Timing Estimation and Limits in TOF-PET Detectors Producing Prompt Photons.

The production of prompt photons providing high photon time densities is a promising avenue to reach ultrahigh coincidence time resolution (CTR) in time-of-flight PET. Detectors producing prompt photons are receiving high interest experimentally, ignited by past exploratory theoretical studies that have anchored some guiding principles. Here, we aim to consolidate and extend the foundations for the analytical modeling of prompt generating detectors. We extend the current models to a larger range of prompt emission kinetics where more stringent requirements on the prompt photon yield rapidly emerge as a limiting factor. Lower bound and estimator evaluations are investigated with different underlying models, notably by merging or keeping separate the prompt and scintillation photon populations. We further show the potential benefits of knowing the proportion of prompt photons within a detection set to improve the CTR by mitigating the detrimental effect of population (prompt vs scintillation) mixing. Taking into account the fluctuations on the average number of detected prompt photons in the model reveals a limited influence when prompt photons are accompanied by fast scintillation (e.g., LSO:Ce:Ca) but a more significant effect when accompanied by slower scintillation (e.g., BGO). Establishing performance characteristics and limitations of prompt generating detectors is paramount to gauging and targeting the best possible timing capabilities they can offer.

Enhanced Extraction of Blood and Tissue Time-Activity Curves in Cardiac Mouse FDG PET Imaging by Means of Constrained Nonnegative Matrix Factorization.

We propose an enhanced method to accurately retrieve time-activity curves (TACs) of blood and tissue from dynamic 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) cardiac images of mice. The method is noninvasive and consists of using a constrained nonnegative matrix factorization algorithm (CNMF) applied to the matrix (A) containing the intensity values of the voxels of the left ventricle (LV) PET image. CNMF factorizes A into nonnegative matrices H and W, respectively, representing the physiological factors (blood and tissue) and their associated weights, by minimizing an extended cost function. We verified our method on 32 C57BL/6 mice, 14 of them with acute myocardial infarction (AMI). With CNMF, we could break down the mouse LV into myocardial and blood pool images. Their corresponding TACs were used in kinetic modeling to readily determine the [18F]FDG influx constant (Ki) required to compute the myocardial metabolic rate of glucose. The calculated Ki values using CNMF for the heart of control mice were in good agreement with those published in the literature. Significant differences in Ki values for the heart of control and AMI mice were found using CNMF. The values of the elements of W agreed well with the LV structural changes induced by ligation of the left coronary artery. CNMF was compared with the recently published method based on robust unmixing of dynamic sequences using regions of interest (RUDUR). A clear improvement of signal separation was observed with CNMF compared to the RUDUR method.

Chemical synthesis of fluorinated and iodinated 17ß-HSD3 inhibitors and evaluation for imaging prostate cancer tumors and tissue biodistribution.

Prostate cancer is the most common cancer among men and the development of new therapeutic agents is needed for its treatment and/or diagnosis. 17ß-hydroxysteroid dehydrogenase type 3 (17ß-HSD3) is involved in the production of androgens, which stimulates the proliferation of prostate cancer cells. Piperazinomethyl-androsterone sulfonamide derivatives were developed as 17ß-HSD3 inhibitors and the concentration of a representative sulfonamide derivative (compound 1) was found to accumulate in prostate tumor tissues relatively to plasma in a mouse xenograft experiment. This finding gives us the opportunity to specifically target the prostate cancer tumors through the development of a radiolabelled version of compound 1 toward targeted molecular radiotherapy or radioimaging diagnosis. The chemical synthesis of fluorinated and iodinated analogs of compound 1 was achieved, leading to a series of compounds with similar levels of inhibition as the initial candidate. From 17ß-HSD3 inhibition activity, molecular modeling and mouse plasma-concentration studies, the most promising compound of this series was selected, its 18F-radiolabelled version (18F-3) synthesized, and imaging/biodistribution studies engaged. When injected in mice, however, 18F-3 uptake in the target tissues (LNCaP[17ß-HSD3] tumors and testicles) was not sufficient to allow their visualization by positron emission tomography. Plasma concentration values of compounds 3-8 administered orally, however, showed that the para-iodo compound 7 is the most metabolically stable and could therefore be an interesting alternative for radiolabelling and radiotreatment.

