Search

Objectives This study investigated whether pulmonary artery (PA) 18F-FDG uptake is associated with hypertension, and if it correlates to elevated pulmonary pressures. Background 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with computed tomography or cardiac magnetic resonance (CMR) has been used to assess inflammation mostly in large arteries of the systemic circulation. Much less is known about inflammation of the vasculature of the pulmonary system and its relationship to pulmonary hypertension (PH). Methods In a single-center cohort of 175 patients with suspected cardiac sarcoidosis, who underwent hybrid thoracic PET/CMR, 18F-FDG uptake in the PA was quantified according to maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) and compared with available results from right heart catheterization (RHC) or transthoracic echocardiography (TTE). Results Thirty-three subjects demonstrated clear 18F-FDG uptake in the PA wall. In the subgroup of patients who underwent RHC (n = 10), the mean PA pressure was significantly higher in the group with PA 18F-FDG uptake compared with the group without uptake (34.4 ± 7.2 mm Hg vs 25.6 ± 9.3 mm Hg; P = 0.003), and 9 (90%) patients with PA 18F-FDG uptake had PH when a mean PA pressure cutoff of 25 mm Hg was used compared with 18 (45%) in the nonuptake group (P Conclusions We demonstrate that 18F-FDG uptake by PET/CMR in the PA is associated with PH and that its intensity correlates with PA pressure.

PURPOSE: This study aimed to (i) develop Magnetization-Prepared Golden-angle RAdial Sparse Parallel (MP-GRASP) MRI using a stack-of-stars trajectory for rapid free-breathing T1 mapping and (ii) extend MP-GRASP to multi-echo acquisition (MP-Dixon-GRASP) for fat/water-separated (water-specific) T1 mapping. METHODS: An adiabatic non-selective 180° inversion-recovery pulse was added to a gradient-echo-based golden-angle stack-of-stars sequence for magnetization-prepared 3D single-echo or 3D multi-echo acquisition. In combination with subspace-based GRASP-Pro reconstruction, the sequence allows for standard T1 mapping (MP-GRASP) or fat/water-separated T1 mapping (MP-Dixon-GRASP), respectively. The accuracy of T1 mapping using MP-GRASP was evaluated in a phantom and volunteers (brain and liver) against clinically accepted reference methods. The repeatability of T1 estimation was also assessed in the phantom and volunteers. The performance of MP-Dixon-GRASP for water-specific T1 mapping was evaluated in a fat/water phantom and volunteers (brain and liver). RESULTS: ROI-based mean T1 values are correlated between the references and MP-GRASP in the phantom (R(2) = 1.0), brain (R(2) = 0.96), and liver (R(2) = 0.73). MP-GRASP achieved good repeatability of T1 estimation in the phantom (R(2) = 1.0), brain (R(2) = 0.99), and liver (R(2) = 0.82). Water-specific T1 is different from in-phase and out-of-phase composite T1 (composite T1 when fat and water signal are mixed in phase or out of phase) both in the phantom and volunteers. CONCLUSION: This work demonstrated the initial performance of MP-GRASP and MP-Dixon-GRASP MRI for rapid 3D T1 mapping and 3D fat/water-separated T1 mapping in the brain (without motion) and in the liver (during free breathing). With fat/water-separated T1 estimation, MP-Dixon-GRASP could be potentially useful for imaging patients with fatty-liver diseases.

