Evaluation of a novel MRI-safe needle guidance toolkit for streamlined arthrography procedures.

Currently, Magnetic Resonance arthrography procedures require two rooms and two imaging modalities: fluoroscopically guided needle insertion in a fluoroscopy suite, followed by diagnostic MRI in a separate MRI suite. The use of fluoroscopy for needle placement exposes patients to ionizing radiation, which is an important concern, especially in pediatrics. The need for two different rooms and coordinating times for these rooms complicates hospital resource scheduling and logistics. In addition, the added delays could expose younger children to additional risks associated with the use of general anesthesia. To address these issues, we propose a new technique to streamline the arthrography procedure. Our proposed technology aims to eliminate exposure to ionizing radiation and to streamline arthrography procedures that are conducted solely under MRI. This toolkit consists of a 3D slicer-based user interface, a spatially unique silicone grid template, and a hand-held needle guidance device. Together, these tools are intended to simplify and shorten the procedure while maintaining accuracy and precision comparable to the current gold standard procedure. In our cadaver study, we evaluated the feasibility and accuracy of our novel MRI-safe Needle Guidance Toolkit for MRI arthrography procedures, achieving an average targeting accuracy of 3.2 ± 1.0 mm. The results presented in this study showed the feasibility and promise of our novel MRI-safe needle guidance toolkit for arthrography procedures.

In situ guidance for MRI interventions using projected feedback.

PURPOSE: To develop and evaluate an augmented reality instrument guidance system for MRI-guided needle placement procedures such as musculoskeletal biopsy and arthrography. Our system guides the physician to insert a needle toward a target while looking at the insertion site without requiring special headgear. METHODS: The system is comprised of a pair of stereo cameras, a projector, and a computational unit with a touch screen. All components are designed to be used within the MRI suite (Zone 4). Multi-modality fiducial markers called VisiMARKERs, detectable in both MRI and camera images, facilitate automatic registration after the initial scan. The navigation feedback is projected directly onto the intervention site allowing the interventionalist to keep their focus on the insertion site instead of a secondary monitor which is often not in front of them. RESULTS: We evaluated the feasibility and accuracy of this system on custom-built shoulder phantoms. Two radiologists used the system to select targets and entry points on initial MRIs of these phantoms over three sessions. They performed 80 needle insertions following the projected guidance. The system targeting error was 1.09 mm, and the overall error was 2.29 mm. CONCLUSION: We demonstrated both feasibility and accuracy of this MRI navigation system. The system operated without any problems inside the MRI suite close to the MRI bore. The two radiologists were able to easily follow the guidance and place the needle close to the target without any intermediate imaging.

Toward Robust Partial-Image Based Template Matching Techniques for MRI-Guided Interventions.

We have developed an MRI-safe needle guidance toolkit for MRI-guided interventions intended to enable accurate positioning for needle-based procedures. The toolkit allows intuitive and accurate needle angulation and entry point positioning according to an MRI-based plan, using a flexible, patterned silicone 2D grid. The toolkit automatically matches the grid on MRI planning images with a physical silicon grid placed conformally on the patient's skin and provides the Interventional Radiologist an easy-to-use guide showing the needle entry point on the silicon grid as well as needle angle information. The radiologist can use this guide along with a 2-degree-of-freedom (rotation and angulation relative to the entry point) hand-held needle guide to place the needle into the anatomy of interest. The initial application that we are considering for this toolkit is arthrography, a diagnostic procedure to evaluate the joint space condition. However, this toolkit could be used for any needle-based and percutaneous procedures such as MRI-guided biopsy and facet joint injection. For matching the images, we adopt a transformation parameter estimation technique using the phase-only correlation method in the frequency domain. We investigated the robustness of this method against rotation, displacement, and Rician noise. The algorithm was able to successfully match all the dataset images. We also investigated the accuracy of identifying the entry point from registered template images as a prerequisite for a future targeting study. Application of the template matching algorithm to locate the needle entry points within the MRI dataset resulted in an average entry point location estimation accuracy of 0.12 ±0.2 mm. This promising result motivates a more detailed assessment of this algorithm in the future including a targeting study on a silicon phantom with embedded plastic targets to investigate the end-to-end accuracy of this automatic template matching algorithm in the interventional MRI room.