Investigation of a Model-based Time-over-threshold Technique for Phoswich Crystal Discrimination.

The best crystal identification (CI) algorithms proposed so far for phoswich detectors are based on adaptive filtering and pulse shape discrimination (PSD). However, these techniques require free running analog to digital converters, which is no longer possible with the ever increasing pixelization of new detectors. We propose to explore the dual-threshold time-over-threshold (ToT) technique, used to measure events energy and time of occurence, as a more robust solution for crystal identification with broad energy windows in phoswich detectors. In this study, phoswich assemblies made of various combinations of LGSO and LYSO scintillators with decay times in the range 30 to 65 ns were investigated for the LabPET II detection front-end. The electronic readout is based on a 4 × 8 APD array where pixels are individually coupled to charge sensitive preamplifiers followed by first order CR-RC shapers with 75 ns peaking time. Crystal identification data were sorted out based on the measurements of likeliness between acquired signals and a time domain model of the analog front-end. Results demonstrate that crystal identification can be successfully performed using a dual-threshold ToT scheme with a discrimination accuracy of 99.1% for LGSO (30 ns)/LGSO (45 ns), 98.1% for LGSO (65 ns)/LYSO (40 ns) and 92.1% for LYSO (32 ns)/LYSO (47 ns), for an energy window of [350-650] keV. Moreover, the method shows a discrimination accuracy >97% for the two first pairs and ~90% for the last one when using a wide energy window of [250-650] keV.

Estrogenic impregnation alters pain expression: analysis through functional neuropeptidomics in a surgical rat model of osteoarthritis.

PURPOSE: Several observational studies suggest that estrogens could bias pain perception. To evaluate the influence of estrogenic impregnation on pain expression, a prospective, randomized, controlled, blinded study was conducted in a Sprague-Dawley rat model of surgically induced osteoarthritis (OA). METHODS: Female rats were ovariectomized and pre-emptive 17ß-estradiol (0.025 mg, 90-day release time) or placebo pellets were installed subcutaneously during the OVX procedures. Thirty-five days after, OA was surgically induced on both 17ß-estradiol (OA-E) and placebo (OA-P) groups. Mechanical hypersensitivity was assessed by static weight-bearing (SWB) and paw withdrawal threshold (PWT) tests. Mass spectrometry coupled with high-performance liquid chromatography (HPLC-MS) was performed to quantify the spinal pronociceptive neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), somatostatin (SST), and dynorphin-A (Dyn-A). RESULTS: Compared to control, ovariectomized rats presented higher SP (P = 0.009) and CGRP (P = 0.017) concentrations. OA induction increased the spinal level of SP (+ 33%, P < 0.020) and decreased the release of BK (- 20%, (P < 0.037)). The OA-E rats at functional assessment put more % body weight on the affected hind limb than OA-P rats at D7 (P = 0.027) and D56 (P = 0.033), and showed higher PWT at D56 (P = 0.009), suggesting an analgesic and anti-allodynic effect of 17ß-estradiol. Interestingly, the 17ß-estradiol treatment counteracted the increase of spinal concentration of Dyn-A (P < 0.016) and CGRP (P < 0.018). CONCLUSION: These results clearly indicate that 17ß-estradiol interfers with the development of central sensitization and confirm that gender dimorphism should be considered when looking at pain evaluation.

The ultra high sensitivity blood counter: a compact, MRI-compatible, radioactivity counter for pharmacokinetic studies inµl volumes.

