.2 × 10 -3  s -1 for 1 and 20 μM, respectively. Finally, C6 cells displayed a 2.4-fold higher fluorescence rate constant than FaDu cells., Conclusions: These data show that the temporal behavior of intracellular SYTOX Green fluorescence enhancement depends substantially on nuclear accumulation and not just on cellular uptake. In addition, it is strongly influenced by the experimental conditions, such as the laser duty cycle, SYTOX Green concentration, and cell line.

The performance of nanomedicine formulations depends on the Enhanced Permeability and Retention (EPR) effect. Prototypic nanomedicine-based drug delivery systems, such as liposomes, polymers and micelles, aim to exploit the EPR effect to accumulate at pathological sites, to thereby improve the balance between drug efficacy and toxicity. Thus far, however, tumor-targeted nanomedicines have not yet managed to achieve convincing therapeutic results, at least not in large cohorts of patients. This is likely mostly due to high inter- and intra-patient heterogeneity in EPR. Besides developing (imaging) biomarkers to monitor and predict EPR, another strategy to address this heterogeneity is the establishment of vessel modulation strategies to homogenize and improve EPR. Over the years, several pharmacological and physical co-treatments have been evaluated to improve EPR-mediated tumor targeting. These include pharmacological strategies, such as vessel permeabilization, normalization, disruption and promotion, as well as physical EPR enhancement via hyperthermia, radiotherapy, sonoporation and phototherapy. In the present manuscript, we summarize exemplary studies showing that pharmacological and physical vessel modulation strategies can be used to improve tumor-targeted drug delivery, and we discuss how these advanced combination regimens can be optimally employed to enhance the (pre-) clinical performance of tumor-targeted nanomedicines., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) ablation is in development for minimally invasive treatment of breast cancer. Cost-effectiveness has not been assessed yet. An early health technology assessment was performed to estimate costs of MR-HIFU ablation, compared to breast conserving treatment (BCT)., Methods: An MR-HIFU treatment model using the dedicated MR-HIFU breast system (Sonalleve, Philips Healthcare) was developed. Input parameters (treatment steps and duration) were based on the analysis of questionnaire data from an expert panel. MR-HIFU experts assessed face validity of the model. Data collected by questionnaires were compared to published data of an MR-HIFU breast feasibility study. Treatment costs for tumours of 1 to 3 cm were calculated., Results: The model structure was considered of acceptable face validity by consulted experts, and questionnaire data and published data were comparable. Costs of MR-HIFU ablation were higher than BCT costs. MR-HIFU best-case scenario costs exceeded BCT costs with approximately €1000. Cooling times and breathing correction contributed most to treatment costs., Conclusions: MR-HIFU ablation is currently not a cost-effective alternative for BCT. MR-HIFU experience is limited, increasing uncertainty of estimations. The potential for cost-effectiveness increases if future research reduces treatment durations and might substantiate equal or improved results.

The incidence of small renal masses (SRMs) sized  <4 cm has increased over the decades (as co-findings/or due to introduction of cross sectional imaging). Currently, partial nephrectomy (PN) or watchful waiting is advised in these patients. Ultimately, 80-90% of these SRMs require surgical treatment and PN is associated with a 15% complication rate. In this aging population, with possible comorbidities and poor health condition, both PN and watchful waiting are non-ideal treatment options. This resulted in an increased need for early, non-invasive treatment strategies such as MR-guided high intensity focused ultrasound (MR-HIFU). (i) To investigate the feasibility of creating a confluent lesion in the kidney using respiratory-gated MR-HIFU under clinical conditions in a pre-clinical study and (ii) to evaluate the reproducibility of the MR-HIFU ablation strategy. Healthy pigs (n  =  10) under general anesthesia were positioned on a clinical MR-HIFU system with integrated cooling. A honeycomb pattern of seven overlapping ablation cells (4  ×  4  ×  10 mm 3 , 450 W, <30 s) was ablated successively in the cortex of the porcine kidney. Both MR thermometry and acoustic energy delivery were respiratory gated using a pencil beam navigator on the contralateral kidney. The non-perfused volume (NPV) was visualized after the last sonication by contrast-enhanced (CE) T 1 -weighted MR (T 1 w) imaging. Cell viability staining was performed to visualize the extent of necrosis., Results: a median NPV of 0.62 ml was observed on CE-T 1 w images (IQR 0.58-1.57 ml, range 0.33-2.75 ml). Cell viability staining showed a median damaged volume of 0.59 ml (IQR 0.24-1.35 ml, range 0-4.1 ml). Overlooking of the false rib, shivering of the pig, and too large depth combined with a large heat-sink effect resulted in insufficient heating in 4 cases. The NPV and necrosed volume were confluent in all cases in which an ablated volume could be observed. Our results demonstrated the feasibility of creating a confluent volume of ablated kidney cortical tissue in vivo with MR-HIFU on a clinically available system using respiratory gating and near-field cooling and showed its reproducibility.

The purpose of this study was to evaluate a novel phased array transducer design rule for therapeutic focused ultrasound applications. This design rule uses the discretized Fermat's spiral to determine the positioning of the transducer elements for a given number of elements and f-number. Using this principle, three variations of Fermat's spiral were generated, aimed at (1) grating lobe minimization, (2) side lobe minimization, and (3) an optimized element packing efficiency. For each spiral, sparse layouts using identical circular elements and fully populated layouts based on additional Voronoi tessellation were evaluated numerically. Evaluation criteria included the element size distribution, beam steering capabilities, focal plane pressure distribution, prefocal pressure distribution, and practical considerations. Finally, one Voronoi-tessellated design with a focal length and aperture diameter of 16 cm and a natural frequency of 1.3 MHz was evaluated experimentally through hydrophone measurements. The numerical evaluation showed that while sparse arrays possess superior beam steering capabilities for a given number of elements, the focal point quality and prefocal pressure distribution is substantially more favorable when using the Voronoi-tessellated designs. Beam steering was shown to be feasible with the tessellated designs for lateral deflections up to 10 mm and axial deflections up to 20 mm. The experimental evaluation showed that such a transducer is capable of inducing 40.00 MPa rarefactional and 237.50 MPa compressional peak pressure levels at 800 W instantaneous acoustic output power under free-field conditions, making the system potentially relevant for thermal ablation therapy, histotripsy applications, and shockwave-enhanced heating.

Ultrasound allows the deposition of thermal and mechanical energies deep inside the human body in a non-invasive way. Ultrasound can be focused within a region with a diameter of about 1mm. The bio-effects of ultrasound can lead to local tissue heating, cavitation, and radiation force, which can be used for 1) local drug release from nanocarriers circulating in the blood, 2) increased extravasation of drugs and/or carriers, and 3) enhanced diffusivity of drugs. When using nanocarriers sensitive to mechanical forces (the oscillating ultrasound pressure waves) and/or sensitive to temperature, the content of the nanocarriers can be released locally. Thermo-sensitive liposomes have been suggested for local drug release in combination with local hyperthermia more than 25 years ago. Microbubbles may be designed specifically to enhance cavitation effects. Real-time imaging methods, such as magnetic resonance, optical and ultrasound imaging have led to novel insights and methods for ultrasound triggered drug delivery. Image guidance of ultrasound can be used for: 1) target identification and characterization; 2) spatio-temporal guidance of actions to release or activate the drugs and/or permeabilize membranes; 3) evaluation of bio-distribution, pharmacokinetics and pharmacodynamics; and 4) physiological read-outs to evaluate the therapeutic efficacy., (Copyright © 2010 Elsevier B.V. All rights reserved.)