Immunotherapies, especially checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) antibodies, have transformed cancer treatment by enhancing the immune systems capability to target and kill cancer cells. However, predicting immunotherapy response remains challenging. 18F-arabinosyl guanine ([18F]F-AraG) is a molecular imaging tracer targeting activated T cells, which may facilitate therapy response assessment by noninvasive quantification of immune cell activity within the tumor microenvironment and elsewhere in the body. The aim of this study was to obtain preliminary data on total-body pharmacokinetics of [18F]F-AraG as a potential quantitative biomarker for immune response evaluation. Methods: The study consisted of 90-min total-body dynamic scans of 4 healthy subjects and 1 non-small cell lung cancer patient who was scanned before and after anti-PD-1 immunotherapy. Compartmental modeling with Akaike information criterion model selection was used to analyze tracer kinetics in various organs. Additionally, 7 subregions of the primary lung tumor and 4 mediastinal lymph nodes were analyzed. Practical identifiability analysis was performed to assess the reliability of kinetic parameter estimation. Correlations of the SUVmean, the tissue-to-blood SUV ratio (SUVR), and the Logan plot slope (K Logan) with the total volume of distribution (V T) were calculated to identify potential surrogates for kinetic modeling. Results: Strong correlations were observed between K Logan and SUVR with V T, suggesting that they can be used as promising surrogates for V T, especially in organs with a low blood-volume fraction. Moreover, practical identifiability analysis suggested that dynamic [18F]F-AraG PET scans could potentially be shortened to 60 min, while maintaining quantification accuracy for all organs of interest. The study suggests that although [18F]F-AraG SUV images can provide insights on immune cell distribution, kinetic modeling or graphical analysis methods may be required for accurate quantification of immune response after therapy. Although SUVmean showed variable changes in different subregions of the tumor after therapy, the SUVR, K Logan, and V T showed consistent increasing trends in all analyzed subregions of the tumor with high practical identifiability. Conclusion: Our findings highlight the promise of [18F]F-AraG dynamic imaging as a noninvasive biomarker for quantifying the immune response to immunotherapy in cancer patients. Promising total-body kinetic modeling results also suggest potentially wider applications of the tracer in investigating the role of T cells in the immunopathogenesis of diseases.

Objective.Contrast recovery coefficient (CRC) is essential for image quality (IQ) assessment in positron emission tomography (PET), typically measured according to the National Electrical Manufacturers Association (NEMA) NU 2 standard. This study quantifies systematic uncertainties of the CRC measurement by a numerical investigation of the effects from scanner-independent parameters like voxel size, region-of-interest (ROI) misplacement, and sphere position on the underlying image grid.Approach.CRC measurements with 2D and 3D ROIs were performed on computer-generated images of a NEMA IQ-like phantom, using voxel sizes of 1-4 mm for sphere diameters of 5-40 mm-first in absence of noise and blurring, then with simulated spatial resolution and image noise with varying noise levels. The systematic uncertainties of the CRC measurement were quantified from above variations of scanner-independent parameters. Subsampled experimental images of a NEMA IQ phantom were additionally used to investigate the impact of ROI misplacement at different noise levels.Main results.In absence of noise and blurring, systematic uncertainties were up to 28.8% and 31.0% with 2D and 3D ROIs, respectively, for the 10 mm sphere, with the highest impact from ROI misplacement. In all cases, smaller spheres showed higher uncertainties with larger voxels. Contrary to prior assumptions, the use of 3D ROIs did not exhibit less susceptibility for parameter changes. Experimental and computer-generated images both demonstrated considerable variations on individual CRC measurements when background coefficient-of-variation exceeded 20%, despite negligible effects on mean CRC.Significance.This study underscores the effect of scanner-independent parameters on reliability, reproducibility, and comparability of CRC measurements. Our findings highlight the trade-off between the benefits of smaller voxel sizes and noise-induced CRC fluctuations, which is not considered in the current version of the NEMA IQ standards. The results furthermore warrant adjustments to the standard to accommodate the advances in sensitivity and spatial resolution of current-generation PET scanners.

