Case Report: Desmoid tumor response to magnetic resonance-guided high intensity focused ultrasound over 4 years.

Desmoid tumors are a rare form of cancer, which show locally aggressive invasion of surrounding tissues and may occur anywhere in the body. Treatment options comprise conservative watch and wait strategies as tumors may show spontaneous regression as well as surgical resection, radiation therapy, nonsteroidal anti-inflammatory drugs (NSAID), chemotherapy, or local thermoablative approaches for progressive disease. The latter comprises cryotherapy, radiofrequency, microwave ablation, or thermal ablation with high intensity focused ultrasound (HIFU) as the only entirely non-invasive option. This report presents a case where a desmoid tumor at the left dorsal humerus was 2 times surgically resected and, after recurrence, thermally ablated with HIFU under magnetic resonance image-guidance (MR-HIFU). In our report, we analyze tumor volume and/or pain score during standard of care (2 years) and after HIFU treatment over a 4-year follow-up period. Results showed MR-HIFU treatment led to complete tumor remission and pain response.

Factors Influencing the Adoption of Magnetic Resonance-Guided High-Intensity Focused Ultrasound for Painful Bone Metastases in Europe, A Group Concept Mapping Study.

Magnetic resonance imaging-guided high-intensity focused ultrasound (MR-HIFU) is an innovative treatment for patients with painful bone metastases. The adoption of MR-HIFU will be influenced by several factors beyond its effectiveness. To identify contextual factors affecting the adoption of MR-HIFU, we conducted a group concept mapping (GCM) study in four European countries. The GCM was conducted in two phases. First, the participants brainstormed statements guided by the focus prompt "One factor that may influence the uptake of MR-HIFU in clinical practice is...". Second, the participants sorted statements into categories and rated the statements according to their importance and changeability. To generate a concept map, multidimensional scaling and cluster analysis were conducted, and average ratings for each (cluster of) factors were calculated. Forty-five participants contributed to phase I and/or II (56% overall participation rate). The resulting concept map comprises 49 factors, organized in 12 clusters: "competitive treatments", "physicians' attitudes", "alignment of resources", "logistics and workflow", "technical disadvantages", "radiotherapy as first-line therapy", "aggregating knowledge and improving awareness", "clinical effectiveness", "patients' preferences", "reimbursement", "cost-effectiveness" and "hospital costs". The factors identified echo those from the literature, but their relevance and interrelationship are case-specific. Besides evidence on clinical effectiveness, contextual factors from 10 other clusters should be addressed to support adoption of MR-HIFU.

Focused Ultrasound and RadioTHERapy for non-invasive palliative pain treatment in patients with bone metastasis: a study protocol for the three armed randomized controlled FURTHER trial.

BACKGROUND: Cancer-induced bone pain (CIBP), caused by bone metastases, is a common complication of cancer and strongly impairs quality of life (QoL). External beam radiotherapy (EBRT) is the current standard of care for treatment of CIBP. However, approximately 45% of patients have no adequate pain response after EBRT. Magnetic resonance image-guided high-intensity focused ultrasound (MR-HIFU) may improve pain palliation in this patient population. The main objective of this trial was to compare MR-HIFU, EBRT, and MR-HIFU + EBRT for the palliative treatment of bone metastases. METHODS/DESIGN: The FURTHER trial is an international multicenter, three-armed randomized controlled trial. A total of 216 patients with painful bone metastases will be randomized in a 1:1:1 ratio to receive EBRT only, MR-HIFU only, or combined treatment with EBRT followed by MR-HIFU. During a follow-up period of 6 months, patients will be contacted at eight time points to retrieve information about their level of pain, QoL, and the occurrence of (serious) adverse events. The primary outcome of the trial is pain response at 14 days after start of treatment. Secondary outcomes include pain response at 14 days after trial enrolment, pain scores (daily until the 21st day and at 4, 6, 12 and 24 weeks), toxicity, adverse events, QoL, and survival. Cost-effectiveness and cost-utility analysis will be conducted. DISCUSSION: The FURTHER trial aims to evaluate the effectiveness and cost-effectiveness of MR-HIFU-alone or in combination with EBRT-compared to EBRT to relieve CIBP. The trial will be performed in six hospitals in four European countries, all of which are partners in the FURTHER consortium. TRIAL REGISTRATION: The FURTHER trial is registered under the Netherlands Trials Register number NL71303.041.19 and ClinicalTrials.gov registration number NCT04307914. Date of trial registration is 13-01-2020.

