Repeated dynamic [18F]FDG PET/CT imaging using a high-sensitivity PET/CT scanner for assessing non-small cell lung cancer patients undergoing induction immuno-chemotherapy followed by hypo-fractionated chemoradiotherapy and consolidative immunotherapy: report from a prospective observational study (GASTO-1067).

OBJECTIVE: The study aims to investigate the role of dynamic [18F]FDG PET/CT imaging by high-sensitivity PET/CT scanner for assessing patients with locally advanced non-small cell lung cancer (LA-NSCLC) who undergo induction immuno-chemotherapy, followed by concurrent hypo-fractionated chemoradiotherapy (hypo-CCRT) and consolidative immunotherapy. METHODS: Patients with unresectable LA-NSCLC are prospectively recruited. Dynamic [18F]FDG PET/CT scans are conducted at four timepoints: before treatment (Baseline), after induction immuno-chemotherapy (Post-IC), during hypo-CCRT (Mid-hypo-CCRT) and after hypo-CCRT (Post-hypo-CCRT). The primary lung tumors (PTs) are manually delineated, and the metabolic features, including the Patlak-Ki (Ki), maximum SUV (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have been evaluated. The expressions of CD3, CD8, CD68, CD163, CD34 and Ki67 in primary lung tumors at baseline are assayed by immunohistochemistry. The levels of blood lymphocytes at four timepoints are analyzed with flow cytometry. RESULTS: Fifteen LA-NSCLC patients are enrolled between December 2020 and December 2022. Baseline Ki of primary tumor yields the highest AUC values of 0.722 and 0.796 for predicting disease progression and patient death, respectively. Patients are classified into the High FDG Ki group (n = 8, Ki > 2.779 ml/min/100 g) and the Low FDG Ki group (n = 7, Ki ≤ 2.779 ml/min/100 g). The High FDG Ki group presents better progression-free survival (P = 0.01) and overall survival (P = 0.025). The High FDG Ki group exhibits more significant reductions in Ki after hypo-CCRT compared to the Low FDG Ki group. Patients with a reduction in Ki > 73.1% exhibit better progression-free survival than those with a reduction ≤ 73.1% in Ki (median: not reached vs. 7.33 months, P = 0.12). The levels of CD3+ T cells (P = 0.003), CD8+ T cells (P = 0.002), CD68+ macrophages (P = 0.071) and CD163+ macrophages (P = 0.012) in primary tumor tissues are higher in the High FDG Ki group. The High FDG Ki group has higher CD3+CD8+ lymphocytes in blood at baseline (P = 0.108), post-IC (P = 0.023) and post-hypo-CCRT (P = 0.041) than the Low FDG Ki group. CONCLUSIONS: The metabolic features in the High FDG Ki group significantly decrease during the treatment, particularly after induction immuno-chemotherapy. The Ki value of primary tumor shows significant relationship with the treatment response and survival in LA-NSCLC patients by the combined immuno-chemoradiotherapy regimen. TRIAL REGISTRATION: ClinicalTrials.gov. NCT04654234. Registered 4 December 2020.

Performance Characteristics of the NeuroEXPLORER, a Next-Generation Human Brain PET/CT Imager.