Total-body PET has come a long way from its first conception to today, with both total-body and long axial field of view (> 1m) scanners now being commercially available world-wide. The conspicuous signal collection efficiency gain, coupled with high spatial resolution, allows for higher sensitivity and improved lesion detection, enhancing several clinical applications not readily available on current conventional PET/CT scanners. This technology can provide (a) reduction in acquisition times with preservation of diagnostic quality images, benefitting specific clinical situations (i.e. pediatric patients) and the use of several existing radiotracers that present transient uptake over time and where small differences in acquisition time can greatly impact interpretation of images; (b) reduction in administered activity with minimal impact on image noise, thus reducing effective dose to the patient, improving staff safety, and helping with logistical concerns for short-lived radionuclides or long-lived radionuclides with poor dosimetry profiles that have had limited use on conventional PET scanners until now; (c) delayed scanning, that has shown to increase the detection of even small and previously occult malignant lesions by improved clearance in regions of significant background activity and by reduced visibility of coexisting inflammatory processes; (d) improvement in image quality, as a consequence of higher spatial resolution and sensitivity of total-body scanners, implying better appreciation of small structures and clinical implications with downstream prognostic consequences for patients; (e) simultaneous total-body dynamic imaging, that allows the measurement of full spatiotemporal distribution of radiotracers, kinetic modeling, and creation of multiparametric images, providing physiologic and biologically relevant data of the entire body at the same time. On the other hand, the higher physical and clinical sensitivity of total-body scanners bring along some limitations and challenges. The strong impact on clinical sensitivity potentially increases the number of false positive findings if the radiologist does not recalibrate interpretation considering the new technique. Delayed scanning causes logistical issues and introduces new interpretation questions for radiologists. Data storage capacity, longer processing and reconstruction time issues are other limitations, but they may be overcome in the near future by advancements in reconstruction algorithms and computing hardware.

The current generation of total-body positron emission tomography (PET) scanners offer significant sensitivity increase with an extended axial imaging extent. With the large volume of lutetium-based scintillation crystals that are used as detector elements in these scanners, there is an increased flux of background radiation originating from ¹⁷⁶Lu decay in the crystals and higher sensitivity for detecting it. Combined with the ability of scanning the entire body in a single bed position, this allows more effective utilization of the lutetium background as a transmission source for estimating 511 keV attenuation coefficients. In this study, utilization of the lutetium background radiation for attenuation correction in total-body PET was studied using Monte Carlo simulations of a 3D whole-body XCAT phantom in the uEXPLORER PET scanner, with particular focus on ultralow-dose PET scans that are now made possible with these scanners. Effects of an increased acceptance angle, reduced scan durations, and Compton scattering on PET quantification were studied. Furthermore, quantification accuracy of lutetium-based attenuation correction was compared for a 20-min scan of the whole body on the uEXPLORER, a one-meter-long, and a conventional 24-cm-long scanner. Quantification and lesion contrast were minimally affected in both long axial field-of-view scanners and in a whole-body 20-min scan, the mean bias in all analyzed organs of interest were within a ±10% range compared to ground-truth activity maps. Quantification was affected in certain organs, when scan duration was reduced to 5 min or a reduced acceptance angle of 17° was used. Analysis of the Compton scattered events suggests that implementing a scatter correction method for the transmission data will be required, and increasing the energy threshold from 250 keV to 290 keV can reduce the computational costs and data rates, with negligible effects on PET quantification. Finally, the current results can serve as groundwork for transferring lutetium-based attenuation correction into research and clinical practice.