Quantification of physiological parameters in preclinical pharmacokinetic studies based on nuclear imaging requires the monitoring of arterial radioactivity over time, known as the arterial input function (AIF). Continuous derivation of the AIF in rodent models is very challenging because of the limited blood volume available for sampling. To address this challenge, an Ultra High Sensitivity Blood Counter (UHS-BC) was developed. The device detects beta particles in real-time using silicon photodiodes, custom low-noise electronics, and 3D-printed plastic cartridges to hold standard catheters. Two prototypes were built and characterized in two facilities. Sensitivities up to 39% for18F and 58% for11C-based positron emission tomography (PET) tracers were demonstrated.99mTc and125I based Single Photon Emission Computed Tomography (SPECT) tracers were detected with greater than 3% and 10% sensitivity, respectively, opening new applications in nuclear imaging and fundamental biology research. Measured energy spectra show all relevant peaks down to a minimum detectable energy of 20 keV. The UHS-BC was shown to be highly reliable, robust towards parasitic background radiation and electromagnetic interference in the PET or MRI environment. The UHS-BC provides reproducible results under various experimental conditions and was demonstrated to be stable over days of continuous operation. Animal experiments showed that the UHS-BC performs accurate AIF measurements using low detection volumes suitable for small animal models in PET, SPECT and PET/MRI investigations. This tool will help to reduce the time and number of animals required for pharmacokinetic studies, thus increasing the throughput of new drug development.

Simplified size adjusted dose reference levels for adult CT examinations: A regional study.

PURPOSE: To investigate retrospective classification of adult patients into small, average, and large based on effective diameter (EDia) from localizer image of computed tomography (CT) scans and to develop regional diagnostic reference levels (DRLs) and achievable doses (AD). METHOD: The patients falling within the mean ± standard deviation (SD) of EDia were classified as average; those below this range as small and above as large. The CTDIvol,dose-length-product (DLP) and size-specific dose estimates (SSDE) of all adult patients undergoing CT examinations in 8 CT facilities for 11 months (Dec. 2019 - Oct. 2020) were evaluated. The 75th and 50th percentile values were compared with national and international values. RESULTS: Of the total of 69,434 CT examinations, nearly 80% fell within average size. The 75th percentile values of CTDIvol and DLP for small patients for abdomen-pelvic exams were nearly half of average sized patients. Similarly, the 75th percentile values for large patients were nearly double. Similar findings were not found for chest exams. Analysis of image quality and dose factors such as noise, mean axial length, slice thickness, mean number of sequences, use of iterative reconstruction and tube current modulation (TCM) resulted in identification of opportunities for improvement and optimization of different CT facilities. CONCLUSIONS: DRLs for adult patients were found to vary widely with patient size and thus establishing DRLs only for standard sized patient is not adequate. Simplified and intuitive methods for size classification was shown to provide meaningful information for optimization for patients outside the standard size adult.

DOI estimation through signal arrival time distribution: a theoretical description including proof of concept measurements.

The challenge to reach 10 ps coincidence time resolution (CTR) in time-of-flight positron emission tomography (TOF-PET) is triggering major efforts worldwide, but timing improvements of scintillation detectors will remain elusive without depth-of-interaction (DOI) correction in long crystals. Nonetheless, this momentum opportunely brings up the prospect of a fully time-based DOI estimation since fast timing signals intrinsically carry DOI information, even with a traditional single-ended readout. Consequently, extracting features of the detected signal time distribution could uncover the spatial origin of the interaction and in return, provide enhancement on the timing precision of detectors. We demonstrate the validity of a time-based DOI estimation concept in two steps. First, experimental measurements were carried out with current LSO:Ce:Ca crystals coupled to FBK NUV-HD SiPMs read out by fast high-frequency electronics to provide new evidence of a distinct DOI effect on CTR not observable before with slower electronics. Using this detector, a DOI discrimination using a double-threshold scheme on the analog timing signal together with the signal intensity information was also developed without any complex readout or detector modification. As a second step, we explored by simulation the anticipated performance requirements of future detectors to efficiently estimate the DOI and we proposed four estimators that exploit either more generic or more precise features of the DOI-dependent timestamp distribution. A simple estimator using the time difference between two timestamps provided enhanced CTR. Additional improvements were achieved with estimators using multiple timestamps (e.g. kernel density estimation and neural network) converging to the Cramér-Rao lower bound developed in this work for a time-based DOI estimation. This two-step study provides insights on current and future possibilities in exploiting the timing signal features for DOI estimation aiming at ultra-fast CTR while maintaining detection efficiency for TOF PET.

