Diffusion-weighted MRI with deep learning for visualizing treatment results of MR-guided HIFU ablation of uterine fibroids.

OBJECTIVES: No method is available to determine the non-perfused volume (NPV) repeatedly during magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablations of uterine fibroids, as repeated acquisition of contrast-enhanced T1-weighted (CE-T1w) scans is inhibited by safety concerns. The objective of this study was to develop and test a deep learning-based method for translation of diffusion-weighted imaging (DWI) into synthetic CE-T1w scans, for monitoring MR-HIFU treatment progression. METHODS: The algorithm was retrospectively trained and validated on data from 33 and 20 patients respectively who underwent an MR-HIFU treatment of uterine fibroids between June 2017 and January 2019. Postablation synthetic CE-T1w images were generated by a deep learning network trained on paired DWI and reference CE-T1w scans acquired during the treatment procedure. Quantitative analysis included calculation of the Dice coefficient of NPVs delineated on synthetic and reference CE-T1w scans. Four MR-HIFU radiologists assessed the outcome of MR-HIFU treatments and NPV ratio based on the synthetic and reference CE-T1w scans. RESULTS: Dice coefficient of NPVs was 71% (± 22%). The mean difference in NPV ratio was 1.4% (± 22%) and not statistically significant (p = 0.79). Absolute agreement of the radiologists on technical treatment success on synthetic and reference CE-T1w scans was 83%. NPV ratio estimations on synthetic and reference CE-T1w scans were not significantly different (p = 0.27). CONCLUSIONS: Deep learning-based synthetic CE-T1w scans derived from intraprocedural DWI allow gadolinium-free visualization of the predicted NPV, and can potentially be used for repeated gadolinium-free monitoring of treatment progression during MR-HIFU therapy for uterine fibroids. KEY POINTS: • Synthetic CE-T1w scans can be derived from diffusion-weighted imaging using deep learning. • Synthetic CE-T1w scans may be used for visualization of the NPV without using a contrast agent directly after MR-HIFU ablations of uterine fibroids.

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.

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

PURPOSE: To demonstrate that proton resonance frequency shift MR thermometry (PRFS-MRT) acquisition with nonselective free induction decay (FID), combined with coil sensitivity profiles, allows spatially resolved B0 drift-corrected thermometry. METHODS: Phantom experiments were performed at 1.5T and 3T. Acquisition of PRFS-MRT and FID were performed during MR-guided high-intensity focused ultrasound heating. The phase of the FIDs was used to estimate the change in angular frequency δωdrift per coil element. Two correction methods were investigated: (1) using the average δωdrift over all coil elements (0th-order) and (2) using coil sensitivity profiles for spatially resolved correction. Optical probes were used for independent temperature verification. In-vivo feasibility of the methods was evaluated in the leg of 1 healthy volunteer at 1.5T. RESULTS: In 30 minutes, B0 drift led to an apparent temperature change of up to -18°C and -98°C at 1.5T and 3T, respectively. In the sonicated area, both corrections had a median error of 0.19°C at 1.5T and -0.54°C at 3T. At 1.5T, the measured median error with respect to the optical probe was -1.28°C with the 0th-order correction and improved to 0.43°C with the spatially resolved correction. In vivo, without correction the spatiotemporal median of the apparent temperature was at -4.3°C and interquartile range (IQR) of 9.31°C. The 0th-order correction had a median of 0.75°C and IQR of 0.96°C. The spatially resolved method had the lowest median at 0.33°C and IQR of 0.80°C. CONCLUSION: FID phase information from individual receive coil elements allows spatially resolved B0 drift correction in PRFS-based MRT.

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.

Use of multiparametric MRI to characterize uterine fibroid tissue types.

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

Thermal combination therapies for local drug delivery by magnetic resonance-guided high-intensity focused ultrasound.