Early economic modeling of magnetic resonance image-guided high intensity focused ultrasound compared to radiotherapy for pain palliation of bone metastases.

Introduction: Magnetic Resonance Image-guided High Intensity Focused Ultrasound (MR-HIFU) is a non-invasive treatment option for palliative patients with painful bone metastases. Early evidence suggests that MR-HIFU is associated with similar overall treatment response, but more rapid pain palliation compared to external beam radiotherapy (EBRT). This modelling study aimed to assess the cost-effectiveness of MR-HIFU as an alternative treatment option for painful bone metastases from the perspective of the German Statutory Health Insurance (SHI). Materials and methods: A microsimulation model with lifelong time horizon and one-month cycle length was developed. To calculate the incremental cost-effectiveness ratio (ICER), strategy A (MR-HIFU as first-line treatment or as retreatment option in case of persistent pain or only partial pain relief after EBRT) was compared to strategy B (EBRT alone) for patients with bone metastases due to breast, prostate, or lung cancer. Input parameters used for the model were extracted from the literature. Results were expressed as EUR per quality-adjusted life years (QALYs) and EUR per pain response (i.e., months spent with complete or partial pain response). Deterministic and probabilistic sensitivity analyses (PSA) were performed to test the robustness of results, and a value of information analysis was conducted. Results: Compared to strategy B, strategy A resulted in additional costs (EUR 399) and benefits (0.02 QALYs and 0.95 months with pain response). In the base case, the resulting ICERs (strategy A vs. strategy B) are EUR 19,845/QALY and EUR 421 per pain response. Offering all patients MR-HIFU as first-line treatment would increase the ICER by 50% (31,048 EUR/QALY). PSA showed that at a (hypothetical) willingness to pay of EUR 20,000/QALY, the probability of MR-HIFU being cost-effective was 52%. The expected value of perfect information (EVPI) for the benefit population in Germany is approximately EUR 190 Mio. Conclusion: Although there is considerable uncertainty, the results demonstrate that introducing MR-HIFU as a treatment alternative for painful bone metastases might be cost-effective for the German SHI. The high EVPI indicate that further studies to reduce uncertainty would be worthwhile.

Hyperthermia-induced doxorubicin delivery from thermosensitive liposomes via MR-HIFU in a pig model.

PURPOSE: Encapsulation of cytotoxic drugs for a localized release is an effective way to increase the therapeutic window of such agents. In this article we present the localized release of doxorubicin (DOX) from phosphatidyldiglycerol (DPPG2) based thermosensitive liposomes using MR-HIFU mediated hyperthermia in a swine model. MATERIALS AND METHODS: German landrace pigs of weights between 37.5 and 53.5 kg received a 30-min infusion of DOX containing thermosensitive liposomes (50 mg DOX/m2). The pigs' biceps femoris was treated locally in two separate target areas with mild hyperthermia using magnetic resonance guided high intensity focused ultrasound, starting 10 min and 60 min after initiation of the infusion, respectively. The pharmacokinetics and biodistribution of DOX were determined and an analysis of the treatment parameters' influence was performed. RESULTS: Compared to untreated tissue, we found a 15-fold and a 7-fold increase in DOX concentration in the muscle volumes that had undergone hyperthermia starting 10 min and 60 min after the beginning of the infusion, respectively. The pharmacokinetic analysis showed a prolonged circulation time of DOX and a correlation between the AUC of extra-liposomal DOX in the bloodstream and the amount of DOX accumulated in the target tissue. CONCLUSIONS: We have demonstrated a workflow for MR-HIFU hyperthermia drug delivery that can be adapted to a clinical setting, showing that HIFU-hyperthermia is a suitable method for local drug release of DOX using DPPG2 based thermosensitive liposomes in stationary targets. Using the developed pharmacokinetic model, an optimization of the drug quantity deposited in the target via the timing of infusion and hyperthermia should be possible.