Funder: Engineering and Physical Sciences Research Council, Funder: Higher Education Funding Council for England, Funder: NIHR Cambridge Biomedical Research Centre, Funder: British Heart Foundation, In recent years, cardiovascular immuno-imaging by positron emission tomography (PET) has undergone tremendous progress in preclinical settings. Clinically, two approved PET tracers hold great potential for inflammation imaging in cardiovascular patients, namely FDG and DOTATATE. While the former is a widely applied metabolic tracer, DOTATATE is a relatively new PET tracer targeting the somatostatin receptor 2 (SST2). In the current study, we performed a detailed, head-to-head comparison of DOTATATE-based radiotracers and [18F]F-FDG in mouse and rabbit models of cardiovascular inflammation. For mouse experiments, we labeled DOTATATE with the long-lived isotope [64Cu]Cu to enable studying the tracer's mode of action by complementing in vivo PET/CT experiments with thorough ex vivo immunological analyses. For translational PET/MRI rabbit studies, we employed the more widely clinically used [68Ga]Ga-labeled DOTATATE, which was approved by the FDA in 2016. DOTATATE's pharmacokinetics and timed biodistribution were determined in control and atherosclerotic mice and rabbits by ex vivo gamma counting of blood and organs. Additionally, we performed in vivo PET/CT experiments in mice with atherosclerosis, mice subjected to myocardial infarction and control animals, using both [64Cu]Cu-DOTATATE and [18F]F-FDG. To evaluate differences in the tracers' cellular specificity, we performed ensuing ex vivo flow cytometry and gamma counting. In mice subjected to myocardial infarction, in vivo [64Cu]Cu-DOTATATE PET showed higher differential uptake between infarcted (SUVmax 1.3, IQR, 1.2-1.4, N = 4) and remote myocardium (SUVmax 0.7, IQR, 0.5-0.8, N = 4, p = 0.0286), and with respect to controls (SUVmax 0.6, IQR, 0.5-0.7, N = 4, p = 0.0286), than [18F]F-FDG PET. In atherosclerotic mice, [64Cu]Cu-DOTATATE PET aortic signal, but not [18F]F-FDG PET, was higher compared to controls (SUVmax 1.1, IQR, 0.9-1.3 and 0.5, IQR, 0.5-0.6, respectively, N = 4, p = 0.0286). In both models, [64Cu]Cu-DOTATATE demonstrated preferential accumulation in macrophages with respect to other myeloid cells, while [18F]F-FDG was taken up by macrophages and other leukocytes. In a translational PET/MRI study in atherosclerotic rabbits, we then compared [68Ga]Ga-DOTATATE and [18F]F-FDG for the assessment of aortic inflammation, combined with ex vivo radiometric assays and near-infrared imaging of macrophage burden. Rabbit experiments showed significantly higher aortic accumulation of both [68Ga]Ga-DOTATATE and [18F]F-FDG in atherosclerotic (SUVmax 0.415, IQR, 0.338-0.499, N = 32 and 0.446, IQR, 0.387-0.536, N = 27, respectively) compared to control animals (SUVmax 0.253, IQR, 0.197-0.285, p = 0.0002, N = 10 and 0.349, IQR, 0.299-0.423, p = 0.0159, N = 11, respectively). In conclusion, we present a detailed, head-to-head comparison of the novel SST2-specific tracer DOTATATE and the validated metabolic tracer [18F]F-FDG for the evaluation of inflammation in small animal models of cardiovascular disease. Our results support further investigations on the use of DOTATATE to assess cardiovascular inflammation as a complementary readout to the widely used [18F]F-FDG.

Subject motion in positron emission tomography (PET) is a key factor that degrades image resolution and quality, limiting its potential capabilities. Correcting for it is complicated due to the lack of sufficient measured PET data from each position. This poses a significant barrier in calculating the amount of motion occurring during a scan. Motion correction can be implemented at different stages of data processing either during or after image reconstruction, and once applied accurately can substantially improve image quality and information accuracy. With the development of integrated PET-MRI (magnetic resonance imaging) scanners, internal organ motion can be measured concurrently with both PET and MRI. In this review paper, we explore the synergistic use of PET and MRI data to correct for any motion that affects the PET images. Different types of motion that can occur during PET-MRI acquisitions are presented and the associated motion detection, estimation and correction methods are reviewed. Finally, some highlights from recent literature in selected human and animal imaging applications are presented and the importance of motion correction for accurate kinetic modelling in dynamic PET-MRI is emphasized. This article is part of the theme issue ‘Synergistic tomographic image reconstruction: part 2’.