Feasibility of magnetic resonance-guided high-intensity focused ultrasound treatment targeting distinct nodular lesions in neurofibromatosis type 1.

BACKGROUND: Patients with Neurofibromatosis Type 1 (NF1) and plexiform neurofibromas (PN) often have radiographically diagnosed distinct nodular lesions (DNL) which can cause pain and weakness. Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) can precisely and accurately deliver heat to thermally ablate target tissue. The aim of this study is to evaluate whole-body MRIs from patients with NF1 and DNL, applying volumetrics and a consistent treatment planning approach to determine the feasibility of MR-HIFU ablation of DNL. METHODS: A retrospective review of whole-body MRI scans from patients with NF1 and PN from CNH and NCI was performed. DNL are defined as lesions >3 cm, distinct from PN and lacking the "central dot" feature. Criteria for MR-HIFU thermal ablation include target location 1-8 cm from skin surface; >1 cm from visible plexus, spinal canal, bladder, bowel, physis; and ability to ablate ≥50% of lesion volume. Lesions in skull and vertebral body were excluded. RESULTS: In 26 patients, 120 DNL were identified. The majority of DNL were located in an extremity (52.5%). Other sites included head/neck (7%), chest (13%), and abdomen/pelvis (28%). The predefined HIFU ablation criteria was not met for 47.5% of lesions (n = 57). The main limitation was proximity to a vital structure or organ (79%). Complete and partial HIFU ablation was feasible for 25% and 27.5% of lesions, respectively. CONCLUSION: Based on imaging review of lesion location, technical considerations and ability to target lesions, thermal ablation with MR-HIFU may be a feasible noninvasive alternative for symptom management in patients with NF1 and symptomatic DNL.

Emerging hyperthermia applications for pediatric oncology.

Local application of hyperthermia has a myriad of effects on the tumor microenvironment as well as the host's immune system. Ablative hyperthermia (typically > 55 °C) has been used both as monotherapy and adjuvant therapy, while mild hyperthermia treatment (39-45 °C) demonstrated efficacy as an adjuvant therapy through enhancement of both chemotherapy and radiation therapy. Clinical integration of hyperthermia has especially great potential in pediatric oncology, where current chemotherapy regimens have reached maximum tolerability and the young age of patients implies significant risks of late effects related to therapy. Furthermore, activation of both local and systemic immune response by hyperthermia suggests that hyperthermia treatments could be used to enhance the anticancer effects of immunotherapy. This review summarizes the state of current applications of hyperthermia in pediatric oncology and discusses the use of hyperthermia in the context of other available treatments and promising pre-clinical research.

Are Current Technical Exclusion Criteria for Clinical Trials of Magnetic Resonance-Guided High-Intensity Focused Ultrasound Too Restrictive?: Early Experiences at a Pediatric Hospital.

Certain technical criteria must be met to ensure the treatment safety of magnetic resonance-guided high-intensity focused ultrasound. We retrospectively reviewed how our enrollment criteria were applied from 2014 to 2017 in a clinical trial of magnetic resonance-guided high-intensity focused ultrasound ablation of recurrent malignant and locally aggressive benign solid tumors. Among the 36 screened patients between 2014 and 2017, more than one-third were excluded for technical exclusion criteria such as the anatomic location and proximity to prosthetics. Overall, patients were difficult to accrue for this trial, given the incidence of these tumors. To increase potential accrual, screening exclusion criteria could be more generalized and centered on the ability to achieve an acceptable treatment safety margin, rather than specifically excluding on the basis of general anatomic areas.

Ultrasound-detected venous changes associated with peripheral intravenous placement in children.