Transarterial radioembolization (TARE) is a locoregional radiopharmaceutical therapy based on the delivery of radioactive ⁹⁰Y microspheres to liver tumors. The importance of personalized dosimetry to make TARE safer and more effective has been demonstrated in recent clinical studies, stressing the need for quantification of the dose-response relationship to ultimately optimize the administered activity before treatment and image it after treatment. ⁹⁰Y dosimetric studies are challenging because of the lack of accurate and precise methods but are best realized with PET combined with Monte Carlo simulations and other image modalities to calculate a segmental dose distribution. The aim of this study was to assess the suitability of imaging ⁹⁰Y PET patients with the total-body PET/CT uEXPLORER and to investigate possible improvements in TARE ⁹⁰Y PET-based dosimetry. The uEXPLORER is the first commercially available ultra-high-resolution (171 cps/kBq) total-body digital PET/CT device with a 194-cm axial PET field of view that enables the whole body to be scanned at a single bed position. Methods: Two PET/CT scanners were evaluated in this study: the Biograph mCT and the total-body uEXPLORER. Images of a National Electrical Manufacturers Association (NEMA) image-quality phantom and 2 patients were reconstructed using our standard clinical oncology protocol. A late portal phase contrast-enhanced CT scan was used to contour the liver segments and create corresponding volumes of interest. To calculate the absorbed dose, Monte Carlo simulations were performed using Geant4 Application for Tomographic Emission (GATE). The absorbed dose and dose-volume histograms were calculated for all 6 spheres (diameters ranging from 10 to 37 mm) of the NEMA phantom, the liver segments, and the entire liver. Differences between the phantom doses and an analytic ground truth were quantified through the root mean squared error. Results: The uEXPLORER showed a higher signal-to-noise ratio at 10- and 13-mm diameters, consistent with its high spatial resolution and system sensitivity. The total liver-absorbed dose showed excellent agreement between the uEXPLORER and the mCT for both patients, with differences lower than 0.2%. Larger differences of up to 60% were observed when comparing the liver segment doses. All dose-volume histograms were in good agreement, with narrower tails for the uEXPLORER in all segments, indicating lower image noise. Conclusion: This patient study is compelling for the use of total-body ⁹⁰Y PET for liver dosimetry. The uEXPLORER scanner showed a better signal-to-noise ratio than mCT, especially in lower-count regions of interest, which is expected to improve dose quantification and tumor dosimetry.

Conventional whole-body static ¹⁸F-FDG PET imaging provides a semiquantitative evaluation of overall glucose metabolism without insight into the specific transport and metabolic steps. Here we demonstrate the ability of total-body multiparametric ¹⁸F-FDG PET to quantitatively evaluate glucose metabolism using macroparametric quantification and assess specific glucose delivery and phosphorylation processes using microparametric quantification for studying recovery from coronavirus disease 2019 (COVID-19). Methods: The study included 13 healthy subjects and 12 recovering COVID-19 subjects within 8 wk of confirmed diagnosis. Each subject had a 1-h dynamic ¹⁸F-FDG scan on the uEXPLORER total-body PET/CT system. Semiquantitative SUV and the SUV ratio relative to blood (SUVR) were calculated for different organs to measure glucose utilization. Tracer kinetic modeling was performed to quantify the microparametric blood-to-tissue ¹⁸F-FDG delivery rate [Formula: see text] and the phosphorylation rate k ₃, as well as the macroparametric ¹⁸F-FDG net influx rate ([Formula: see text]). Statistical tests were performed to examine differences between healthy subjects and recovering COVID-19 subjects. The effect of COVID-19 vaccination was also investigated. Results: We detected no significant difference in lung SUV but significantly higher lung SUVR and [Formula: see text] in COVID-19 recovery, indicating improved sensitivity of kinetic quantification for detecting the difference in glucose metabolism. A significant difference was also observed in the lungs with the phosphorylation rate k ₃ but not with [Formula: see text], which suggests that glucose phosphorylation, rather than glucose delivery, drives the observed difference of glucose metabolism. Meanwhile, there was no or little difference in bone marrow ¹⁸F-FDG metabolism measured with SUV, SUVR, and [Formula: see text] but a significantly higher bone marrow [Formula: see text] in the COVID-19 group, suggesting a difference in glucose delivery. Vaccinated COVID-19 subjects had a lower lung [Formula: see text] and a higher spleen [Formula: see text] than unvaccinated COVID-19 subjects. Conclusion: Higher lung glucose metabolism and bone marrow glucose delivery were observed with total-body multiparametric ¹⁸F-FDG PET in recovering COVID-19 subjects than in healthy subjects, implying continued inflammation during recovery. Vaccination demonstrated potential protection effects. Total-body multiparametric PET of ¹⁸F-FDG can provide a more sensitive tool and more insights than conventional whole-body static ¹⁸F-FDG imaging to evaluate metabolic changes in systemic diseases such as COVID-19.