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

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

High Intensity Focused Ultrasound for Treatment of Bone Malignancies-20 Years of History.

High Intensity Focused Ultrasound (HIFU) is the only non-invasive method for percutaneous thermal ablation of tissue, with treatments typically performed either under magnetic resonance imaging or ultrasound guidance. Since this method allows efficient heating of bony structures, it has found not only early use in treatment of bone pain, but also in local treatment of malignant bone tumors. This review of 20 years of published studies shows that HIFU is a very efficient method for rapid pain relief, can provide local tumor control and has a very patient-friendly safety profile.

Visualization of thermal washout due to spatiotemporally heterogenous perfusion in the application of a model-based control algorithm for MR-HIFU mediated hyperthermia.

PURPOSE: This article will report results from the in-vivo application of a previously published model-predictive control algorithm for MR-HIFU hyperthermia. The purpose of the investigation was to test the controller's in-vivo performance and behavior in the presence of heterogeneous perfusion. MATERIALS AND METHODS: Hyperthermia at 42°C was induced and maintained for up to 30 min in a circular section of a thermometry slice in the biceps femoris of German landrace pigs (n=5) using a commercial MR-HIFU system and a recently developed MPC algorithm. The heating power allocation was correlated with heat sink maps and contrast-enhanced MRI images. The temporal change in perfusion was estimated based on the power required to maintain hyperthermia. RESULTS: The controller performed well throughout the treatments with an absolute average tracking error of 0.27 ± 0.15 °C and an average difference of 1.25 ± 0.22 °C between T10 and T90. The MPC algorithm allocates additional heating power to sub-volumes with elevated heat sink effects, which are colocalized with blood vessels visible on contrast-enhanced MRI. The perfusion appeared to have increased by at least a factor of ∼1.86 on average. CONCLUSIONS: The MPC controller generates temperature distributions with a narrow spectrum of voxel temperatures inside the target ROI despite the presence of spatiotemporally heterogeneous perfusion due to the rapid thermometry feedback available with MR-HIFU and the flexible allocation of heating power. The visualization of spatiotemporally heterogeneous perfusion presents new research opportunities for the investigation of stimulated perfusion in hypoxic tumor regions.

Feasibility study of MR-guided pancreas ablation using high-intensity focused ultrasound in a healthy swine model.

Purpose: Pancreatic cancer is typically diagnosed in a late stage with limited therapeutic options. For those patients, ultrasound-guided high-intensity focused ultrasound (US-HIFU) can improve local control and alleviate pain. However, MRI-guided HIFU (MR-HIFU) has not yet been studied extensively in this context. To facilitate related research and accelerate clinical translation, we report a workflow for the in vivo HIFU ablation of the porcine pancreas under MRI guidance.Materials and methods: The pancreases of five healthy German landrace pigs (35-58 kg) were sonicated using a clinical MR-HIFU system. Acoustic access to the pancreas was supported by a specialized diet and a hydrogel compression device for bowel displacement. Organ motion was suspended using periods of apnea. The size of the resulting thermal lesions was assessed using the thermal threshold- and dose profiles, non-perfused volume, and gross examination. The effect of the compression device on beam path length was assessed using MRI imaging.Results: Eight of ten treatments resulted in clearly visible damage in the target tissue upon gross examination. Five treatments resulted in coagulative necrosis. Good agreement between the four metrics for lesion size and a clear correlation between the delivered energy dose and the resulting lesion size were found. The compression device notably shortened the intra-abdominal beam path.Conclusions: We demonstrated a workflow for HIFU treatment of the porcine pancreas in-vivo under MRI-guidance. This development bears significance for the development of MR-guided HIFU interventions on the pancreas as the pig is the preferred animal model for the translation of pre-clinical research into clinical application.

Abscopal Effects in Radio-Immunotherapy-Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition.

