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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.

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

Highlights • Combined treatment of EBRT and MR-HIFU is feasible and well tolerated by patients. • Clinical outcomes of combined treatment of EBRT and MR-HIFU are promising. • Superiority of combined treatment over standard EBRT needs to be evaluated in a comparative study., 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.

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. 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. 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

Purpose: Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically “cold” tumors into responsive “hot” tumors. Experimental Design: We treated Results: Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances antitumor response, improving survival from 0% to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL2, IFNγ, and DAMPs, whereas immune regulators like CD4+Foxp3+, IL10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4+, CD8α+, and CD8α+CD11c+ cells, CD11c+ in regional lymph nodes, and decrease in circulating IL10 compared with untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared with tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival, P < 0.0001). This combination treatment significantly also induces CD4+CD44+hiCD62L+low and CD8α+CD44+hiCD62L+low population and is adoptively transferable, imparting immunity, slowing subsequent de novo tumor engraftment. Conclusions: Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model and promises a novel yet efficacious immunoadjuvant modality to overcome therapeutic resistance.

Background: Over the past decades, breast cancer treatment has evolved from extensive disfiguring surgery to less invasive procedures. In patients with small localized tumors breast conserving therapy (BCT) has become the standard of care. However, surgery still involves risks associated with general anesthesia and complications such as bleeding, infection and suboptimal cosmetic results. Conversely, Magnetic Resonance-guided High intensity Focused Ultrasound (MR-HIFU) ablation of breast cancer is an entirely non-invasive procedure that can be performed under procedural sedation and analgesia (PSA). With MR-HIFU, a focused ultrasound beam penetrates through soft tissues and causes localized heating (55-70°C) of a target. Magnetic resonance imaging (MRI) is used for target-identification and real-time temperature-monitoring (MR thermometry). In a previous phase I study in ten breast cancer patients, tumors were deliberately partially ablated and safety and accuracy of a dedicated MR-HIFU breast system (Profound Medical) was shown.1,2 This system’s lateral sonication approach and wide aperture reduce the risk of heating heart, lungs and skin to a minimum.3 In the current study we aim to demonstrate that complete breast tumor ablation with MR-HIFU is feasible. Trial design: Single-arm phase II study in patients with primary breast cancer. We will use a dedicated MR-HIFU breast system (Profound Medical) to ablate breast tumors before BCT or mastectomy, in a treat-and-resect protocol. We will perform MRI before MR-HIFU, during the MR HIFU session and one week after to evaluate radiologic response. Primary endpoint is efficacy, assessed by percentages of necrotic and residual viable tumor. Secondary endpoint is safety, assessed by adverse events and cosmetic changes. Descriptive statistics will be used. Eligibility criteria Non-pregnant, non-lactating women ≥18 years of age, weighing < 90 kg, who have: histologically proven invasive breast cancer, cT1-2 N0-2 Mx, subtypes invasive ductal carcinoma or invasive carcinoma ‘not otherwise specified’ / ‘no special type’ a tumor in reach of the HIFU beams, diameter ≤ 3.0 cm and distance ≥1.5 cm to skin, nipple and pectoral wall WHO-Performance Score ≤2 a body size fitting in the MR bore and the ability to lie in prone position no prior treatment with neoadjuvant chemotherapy in the past 3 months no prior radiotherapy, thermal therapy or surgery in the targeted breast no contraindications to PSA, MRI or MRI contrast agents no conditions that may interfere with MR-HIFU such as a pacemaker, scar tissue, breast prosthesis or surgical clips no extensive intraductal components, determined on biopsy Additionally, patients may be excluded when the risk of adjuvant over- or undertreatment (due to performing Bloom and Richardson grading on the tumor biopsy) is considered too high. Target accrual 10 patients (present: 0, IRB approval obtained) Conclusion In this phase II trial we aim to show the feasibility of complete tumor ablation of breast cancer with a dedicated MR-HIFU breast system. This approach could lead to a non-invasive treatment alternative for selected patients with primary breast cancer. References 1Merckel 2016, Eur Radiol; 2Deckers 2015, Phys Med Biol; 3Merckel 2013, Cardiovasc Intervent Radiol; Acknowledgements Financial support of Center for Translational Molecular Medicine and Vrienden UMC Utrecht. Profound Medical provides non-financial support. Contact information Josanne de Maar, j.s.demaar@umcutrecht.nl ClinicalTrials.gov Identifier: NCT02407613 Citation Format: Josanne Sophia de Maar, Roel Deckers, Lambertus Wilhelmus Bartels, Thijs van Dalen, Joost van Gorp, Paul J van Diest, Arjen J Witkamp, H. H.B. Vaessen, Maria NicoleGerardineJohanna Aleida Braat, Chrit Moonen. Efficacy of magnetic resonance-guided high intensity focused ultrasound for the ablation of breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-07-01.