This study investigated whether pulmonary artery (PA)In a single-center cohort of 175 patients with suspected cardiac sarcoidosis, who underwent hybrid thoracic PET/CMR,Thirty-three subjects demonstrated clearWe demonstrate that

Acute bacterial endocarditis is a rapid, difficult to manage, and frequently lethal disease. Potent antibiotics often cannot efficiently kill Staphylococcus aureus that colonizes the heart’s valves. S. aureus relies on virulence factors to evade therapeutics and the host’s immune response, usurping the host’s clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor–binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we codeveloped therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, are bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor–binding protein in mice with S. aureus endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal, and improved survival. Aortic or tricuspid S. aureus endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging. Our data map a route toward adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.

Despite well-established dosimetry in clinical radiotherapy, dose measurements in pre-clinical and radiobiology studies are frequently inadequate, thus undermining the reliability and reproducibility of published findings. The lack of suitable dosimetry protocols, coupled with the increasing complexity of pre-clinical irradiation platforms, undermines confidence in preclinical studies and represents a serious obstacle in the translation to clinical practice. To accurately measure output of a pre-clinical radiotherapy unit, appropriate Codes of Practice (CoP) for medium energy x-rays needs to be employed. However, determination of absorbed dose to water (Dw) relies on application of backscatter factor (Bw) employing in-air method or carrying out in-phantom measurement at the reference depth of 2 cm in a full backscatter (i.e. 30 × 30 × 30 cm3) condition. Both of these methods require thickness of at least 30 cm of underlying material, which are never fulfilled in typical pre-clinical irradiations. This work is focused on evaluation the effects of the lack of recommended reference conditions in dosimetry measurements for pre-clinical settings and is aimed at extending the recommendations of the current CoP to practical experimental conditions and highlighting the potential impact of the lack of correct backscatter considerations on radiobiological studies. ispartof: PHYSICS IN MEDICINE AND BIOLOGY vol:65 issue:8 ispartof: location:England status: published

Although the first nanomedicine was clinically approved more than two decades ago, nanoparticles' (NP) in vivo behavior is complex and the immune system's role in their application remains elusive. At present, only passive-targeting nanoformulations have been clinically approved, while more complicated active-targeting strategies typically fail to advance from the early clinical phase stage. This absence of clinical translation is, among others, due to the very limited understanding for in vivo targeting mechanisms. Dynamic in vivo phenomena such as NPs' real-time targeting kinetics and phagocytes' contribution to active NP targeting remain largely unexplored. To better understand in vivo targeting, monitoring NP accumulation and distribution at complementary levels of spatial and temporal resolution is imperative. Here, we integrate in vivo positron emission tomography/computed tomography imaging with intravital microscopy and flow cytometric analyses to study αvβ3-integrin-targeted cyclic arginine-glycine-aspartate decorated liposomes and oil-in-water nanoemulsions in tumor mouse models. We observed that ligand-mediated accumulation in cancerous lesions is multifaceted and identified "NP hitchhiking" with phagocytes to contribute considerably to this intricate process. We anticipate that this understanding can facilitate rational improvement of nanomedicine applications and that immune cell-NP interactions can be harnessed to develop clinically viable nanomedicine-based immunotherapies. This work was supported by the Central Norway Regional Health Authority ‘Helse Midt-Norge’ [AMS: PhD stipend (90062100) and travel grant (90284100); SH: researcher grant (90262100)], the National Institutes of Health (WJMM: R01 CA220234, TR: P30 CA00574), the American Heart Association (CPM: 16SDG31390007), the Norwegian Research Council (SH: 230788/F20), and the Tromsø Research Foundation and Trond Mohn Foundation (SH: 180 °N project). Sí