HIGHLIGHTS: Ultrasound shows several venous changes in pediatric PIV-containing veins. Changes were visualized by ultrasound in the absence of physical exam findings. Venous luminal narrowing, wall thickening, and thrombosis may explain PIV failure. BACKGROUND: Peripheral intravenous catheters (PIVs) are routinely used for venous access in hospitalized pediatric patients to administer fluids and medications and to aspirate blood. Unfortunately, PIVs do not remain functional for the entire duration of intravascular need. We hypothesized that PIV malfunction may be related to venous changes that can be visualized with ultrasound (US) imaging. The purpose of this study was to describe and document such changes in pediatric patients. METHODS: This Institutional Review Board-approved study was performed at a tertiary pediatric medical center. Patients underwent US scans of their PIV-containing veins, documenting venous characteristics such as depth, diameter, wall thickness, blood flow, valves, branch points, and presence of thrombus. Patient demographics and PIV characteristics were also recorded. RESULTS: Data from 30 patients including 12 males and 18 females with a mean age of 11 years were analyzed. Mean venous depth and diameter were 2.07 ± 0.13 and 2.02 ± 0.18 mm, respectively. Mean PIV dwell time at time of evaluation was 3.3 days. PIV-associated venous changes were seen in 73% of accessed veins and included lumen narrowing (47%), wall thickening (33%), presence of thrombus (20%), and absence of blood flow around the PIV tip (40%). CONCLUSION: PIV-associated venous changes are seen with US in the majority of pediatric patients with indwelling PIVs but are not necessarily appreciated on physical exam. These changes may help explain the high rate of pediatric PIV device failure. Given the small sample size, further investigation is needed to better characterize PIV-associated venous changes in children.

Feasibility of targeting canine soft tissue sarcoma with MR-guided high-intensity focused ultrasound.

PURPOSE: Magnetic resonance imaging-guided high-intensity-focused ultrasound (MR-HIFU) is a non-invasive treatment modality that precisely focuses ultrasound energy within a tumour and can be customised to result in a wide range of local bioeffects. The purpose of this study was to determine the feasibility of using MR-HIFU to treat soft tissue sarcoma (STS) in dogs. MATERIALS AND METHODS: Medical records of dogs admitted to the Virginia-Maryland College of Veterinary Medicine from 1 January 2012 to 31 December 2016 were searched for a diagnosis of sarcoma with available cross-sectional imaging of the tumour (MRI or CT). Fifty-three (53) dogs were eligible for inclusion. Tumor tissue (in bone as well as in soft tissue) was considered targetable unless: (1) the ultrasound path was completely obstructed by bone or gas and (2) the MR-HIFU target was within the spinal cord or less than 1 cm from the margin of the spinal cord. Tumors were categorised as <50% targetable, ≥50% targetable or non-targetable. RESULTS: Eighty-one percent of STS (81.1%, 43/53) were targetable. The head/spine tumour sites had the highest proportion of non-targetable tumours (36%, 9/25). The majority of truncal and axillary tumours were ≥50% targetable (88.9%, 16/18) ,and all extremity tumours were considered ≥50% targetable (100%, 5/5). CONCLUSIONS: The majority of STS were targetable. This is the first study to evaluate MR-HIFU targetability of canine STS. HIFU has potential as a therapeutic modality for treating STS in dogs, and this veterinary application is a possible model for treatment of naturally occurring STS in humans.

Enhanced Drug Delivery to the Skin Using Liposomes.

BACKGROUND: Enhancing drug delivery to the skin has importance in many therapeutic strategies. In particular, the outcome in vascularized composite allotransplantation mainly depends on systemic immunosuppression to prevent and treat episodes of transplant rejection. However, the side effects of systemic immunosuppression may introduce substantial risk to the patient and are weighed against the expected benefits. Successful enhancement of delivery of immunosuppressive agents to the most immunogenic tissues would allow for a reduction in systemic doses, thereby minimizing side effects. Nanoparticle-assisted transport by low temperature-sensitive liposomes (LTSLs) has shown some benefit in anticancer therapy. Our goal was to test whether delivery of a marker agent to the skin could be selectively enhanced. METHODS: In an in vivo model, LTSLs containing doxorubicin (dox) as a marker were administered intravenously to rats that were exposed locally to mild hyperthermia. Skin samples of the hyperthermia treated hind limb were compared with skin of the contralateral normothermia hind limb. Tissue content of dox was quantified both via high-performance liquid chromatography and via histology in skin and liver. RESULTS: The concentration of dox in hyperthermia-treated skin was significantly elevated over both normothermic skin and liver. (P < 0.02). CONCLUSIONS: We show here that delivery of therapeutics to the skin can be targeted and enhanced using LTSLs. Targeting drug delivery with this method may reduce the systemic toxicity seen in a systemic free-drug administration. Development of more hydrophilic immunosuppressants in the future would increase the applicability of this system in the treatment of rejection reactions in vascularized composite allotransplantation. The treatment of other skin condition might be another potential application.