Heart failure remains a major source of late morbidity and mortality after myocardial infarction (MI). The temporospatial presence of activated fibroblasts in the injured myocardium predicts the quality of cardiac remodeling after MI. Therefore, monitoring of activated fibroblasts is of great interest for studying cardiac remodeling after MI. Fibroblast activation protein (FAP) expression is upregulated in activated fibroblasts. This study investigated the feasibility of imaging activated fibroblasts with a new ⁶⁸Ga-labeled FAP inhibitor (⁶⁸Ga-FAPI-04) for PET imaging of fibroblast activation in a preclinical model of MI. Methods: MI and sham-operated rats were scanned with ⁶⁸Ga-FAPI-04 PET/CT (1, 3, 6, 14, 23, and 30 d after MI) and with ¹⁸F-FDG (3 d after MI). Dynamic ⁶⁸Ga-FAPI-04 PET and blocking studies were performed on MI rats 7 d after coronary ligation. After in vivo scans, the animals were euthanized and their hearts harvested for ex vivo analyses. Cryosections were prepared for autoradiography, hematoxylin and eosin (H&E), and immunofluorescence staining. Results: ⁶⁸Ga-FAPI-04 uptake in the injured myocardium peaked on day 6 after coronary ligation. The tracer accumulated intensely in the MI territory, as identified by decreased ¹⁸F-FDG uptake and confirmed by PET/MR and H&E staining. Autoradiography and H&E staining of cross-sections revealed that ⁶⁸Ga-FAPI-04 accumulated mainly at the border zone of the infarcted myocardium. In contrast, there was only minimal uptake in the infarct of the blocked rats, comparable to the uptake in the remote noninfarcted myocardium (PET image-derived ratio of infarct uptake to remote uptake: 6 ± 2). Immunofluorescence staining confirmed the presence of FAP-positive myofibroblasts in the injured myocardium. Morphometric analysis of the whole-heart sections demonstrated 3- and 8-fold higher FAP-positive fibroblast density in the border zone than in the infarct center and remote area, respectively. Conclusion: ⁶⁸Ga-FAPI-04 represents a promising radiotracer for in vivo imaging of post-MI fibroblast activation. Noninvasive imaging of activated fibroblasts may have significant diagnostic and prognostic value, which could aid clinical management of patients after MI.

Autoimmune inflammatory arthritides (AIA), such as psoriatic arthritis and rheumatoid arthritis, are chronic systemic conditions that affect multiple joints of the body. Recently, total-body (TB) PET/CT scanners exhibiting superior technical characteristics (total-body coverage, geometric sensitivity) that could benefit AIA evaluation, compared with conventional PET/CT systems, have become available. The objectives of this work were to assess the performance of an ultra-low-dose, ¹⁸F-FDG TB PET/CT acquisition protocol for evaluating systemic joint involvement in AIA and to report the association of TB PET/CT measures with joint-by-joint rheumatologic examination and standardized rheumatologic outcome measures. Methods: Thirty participants (24 with AIA and 6 with osteoarthritis) were prospectively enrolled in this single-center, observational study. All participants underwent a TB PET/CT scan for 20 min starting at 40 min after intravenous injection of 78.1 ± 4.7 MBq of ¹⁸F-FDG. Qualitative and quantitative evaluation of ¹⁸F-FDG uptake and joint involvement were performed from the resulting images and compared with the rheumatologic assessments. Results: TB PET/CT enabled the visualization of ¹⁸F-FDG uptake at joints of the entire body, including those of the hands and feet, in a single bed position, and in the same phase of radiotracer uptake. A range of pathologies consistent with AIA (and non-AIA in the osteoarthritis group) were visualized, and the feasibility of extracting PET measures from joints examined by rheumatologic assessments was demonstrated. Of 1,997 evaluable joints, there was concordance between TB PET qualitative assessments and joint-by-joint rheumatologic evaluation in the AIA and non-AIA cohorts for 69.9% and 91.1% joints, respectively, and an additional 20.1% and 8.8% joints, respectively, deemed negative on rheumatologic examination showed PET positivity. On the other hand, 10.0% and 0% joints in the AIA and non-AIA cohorts, respectively, were positive on rheumatologic evaluation but negative on TB PET. Quantitative measures from TB PET in the AIA cohort demonstrated a moderate-to-strong correlation (Spearman ρ = 0.53-0.70, P < 0.05) with the rheumatologic outcome measures. Conclusion: Systemic joint evaluation in AIA (and non-AIA) is feasible with a TB PET/CT system and an ultra-low-dose protocol. Our results provide the foundation for future larger studies to evaluate the possible improvements in AIA joint assessment via the TB PET/CT technology.