Performance evaluation of the mouse version of the LabPET II PET scanner.

The LabPET II is a new positron emission tomography technology platform designed to achieve submillimetric spatial resolution imaging using fully pixelated avalanche photodiodes-based detectors and highly integrated parallel front-end processing electronics. The detector was designed as a generic building block to develop devices for preclinical imaging of small to mid-sized animals and for clinical imaging of the human brain. The aim of this work is to assess the physical characteristics and imaging performance of the mouse version of LabPET II scanner following the NEMA NU4-2008 standard and using high resolution phantoms and in vivo imaging applications. A reconstructed spatial resolution of 0.78 mm (0.5 µ l) is measured close to the center of the radial field of view. With an energy window of 350 650 keV, the system absolute sensitivity is 1.2% and its maximum noise equivalent count rate reaches 61.1 kcps at 117 MBq. Submillimetric spatial resolution is achieved in a hot spot phantom and tiny bone structures were resolved with unprecedented contrast in the mouse. These results provide convincing evidence of the capabilities of the LabPET II technology for biomolecular imaging in preclinical research.

Improvement of Spatial Resolution with Iterative PET Reconstruction using UltraFast TOF.

The impact of Time-of-Flight (TOF) on positron emission tomography (PET) spatial resolution is generally considered negligible. In this work, a two-step approach based on simulations of two-dimensional scanner configurations is taken to show that ultra-fast TOF has the potential to overcome the limitation induced by the physical size of detectors on spatial resolution. An estimation of the lower bound on spatial resolution using point sources is provided, followed by a qualitative assessment of the resolution obtained using a Hot Spot phantom. The impact of detector width, TOF resolution and TOF binning on the achieved spatial resolution is also studied. While gain beyond the expected blur due to detector size is demonstrated, the detector size remains one limiting factor albeit less prominent. The dependence on acquisition statistics to reach the full potential of TOF-induced gain in spatial resolution is demonstrated. A simulated brain phantom acquired with a fictive three-dimensional PET scanner was qualitatively analyzed and structures smaller than the typical limit are clearly made visible by reconstructing the images with a ∼13-ps TOF resolution. A potential application of this feature of ultra-fast TOF would be the design of clinical PET scanners achieving spatial resolution beyond the current state-of-the-art.

Cross-Species Physiological Assessment of Brain Estrogen Receptor Expression Using 18F-FES and 18F-4FMFES PET Imaging.