Magnetic Resonance Imaging-guided High-intensity Focused Ultrasound Applications in Pediatrics: Early Experience at Children's National Medical Center.

Magnetic resonance imaging-guided high-intensity focused ultrasound (MR-HIFU) is a novel technology that integrates magnetic resonance imaging with therapeutic ultrasound. This unique approach provides a completely noninvasive method for precise thermal ablation of targeted tissues with real-time imaging feedback. Over the past 2 decades, MR-HIFU has shown clinical success in several adult applications ranging from treatment of painful bone metastases to uterine fibroids to prostate cancer and essential tremor. Although clinical experience in pediatrics is relatively small, the advantages of a completely noninvasive and radiation-free therapy are especially attractive to growing children. Unlike elderly patients, young children must deal with an entire lifetime of negative effects related to collateral tissue damage associated with invasive surgery, side effects of chemotherapy, and risk of secondary malignancy due to radiation exposure. These reasons provide a clear rationale and strong motivation to further advance clinical utility of MR-HIFU in pediatrics. We begin with an introduction to MR-HIFU technology and the clinical experience in adults. We then describe our early institutional experience in using MR-HIFU ablation to treat symptomatic benign, locally aggressive, and metastatic tumors in children and young adults. We also review some limitations and challenges encountered in treating pediatric patients and highlight additional pediatric applications which may be feasible in the near future.

Mechanical fractionation of tissues using microsecond-long HIFU pulses on a clinical MR-HIFU system.

PURPOSE: High intensity focussed ultrasound (HIFU) can non-invasively treat tumours with minimal or no damage to intervening tissues. While continuous-wave HIFU thermally ablates target tissue, the effect of hundreds of microsecond-long pulsed sonications is examined in this work. The objective of this study was to characterise sonication parameter-dependent thermomechanical bioeffects to provide the foundation for future preclinical studies and facilitate clinical translation. METHODS AND MATERIALS: Acoustic power, number of cycles/pulse, sonication time and pulse repetition frequency (PRF) were varied on a clinical magnetic resonance imaging (MRI)-guided HIFU (MR-HIFU) system. Ex vivo porcine liver, kidney and cardiac muscle tissue samples were sonicated (3 × 3 grid pattern, 1 mm spacing). Temperature, thermal dose and T2 relaxation times were quantified using MRI. Lesions were histologically analysed using H&E and vimentin stains for lesion structure and viability. RESULTS: Thermomechanical HIFU bioeffects produced distinct types of fractionated tissue lesions: solid/thermal, paste-like and vacuolated. Sonications at 20 or 60 Hz PRF generated substantial tissue damage beyond the focal region, with reduced viability on vimentin staining, whereas H&E staining indicated intact tissue. Same sonication parameters produced dissimilar lesions in different tissue types, while significant differences in temperature, thermal dose and T2 were observed between the parameter sets. CONCLUSION: Clinical MR-HIFU system was utilised to generate distinct types of lesions and to produce targeted thermomechanical bioeffects in ex vivo tissues. The results guide HIFU research on thermomechanical tissue bioeffects, inform future studies and advice sonication parameter selection for direct tumour ablation or immunomodulation using a clinical MR-HIFU system.

Drug release kinetics of temperature sensitive liposomes measured at high-temporal resolution with a millifluidic device.