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.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).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.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.• 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.

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.

Magnetic resonance-guided focused ultrasound (MRgFUS) is a completely non-invasive technology that has been approved by FDA to treat several diseases. This report, prepared by the American Association of Physicist in Medicine (AAPM) Task Group 241, provides background on MRgFUS technology with a focus on clinical body MRgFUS systems. The report addresses the issues of interest to the medical physics community, specific to the body MRgFUS system configuration, and provides recommendations on how to successfully implement and maintain a clinical MRgFUS program. The following sections describe the key features of typical MRgFUS systems and clinical workflow and provide key points and best practices for the medical physicist. Commonly used terms, metrics and physics are defined and sources of uncertainty that affect MRgFUS procedures are described. Finally, safety and quality assurance procedures are explained, the recommended role of the medical physicist in MRgFUS procedures is described, and regulatory requirements for planning clinical trials are detailed. Although this report is limited in scope to clinical body MRgFUS systems that are approved or currently undergoing clinical trials in the United States, much of the material presented is also applicable to systems designed for other applications.

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

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, 2D imaging could improve the temporal resolution of T 1 mapping, but T 1 values need to be corrected for the errors due to the non‐uniform slice excitation. We propose an approach for dynamic 2D T 1 mapping with a look‐up table correction, and we evaluate its performance over a wide range of T1 values.

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) 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.

Current therapy for hypervascular cancers, e.g., hepatocellular carcinoma, includes occlusion of the tumor blood supply by arterial infusion of embolic microspheres (beads) suspended in iodine-based contrast under fluoroscopic guidance. Available radiopaque, imageable beads use iodine as the radiopacifier and cannot be differentiated from contrast. This study aimed to synthesize and characterize imageable beads using bismuth as the radiopacifier that could be distinguished from iodine contrast based upon the difference in the binding energy of k-shell electrons (k-edge). Radiodense bismuth beads were successfully synthesized some with uniform bismuth distribution across the beads. The beads were spherical and could be infused through clinical microcatheters. The bismuth beads could be imaged with clinical dual-energy computed tomography (CT), where iodine-based contrast could be distinguished from the microspheres. The ability to separate iodine from bismuth may enhance the diagnostic information acquired on follow-up CT, identifying the distribution of the embolic beads separately from the contrast. Furthermore, with sequential use of iodine- and bismuth-based beads, the two radiopaque beads could be spatially distinguished on imaging, which may enable the development of dual drug delivery and dual tracking.

IntroductionIn 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 analysisThis 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 disseminationThis 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 numbersNCT03749850, EudraCT 2015-005582-23.