The collaboration of Yale, the University of California, Davis, and United Imaging Healthcare has successfully developed the NeuroEXPLORER, a dedicated human brain PET imager with high spatial resolution, high sensitivity, and a built-in 3-dimensional camera for markerless continuous motion tracking. It has high depth-of-interaction and time-of-flight resolutions, along with a 52.4-cm transverse field of view (FOV) and an extended axial FOV (49.5 cm) to enhance sensitivity. Here, we present the physical characterization, performance evaluation, and first human images of the NeuroEXPLORER. Methods: Measurements of spatial resolution, sensitivity, count rate performance, energy and timing resolution, and image quality were performed adhering to the National Electrical Manufacturers Association (NEMA) NU 2-2018 standard. The system's performance was demonstrated through imaging studies of the Hoffman 3-dimensional brain phantom and the mini-Derenzo phantom. Initial 18F-FDG images from a healthy volunteer are presented. Results: With filtered backprojection reconstruction, the radial and tangential spatial resolutions (full width at half maximum) averaged 1.64, 2.06, and 2.51 mm, with axial resolutions of 2.73, 2.89, and 2.93 mm for radial offsets of 1, 10, and 20 cm, respectively. The average time-of-flight resolution was 236 ps, and the energy resolution was 10.5%. NEMA sensitivities were 46.0 and 47.6 kcps/MBq at the center and 10-cm offset, respectively. A sensitivity of 11.8% was achieved at the FOV center. The peak noise-equivalent count rate was 1.31 Mcps at 58.0 kBq/mL, and the scatter fraction at 5.3 kBq/mL was 36.5%. The maximum count rate error at the peak noise-equivalent count rate was less than 5%. At 3 iterations, the NEMA image-quality contrast recovery coefficients varied from 74.5% (10-mm sphere) to 92.6% (37-mm sphere), and background variability ranged from 3.1% to 1.4% at a contrast of 4.0:1. An example human brain 18F-FDG image exhibited very high resolution, capturing intricate details in the cortex and subcortical structures. Conclusion: The NeuroEXPLORER offers high sensitivity and high spatial resolution. With its long axial length, it also enables high-quality spinal cord imaging and image-derived input functions from the carotid arteries. These performance enhancements will substantially broaden the range of human brain PET paradigms, protocols, and thereby clinical research applications.

Chemical Structure Diversity and Extensive Biological Functions of Specialized Metabolites in Rice.

Rice (Oryza sativa L.) is thought to have been domesticated many times independently in China and India, and many modern cultivars are available. All rice tissues are rich in specialized metabolites (SPMs). To date, a total of 181 terpenoids, 199 phenolics, 41 alkaloids, and 26 other types of compounds have been detected in rice. Some volatile sesquiterpenoids released by rice are known to attract the natural enemies of rice herbivores, and play an indirect role in defense. Momilactone, phytocassane, and oryzalic acid are the most common diterpenoids found in rice, and are found at all growth stages. Indolamides, including serotonin, tryptamine, and N-benzoylserotonin, are the main rice alkaloids. The SPMs mainly exhibit defense functions with direct roles in resisting herbivory and pathogenic infections. In addition, phenolics are also important in indirect defense, and enhance wax deposition in leaves and promote the lignification of stems. Meanwhile, rice SPMs also have allelopathic effects and are crucial in the regulation of the relationships between different plants or between plants and microorganisms. In this study, we reviewed the various structures and functions of rice SPMs. This paper will provide useful information and methodological resources to inform the improvement of rice resistance and the promotion of the rice industry.

Esterification with a Long-Chain Fatty Acid Elevates the Exposure Toxicity of Tigliane Diterpenoids from Euphorbia fischeriana Roots against Nematodes.

In this study, two tigliane diterpenoids, 12-deoxyphorbol-13-hexadecanoate and 12-deoxyphorbol-13-acetate (prostratin), were identified from the methanol extract of the roots of Euphorbia fischeriana and were found to have the ability to significantly reduce the survival of Caenorhabditis elegans. It was determined that exposure to these two compounds had toxic effects on the growth, reproduction, locomotion behavior, and accumulation of lipids and lipofuscin of the nematodes. Moreover, the transcription levels of the genes associated with lipid accumulation, apoptosis, insulin, and nuclear hormone synthesis in C. elegans were significantly influenced. Interestingly, 12-deoxyphorbol-13-hexadecanoate produced exposure toxicity at lower concentrations than that of prostratin. Pearson correlation analysis indicates that the elevated exposure toxicity of 12-deoxyphorbol-13-hexadecanoate may be the result of differing transcription levels, which result from the differential expression of fat-6, egl-38, and cep-1. These results reveal that esterification with a long-chain fatty acid elevates the exposure toxicity of this tigliane diterpenoid, thus providing a basis for the application of tigliane diterpenoids in plant-derived nematicides.