PURPOSE: A retrospective analysis was performed of preclinical and clinical data acquired during the evaluation of the estrogen receptor (ER) PET tracer 4-fluoro-11ß-methoxy-16α-[18F]-fluoroestradiol (4FMFES) and its comparison with 16α-[18F]-fluoroestradiol (FES) in mice, rats, and humans with a focus on the brain uptake. PROCEDURES: Breast cancer tumor-bearing female BALB/c mice from a previous study and female Sprague-Dawley rats (control and ovariectomized) were imaged by 4FMFES or FES-PET imaging. Immediately after, low-dose CT was performed in the same bed position. Semi-quantitative analysis was conducted to extract %ID/g data. Small cohorts of mice and rats were imaged with 4FMFES in an ultra-high-resolution small animal PET scanner prototype (LabPET II). Rat brains were dissected and imaged separately with both PET and autoradiography. In parallel, 31 breast cancer patients were enrolled in a clinical phase II study to compare 4FMFES with FES for oncological assessment. Since the head was included in the field of view, brain uptake of discernable foci was measured and reported as SUVMax. RESULTS: Regardless of the species studied, 4FMFES and FES uptake were relatively uniform in most regions of the brain, except for bilateral foci at the base of the skull, at the midsection of the brain. Anatomical localization of the PET signal using CT image fusion indicates that the signal origins from the pituitary in all studied species. 4FMFES yielded lower pituitary uptake than FES in patients, but an inverse trend was observed in rodents. 4FMFES pituitary contrast was higher than FES in all assessed groups. High-resolution small animal imaging of the brain of rats and mice revealed a supplemental signal anterior to the pituitary, which is likely to be the medial preoptic area. Dissection data further confirmed those findings and revealed additional signals corresponding to the arcuate and ventromedial nuclei, along with the medial and cortical amygdala. CONCLUSION: 4FMFES allowed visualization of ER expression in the pituitary in humans and two different rodent species with better contrast than FES. Improvement in clinical spatial resolution might allow visualization and analysis of other ER-rich brain areas in humans. Further work is now possible to link 4FMFES pituitary uptake to cognitive functions.

Experimental validation of a coincidence time resolution metric including depth-of-interaction bias for TOF-PET.

Depth-of-interaction (DOI) variability of annihilation photons is known to be a source of coincidence time resolution (CTR) degradation for fast time-of-flight-positron emission tomography detectors. An analytical model was recently proposed to explicitly include the DOI time bias separately from variance-related statistical factors, such as scintillation photon emission and photosensor jitter, in the CTR evaluation. In the present work, an experimental validation of this new model is provided. An unconventional signal readout configuration was used to magnify the DOI bias with 20 mm long LYSO:Ce crystals. In a head-to-head orientation of the crystals, simulations performed using the metric with DOI bias exhibited a much better agreement (within 21 ps) with the experimentally measured CTR of 413 ± 8 ps full-width at half maximum, whereas simulations without DOI bias underestimated the CTR by 138 ps. The metric including DOI bias was shown to also be effective at predicting the CTR of the head-to-head setup (without DOI information) using data from a DOI-collimated experimental setup (with partial DOI information). With the development of new low-variance ultra-fast detectors, the DOI timing blur will become increasingly important and will need to be taken into account in analytical predictions and in some experimental measurements through the proposed metric.

Dual-Threshold Time-over-Threshold Nonlinearity Correction for PET Detectors.

The Time-over-Threshold (ToT) analog-to-digital signal processing approach provides a power-efficient and cost-effective technique to extract all relevant information from detectors in high-energy physics and Positron Emission Tomography (PET) imaging. In this work, three calibration methods were investigated to correct the inherent nonlinear response of the ToT data using 1) γ-ray sources of various energies, 2) internal electronic gain variation in the LabPET II ASIC in combination with a single energy γ-ray source, and 3) internal gain variation along with an embedded pulse charge generator in replacement of a γ-ray source. The electronic gain calibration technique was shown to achieve equivalent correction accuracy as the γ-ray sources calibration. Furthermore, this method has the advantage of allowing a faster calibration requiring only one single γ-ray source (e.g., 511 keV) and a quick automated routine to sweep the internal gain. The last technique would be the most convenient method, provided that the signal pulse shape would be similar to the detector signal responding to a typical γ-ray event. Whereas the concept was demonstrated with a step pulse, extensive processing would be required to recover the nonlinearity correction factors for the detector pulse shape. After calibration, the 511-keV energy resolution of typical LabPET II detectors was only slightly degraded, by less than 12% and 8% for methods 1) and 2), respectively, relative to a conventional ADC-based data acquisition system. The feasibility of fast and accurate calibration for the nonlinearity correction of ToT data in PET imaging was demonstrated, making a daily quality control within reach.

