Intravoxel incoherent motion (IVIM)-derived perfusion fraction mapping for the visual evaluation of MR-guided high intensity focused ultrasound (MR-HIFU) ablation of uterine fibroids.

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/mm2 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.

Workflow for automatic renal perfusion quantification using ASL-MRI and machine learning.

PURPOSE: Clinical applicability of renal arterial spin labeling (ASL) MRI is hampered because of time consuming and observer dependent post-processing, including manual segmentation of the cortex to obtain cortical renal blood flow (RBF). Machine learning has proven its value in medical image segmentation, including the kidneys. This study presents a fully automatic workflow for renal cortex perfusion quantification by including machine learning-based segmentation. METHODS: Fully automatic workflow was achieved by construction of a cascade of 3 U-nets to replace manual segmentation in ASL quantification. All 1.5T ASL-MRI data, including M0 , T1 , and ASL label-control images, from 10 healthy volunteers was used for training (dataset 1). Trained cascade performance was validated on 4 additional volunteers (dataset 2). Manual segmentations were generated by 2 observers, yielding reference and second observer segmentations. To validate the intended use of the automatic segmentations, manual and automatic RBF values in mL/min/100 g were compared. RESULTS: Good agreement was found between automatic and manual segmentations on dataset 1 (dice score = 0.78 ± 0.04), which was in line with inter-observer variability (dice score = 0.77 ± 0.02). Good agreement was confirmed on dataset 2 (dice score = 0.75 ± 0.03). Moreover, similar cortical RBF was obtained with automatic or manual segmentations, on average and at subject level; with 211 ± 31 mL/min/100 g and 208 ± 31 mL/min/100 g (P < .05), respectively, with narrow limits of agreement at -11 and 4.6 mL/min/100 g. RBF accuracy with automated segmentations was confirmed on dataset 2. CONCLUSION: Our proposed method automates ASL quantification without compromising RBF accuracy. With quick processing and without observer dependence, renal ASL-MRI is more attractive for clinical application as well as for longitudinal and multi-center studies.

Synthetic CT for the planning of MR-HIFU treatment of bone metastases in pelvic and femoral bones: a feasibility study.

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.

Interleaved water and fat MR thermometry for monitoring high intensity focused ultrasound ablation of bone lesions.

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 T1 -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.

Exploring label dynamics of velocity-selective arterial spin labeling in the kidney.

PURPOSE: Velocity-selective arterial spin labeling (VSASL) has been proposed for renal perfusion imaging to mitigate planning challenges and effects of arterial transit time (ATT) uncertainties. In VSASL, label generation may shift in the vascular tree as a function of cutoff velocity. Here, we investigate label dynamics and especially the ATT of renal VSASL and compared it with a spatially selective pulsed arterial spin labeling technique, flow alternating inversion recovery (FAIR). METHODS: Arterial spin labeling data were acquired in 7 subjects, using free-breathing dual VSASL and FAIR with five postlabeling delays: 400, 800, 1200, 2000, and 2600 ms. The VSASL measurements were acquired with cutoff velocities of 5, 10, and 15 cm/s, with anterior-posterior velocity-encoding direction. Cortical perfusion-weighted signal, temporal SNR, quantified renal blood flow, and arterial transit time were reported. RESULTS: In contrast to FAIR, renal VSASL already showed fairly high signal at the earliest postlabeling delays, for all cutoff velocities. The highest VSASL signal and temporal SNR was obtained with a cutoff velocity of 10 cm/s at postlabeling delay = 800 ms, which was earlier than for FAIR at 1200 ms. Fitted ATT on VSASL was ≤ 0 ms, indicating ATT insensitivity, which was shorter than for FAIR (189 ± 79 ms, P < .05). Finally, the average cortical renal blood flow measured with cutoff velocities of 5 cm/s (398 ± 84 mL/min/100 g) and 10 cm/s (472 ± 160 mL/min/100 g) were similar to renal blood flow measured with FAIR (441 ± 84 mL/min/100 g) (P > .05) with good correlations on subject level. CONCLUSION: Velocity-selective arterial spin labeling in the kidney reduces ATT sensitivity compared with the recommended pulsed arterial spin labeling method, as well as if cutoff velocity is increased to reduce spurious labeling due to motion. Thus, VSASL has potential as a method for time-efficient, single-time-point, free-breathing renal perfusion measurements, despite lower tSNR than FAIR.

Rapid 2D variable flip angle method for accurate and precise T1 measurements over a wide range of T1 values.