PURPOSE: Current release assays have inadequate temporal resolution ( ∼ 10 s) to characterise temperature sensitive liposomes (TSL) designed for intravascular triggered drug release, where release within the first few seconds is relevant for drug delivery. MATERIALS AND METHODS: We developed a novel release assay based on a millifluidic device. A 500 µm capillary tube was heated by a temperature-controlled Peltier element. A TSL solution encapsulating a fluorescent compound was pumped through the tube, producing a fluorescence gradient along the tube due to TSL release. Release kinetics were measured by analysing fluorescence images of the tube. We measured three TSL formulations: traditional TSL (DPPC:DSPC:DSPE-PEF2000,80:15:5), MSPC-LTSL (DPPC:MSPC:DSPE-PEG2000,85:10:5) and MPPC-LTSL (DPPC:MMPC:PEF2000,86:10:4). TSL were loaded with either carboxyfluorescein (CF), Calcein, tetramethylrhodamine (TMR) or doxorubicin (Dox). TSL were diluted in one of the four buffers: phosphate buffered saline (PBS), 10% bovine serum albumin (BSA) solution, foetal bovine serum (FBS) or human plasma. Release was measured between 37-45 °C. RESULTS: The millifluidic device allowed measurement of release kinetics within the first few seconds at ∼5 ms temporal resolution. Dox had the fastest release and highest release %, followed by CF, Calcein and TMR. Of the four buffers, release was fastest in human plasma, followed by FBS, BSA and PBS. CONCLUSIONS: The millifluidic device allows measurement of TSL release at unprecedented temporal resolution, thus allowing adequate characterisation of TSL release at time scales relevant for intravascular triggered drug release. The type of buffer and encapsulated compound significantly affect release kinetics and need to be considered when designing and evaluating novel TSL-drug combinations.

Technical aspects of osteoid osteoma ablation in children using MR-guided high intensity focussed ultrasound.

BACKGROUND: Osteoid osteoma (OO) is a painful bone tumour occurring in children and young adults. Magnetic resonance imaging-guided high intensity focussed ultrasound (MR-HIFU) allows non-invasive treatment without ionising radiation exposure, in contrast to the current standard of care treatment with radiofrequency ablation (RFA). This report describes technical aspects of MR-HIFU ablation in the first 8 paediatric OO patients treated in a safety and feasibility clinical trial (total enrolment of up to 12 patients). MATERIALS AND METHODS: OO lesions and adjacent periosteum were treated with MR-HIFU ablation in 5-20 sonications (sonication duration = 16-48 s, frequency = 1.2 MHz, acoustic power = 20-160 W). Detailed treatment workflow, patient positioning and coupling strategies, as well as temperature and tissue perfusion changes were summarised and correlated. RESULTS: MR-HIFU ablation was feasible in all eight cases. Ultrasound standoff pads were shaped to conform to extremity contours providing acoustic coupling and aided patient positioning. The energy delivered was 10 ± 7 kJ per treatment, raising maximum temperature to 83 ± 3 °C. Post ablation contrast-enhanced MRI showed ablated volumes ranging 0.46-19.4 cm3 extending further into bone (7 ± 4 mm) than into soft tissue (4 ± 6 mm, p = 0.01, Mann-Whitney). Treatment time ranged 30-86 min for sonication and 160 ± 40 min for anaesthesia. No serious treatment-related adverse events were observed. Complete pain relief with no medication occurred in 7/8 patients within 28 days following treatment. CONCLUSIONS: MR-HIFU ablation of painful OO appears technically feasible in children and it may become a non-invasive and radiation-free alternative for painful OO. Therapy success, efficiency, and applicability may be improved through specialised equipment designed more specifically for extremity bone ablation.

Comparison of Noninvasive High-Intensity Focused Ultrasound with Radiofrequency Ablation of Osteoid Osteoma.