Item does not contain fulltext Nanomedicine research produces hundreds of studies every year, yet very few formulations have been approved for clinical use. This is due in part to a reliance on murine studies, which have limited value in accurately predicting translational efficacy in larger animal models and humans. Here, we report the scale-up of a nanoimmunotherapy from mouse to large rabbit and porcine atherosclerosis models, with an emphasis on the solutions we implemented to overcome production and evaluation challenges. Specifically, we integrated translational imaging readouts within our workflow to both analyze the nanoimmunotherapeutic's in vivo behavior and assess treatment response in larger animals. We observed our nanoimmunotherapeutic's anti-inflammatory efficacy in mice, as well as rabbits and pigs. Nanoimmunotherapy-mediated reduction of inflammation in the large animal models halted plaque progression, supporting the approach's translatability and potential to acutely treat atherosclerosis.

Acute bacterial endocarditis is a rapid, difficult to manage and frequently lethal disease. Potent antibiotics often cannot efficiently kill Staphylococcus aureus (S. aureus) that colonizes the heart’s valves. S. aureus relies on virulence factors to evade therapeutics and the host’s immune response, usurping the host’s clotting system by activating circulating prothrombin with staphylocoagulase and von Willebrand factor-binding protein. An insoluble fibrin barrier then forms around the bacterial colony, shielding the pathogen from immune cell clearance. Targeting virulence factors may provide previously unidentified avenues to better diagnose and treat endocarditis. To tap into this unused therapeutic opportunity, we co-developed therapeutics and multimodal molecular imaging to probe the host-pathogen interface. We introduced and validated a family of small-molecule optical and positron emission tomography (PET) reporters targeting active thrombin in the fibrin-rich environment of bacterial colonies. The imaging agents, based on the clinical thrombin inhibitor dabigatran, bound to heart valve vegetations in mice. Using optical imaging, we monitored therapy with antibodies neutralizing staphylocoagulase and von Willebrand factor binding protein in mice with S. aureus endocarditis. This treatment deactivated bacterial defenses against innate immune cells, decreased in vivo imaging signal and improved survival. Aortic or tricuspid S. aureus endocarditis in piglets was also successfully imaged with clinical PET/magnetic resonance imaging (MRI). Our data map a route towards adjuvant immunotherapy for endocarditis and provide efficient tools to monitor this drug class for infectious diseases.

Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.

The investigation of the performance of different positron emission tomography (PET) reconstruction and motion compensation methods requires accurate and realistic representation of the anatomy and motion trajectories as observed in real subjects during acquisitions. The generation of well-controlled clinical datasets is difficult due to the many different clinical protocols, scanner specifications, patient sizes, and physiological variations. Alternatively, computational phantoms can be used to generate large data sets for different disease states, providing a ground truth. Several studies use registration of dynamic images to derive voxel deformations to create moving computational phantoms. These phantoms together with simulation software generate raw data. This paper proposes a method for the synthesis of dynamic PET data using a fast analytic method. This is achieved by incorporating realistic models of respiratory motion into a numerical phantom to generate datasets with continuous and variable motion with magnetic resonance imaging (MRI)-derived motion modeling and high resolution MRI images. In this paper, data sets for two different clinical traces are presented, 18F-FDG and 68Ga-PSMA. This approach incorporates realistic models of respiratory motion to generate temporally and spatially correlated MRI and PET data sets, as those expected to be obtained from simultaneous PET–MRI acquisitions.