Immune checkpoint inhibition (ICI) targeting the programmed death receptor 1 (PD-1) has shown promising results in the fight against cancer. Systemic anti-tumor reactions due to radiation therapy (RT) can lead to regression of non-irradiated lesions (NiLs), termed "abscopal effect" (AbE). Combination of both treatments can enhance this effect. The aim of this study was to evaluate AbEs during anti-PD-1 therapy and irradiation. We screened 168 patients receiving pembrolizumab or nivolumab at our center. Inclusion criteria were start of RT within 1 month after the first or last application of pembrolizumab (2 mg/kg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks) and at least one metastasis outside the irradiation field. We estimated the total dose during ICI for each patient using the linear quadratic (LQ) model expressed as 2 Gy equivalent dose (EQD2) using α/ß of 10 Gy. Radiological images were required showing progression or no change in NiLs before and regression after completion of RT(s). Images must have been acquired at least 4 weeks after the onset of ICI or RT. The surface areas of the longest diameters of the short- and long-axes of NiLs were measured. One hundred twenty-six out of 168 (75%) patients received ICI and RT. Fifty-three percent (67/126) were treated simultaneously, and 24 of these (36%) were eligible for lesion analysis. AbE was observed in 29% (7/24). One to six lesions (mean = 3 ± 2) in each AbE patient were analyzed. Patients were diagnosed with malignant melanoma (MM) (n = 3), non-small cell lung cancer (NSCLC) (n = 3), and renal cell carcinoma (RCC) (n = 1). They were irradiated once (n = 1), twice (n = 2), or three times (n = 4) with an average total EQD2 of 120.0 ± 37.7 Gy. Eighty-two percent of RTs of AbE patients were applied with high single doses. MM patients received pembrolizumab, NSCLC, and RCC patients received nivolumab for an average duration of 45 ± 35 weeks. We demonstrate that 29% of the analyzed patients showed AbE. Strict inclusion criteria were applied to distinguish the effects of AbE from the systemic effect of ICI. Our data suggest the clinical existence of systemic effects of irradiation under ICI and could contribute to the development of a broader range of cancer treatments.

Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU): Overview of Emerging Applications (Part 2).

BACKGROUND: High-intensity focused ultrasound (HIFU) allows noninvasive heating of deep-seated tissues. Guidance under magnetic resonance imaging (MR-HIFU) offers spatial targeting based on anatomical MR images as well as MR-based near-real-time temperature maps. Temperature feedback allows delivery of a well-defined thermal dose enabling new applications such as the ablation of malignant tissue. METHODS: Peer-reviewed publications on MR-HIFU were studied and are summarized in this review. Literature was restricted to applications in oncology. RESULTS: Several MR-HIFU-based applications for the treatment of malignant diseases are currently part of clinical trials or translational research. Recent trials regarding the treatment of prostate cancer with MR-HIFU have already shown this to be a safe and patient-friendly method. For the treatment of breast cancer and malignancies within abdominal organs, MR-HIFU has been applied so far only in proof of concept studies. CONCLUSION: MR-HIFU is currently being investigated for the ablative treatment of malignant tissue in a variety of oncological applications. For example, the transrectal as well as transurethral ablation of prostate cancer using MR-HIFU was shown to be a patient-friendly, safe alternative to other local treatment options with low side effects. KEY POINTS: · MR guidance offers high soft tissue contrast for treatment planning, near-real-time temperature monitoring, and post-interventional therapy evaluation.. · Special HIFU transducers and technological solutions are available for the treatment of e. g. prostate cancer, breast cancer or abdominal malignancies.. CITATION FORMAT: · Siedek F, Yeo SY, Heijman E et al. MR-Guided High-Intensity Focused Ultrasound (MR-HIFU): Overview of Emerging Applications (Part 2). Fortschr Röntgenstr 2019; 191: 531 - 539.

Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU): Technical Background and Overview of Current Clinical Applications (Part 1).