OBJECTIVE: To evaluate clinical feasibility and safety of magnetic resonance imaging-guided high-intensity focused ultrasound (MR-HIFU) treatment of symptomatic osteoid osteoma and to compare clinical response with standard of care treatment. STUDY DESIGN: Nine subjects with radiologically confirmed, symptomatic osteoid osteoma were treated with MR-HIFU in an institutional review board-approved clinical trial. Treatment feasibility and safety were assessed. Clinical response was evaluated in terms of analgesic requirement, visual analog scale pain score, and sleep quality. Anesthesia, procedure, and recovery times were recorded. This MR-HIFU group was compared with a historical control group of 9 consecutive patients treated with radiofrequency ablation. RESULTS: Nine subjects (7 male, 2 female; 16 ± 6 years) were treated with MR-HIFU without technical difficulties or any serious adverse events. There was significant decrease in their median pain scores 4 weeks within treatment (6 vs 0, P < .01). Total pain resolution and cessation of analgesics were achieved in 8 of 9 patients after 4 weeks. In the radiofrequency ablation group, 9 patients (8 male, 1 female; 10 ± 6 years) were treated in routine clinical practice. All 9 demonstrated complete pain resolution and cessation of medications by 4 weeks with a significant decrease in median pain scores (9 vs 0, P < .001). One developed a second-degree skin burn, but there were no other adverse events. Procedure times and treatment charges were comparable between the 2 groups. CONCLUSION: This pilot study shows that MR-HIFU treatment of osteoid osteoma refractory to medical therapy is feasible and can be performed safely in pediatric patients. Clinical response is comparable with standard of care treatment but without any incisions or exposure to ionizing radiation. TRIAL REGISTRATION: ClinicalTrials.govNCT02349971.

Boiling histotripsy lesion characterization on a clinical magnetic resonance imaging-guided high intensity focused ultrasound system.

PURPOSE: High intensity focused ultrasound (HIFU) is a non-invasive therapeutic technique that can thermally ablate tumors. Boiling histotripsy (BH) is a HIFU approach that can emulsify tissue in a few milliseconds. Lesion volume and temperature effects for different BH sonication parameters are currently not well characterized. In this work, lesion volume, temperature distribution, and area of lethal thermal dose were characterized for varying BH sonication parameters in tissue-mimicking phantoms (TMP) and demonstrated in ex vivo tissues. METHODS: The following BH sonication parameters were varied using a clinical MR-HIFU system (Sonalleve V2, Philips, Vantaa, Finland): acoustic power, number of cycles/pulse, total sonication time, and pulse repetition frequency (PRF). A 3×3×3 pattern was sonicated inside TMP's and ex vivo tissues. Post sonication, lesion volumes were quantified using 3D ultrasonography and temperature and thermal dose distributions were analyzed offline. Ex vivo tissues were sectioned and stained with H&E post sonication to assess tissue damage. RESULTS: Significant increase in lesion volume was observed while increasing the number of cycles/pulse and PRF. Other sonication parameters had no significant effect on lesion volume. Temperature full width at half maximum at the end of sonication increased significantly with all parameters except total sonication time. Positive correlation was also found between lethal thermal dose and lesion volume for all parameters except number of cycles/pulse. Gross pathology of ex vivo tissues post sonication displayed either completely or partially damaged tissue at the focal region. Surrounding tissues presented sharp boundaries, with little or no structural damage to adjacent critical structures such as bile duct and nerves. CONCLUSION: Our characterization of effects of HIFU sonication parameters on the resulting lesion demonstrates the ability to control lesion morphologic and thermal characteristics with a clinical MR-HIFU system in TMP's and ex vivo tissues. We demonstrate that this system can produce spatially precise lesions in both phantoms and ex vivo tissues. The results provide guidance on a preliminary set of BH sonication parameters for this system, with a potential to facilitate BH translation to the clinic.

Magnetic Resonance-Guided Drug Delivery.

The use of clinical imaging modalities for the guidance of targeted drug delivery systems, known as image-guided drug delivery (IGDD), has emerged as a promising strategy for enhancing antitumor efficacy. MR imaging is particularly well suited for IGDD applications because of its ability to acquire images and quantitative measurements with high spatiotemporal resolution. The goal of IGDD strategies is to improve treatment outcomes by facilitating planning, real-time guidance, and personalization of pharmacologic interventions. This article reviews basic principles of targeted drug delivery and highlights the current status, emerging applications, and future paradigms of MR-guided drug delivery.

A method to convert MRI images of temperature change into images of absolute temperature in solid tumours.