Several thermal-therapy strategies such as thermal ablation, hyperthermia-triggered drug delivery from temperature-sensitive liposomes (TSLs), and combinations of the above were investigated in a rhabdomyosarcoma rat tumor model (n = 113). Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) was used as a noninvasive heating device with precise temperature control for image-guided drug delivery. For the latter, TSLs were prepared, coencapsulating doxorubicin (dox) and [Gd(HPDO3A)(H2O)], and injected in tumor-bearing rats before MR-HIFU treatment. Four treatment groups were defined: hyperthermia, ablation, hyperthermia followed by ablation, or no HIFU. The intratumoral TSL and dox distribution were analyzed by single-photon emission computed tomography (SPECT)/computed tomography (CT), autoradiography, and fluorescence microscopy. Dox biodistribution was quantified and compared with that of nonliposomal dox. Finally, the treatment efficacy of all heating strategies plus additional control groups (saline, free dox, and Caelyx) was assessed by tumor growth measurements. All HIFU heating strategies combined with TSLs resulted in cellular uptake of dox deep into the interstitial space and a significant increase of tumor drug concentrations compared with a treatment with free dox. Ablation after TSL injection showed [Gd(HPDO3A)(H2O)] and dox release along the tumor rim, mirroring the TSL distribution pattern. Hyperthermia either as standalone treatment or before ablation ensured homogeneous TSL, [Gd(HPDO3A)(H2O)], and dox delivery across the tumor. The combination of hyperthermia-triggered drug delivery followed by ablation showed the best therapeutic outcome compared with all other treatment groups due to direct induction of thermal necrosis in the tumor core and efficient drug delivery to the tumor rim.

Multiparametric MRI analysis for the evaluation of MR-guided high intensity focused ultrasound tumor treatment.

For the clinical application of high intensity focused ultrasound (HIFU) for thermal ablation of malignant tumors, accurate treatment evaluation is of key importance. In this study, we have employed a multiparametric MRI protocol, consisting of quantitative T1, T2, ADC, amide proton transfer (APT), T1ρ and DCE-MRI measurements, to evaluate MR-guided HIFU treatment of subcutaneous tumors in rats. K-means clustering using all different combinations of the endogenous contrast MRI parameters (feature vectors) was performed to segment the multiparametric data into tissue populations with similar MR parameter values. The optimal feature vector for identification of the extent of non-viable tumor tissue after HIFU treatment was determined by quantitative comparison between clustering-derived and histology-derived non-viable tumor fractions. The highest one-to-one correspondence between these clustering-based and histology-based non-viable tumor fractions was observed for the feature vector {ADC, APT-weighted signal} (R(2) to line of identity (R(2)y=x) = 0.92) and the strongest agreement was seen 3 days after HIFU (R(2)y=x = 0.97). To compare the multiparametric MRI analysis results with conventional HIFU monitoring and evaluation methods, the histology-derived non-viable tumor fractions were also quantitatively compared with non-perfused tumor fractions (derived from the level of contrast enhancement in the DCE-MRI measurements) and 240 CEM tumor fractions (i.e. thermal dose > 240 cumulative equivalent minutes at 43 °C). The correlation between histology-derived non-viable tumor fractions directly after HIFU and the 240 CEM fractions was high, but not significant. The non-perfused fractions overestimated the extent of non-viable tumor tissue directly after HIFU, whereas an underestimation was observed 3 days after HIFU. In conclusion, we have shown that a multiparametric MR analysis, especially based on the ADC and the APT-weighted signal, can potentially be used to determine the extent of non-viable tumor tissue 3 days after HIFU treatment. We expect that this method can be incorporated in the current clinical workflow of MR-HIFU ablation therapies.

Tumour hyperthermia and ablation in rats using a clinical MR-HIFU system equipped with a dedicated small animal set-up.

PURPOSE: We report on the design, performance, and specifications of a dedicated set-up for the treatment of rats on a clinical magnetic resonance high intensity focused ultrasound (MR-HIFU) system. MATERIALS AND METHODS: The small animal HIFU-compatible 4-channel MR receiver volume coil and animal support were designed as add-on to a clinical 3T Philips Sonalleve MR-HIFU system. Prolonged hyperthermia (T ≈ 42°C, 15 min) and thermal ablation (T = 65°C) was performed in vivo on subcutaneous rat tumours using 1.44 MHz acoustic frequency. The direct treatment effect was assessed with T(2)-weighted imaging and dynamic contrast enhanced (DCE-) MRI as well as histology. RESULTS: The developed HIFU-compatible coil provided an image quality that was comparable to conventional small animal volume coils (i.e. without acoustic window), and a SNR increase by a factor of 10 as compared to the coil set-up used for clinical MR-HIFU therapy. The use of an animal support minimised far field heating and allowed precise regulation of the animal body core temperature, which varied <1°C during treatment. CONCLUSIONS: The results demonstrated that, by using a designated set-up, both controlled hyperthermia and thermal ablation treatment of malignant tumours in rodents can be performed on a clinical MR-HIFU system. This approach provides all the advantages of clinical MR-HIFU, such as volumetric heating, temperature feedback control and a clinical software interface for use in rodent treatment. The use of a clinical system moreover facilitates a rapid translation of the developed protocols into the clinic.