Cross-validation of a non-invasive positron detector to measure the arterial input function for pharmacokinetic modelling in dynamic positron emission tomography.

Kinetic modeling of positron emission tomography (PET) data can assess index rate of uptake, metabolism and predict disease progression more accurately than conventional static PET. However, it requires knowledge of the time-course of the arterial blood radioactivity concentration, called the arterial input function (AIF). The gold standard to acquire the AIF is by invasive means. The purpose of this study was to validate a previously developed dual readout scintillating fiber-based non-invasive positron detector, hereinafter called non-invasive detector (NID), developed to determine the AIF for dynamic PET measured from the human radial artery. The NID consisted of a 3 m long plastic scintillating fiber with each end coupled to a 5 m long transmission fiber followed by a silicon photomultiplier. The scintillating fiber was enclosed inside the grooves of a plastic cylindrical shell. Two sets of experiments were performed to test the NID against a previously validated microfluidic positron detector. A closed-loop microfluidic system combined with a wrist phantom was used. During the first experiment, the three PET radioisotopes 18F, 11C and 68Ga were tested. After optimizing the detector, a second series of tests were performed using only 18F and 11C. The maximum pulse amplitude to electronic noise ratio was 52 obtained with 11C. Linear regressions showed a linear relation between the two detectors. These preliminary results show that the NID can accurately detect positrons from a patient's wrist and has the potential to non-invasively measure the AIF during a dynamic PET scan. The accuracy of these measurements needs to be determined.

A Thermal Model of the LabPET II ASIC.

The LabPET II detection module is the building block of PET scanners for ultra-high-resolution imaging of small to mid-sized animals and the human brain. For optimal performance, it must be operated at a stable temperature. The detection module is composed of four APD-LYSO detector arrays with two flip-chip ASICs mounted on the backside of an interposer generating 550 mW each. Currently, the scanner architecture includes an air cavity around the electronics and smaller cavities close to the detectors. Cooling down the front-end electronics located in these small cavities becomes problematic as the number of modules increases to address the different targeted configurations of the LabPET II scanners from mouse to human brain geometries. A basic knowledge of the heat distribution is necessary to develop an efficient thermal management in all cases. The aim of this work is to build a model of the LabPET II ASIC and associated PCB for enabling heat flow simulations and circumscribe the thermal management requirements. The Flow Simulation module (SolidWorks), was used to build the thermal model. The ASIC and the interconnection with the PCB were reproduced accurately while some adjacent structures were simplified to ease the simulation burden. The model was applied to simulate three different configurations of printed-circuit boards carrying the ASICs and other components where a fan is turned on/off to create a forced airflow. Each simulation was compared to some experimental measurements. A temperature difference of less than 5 degree Celsius between the simulations and experimental measurements is noticed, giving confidence that the thermal model of the ASIC is valid and transferable to different mechanical assemblies.

A preclinical PET dual-tracer imaging protocol for ER and HER2 phenotyping in breast cancer xenografts.