BACKGROUND: Extracorporeal high-intensity focused ultrasound (HIFU) is a promising method for the noninvasive thermal ablation of benign and malignant tissue. Current HIFU treatments are performed under ultrasound (US-HIFU) or magnetic resonance (MR-HIFU) image guidance offering integrated therapy planning, real-time control (spatial and temperature guidance) and evaluation. METHODS: This review is based on publications in peer-reviewed journals addressing thermal ablation using HIFU and includes our own clinical results as well. The technical background of HIFU is explained with an emphasis on MR-HIFU applications. A brief overview of the most commonly performed CE-approved clinical applications for MR-HIFU is given. RESULTS: Over the last decade, several HIFU-based applications have received clinical approval in various countries. In particular, MR-HIFU is now approved for the clinical treatment of uterine fibroids, palliation of bone pain, ablation of the prostate and treatment of essential tremor as a first neurological application. CONCLUSION: MR-HIFU is a patient-friendly noninvasive method for thermal ablation which has received clinical approval for several applications. Overall, clinical data demonstrate treatment efficacy, safety and cost efficiency. KEY POINTS: · HIFU is a promising technique for noninvasive thermal ablation of tissue.. · HIFU is typically performed under image guidance using either diagnostic ultrasound (US-HIFU) or MRI (MR-HIFU).. · The preferred image guidance modality depends on the application.. · MR guidance offers improved soft-tissue contrast for treatment planning, near real-time and noninvasive temperature monitoring and post-interventional therapy evaluation.. · MR-HIFU is CE-approved for treatment of uterine fibroids, alleviation of bone pain, prostate tissue ablation and treatment of essential tremor.. CITATION FORMAT: · Siedek F, Yeo S, Heijman E et al. Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MR-HIFU): Technical Background and Overview of Current Clinical Applications (Part 1). Fortschr Röntgenstr 2019; 191: 522 - 530.

Corrigendum: Abscopal Effects in Radio-Immunotherapy-Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition.

[This corrects the article DOI: 10.3389/fphar.2019.00511.].

Uterine fibroids: Influence of "T2-Rim sign" on immediate therapeutic responses to magnetic resonance imaging-guided high-intensity focused ultrasound ablation.

OBJECTIVES: To investigate the influence of a high-signal-intensity peripheral rim on T2-weighted MR images (i.e., T2-rim sign) on the immediate therapeutic responses of MR-guided high intensity focused ultrasound (MR-HIFU) ablation of uterine fibroids. METHODS: This retrospective study was approved by the institutional review board, and patient informed consent was obtained for MR-HIFU ablation. In total, 196 fibroids (diameter 6.2±2.6cm) in 123 women (age 43.4±5.0 years) who underwent MR-HIFU ablation from January 2013 to April 2016 were included. The effects of a T2-rim sign on the immediate therapeutic responses (non-perfused volume [NPV] ratio, ablation efficiency [NPV/treatment cell volume], ablation quality [grade 1-5, poor to excellent]) were investigated with univariable and multivariable analyses using generalized estimating equation (GEE) analysis. In multivariable analysis, T2 signal intensity ratio of fibroids-to-skeletal muscle, relative peak enhancement of fibroids, and subcutaneous fat thickness were also considered. RESULTS: The presence of a T2-rim sign significantly lowered the NPV ratio (54.0±28.0% vs. 83.7±17.7%), ablation efficiency (0.6±0.5 vs. 1.3±0.6), ablation quality (3.1±1.2 vs. 4.2±0.8), (P<0.0001). GEE analysis showed that the presence of a T2-rim sign was independently significant for ablation efficiency and ablation quality (P<0.05). CONCLUSION: Uterine fibroids with a T2-rim sign showed significantly poorer immediate therapeutic responses to MR-HIFU ablation.

Bone metastasis treatment using magnetic resonance-guided high intensity focused ultrasound.

OBJECTIVES: Bone pain resulting from cancer metastases reduces a patient's quality of life. Magnetic Resonance-guided High Intensity Focused Ultrasound (MR-HIFU) is a promising alternative palliative thermal treatment technique for bone metastases that has been tested in a few clinical studies. Here, we describe a comprehensive pre-clinical study to investigate the effects, and efficacy of MR-HIFU ablation for the palliative treatment of osteoblastic bone metastases in rats. MATERIALS AND METHODS: Prostate cancer cells (MATLyLu) were injected intra-osseously in Copenhagen rats. Upon detection of pain, as determined with a dynamic weight bearing (DWB) system, a MR-HIFU system was used to thermally ablate the bone region with tumor. Treatment effect and efficacy were assessed using magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT) with technetium-99m medronate ((99m)Tc-MDP), micro-computed tomography (µCT) and histology. RESULTS: DWB analysis demonstrated that MR-HIFU-treated animals retained 58.6 ± 20.4% of limb usage as compared to 2.6 ± 6.3% in untreated animals (P=0.003). MR-HIFU delayed tumor specific growth rates (SGR) from 29 ± 6 to 13 ± 5%/day (P<0.001). Untreated animals (316.5 ± 78.9 mm(3)) had a greater accumulation of (99m)Tc-MDP than HIFU-treated animals (127.0 ± 42.7 mm(3), P=0.004). The total bone volume increase for untreated and HIFU-treated animals was 15.6 ± 9.6% and 3.0 ± 4.1% (P=0.004), respectively. Histological analysis showed ablation of nerve fibers, tumor, inflammatory and bone cells. CONCLUSIONS: Our study provides a detailed characterization of the effects of MR-HIFU treatment on bone metastases, and provides fundamental data, which may motivate and advance its use in the clinical treatment of painful bone metastases with MR-HIFU.