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.

Smoothelin-B deficiency results in reduced arterial contractility, hypertension, and cardiac hypertrophy in mice.

BACKGROUND: Smoothelins are actin-binding proteins that are abundantly expressed in healthy visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Their expression is strongly associated with the contractile phenotype of smooth muscle cells. Analysis of mice lacking both smoothelins (Smtn-A/B(-/-) mice) previously revealed a critical role for smoothelin-A in intestinal smooth muscle contraction. Here, we report on the generation and cardiovascular phenotype of mice lacking only smoothelin-B (Smtn-B(-/-)). METHODS AND RESULTS: Myograph studies revealed that the contractile capacity of the saphenous and femoral arteries was strongly reduced in Smtn-B(-/-) mice, regardless of the contractile agonist used to trigger contraction. Arteries from Smtn-A/B(-/-) compound mutant mice exhibited a similar contractile deficit. Smtn-B(-/-) arteries had a normal architecture and expressed normal levels of other smooth muscle cell-specific genes, including smooth muscle myosin heavy chain, alpha-smooth muscle actin, and smooth muscle-calponin. Decreased contractility of Smtn-B(-/-) arteries was paradoxically accompanied by increased mean arterial pressure (20 mm Hg) and concomitant cardiac hypertrophy despite normal parasympathetic and sympathetic tone in Smtn-B(-/-) mice. Magnetic resonance imaging experiments revealed that cardiac function was not changed, whereas distension of the proximal aorta during the cardiac cycle was increased in Smtn-B(-/-) mice. However, isobaric pulse wave velocity and pulse pressure measurements indicated normal aortic distensibility. CONCLUSIONS: Collectively, our results identify smoothelins as key determinants of arterial smooth muscle contractility and cardiovascular performance. Studies on mutations in the Smtn gene or alterations in smoothelin levels in connection to hypertension in humans are warranted.

Quantification of left ventricular volumes and ejection fraction in mice using PET, compared with MRI.

UNLABELLED: PET has become an important noninvasive imaging technique in cardiovascular research for the characterization of mouse models in vivo. This modality offers unique insight into biochemical changes on a molecular level, with excellent sensitivity. However, morphologic and functional changes may be of equal importance for a thorough assessment of left ventricular (LV) pathophysiology. Although echocardiography and MRI are widely considered the imaging techniques of choice for the assessment of these parameters, their use with PET considerably increases study complexity and decreases cost- and time-efficiency. In this study, a novel method for the additional quantification of LV volumes and ejection fraction (EF) from PET was evaluated using cardiac MRI as the reference method. METHODS: The radiolabeled glucose derivative 18F-FDG was injected into 33 mice (6 mice with previous permanent occlusion of the left anterior descending artery [LAD], 15 mice with a temporary 30-min occlusion of the LAD, and 12 mice without previous surgery). 18F-FDG uptake within the LV myocardium was measured using a dedicated small-animal PET scanner. After we reconstructed the images into 16 electrocardiogram (ECG)-gated frames, we determined the LV cavity volumes in end-diastole (EDV) and end-systole (ESV) and the EF using a semiautomatic segmentation algorithm based on elastic surfaces. A 6.3-T cardiac MRI examination was performed in the same animals using an ECG-triggered and respiratory-gated multislice cine sequence. The MR images were segmented with a semiautomatic algorithm using commercially available software. RESULTS: Overall, measurements from PET agreed well with those obtained by MRI. Mean EDV and ESV were slightly overestimated by PET (86+/-43 microL and 44+/-42 microL), compared with MRI (73+/-44 microL and 41+/-46 microL); mean (+/-SD) EF was similar (PET, 55+/-19 microL; MRI, 54+/-18 microL). Correlation between PET and MRI was excellent for EDV (0.97) and ESV (0.96) and good for EF (0.86). The slope of the regression line was nearly perfect for EDV (0.98) and EF (1.01) and slightly below 1 for ESV (0.90), indicating a good separation of abnormal and normal values with PET. The y-intercept was above zero for EDV (15 microL) and ESV (7 microL) and near to zero for EF (0.2%). CONCLUSION: The quantification of LV volumes and EF in mice with PET is both efficient and accurate. This method allows for combined molecular and functional imaging of the left ventricle within a single scan, obviating additional sophisticated MRI in many cases.