BACKGROUND: Nuclear medicine is on the constant search of precision radiopharmaceutical approaches to improve patient management. Although discordant expression of the estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2) in breast cancer is a known dilemma for appropriate patient management, traditional tumor sampling is often difficult or impractical. While 2-deoxy-2[18F]fluoro-D-glucose (18F-FDG)-positron emission tomography (PET) is an option to detect subclinical metastases, it does not provide phenotype information. Radiolabeled antibodies are able to specifically target expressed cell surface receptors. However, their long circulating half-lives (days) require labeling with long-lived isotopes, such as 89Zr, in order to allow sufficient time for tracer clearance from the blood compartment and to accumulate adequately in target tumors and, thus, generate high-quality PET images. The aim of this study was to develop a dual-tracer PET imaging approach consisting of a fast-clearing small molecule and a slow-clearing antibody. This approach was evaluated in a model consisting of mice harboring separate breast cancer xenografts with either an ER+/HER2- or ER-/HER2+ phenotype, comparable to human metastatic disease with intertumor heterogeneity. Lastly, the aim of our study was to determine the feasibility of specifically identifying these two important phenotypes in an acceptable time window. METHODS: Female nude mice were subcutaneously implanted on opposite shoulders with the ER+/HER2- and ER-/HER2+ MCF-7 and JIMT-1 tumor cell lines, respectively. A second model was developed consisting of mice implanted orthotopically with either MCF-7 or JIMT-1 cells. Pharmacokinetic analysis, serial PET imaging, and biodistribution were first performed for [89Zr]Zr-DFO-trastuzumab (89Zr-T) up to 8 days post-injection (p.i.) in JIMT-1 bearing mice. Region-of-interest (ROI) and biodistribution-derived uptake (% injected-activity/gram of tissue [%IA/g]) values and tumor-to-background ratios were obtained. Results were compared in order to validate ROI and identify early time points that provided high contrast tumor images. For the dual-tracer approach, cohorts of tumor-bearing mice were then subjected to sequential tracer PET imaging. On day 1, mice were administered 4-fluoro-11ß-methoxy-16α-[18F]-fluoroestradiol (4FMFES) which targets ER and imaged 45 min p.i. This was immediately followed by the injection of 89Zr-T. Mice were then imaged on day 3 or day 7. ROI analysis was performed, and uptake was calculated in tumors and selected healthy organs for all radiotracers. Quality of tumor targeting for all tracers was evaluated by tumor contrast visualization, tumor and normal tissue uptake, and tumor-to-background ratios. RESULTS: 89Zr-T provided sufficiently high tumor and low background uptake values that furnished high contrast tumor images by 48 h p.i. For the dual-tracer approach, 4FMFES provided tumor uptake values that were significantly increased in MCF-7 tumors. When 89Zr-T-PET was combined with 18F-4FMFES-PET, the entire dual-tracer sequential-imaging procedure provided specific high-quality contrast images of ER+/HER2- MCF-7 and ER-/HER2+ JIMT-1 tumors for 4FMFES and 89Zr-T, respectively, as short as 72 h from start to finish. CONCLUSIONS: This protocol can provide high contrast images of tumors expressing ER or HER2 within 3 days from injection of 4FMFES to final scan of 89Zr-T and, hence, provides a basis for future dual-tracer combinations that include antibodies.

MRI-compatibility study of a PET-insert based on a low-profile detection front-end with submillimeter spatial resolution.

PURPOSE: The LabPET II detection module is a potential candidate to create an magnetic resonance imaging (MRI) compatible positron emission tomography (PET)-insert with submillimeter spatial resolution for small animal applications. However, the feasibility of such an insert is hampered by the large radial size of the LabPET II front-end electronics and by components containing ferromagnetic materials. In this paper, a new low-profile front-end design based on the LabPET II architecture, called "low-profile detection module," is investigated. MATERIALS AND METHODS: The performance of the low-profile detection module in the presence of MRI-like RF signals and gradient coil pulses was independently examined. The baseline of the analog signal, its RMS noise level, and the energy resolution, determined by a dual time-over-threshold (dTOT) method for each pixel of the new low-profile detection module, was measured in the presence of RF signals at different frequencies equivalent to the Larmor frequency of 3, 7, and 9.4 T MRI. The same parameters were investigated in the presence of a gradient coil switching at frequencies from 10 to 100 kHz. The performance of the low-profile detection module inside a 7 T MRI and its effects on an MR image have also been studied using gradient echo sequences. The same measurements were repeated for the shielded low-profile detection module, inside and outside the MRI. RESULTS: Our results show that pulses in both the kilohertz and megahertz ranges cause up to 50% increase in the noise level of the baseline (DC analog signal at the output of the shaper filter) and up to 17% degradation in TOT energy resolution. By inserting a conducting composite layer as shielding around the low-profile detection module, these degrading effects were avoided. The performance measurement of the low-profile PET detection module inside a 7 T small animal MRI scanner confirmed that the shielded low-profile detection module behavior was similar inside and outside the MRI bore. In addition, gradient echo images of a water-filled phantom without and with the shielded and unshielded low-profile detection modules were acquired. The results demonstrated no evidence of artifacts in the MR image, either due to eddy currents or ferromagnetic materials with the shielded modules. CONCLUSION: A low-profile detection module based on the LabPET II technology was shown to be a viable candidate as a PET-insert for simultaneous PET/MRI applications considering its thin radial size and its EMI immunity due to placing it between two electronic boards. In comparison to the standard LabPET II detection module, it provides better performance in the presence of electromagnetic interferences, but a shielding layer is still required. When properly shielded, the proposed low-profile detection module can be operated inside an MRI without degrading the PET count rate or the MRI performance.