PURPOSE: During hyperthermia (HT), the therapeutic response of tumours varies substantially within the target temperature range (39-43 °C). Current thermometry methods are either invasive or measure only temperature change, which limits the ability to study tissue responses to HT. This study combines manganese-containing low temperature sensitive liposomes (Mn-LTSL) with proton resonance frequency shift (PRFS) thermometry to measure absolute temperature in tumours with high spatial and temporal resolution using MRI. METHODS: Liposomes were loaded with 300 mM MnSO(4). The phase transition temperature (T(m)) of Mn-LTSL samples was measured by differential scanning calorimetry (DSC). The release of manganese from Mn-LTSL in saline was characterised with inductively coupled plasma atomic emission spectroscopy. A 2T GE small animal scanner was used to acquire dynamic T1-weighted images and temperature change images of Mn-LTSL in saline phantoms and fibrosarcoma-bearing Fisher-344 rats receiving hyperthermia after Mn-LTSL injection. RESULTS: The T(m) of Mn-LTSL in rat blood was 42.9 ± 0.2 °C (DSC). For Mn-LTSL samples (0.06 mM-0.5 mM Mn(2+) in saline) heated monotonically from 30 °C to 50 °C, a peak in the rate of MRI signal enhancement occurred at 43.1° ± 0.3 °C. The same peak in signal enhancement rate was observed during heating of fibrosarcoma tumours (N = 3) after injection of Mn-LTSL, and the peak was used to convert temperature change images into absolute temperature. Accuracies of calibrated temperature measurements were in the range 0.9-1.8 °C. CONCLUSION: The release of Mn(2+) from Mn-LTSL affects the rate of MR signal enhancement which enables conversion of MRI-based temperature change images to absolute temperature.

CEM43°C thermal dose thresholds: a potential guide for magnetic resonance radiofrequency exposure levels?

OBJECTIVE: To define thresholds of safe local temperature increases for MR equipment that exposes patients to radiofrequency fields of high intensities for long duration. These MR systems induce heterogeneous energy absorption patterns inside the body and can create localised hotspots with a risk of overheating. METHODS: The MRI + EUREKA research consortium organised a "Thermal Workshop on RF Hotspots". The available literature on thresholds for thermal damage and the validity of the thermal dose (TD) model were discussed. RESULTS/CONCLUSIONS: The following global TD threshold guidelines for safe use of MR are proposed: 1. All persons: maximum local temperature of any tissue limited to 39 °C 2. Persons with compromised thermoregulation AND (a) Uncontrolled conditions: maximum local temperature limited to 39 °C (b) Controlled conditions: TD < 2 CEM43°C 3. Persons with uncompromised thermoregulation AND (a) Uncontrolled conditions: TD < 2 CEM43°C (b) Controlled conditions: TD < 9 CEM43°C The following definitions are applied: Controlled conditions A medical doctor or a dedicated trained person can respond instantly to heat-induced physiological stress Compromised thermoregulation All persons with impaired systemic or reduced local thermoregulation KEY POINTS: • Standard MRI can cause local heating by radiofrequency absorption. • Monitoring thermal dose (in units of CEM43°C) can control risk during MRI. • 9 CEM43°C seems an acceptable thermal dose threshold for most patients. • For skin, muscle, fat and bone,16 CEM43°C is likely acceptable.

Reduction of peak acoustic pressure and shaping of heated region by use of multifoci sonications in MR-guided high-intensity focused ultrasound mediated mild hyperthermia.