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.

Interleaved Mapping of Temperature and Longitudinal Relaxation Rate to Monitor Drug Delivery During Magnetic Resonance-Guided High-Intensity Focused Ultrasound-Induced Hyperthermia.

OBJECTIVES: Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a method to heat lesions noninvasively to a stable, elevated temperature and a well-suited method to induce local hyperthermia (41°C-43°C) in deep-seated tissues. Magnetic Resonance (MR) imaging provides therapy planning on anatomical images and offers temperature feedback based on near-real-time MR thermometry. Although constant acquisition of MR thermometry data is crucial to ensure prolonged hyperthermia, it limits the freedom to perform measurements of other MR parameters, which are of interest during hyperthermia treatments. In image-guided drug delivery applications, co-encapsulation of paramagnetic MR contrast agents with a drug inside temperature-sensitive liposomes (TSLs) allows to visualize hyperthermia-triggered drug delivery through changes of the longitudinal relaxation rate R1. While the drug accumulates in the heated tumor tissue, R1 changes can be used for an estimate of the tumor drug concentration. The main objective of this study was to demonstrate that interleaved MR sequences are able to monitor temperature with an adequate temporal resolution and could give a reasonable estimate of the achieved tumor drug concentration through R1 changes. To this aim, in vitro validation tests and an in vivo proof-of-concept study were performed. MATERIALS AND METHODS: All experiments were performed on a clinical 3-T MR-HIFU system adapted with a preclinical setup. The validity of the R1 values and the temperature maps stability were evaluated in phantom experiments and in ex vivo porcine muscle tissue. In vivo experiments were performed on rats bearing a 9L glioma tumor on their hind limb. All animals (n = 4 HIFU-treated, n = 4 no HIFU) were injected intravenously with TSLs co-encapsulating doxorubicin and gadoteridol as contrast agent. The TSL injection was followed by either 2 times 15 minutes of MR-HIFU-induced hyperthermia or a sham treatment. R1 maps were acquired before, during, and after sonication, using a single slice Inversion Recovery Look-Locker (IR-LL) sequence (field of view [FOV], 50 × 69 mm; in-plane resolution, 0.52 × 0.71 mm; slice thickness, 3 mm; 23 phases of 130 milliseconds; 1 full R1 map every 2 minutes). The R1 maps acquired during treatment were interleaved with 2 perpendicular proton resonance frequency shift (PRFS) MR thermometry slices (dynamic repetition time, 8.6 seconds; FOV, 250 × 250 mm; 1.4 × 1.4 mm in-plane resolution; 4 mm slice thickness). Tumor doxorubicin concentrations were determined fluorometrically. RESULTS: In vitro results showed a slight but consistent overestimation of the measured R1 values compared with calibrated R1 values, regardless whether the R1 was acquired with noninterleaved IR-LL or interleaved. The average treatment cell temperature had a slightly higher temporal standard deviation for the interleaved PRFS sequence compared with the noninterleaved PRFS sequence (0.186°C vs 0.101°C, respectively). The prolonged time in between temperature maps due to the interleaved IR-LL sequence did not degrade the temperature stability during MR-HIFU treatment (Taverage = 40.9°C ± 0.3°C). Upon heat treatment, some tumors showed an R1 increase in a large part of the tumor while other tumors hardly showed any ΔR1. The tumor doxorubicin concentration showed a linear correlation with the average ΔR1 during both sonications (n = 8, Radj = 0.933), which was higher than for the ΔR1 measured after tumor cooldown (averaged for both sonications, n = 8, Radj = 0.877). CONCLUSIONS: The new approach of interleaving different MR sequences was applied to simultaneously acquire R1 maps and PRFS thermometry scans during a feedback-controlled MR-HIFU-induced hyperthermia treatment. Interleaved acquisition did not compromise speed or accuracy of each scan. The ΔR1 acquired during treatment was used to visualize and quantify hyperthermia-triggered release of gadoteridol from TSLs and better reflected the intratumoral doxorubicin concentrations than the ΔR1 measured after cooldown of the tumor, exemplifying the benefit of interleaving R1 maps with temperature maps during drug delivery. Our study serves as an example for interleaved MR acquisition schemes, which introduce a higher flexibility in speed, sequence optimization, and timing.