Publisher Correction: Dichotomic effects of clinically used drugs on tumor growth, bone remodeling and pain management.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Performance investigation of LabPET II detector technology in an MRI-like environment.

The EMI-compatibility of the LabPET II detection module (DM) to develop a high-resolution simultaneous PET/MRI system is investigated. The experimental set-up evaluates the performance of two LabPET II DMs in close proximity to RF coils excited at three different frequencies mimicking the electromagnetic environments of 3 T, 7 T, and 9.4 T MRI scanners. A gradient coil, with switching frequency from 10 kHz to 100 kHz, also surrounds one of the DMs to investigate the effects of the gradient field on the individual detector performance, such as the baseline of the DC-voltage and noise level along with both the energy and coincidence time resolutions. Measurements demonstrate a position shift of the energy photopeaks (⩽9%) and a slight deterioration of the energy and coincidence time resolutions in the presence of electromagnetic interferences from the gradient and RF coils. The electromagnetic interferences cause an average degradation of up to ~50% of the energy resolution (in time-over-threshold spectra) and up to 18% of the timing resolution. Based on these results, a modified version of the DM, including a composite shielding as well as an improved heat pipe-based cooling mechanism, capable of stabilizing the temperature of the DM at ~40 °C, is proposed and investigated. This shielded version shows no evidence of performance degradation inside an MRI-like environment. The experimental results demonstrate that a properly shielded version of the LabPET II DM is a viable candidate for an MR-compatible PET scanner.

Dichotomic effects of clinically used drugs on tumor growth, bone remodeling and pain management.

Improvements in the survival of breast cancer patients have led to the emergence of bone health and pain management as key aspects of patient's quality of life. Here, we used a female rat MRMT-1 model of breast cancer-induced bone pain to compare the effects of three drugs used clinically morphine, nabilone and zoledronate on tumor progression, bone remodeling and pain relief. We found that chronic morphine reduced the mechanical hypersensitivity induced by the proliferation of the luminal B aggressive breast cancer cells in the tumor-bearing femur and prevented spinal neuronal and astrocyte activation. Using MTT cell viability assay and MRI coupled to 18FDG PET imaging followed by ex vivo 3D µCT, we further demonstrated that morphine did not directly exert tumor growth promoting or inhibiting effects on MRMT-1 cancer cells but induced detrimental effects on bone healing by disturbing the balance between bone formation and breakdown. In sharp contrast, both the FDA-approved bisphosphonate zoledronate and the synthetic cannabinoid nabilone prescribed as antiemetics to patients receiving chemotherapy were effective in limiting the osteolytic bone destruction, thus preserving the bone architecture. The protective effect of nabilone on bone metabolism was further accompanied by a direct inhibition of tumor growth. As opposed to zoledronate, nabilone was however not able to manage bone tumor-induced pain and reactive gliosis. Altogether, our results revealed that morphine, nabilone and zoledronate exert disparate effects on tumor growth, bone metabolism and pain control. These findings also support the use of nabilone as an adjuvant therapy for bone metastases.