Structurally diverse specialized metabolites of maize and their extensive biological functions.

Maize originated in southern Mexico and various hybrid varieties have been bred during domestication. All maize tissues are rich in specialized plant metabolites (SPMs), which allow the plants to resist the stresses of herbivores and pathogens or environmental factors. To date, a total of 95 terpenoids, 91 phenolics, 31 alkaloids, and 6 other types of compounds have been identified from maize. Certain volatile sesquiterpenes released by maize plants attract the natural enemies of maize herbivores and provide an indirect defensive function. Kauralexins and dolabralexins are the most abundant diterpenoids in maize and are known to regulate and stabilize the maize rhizosphere microbial community. Benzoxazinoids and benzoxazolinones are the main alkaloids in maize and are found in maize plants at the highest concentrations at the seedling stage. These two kinds of alkaloids directly resist herbivory and pathogenic infection. Phenolics enhance the cross-links between maize cell walls. Meanwhile, SPMs also regulate plant-plant relationships. In conclusion, SPMs in maize show a large diversity of chemical structures and broad-spectrum biological activities. We use these to provide ideas and information to enable the improvement of maize resistances through breeding and to promote the rapid development of the maize industry.

Inoculation with carbofuran-degrading rhizobacteria promotes maize growth through production of IAA and regulation of the release of plant-specialized metabolites.

Toxic residues of the insecticide carbofuran in farmland is an urgent problem, and high concentrations of carbofuran have been found in the rhizoshperic soil of maize treated with seed coating agents 120-180 days after planting. Using an enrichment co-culture method, we identify a bacterial strain obtained from these carbofuran-contaminated rhizosphere soils as Leclercia adecarboxylata MCH-1. This strain exhibited a significant ability to degrade both carbofuran and 3-keto carbofuran, with total degradation of 55.6 ± 4.6% and 75.7 ± 3.4%, respectively, 24 h following start of co-culture. Further activity screening revealed that the inoculation of maize roots with L. adecarboxylata MCH-1 promoted maize seedling growth. Quantitative analysis demonstrated that this bacterial strain had the ability to synthesize the phytohormone IAA. Simultaneously, the concentration of IAA in the rhizospheric soil increased following inoculation of maize roots with L. adecarboxylata MCH-1. Moreover, the concentrations of plant specialized metabolites, including phenolics, terpenoids, and alkaloids, decreased in maize seedlings and were elevated in the rhizospheric soil after maize roots had been inoculated with the MCH-1 strain. Interestingly, the growth of the strain MCH-1 was improved by co-culture with root exudates obtained from the rhizospheric soil, specifically 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, and zealexin A1 (ZA1). Taken together, our results suggest that the carbofuran-degrading rhizobacterium L. adecarboxylata MCH-1 is able to interact with maize plants through the regulation of maize root exudates. Moreover, inoculation with L. adecarboxylata MCH-1 promotes maize growth through the production of IAA and regulation of the release of plant specialized metabolites. Our results provide a new model organism for the remediation of farmland soils from pollution with carbofuran residues.

An open, prospective cohort study of VV116 in Chinese participants infected with SARS-CoV-2 omicron variants.