A Digital Preclinical PET/MRI Insert and Initial Results.

Combining Positron Emission Tomography (PET) with Magnetic Resonance Imaging (MRI) results in a promising hybrid molecular imaging modality as it unifies the high sensitivity of PET for molecular and cellular processes with the functional and anatomical information from MRI. Digital Silicon Photomultipliers (dSiPMs) are the digital evolution in scintillation light detector technology and promise high PET SNR. DSiPMs from Philips Digital Photon Counting (PDPC) were used to develop a preclinical PET/RF gantry with 1-mm scintillation crystal pitch as an insert for clinical MRI scanners. With three exchangeable RF coils, the hybrid field of view has a maximum size of 160 mm × 96.6 mm (transaxial × axial). 0.1 ppm volume-root-mean-square B 0-homogeneity is kept within a spherical diameter of 96 mm (automatic volume shimming). Depending on the coil, MRI SNR is decreased by 13% or 5% by the PET system. PET count rates, energy resolution of 12.6% FWHM, and spatial resolution of 0.73 mm (3) (isometric volume resolution at isocenter) are not affected by applied MRI sequences. PET time resolution of 565 ps (FWHM) degraded by 6 ps during an EPI sequence. Timing-optimized settings yielded 260 ps time resolution. PET and MR images of a hot-rod phantom show no visible differences when the other modality was in operation and both resolve 0.8-mm rods. Versatility of the insert is shown by successfully combining multi-nuclei MRI ((1)H/(19)F) with simultaneously measured PET ((18)F-FDG). A longitudinal study of a tumor-bearing mouse verifies the operability, stability, and in vivo capabilities of the system. Cardiac- and respiratory-gated PET/MRI motion-capturing (CINE) images of the mouse heart demonstrate the advantage of simultaneous acquisition for temporal and spatial image registration.

Magnetic resonance guided high-intensity focused ultrasound mediated hyperthermia improves the intratumoral distribution of temperature-sensitive liposomal doxorubicin.

OBJECTIVES: The aim of this study was to investigate the intratumoral distribution of a temperature-sensitive liposomal carrier and its encapsulated compounds, doxorubicin, and a magnetic resonance (MR) imaging contrast agent after high-intensity focused ultrasound (HIFU)-mediated hyperthermia-induced local drug release. MATERIALS AND METHODS: (111)In-labeled temperature-sensitive liposomes encapsulating doxorubicin and [Gd(HPDO3A) (H(2)O)] were injected intravenously in the tail vein of rats (n = 12) bearing a subcutaneous rhabdomyosarcoma tumor on the hind leg. Immediately after the injection, local tumor hyperthermia (2 × 15 minutes) was applied using a clinical 3 T MR-HIFU system. Release of [Gd(HPDO3A)(H(2)O)] was studied in vivo by measuring the longitudinal relaxation rate R(1) with MR imaging. The presence of the liposomal carriers and the intratumoral distribution of doxorubicin were imaged ex vivo with autoradiography and fluorescence microscopy, respectively, for 2 different time points after injection (90 minutes and 48 hours). RESULTS: In hyperthermia-treated tumors, radiolabeled liposomes were distributed more homogeneously across the tumor than in the control tumors (coefficient of variation(hyp, 90 min) = 0.7 ± 0.2; coefficient of variation(cntrl, 90 min) = 1.1 ± 0.2). At 48 hours after injection, the liposomal accumulation in the tumor was enhanced in the hyperthermia group in comparison with the controls. A change in R(1) was observed in the HIFU-treated tumors, suggesting release of the contrast agent. Fluorescence images showed perivascular doxorubicin in control tumors, whereas in the HIFU-treated tumors, the delivered drug was spread over a much larger area and also taken up by tumor cells at a larger distance from blood vessels. CONCLUSIONS: Treatment with HIFU hyperthermia not only improved the immediate drug delivery, bioavailability, and intratumoral distribution but also enhanced liposomal accumulation over time. The sum of these effects may have a significant contribution to the therapeutic outcome.

SPECT/CT imaging of temperature-sensitive liposomes for MR-image guided drug delivery with high intensity focused ultrasound.