PURPOSE: To perform dynamic T1 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 T1 mapping over a range of T1 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 T1 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 T1 , maximum errors were calculated for six T1 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 T1 . 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 T1 values, the FA pair, and the RF pulse shape. FA pairs leading to <5% errors in T1 can be identified for the common RF shapes, for T1 values between 50 ms and 1250 ms. CONCLUSIONS: 2D VFA T1 mapping with Bloch-simulation-based correction can deliver T1 estimates that are accurate and precise to within 5% over a wide T1 range.

Field drift correction of proton resonance frequency shift temperature mapping with multichannel fast alternating nonselective free induction decay readouts.

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 B0 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 δωdrift per coil element. Two correction methods were investigated: (1) using the average δωdrift 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, B0 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 B0 drift correction in PRFS-based MRT.

Influence of labeling parameters and respiratory motion on velocity-selective arterial spin labeling for renal perfusion imaging.

PURPOSE: Arterial transit time uncertainties and challenges during planning are potential issues for renal perfusion measurement using spatially selective arterial spin labeling techniques. To mitigate these potential issues, a spatially non-selective technique, such as velocity-selective arterial spin labeling (VSASL), could be an alternative. This article explores the influence of VSASL sequence parameters and respiratory induced motion on VS-label generation. METHODS: VSASL data were acquired in human subjects (n = 15), with both single and dual labeling, during paced-breathing, while essential sequence parameters were systematically varied; (1) cutoff velocity, (2) labeling gradient orientation and (3) post-labeling delay (PLD). Pseudo-continuous ASL was acquired as a spatially selective reference. In an additional free-breathing single VSASL experiment (n = 9) we investigated respiratory motion influence on VS-labeling. Absolute renal blood flow (RBF), perfusion weighted signal (PWS), and temporal signal-to-noise ratio (tSNR) were determined. RESULTS: (1) With decreasing cutoff velocity, tSNR and PWS increased. However, undesired tissue labeling occurred at low cutoff velocities (≤ 5.4 cm/s). (2) Labeling gradient orientation had little effect on tSNR and PWS. (3) For single VSASL high signal appeared in the kidney pedicle at PLD < 800 ms, and tSNR and PWS decreased with increasing PLD. For dual VSASL, maximum tSNR occurred at PLD = 1200 ms. Average cortical RBF measured with dual VSASL (264 ± 34 mL/min/100 g) at a cutoff velocity of 5.4 cm/s, and feet-head labeling was slightly lower than with pseudo-continuous ASL (283 ± 55 mL/min/100 g). CONCLUSION: With well-chosen sequence parameters, tissue labeling induced by respiratory motion can be minimized, allowing to obtain good quality RBF maps using planning-free labeling with dual VSASL.

Development and clinical evaluation of a 3-step modified manipulation protocol for MRI-guided high-intensity focused ultrasound of uterine fibroids.

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 Focused Ultrasound Myoma Outcome Study (FUMOS); a retrospective cohort study on long-term outcomes of MR-HIFU 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.

Use of multiparametric MRI to characterize uterine fibroid tissue types.

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; ρs = 0.82), ADC all b-values (p = 0.004; ρs = 0.31), ADC high b-values (p < 0.001; ρs = 0.44) and long-TE ADC low b-values (p = 0.004; ρs = 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.

Potential Use of Extracellular Vesicles Generated by Microbubble-Assisted Ultrasound as Drug Nanocarriers for Cancer Treatment.

Extracellular vesicles (EVs)-carrying biomolecules derived from parental cells have achieved substantial scientific interest for their potential use as drug nanocarriers. Ultrasound (US) in combination with microbubbles (MB) have been shown to trigger the release of EVs from cancer cells. In the current study, the use of microbubbles-assisted ultrasound (USMB) to generate EVs containing drug cargo was investigated. The model drug, CellTracker™ green fluorescent dye (CTG) or bovine serum albumin conjugated with fluorescein isothiocyanate (BSA FITC) was loaded into primary human endothelial cells in vitro using USMB. We found that USMB loaded CTG and BSA FITC into human endothelial cells (HUVECs) and triggered the release of EVs containing these compounds in the cell supernatant within 2 h after treatment. The amount of EV released seemed to be correlated with the increase of US acoustic pressure. Co-culturing these EVs resulted in uptake by the recipient tumour cells within 4 h. In conclusion, USMB was able to load the model drugs into endothelial cells and simultaneously trigger the release of EVs-carrying model drugs, highlighting the potential of EVs as drug nanocarriers for future drug delivery in cancer.