Omicron variant of SARS-CoV-2 has become the predominant variant worldwide. VV116 is an oral drug with robust anti-SARS-CoV-2 efficacy in preclinical studies. We conducted an open, prospective cohort study to evaluate its safety and effectiveness in Chinese participants infected with the omicron variant from March 8th, 2022 to March 24th, 2022. 136 hospitalized nonsevere patients confirmed with COVID-19 were enrolled including 60 patients who received VV116 (300 mg, BID×5 days) in the treatment group and 76 patients who didn't receive VV116 in the control group besides standard treatment. Viral load shedding time and adverse events were collected during the follow-up. There was no significant difference in baseline characteristics between the VV116 group and the control group, except for a higher symptom prevalence in the control group (P = 0.021). The median time from the first positive test to the first VV116 administration was 5 (range: 2-10) days. Participants who received VV116 within 5 days since the first positive test had a shorter viral shedding time than the control group (8.56 vs 11.13 days), and cox regression analysis showed adjusted HR of 2.37 [95%CI 1.50-3.75], P < 0.001. In symptomatic subgroup, VV116 group had a shorter viral shedding time than the control group (P = 0.016). A total of 9 adverse events with no serious adverse events were reported in the VV116 group, all of them were resolved without intervention. VV116 is a safe, effective oral antiviral drug, which shows a better performance within the early onset of omicron infection.

Root exudate sesquiterpenoids from the invasive weed Ambrosia trifida regulate rhizospheric Proteobacteria.

The adaption of Ambrosia trifida to the environment to which it has been introduced is crucial to its successful invasion. Microbial diversity analyses suggested that the abundance of Proteobacteria was relatively high in rhizospheric soil surrounding A. trifida roots. Three of these bacterial taxa were isolated and identified as Acinetobacter sp. LHD-1, Pseudomonas sp. LHD-12, and Enterobacter sp. LHD-19. Furthermore, three sesquiterpenoids were authenticated as the main metabolites in the root exudates of A. trifida, and include one new germacrane sesquiterpenoid (1E,4E)-germacrdiene-6ß,15-diol (2) and two known sesquiterpenoids, (E)-4ß,5α-epoxy-7αH-germacr-1(10)-ene-2ß,6ß-diol (1) and (2R)-δ-cadin-4-ene-2,10-diol (3). Their chemical structures were elucidated using NMR spectroscopy and single crystal X-ray diffraction analyses. In UPLC-MS/MS analyses, compounds 1-3 showed values of 10.29 ± 2.21, 0.02 ± 0.01, and 0.78 ± 0.52 µg/g FW, respectively, in A. trifida rhizospheric soil. Interestingly, those compounds were able to inhibit the growth of Acinetobacter sp. LHD-1 and promote the growth of Enterobacter sp. LHD-19 where concentrations were close to those secreted into rhizospheric soil. Furthermore, the rhizospheric bacteria Acinetobacter sp. LHD-1 and Enterobacter sp. LHD-19 were able to regulate the growth of A. trifida seedlings in potted planting verification experiments. Interestingly, root exudate sesquiterpenoids could also improve the concentration of IAA in Enterobacter sp. LHD-19, indicating that this bacterium may promote plant growth through regulating the IAA pathway. These results provided new evidence for the rapid adaptation of plants to new environments, allowing their invasive behavior.

Potential and Most Relevant Applications of Total Body PET/CT Imaging.

ABSTRACT: The introduction of total body (TB) PET/CT instruments over the past 2 years has initiated a new and exciting era in medical imaging. These instruments have substantially higher sensitivity (up to 68 times) than conventional modalities and therefore allow imaging the entire body over a short period. However, we need to further refine the imaging protocols of this instrument for different indications. Total body PET will allow accurate assessment of the extent of disease, particularly, including the entire axial and appendicular skeleton. Furthermore, delayed imaging with this instrument may enhance the sensitivity of PET for some types of cancer. Also, this modality may improve the detection of venous thrombosis, a common complication of cancer and chemotherapy, in the extremities and help prevent pulmonary embolism. Total body PET allows assessment of atherosclerotic plaques throughout the body as a systematic disease. Similarly, patients with widespread musculoskeletal disorders including both oncologic and nononcologic entities, such as degenerative joint disease, rheumatoid arthritis, and osteoporosis, may benefit from the use of TB-PET. Finally, quantitative global disease assessment provided by this approach will be superior to conventional measurements, which do not reflect overall disease activity. In conclusion, TB-PET imaging may have a revolutionary impact on day-to-day practice of medicine and may become the leading imaging modality in the future.