The goal of this study was to investigate the blood kinetics and biodistribution of temperature-sensitive liposomes (TSLs) for MR image-guided drug delivery. The co-encapsulated doxorubicin and [Gd(HPDO3A)(H2O)] as well as the ¹¹¹In-labeled liposomal carrier were quantified in blood and organs of tumor bearing rats. After TSL injection, mild hyperthermia (T=42 °C) was induced in the tumor using high intensity focused ultrasound under MR image-guidance (MR-HIFU). The biodistribution of the radiolabeled TSLs was investigated using SPECT/CT imaging, where the highest uptake of ¹¹¹In-labeled TSLs was observed in the spleen and liver. The MR-HIFU-treated tumors showed 4.4 times higher liposome uptake after 48 h in comparison with controls, while the doxorubicin concentration was increased by a factor of 7.9. These effects of HIFU-treatment are promising for applications in liposomal drug delivery to tumors.

Magnetic resonance imaging of high intensity focused ultrasound mediated drug delivery from temperature-sensitive liposomes: an in vivo proof-of-concept study.

Temperature-sensitive liposomes (TSLs) co-encapsulating doxorubicin and 250 mM [Gd(HPDO3A)(H2O)] were evaluated for HIFU-mediated drug delivery under MR image guidance. In vitro studies showed simultaneous and quantitative release of the drug and the MRI contrast agent from the lumen of the TSLs at 42°C, while no leakage was observed over 1 h at 37°C. In a proof-of-concept study, local hyperthermia has been applied for 30 min in 9L rat tumors using a clinical MR-HIFU system. The local temperature-triggered release of [Gd(HPDO3A)(H2O)] was monitored with interleaved T1 mapping of the tumor tissue. A good correlation between the ΔR1, the uptake of doxorubicin and the gadolinium concentration in the tumor was found, implying that the in vivo release of doxorubicin from TSLs can be probed in situ with the longitudinal relaxation time of the co-released MRI contrast agent.

A novel approach to identify non-palpable breast lesions combining fluorescent liposomes and magnetic resonance-guided high intensity focused ultrasound-triggered release.

The combination of fluorescein-containing liposomes (FCL) and magnetic resonance-guided high intensity focused ultrasound (MR-HIFU)-triggered release is a promising approach for lesion demarcation and more efficient removal of non-palpable breast lesions. Exposure of FCL to ablation temperatures (60 °C) using MR-HIFU would result in palpable, stained tumors, which are more easy to identify during surgical resection. In this study, proof-of-concept concerning fluorescent FCL for MR-HIFU-triggered release and tumor demarcation of non-palpable breast lesions is presented. Ex vivo experiments in human blood and porcine muscle tissue showed increased label release from the liposomes, clear fluorescence enhancement and diffusion of the released compound after heating to 60 °C. Next, fluorescein release of FCL was observed after MR-HIFU-mediated mild hyperthermia (42 °C) and ablation temperature (60 °C) for a short period (30s), which is in line with the clinically relevant MR-HIFU treatment parameters. These results indicate the potential of the FCL as a tool to improve tumor demarcation in patients by MR-HIFU-triggered release. Therefore, this method may offer a new tool for efficient surgical resection of non-palpable breast tumor lesions by enabling proper discrimination between tumor tissue and adjacent healthy tissue.

On the use of steady-state signal equations for 2D TrueFISP imaging.

To explain the signal behavior in 2D-TrueFISP imaging, a slice excitation profile should be considered that describes a variation of effective flip angles and magnetization phases after excitation. These parameters can be incorporated into steady-state equations to predict the final signal within a pixel. The use of steady-state equations assumes that excitation occurs instantaneously, although in reality this is a nonlinear process. In addition, often the flip angle variation within the slice excitation profile is solely considered when using steady-state equations, while TrueFISP is especially known for its sensitivity to phase variations. The purpose of this study was therefore to evaluate the precision of steady-state equations in calculating signal intensities in 2D TrueFISP imaging. To that end, steady-state slice profiles and corresponding signal intensities were calculated as function of flip angle, RF phase advance and pulse shape. More complex Bloch simulations were considered as a gold standard, which described every excitation within the sequence until steady state was reached. They were used to analyze two different methods based on steady-state equations. In addition, measurements on phantoms were done with corresponding imaging parameters. Although the Bloch simulations described the steady-state slice profile formation better than methods based on steady-state equations, the latter performed well in predicting the steady-state signal resulting from it. In certain cases the phase variation within the slice excitation profile did not even have to be taken into account.