Investigation of the influence of B0 drift on the performance of the PLANET method and an algorithm for drift correction.

PURPOSE: The PLANET method was designed to simultaneously reconstruct maps of T1 and T2 , the off-resonance, the RF phase, and the banding free signal magnitude. The method requires a stationary B0 field over the course of a phase-cycled balanced SSFP acquisition. In this work we investigated the influence of B0 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 T1 and T2 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 B0 drift and have proposed a drift correction method.

On the accuracy and precision of PLANET for multiparametric MRI using phase-cycled bSSFP imaging.

PURPOSE: In this work we demonstrate how sequence parameter settings influence the accuracy and precision in T1 , T2 , 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 T1 and T2 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.

Enabling free-breathing background suppressed renal pCASL using fat imaging and retrospective motion correction.

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.

Hyperthermia-triggered release of hypoxic cell radiosensitizers from temperature-sensitive liposomes improves radiotherapy efficacy in vitro.

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.

A planning strategy for combined motion-assisted/gated MR guided focused ultrasound treatment of the pancreas.

Objective: To develop and evaluate a combined motion-assisted/gated MRHIFU heating strategy designed to accelerate the treatment procedure by reducing the required number of sonications to ablate a target volume in the pancreas. Methods: A planning method for combined motion-assisted/gated MRHIFU using 4D-MRI and motion characterization is introduced. Six healthy volunteers underwent 4D-MRI for target motion characterization on a 3.0-T clinical scanner. Using displacement patterns, simulations were performed for all volunteers for three sonication approaches: gated, combined motion-assisted/gated, and static. The number of sonications needed to ablate the pancreas head was compared. The influence of displacement amplitude and target volume size was investigated. Spherical target volumes (8, 15, 20 and 34 mL) and displacement amplitudes ranging from 5 to 25 mm were evaluated. For this case, the number of sonications required to ablate the whole target was determined. Results: The number of required sonications was lowest for a static target, 62 on average (range 49-78). The gated approach required most sonications, 126 (range 97-159). The combined approach was almost as efficient as the hypothetical static case, with an average of 78 (range 53-123). Simulations showed that with a 5-mm displacement amplitude, the target could be treated by making use of motion-assisted MRHIFU sonications only. In that case, this approach allowed the lowest number of sonication, while for 10 mm and above, the number of required sonications increased. Conclusion: The use of a combined motion-assisted/gated MRHIFU strategy may accelerate tumor ablation in the pancreas when respiratory-induced displacement amplitudes are between 5 and 10 mm.

PLANET: An ellipse fitting approach for simultaneous T1 and T2 mapping using phase-cycled balanced steady-state free precession.

PURPOSE: To demonstrate the feasibility of a novel, ellipse fitting approach, named PLANET, for simultaneous estimation of relaxation times T1 and T2 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 T1 and T2 , the banding free magnitude, and the off-resonance are calculated from the fitting results. RESULTS: Maps of T1 and T2 , 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 T1 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.

Fluid filling of the digestive tract for improved proton resonance frequency shift-based MR thermometry in the pancreas.

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.

Microbubbles-Assisted Ultrasound Triggers the Release of Extracellular Vesicles.

Microbubbles-assisted ultrasound (USMB) has shown promise in improving local drug delivery. The formation of transient membrane pores and endocytosis are reported to be enhanced by USMB, and they contribute to cellular drug uptake. Exocytosis also seems to be linked to endocytosis upon USMB treatment. Based on this rationale, we investigated whether USMB triggers exocytosis resulting in the release of extracellular vesicles (EVs). USMB was performed on a monolayer of head-and-neck cancer cells (FaDu) with clinically approved microbubbles and commonly used ultrasound parameters. At 2, 4, and 24 h, cells and EV-containing conditioned media from USMB and control conditions (untreated cells, cells treated with microbubbles and ultrasound only) were harvested. EVs were measured using flow cytometric immuno-magnetic bead capture assay, immunogold electron microscopy, and western blotting. After USMB, levels of CD9 exposing-EVs significantly increased at 2 and 4 h, whereas levels of CD63 exposing-EVs increased at 2 h. At 24 h, EV levels were comparable to control levels. EVs released after USMB displayed a heterogeneous size distribution profile (30-1200 nm). Typical EV markers CD9, CD63, and alix were enriched in EVs released from USMB-treated FaDu cells. In conclusion, USMB treatment triggers exocytosis leading to the release of EVs from FaDu cells.