We have carried out a PET performance evaluation a silicon photo-multiplier (SiPM) based PET scanner designed for fully simultaneous pre-clinical PET/MR studies. The PET scanner has an inner diameter of 20 cm with an LYSO crystal size of 1.3 by 1.3 by 10 mm. The axial PET field of view (FOV) is 30.2 mm. The PET detector modules, which incorporate SiPMs, have been designed to be MR-compatible allowing them to be located directly within a Philips Achieva 3T MR scanner. The spatial resolution of the system measured using a point source in a non-active background, is just under 2.3 mm full width at half maximum (FWHM) in the transaxial direction when single slice rebinning (SSRB) and 2D filtered back-projection (FBP) is used for reconstruction, and 1.3 mm FWHM when resolution modeling is employed. The system sensitivity is 0.6% for a point source at the center of the FOV. The true coincidence count rate shows no sign of saturating at 30 MBq, at which point the randoms fraction is 8.2%, and the scatter fraction for a rat sized object is approximately 23%. Artifact-free images of phantoms have been obtained using FBP and iterative reconstructions. The performance is currently limited because only one of three axial ring positions is populated with detectors, and due to limitations of the first-generation detector readout ASIC used in the system. The performance of the system as described is sufficient for simultaneous PET-MR imaging of rat-sized animals and large organs within the mouse. This is demonstrated with dynamic PET and MR data acquired simultaneously from a mouse injected with a dual-labeled PET/MR probe.

Positron Emission Tomography (PET) is an imaging method affected by artifacts caused by patient motion. PET-MR simultaneous acquisition may provide the means to correct for the effects of motion. This study investigates the creation of a deformable PVA cryogel phantom for motion correction purposes in PET-MR. This phantom has to contain the appropriate concentration of PVA and a sufficient amount of radioactive tracer along with gadolinium contrast agent. The effect of modifying the standard PVA cryogel process were assessed by measuring differences in the Young's modulus and also the diffusion of radiotracer inside the phantom. The alteration of the freeze-thaw cycle decreased the Young's modulus up to 50% by comparison with the standard MRI cryogel phantom. The diffusion speed on the other hand was found to be at 2 mm h-1 inside a 10% p.w. cryogel. The results are demonstrated with a simultaneous PET-MR experiment. The new approach of cryogel preparation provides the opportunity to create a PET and MR visible phantom with structural complexity and customized shape, which is capable of reproducible deformations when reproducible pressure is applied. The methodology to build the phantom can be used in other simultaneous or sequential imaging modalities such as SPECT and ultrasound.

The full potential of simultaneous PET and MRI image acquisition, such as dynamic studies or motion compensation, can only be explored if the data of both modalities are temporally synchronized. These hybrid imaging systems are often realized as custom made PET inserts for commercially available MRI scanner. Unfortunately, the standard MRIs do not always offer easily programmable synchronization outputs, nor can they be modified. Here, we demonstrate a simple method for temporal synchronization that does not require a connection to the MRI. It uses the normally undesired effect of induced voltages on the PET electronics by switching MRI gradients. In our preclinical PET/RF inserts the PET detector electronics are located in RF-tight housings between the gradient coil and the RF coil. Unlike RF fields, gradient fields penetrate the housings due to their relatively low frequencies. A dedicated coil system was made from traces and vias on the PET detector board. It captures induced voltages from the switching gradients and a time-stamped gradient trigger message is added to the PET data stream. Temporal alignment between PET and MRI data can be made at the beginning of each MRI sequence by detecting its first gradient or by recognizing its preparation phase. From then on, the MRI time can be translated to the PET time. Detecting the preparation phase of an MRI sequence was tested with a standard survey sequence (for brain) using the PET/RF insert “Hyperion I” inside a Philips 3T Achieva MRI. The three crusher gradient pulses (slew rate = 25 mT/m/ms) used during noise level determination can clearly be recognized in the data from the sensors. As a first application the sensors were used to synchronize PET and MRI time to facilitate MRI based PET motion compensation of a deforming breathing phantom.

The images shown prove the feasibility of our method for the production of an anatomically relevant phantom that can be used to represent a 177Lu-DOTATATE or other radiopharmaceutical distribution in patients for the purpose of investigating image quantification for applications such as dosimetry or functional volume segmentation. The images produced are similar in appearance to those acquired for real patients. The use of a range of sphere diameters mimics the range of lesion sizes that take up activity in tumours.