Effects of magnetic resonance-guided high-intensity focused ultrasound ablation on bone mechanical properties and modeling.

BACKGROUND: Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a promising technique for palliative treatment of bone pain. In this study, the effects of MR-HIFU ablation on bone mechanics and modeling were investigated. METHODS: A total of 12 healthy rat femurs were ablated using 10 W for 46 ± 4 s per sonication with 4 sonications for each femur. At 7 days after treatments, all animals underwent MR and single photon emission computed tomography/computed tomography (SPECT/CT) imaging. Then, six animals were euthanized. At 1 month following ablations, the remaining six animals were scanned again with MR and SPECT/CT prior to euthanization. Thereafter, both the HIFU-treated and contralateral control bones of three animals from each time interval were processed for histology, whereas the remaining bones were subjected to micro-CT (µCT), three-point bending tests, and micro-finite element (micro-FE) analyses. RESULTS: At 7 days after HIFU ablations, edema formation around the treated bones coupled with bone marrow and cortical bone necrosis was observed on MRI and histological images. SPECT/CT and µCT images revealed presence of bone modeling through an increased uptake of (99m)Tc-MDP and formation of woven bone, respectively. At 31 days after ablations, as illustrated by imaging and histology, healing of the treated bone and the surrounding soft tissue was noted, marked by decreased in amount of tissue damage, formation of scar tissue, and sub-periosteal reaction. The results of three-point bending tests showed no significant differences in elastic stiffness, ultimate load, and yield load between the HIFU-treated and contralateral control bones at 7 days and 1 month after treatments. Similarly, the elastic stiffness and Young's moduli determined by micro-FE analyses at both time intervals were not statistically different. CONCLUSIONS: Multimodality imaging and histological data illustrated the presence of HIFU-induced bone damage at the cellular level, which activated the bone repair mechanisms. Despite that, these changes did not have a mechanical impact on the bone.

Temperature-sensitive paramagnetic liposomes for image-guided drug delivery: Mn(2+) versus [Gd(HPDO3A)(H2O)].

Temperature-sensitive liposomes (TSLs) loaded with doxorubicin (Dox), and Magnetic Resonance Imaging contrast agents (CAs), either manganese (Mn(2+)) or [Gd(HPDO3A)(H2O)], provide the advantage of drug delivery under MR image guidance. Encapsulated MRI CAs have low longitudinal relaxivity (r1) due to limited transmembrane water exchange. Upon triggered release at hyperthermic temperature, the r1 will increase and hence, provides a means to monitor drug distribution in situ. Here, the effects of encapsulated CAs on the phospholipid bilayer and the resulting change in r1 were investigated using MR titration studies and (1)H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles. Our results show that Mn(2+) interacted with the phospholipid bilayer of TSLs and consequently, reduced doxorubicin retention capability at 37°C within the interior of the liposomes over time. Despite that, Mn(2+)-phospholipid interaction resulted in higher r1 increase, from 5.1±1.3mM(-1)s(-1) before heating to 32.2±3mM(-1)s(-1) after heating at 60MHz and 37°C as compared to TSL(Gd,Dox) where the longitudinal relaxivities before and after heating were 1.2±0.3mM(-1)s(-1) and 4.4±0.3mM(-1)s(-1), respectively. Upon heating, Dox was released from TSL(Mn,Dox) and complexation of Mn(2+) to Dox resulted in a similar Mn(2+) release profile. From 25 to 38°C, r1 of [Gd(HPDO3A)(H2O)] gradually increased due to increase transmembrane water exchange, while no Dox release was observed. From 38°C, the release of [Gd(HPDO3A)(H2O)] and Dox was irreversible and the release profiles coincided. By understanding the non-covalent interactions between the MRI CAs and phospholipid bilayer, the properties of the paramagnetic TSLs can be tailored for MR guided drug delivery.