Simple Summary In early-stage (cT1-2N0) oral cancer, occult lymph node metastases are present in 20–30% of patients. Accordingly, accurate staging of the clinically negative cervical nodal basin is warranted in these patients. Sentinel lymph node biopsy has proven to reliably stage the clinically negative cervical nodal basin in early-stage oral cancer. However, due to the limited resolution of conventional sentinel lymph node imaging, occult lymph node metastasis may be missed in particular circumstances. Therefore, technical developments are necessary to bring the diagnostic accuracy of sentinel lymph node biopsy, in early-stage oral cancer, to a higher level. This review evaluates novel sentinel lymph node imaging techniques for early-stage oral cancer, such as MR lymphography, CT lymphography, PET lymphoscintigraphy and contrast-enhanced lymphosonography. Their reported diagnostic accuracy is described and their relative merits, disadvantages and potential applications are outlined. Abstract Sentinel lymph node biopsy (SLNB) is a diagnostic staging procedure that aims to identify the first draining lymph node(s) from the primary tumor, the sentinel lymph nodes (SLN), as their histopathological status reflects the histopathological status of the rest of the nodal basin. The routine SLNB procedure consists of peritumoral injections with a technetium-99m [99mTc]-labelled radiotracer followed by lymphoscintigraphy and SPECT-CT imaging. Based on these imaging results, the identified SLNs are marked for surgical extirpation and are subjected to histopathological assessment. The routine SLNB procedure has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC). However, an infamous limitation arises in situations where SLNs are located in close vicinity of the tracer injection site. In these cases, the hotspot of the injection site can hide adjacent SLNs and hamper the discrimination between tracer injection site and SLNs (shine-through phenomenon). Therefore, technical developments are needed to bring the diagnostic accuracy of SLNB for early-stage OSCC to a higher level. This review evaluates novel SLNB imaging techniques for early-stage OSCC: MR lymphography, CT lymphography, PET lymphoscintigraphy and contrast-enhanced lymphosonography. Furthermore, their reported diagnostic accuracy is described and their relative merits, disadvantages and potential applications are outlined.

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., 21 pages, 9 figures, 1 table

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 &beta, 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 &beta, 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 &beta, glucuronidase, which in turn converted the prodrug released from the DOX-propGA3-nanogels into doxorubicin. &beta, glucuronidase liberated from cells exposed to HIFU increased the cytotoxicity of DOX-propGA3-nanogels to a similar extend as bovine &beta, glucuronidase, whereas in the absence of either bovine &beta, glucuronidase or &beta, 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.

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&trade, 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.

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 (

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. 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. 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. 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. Registry number NL56182.075.16 • 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.

Genetic and phenotypic tumour heterogeneity is an important cause of therapy resistance. Moreover, non-uniform spatial drug distribution in cancer treatment may cause pseudo-resistance, meaning that a treatment is ineffective because the drug does not reach its target at sufficient concentrations. Together with tumour heterogeneity, non-uniform drug distribution causes "therapy heterogeneity": a spatially heterogeneous treatment effect. Spatial heterogeneity in drug distribution occurs on all scales ranging from interpatient differences to intratumour differences on tissue or cellular scale. Nanomedicine aims to improve the balance between efficacy and safety of drugs by targeting drug-loaded nanoparticles specifically to tumours. Spatial heterogeneity in nanoparticle and payload distribution could be an important factor that limits their efficacy in patients. Therefore, imaging spatial nanoparticle distribution and imaging the tumour environment giving rise to this distribution could help understand (lack of) clinical success of nanomedicine. Imaging the nanoparticle, drug and tumour environment can lead to improvements of new nanotherapies, increase understanding of underlying mechanisms of heterogeneous distribution, facilitate patient selection for nanotherapies and help assess the effect of treatments that aim to reduce heterogeneity in nanoparticle distribution. In this review, we discuss three groups of imaging modalities applied in nanomedicine research: non-invasive clinical imaging methods (nuclear imaging, MRI, CT, ultrasound), optical imaging and mass spectrometry imaging. Because each imaging modality provides information at a different scale and has its own strengths and weaknesses, choosing wisely and combining modalities will lead to a wealth of information that will help bring nanomedicine forward.

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.

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.

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.

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.

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.