PURPOSE: Ablative hyperthermia (>55 °C) has been used as a definitive treatment for accessible solid tumors not amenable to surgery, whereas mild hyperthermia (40-45 °C) has been shown effective as an adjuvant for both radiotherapy and chemotherapy. An optimal mild hyperthermia treatment is spatially accurate, with precise and homogeneous heating limited to the target region while also limiting the likelihood of unwanted thermal or mechanical bioeffects (tissue damage, vascular shutoff). Magnetic resonance imaging-guided high-intensity focused ultrasound (MR-HIFU) can noninvasively heat solid tumors under image-guidance. In a mild hyperthermia setting, a sonication approach utilizing multiple concurrent foci may provide the benefit of reducing acoustic pressure in the focal region (leading to reduced or no mechanical effects), while providing better control over the heating. The objective of this study was to design, implement, and characterize a multifoci sonication approach in combination with a mild hyperthermia heating algorithm, and compare it to the more conventional method of electronically sweeping a single focus. METHODS: Simulations (acoustic and thermal) and measurements (acoustic, with needle hydrophone) were performed. In addition, heating performance of multifoci and single focus sonications was compared using a clinical MR-HIFU platform in a phantom (target = 4-16 mm), in normal rabbit thigh muscle (target = 8 mm), and in a Vx2 tumor (target = 8 mm). A binary control algorithm was used for real-time mild hyperthermia feedback control (target range = 40.5-41 °C). Data were analyzed for peak acoustic pressure and intensity, heating energy efficiency, temperature accuracy (mean), homogeneity of heating (standard deviation [SD], T10 and T90), diameter and length of the heated region, and thermal dose (CEM(43)). RESULTS: Compared to the single focus approach, multifoci sonications showed significantly lower (67% reduction) peak acoustic pressures in simulations and hydrophone measurements. In a rabbit Vx2 tumor, both single focus and multifoci heating approaches were accurate (mean = 40.82±0.12 °C [single] and 40.70±0.09 °C [multi]) and precise (standard deviation = 0.65±0.05 °C [single] and 0.64±0.04 °C [multi]), producing homogeneous heating (T(10-90) = 1.62 °C [single] and 1.41 °C [multi]). Heated regions were significantly shorter in the beam path direction (35% reduction, p < 0.05, Tukey) for multifoci sonications, i.e., resulting in an aspect ratio closer to one. Energy efficiency was lower for the multifoci approach. Similar results were achieved in phantom and rabbit muscle heating experiments. CONCLUSIONS: A multifoci sonication approach was combined with a mild hyperthermia heating algorithm, and implemented on a clinical MR-HIFU platform. This approach resulted in accurate and precise heating within the targeted region with significantly lower acoustic pressures and spatially more confined heating in the beam path direction compared to the single focus sonication method.The reduction in acoustic pressure and improvement in spatial control suggest that multifoci heating is a useful tool in mild hyperthermia applications for clinical oncology.

Mild hyperthermia with magnetic resonance-guided high-intensity focused ultrasound for applications in drug delivery.

PURPOSE: Mild hyperthermia (40-45 °C) is a proven adjuvant for radiotherapy and chemotherapy. Magnetic resonance guided high intensity focused ultrasound (MR-HIFU) can non-invasively heat solid tumours under image guidance. Low temperature-sensitive liposomes (LTSLs) release their drug cargo in response to heat (>40 °C) and may improve drug delivery to solid tumours when combined with mild hyperthermia. The objective of this study was to develop and implement a clinically relevant MR-HIFU mild hyperthermia heating algorithm for combination with LTSLs. MATERIALS AND METHODS: Sonications were performed with a clinical MR-HIFU platform in a phantom and rabbits bearing VX2 tumours (target = 4-16 mm). A binary control algorithm was used for real-time mild hyperthermia feedback control (target = 40-41 °C). Drug delivery with LTSLs was measured with HPLC. Data were compared to simulation results and analysed for spatial targeting accuracy (offset), temperature accuracy (mean), homogeneity of heating (standard deviation (SD), T10 and T90), and thermal dose (CEM43). RESULTS: Sonications in a phantom resulted in better temperature control than in vivo. Sonications in VX2 tumours resulted in mean temperatures between 40.4 °C and 41.3 °C with a SD of 1.0-1.5 °C (T10 = 41.7-43.7 °C, T90 = 39.0-39.6 °C), in agreement with simulations. 3D spatial offset was 0.1-3.2 mm in vitro and 0.6-4.8 mm in vivo. Combination of MR-HIFU hyperthermia and LTSLs demonstrated heterogeneous delivery to a partially heated VX2 tumour, as expected. CONCLUSIONS: An MR-HIFU mild hyperthermia heating algorithm was developed, resulting in accurate and homogeneous heating within the targeted region in vitro and in vivo, which is suitable for applications in drug delivery.