Respiratory motion can degrade PET image quality and various correction approaches have been investigated. A novel method, applicable to simultaneous PET-MR is to measure the motion with the MR and correct the PET data with the known motion fields. This study investigates the effectiveness of motion correction for PET-MR acquisition with phantom studies. It incorporates the improved motion estimation or a simultaneously acquired MR with the realism of a respiratory driven motion and the deformability of the PVA cryogel phantom. PVA cryogel has been used for motion modeling because of its elastic properties. Motion is transferred with a hydraulic system to the MR room, inside the PET insert. The MR-compatible PET insert uses silicon photomultiplier photodetectors and acquisition is capable of being synchronized with the MRI. Spatial registration between PET and MR is essential for accurate motion correction using MRI derived motion fields. We have performed simultaneous PET and MR acquisition of a non-rigid continuously deformable phantom PET and MR visible phantom. Calibration procedures were used to ensure that PET and MR acquisitions were accurately aligned both spatially and temporally. The final step of this study is the motion correction by using known techniques such as Motion Compensated Image Reconstruction (MCIR) and Reconstruct-Transform-Average (RTA). We have demonstrated that the temporally and spatially correlated PET and MR datasels can be used to motion correct the PET acquisition

Efforts to characterise the factors that affect the accuracy of image based quantification in nuclear medicine imaging and the development of methods to correct for them are often based in the first instance on phantom experiments using radioactive test objects. Poly-vinyl alcohol (PVA) cryogel is a tissue-equivalent material that sees widespread use as a medical imaging phantom material in other imaging modalities but is not in common use in nuclear medicine. We present a simple method to manufacture radioactive PVA cryogel test objects using moulds designed and made in house. Six spherical test objects were produced with diameters ranging from 0.5 to 4 cm without the need for an outer layer of attenuating material. The test objects were made using 10% PVA solution mixed with 177Lu to give an activity concentration of approximately 0.3 MBq ml−1. The mixture was injected into the moulds and frozen at approximately −20 °C for approximately 14 h then allowed to thaw for approximately 6 h. SPECT/CT images of the test objects were acquired both in air and with the test objects inserted into a torso phantom. The images obtained demonstrate the feasibility of our method for the production of anatomically relevant phantoms for testing image quantification and functional volume segmentation regimes.

Positron Emission Tomography (PET) is an imaging method affected by motion artifacts. PET-MR simultaneous acquisition may provide a means to correct for the effects of motion. Evaluation and development of motion correction techniques requires the development of phantoms capable for continuous and realistic motion. For this study, phantoms have been developed for sequential or simultaneous PET-MR motion-correction experiments. The phantoms contain different levels of deformation. While the first phantom is consisted of rigid materials, the new approach is the use of polyvinyl alcohol (PVA) cryogel phantom for this study. The elasticity of the PVA cryogel, combined with the motion by a computer guided motor unit provides the necessary complexity and accuracy of motion, required for sequential or simultaneous PET-MR experiments with motion incorporation. These phantoms, combined with the already established methodology, could provide the advantage to address issues such as the optimization of gating and motion estimation/correction algorithms in PET.

In simultaneous PET-MR systems, the emitted positrons trajectory is influenced by the magnetic field. The aim of this study is to define that influence to the positron annihilation distribution. Monte Carlo methods have been applied, using GATE. Several isotopes were studied, in various types of materials and with different magnetic field strengths. The results showed variations in the positron range between different components and especially between the lung and water. Measurements of the 1-D positron annihilation distance indicated a reduction of the mean positron annihilation distance for 82Rb of ~25%, 68Ga of 19% and 18F of 3.5%, at 3 Tesla. When the magnetic field was increased to 9.5 Tesla, the reduction was significant for all isotopes, and mainly for 68Ga and 82Rb, with approximately 41% reduction of the mean positron annihilation distance in water. Finally, the positron annihilation distribution varies according to the alignment with the magnetic field lines. The results of this study could be used to improve positron annihilation correction algorithms for simultaneous PET-MR acquisition, by taking under consideration the non-isotropic distribution.