Absolute quantification of regional tissue concentration of radioactivity in positron emission tomography (PET) is a critical parameter-of-interest across various clinical and research applications and is affected by a complex interplay of factors including scanner calibration, data corrections, and image reconstruction. The emergence of long axial field-of-view (FOV) PET systems widens the dynamic range accessible to PET and creates new opportunities in reducing scan time and radiation dose, delayed or low radioactivity imaging, as well as kinetic modeling of the entire human. However, these imaging regimes impose challenging conditions for accurate quantification due to constraints from image reconstruction, low count conditions, as well as large and rapidly changing radioactivity distribution across a large axial FOV. We comprehensively evaluated the quantitative accuracy of the uEXPLORER total-body scanner in conditions that encompass existing and potential imaging applications (such as dynamic imaging and ultralow-dose imaging) using a set of total-body specific phantom and human measurements. Through these evaluations we demonstrated a relative count rate accuracy of ±3%-4% using the NEMA NU 2-2018 protocol, an axial uniformity spread of ±3% across the central 90% axial FOV, and a 3% activity bias spread from 17 to 474 MBq¹⁸F-FDG in a 210 cm long cylindrical phantom. Region-of-interest quantification spread of 1% was found by simultaneously scanning three NEMA NU 2 image quality phantoms, as well as relatively stable volume-of-interest quantification across 0.2%-100% of total counts through re-sampled datasets. In addition, an activity bias spread of -2% to +1% post-bolus injections in human subjects was found. Larger bias changes during the bolus injection phase in humans indicated the difficulty in providing accurate PET data corrections for complex activity distributions across a large dynamic range. Our results overall indicated that the quantitative performance achieved with the uEXPLORER scanner was uniform across the axial FOV and provided the accuracy necessary to support a wide range of imaging applications.

Introduction and objectives

Wound healing after myocardial infarction (MI) is a dynamic and complex multiple phase process, and a coordinated cellular response is required for proper scar formation. The current paradigm suggests that pro-inflammatory monocytes infiltrate the MI zone during the initial pro-inflammatory phase and differentiate into inflammatory macrophages, and then switch their phenotypes to anti-inflammatory during the reparative phase. Visualization of the reparative phase post-MI is of great interest because it may reveal delayed resolution of inflammation, which in turn predicts adverse cardiac remodeling. Imaging of anti-inflammatory macrophages may also be used to assess therapy approaches aiming to modulate the inflammatory response in order to limit MI size. Reparative macrophages can be distinguished from inflammatory macrophages by the surface marker mannose receptor (MR, CD206). In this study we evaluated the feasibility of ⁶⁸Ga-NOTA-anti-MMR Nb for imaging of MR on alternatively activated macrophages in murine MI models.

Methods

Wildtype and MR-knockout mice and Wistar rats were subjected to MI via permanent ligation of the left coronary artery. Non-operated or sham-operated animals were used as controls. MR expression kinetics on cardiac macrophages was measured in mice using flow cytometry. PET/CT scans were performed 1 h after intravenous injection of ⁶⁸Ga-NOTA-anti-MMR Nb. Mice and rats were euthanized and hearts harvested for ex vivo PET/MRI, autoradiography, and staining. As a non-targeting negative control, ⁶⁸Ga-NOTA-BCII10 was used.

Results

In vivo-PET/CT scans showed focal radioactivity signals in the infarcted myocardium for ⁶⁸Ga-NOTA-anti-MMR Nb which were confirmed by ex vivo-PET/MRI scans. In autoradiography images, augmented uptake of the tracer was observed in infarcts, as verified by the histochemistry analysis. Immunofluorescence staining demonstrated the presence and co-localization of CD206- and CD68-positive cells, in accordance to infarct zone. No in vivo or ex vivo signal was observed in the animals injected with control Nb or in the sham-operated animals. ⁶⁸Ga-NOTA-anti-MMR Nb uptake in the infarcts of MR-knockout mice was negligibly low, confirming the specificity of ⁶⁸Ga-NOTA-anti-MMR Nb to MR.

Conclusion

This exploratory study highlights the potential of ⁶⁸Ga-NOTA-anti-MMR Nb to image MR-positive macrophages that are known to play a pivotal role in wound healing that follows acute MI.