Internalization of paramagnetic phosphatidylserine-containing liposomes by macrophages.

BACKGROUND: Inflammation plays an important role in many pathologies, including cardiovascular diseases, neurological conditions and oncology, and is considered an important predictor for disease progression and outcome. In vivo imaging of inflammatory cells will improve diagnosis and provide a read-out for therapy efficacy. Paramagnetic phosphatidylserine (PS)-containing liposomes were developed for magnetic resonance imaging (MRI) and confocal microscopy imaging of macrophages. These nanoparticles also provide a platform to combine imaging with targeted drug delivery. RESULTS: Incorporation of PS into liposomes did not affect liposomal size and morphology up to 12 mol% of PS. Liposomes containing 6 mol% of PS showed the highest uptake by murine macrophages, while only minor uptake was observed in endothelial cells. Uptake of liposomes containing 6 mol% of PS was dependent on the presence of Ca2+ and Mg2+. Furthermore, these 6 mol% PS-containing liposomes were mainly internalized into macrophages, whereas liposomes without PS only bound to the macrophage cell membrane. CONCLUSIONS: Paramagnetic liposomes containing 6 mol% of PS for MR imaging of macrophages have been developed. In vitro these liposomes showed specific internalization by macrophages. Therefore, these liposomes might be suitable for in vivo visualization of macrophage content and for (visualization of) targeted drug delivery to inflammatory cells.

Anti-tumor activity of liposomal glucocorticoids: The relevance of liposome-mediated drug delivery, intratumoral localization and systemic activity.

Tumor-associated inflammation has been recognized as an important tumor growth propagator and, therefore, represents an attractive target for anti-cancer therapy. In the current study, inspired by recent findings on the anti-tumor activity of liposomal glucocorticoids, we introduce paramagnetic and fluorescent liposomes, encapsulating prednisolone phosphate (PLP), to evaluate the local delivery of liposomal glucocorticoids to the tumor and its importance for the therapeutic response. The new multifunctional liposomes (Gd-PLP-L) (120nm diameter, 5.8mg PLP/60µmol lipid, bioexponential blood-clearance kinetics (T(1/2α)=2.4±0.5h, T(1/2ß)=42.0±12.4h), drug leakage of 15%/72h (in vitro)), containing 25mol% Gd-DTPA-lipid and 0.1mol% of rhodamine-lipid, were tested in B16F10 melanoma subcutaneously inoculated in C57BL/6 mice, and compared to the original PLP formulation (PLP-L). A single dose of Gd-PLP-L (20mgPLP/kg/week, i.v.) was found to significantly inhibit tumor growth compared to non-treated mice (P<0.05), similarly to PLP-L. The accumulation efficacy of the liposomal agent in the tumor was assessed with MRI, using the increase in the longitudinal relaxation rate (ΔR(1)) as a marker. Interestingly, large inter-tumor differences in ΔR(1) (0.009-0.063s(-1), 24h post-administration), corresponding to highly variable intratumoral Gd-PLP-L levels, did not correlate to the effectiveness of tumor growth inhibition. Uptake of liposomes by tumor-associated macrophages (TAM), determined by ex-vivo fluorescence microscopy, was limited to only 5% of the TAM population. Furthermore, the therapy did not lead to TAM depletion. Importantly, a 90% drop in white blood cell count both after Gd-PLP-L and PLP-L administration was observed. This depletion may reduce tumor infiltration of monocytes, which stimulate angiogenesis, and, thus, possibly co-contributes to the anti-tumor effects. In conclusion, MRI provides a powerful instrument to monitor the delivery of liposomal therapeutics to tumors and guided us to reveal that the activity of liposomal glucocorticoids is not limited to the tumor site only.