Degraded Metabolites of Phlorizin Promote Germination of Valsa mali var. mali in its Host Malus spp.

Plant pathogenic fungi are able to utilize the principal metabolites of their hosts, which is one reason pathogens can so seriously harm the plants, although the mechanisms behind this utilization are not always clear. Valsa mali var. mali is a pathogenic fungus specific to the plant genus Malus. The fungus can seriously endanger apple crops and has caused serious economic losses. Phlorizin (1), the principal component in the stems, roots, and leaves of Malus pumila and M. sieversii, was able to promote spore germination of Valsa mali var. mali (Vmm-30) significantly over 120-168 h in a non-nutritional suspension. Compared with the control, the concentrations of nine phenolic compounds (3-11) in the stems of M. pumila increased after inoculation with Vmm-30. Moreover, compounds 3, 4, and 9-11 were able to promote the germination of Vmm-30 spores over 24-36 h, which was a significantly shorter time than that of phlorizin. High-performance liquid chromatography with diode-array detection (HPLC-DAD) and ultraperformance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) analyses further suggested that compounds 2-11 were the degradation products of phlorizin (1) and are produced through carbon oxidation cracking, decarboxylation, and oxidation reactions. This suggests that the degradation of phlorizin is able to effectively promote the growth of Vmm-30. The Vmm-30 strain is therefore able to utilize the principal metabolite phlorizin to generate a series of degradation products, which further promote its germination and the infection of its host plants in the genus Malus.

Whole-Body Parametric Imaging of 18F-FDG PET Using uEXPLORER with Reduced Scanning Time.

Parametric imaging of the net influx rate (Ki ) in 18F-FDG PET has been shown to provide improved quantification and specificity for cancer detection compared with SUV imaging. Current methods of generating parametric images usually require a long dynamic scanning time. With the recently developed uEXPLORER scanner, a dramatic increase in sensitivity has reduced the noise in dynamic imaging, making it more robust to use a nonlinear estimation method and flexible protocols. In this work, we explored 2 new possible protocols besides the standard 60-min one for the possibility of reducing scanning time for Ki imaging. Methods: The gold standard protocol (protocol 1) was conventional dynamic scanning with a 60-min scanning time. The first proposed protocol (protocol 2) included 2 scanning periods: 0-4 min and 54-60 min after injection. The second proposed protocol (protocol 3) consisted of a single scanning period from 50 to 60 min after injection, with a second injection applied at 56 min. The 2 new protocols were simulated from the 60-min standard scans. A hybrid input function combining the population-based input function and the image-derived input function (IDIF) was used. The results were also compared with the IDIF acquired from protocol 1. A previously developed maximum-likelihood approach was used to estimate the Ki images. In total, 7 cancer patients imaged using the uEXPLORER scanner were enrolled in this study. Lesions were identified from the patient data, and the lesion Ki values were compared among the different protocols. Results: The acquired hybrid input function was comparable in shape to the IDIF for each patient. The average difference in area under the curve was about 3%, suggesting good quantitative accuracy. The visual difference between the Ki images generated using IDIF and those generated using the hybrid input function was also minimal. The acquired Ki images using different protocols were visually comparable. The average Ki difference in the lesions was 2.8% ± 2.1% for protocol 2 and 1% ± 2.2% for protocol 3. Conclusion: The results suggest that it is possible to acquire Ki images using the nonlinear estimation approach with a much-reduced scanning time. Between the 2 new protocols, the protocol with dual injection shows the greatest promise in terms of practicality.

Baicalin attenuates diet-induced obesity partially through promoting thermogenesis in adipose tissue.

BACKGROUND: Adipose tissues have essential roles on energy homeostasis and the development of metabolic syndrome and obesity, they have become critical targets for treating obesity and metabolic disorders. Baicalin is a flavonoid that derived from the root of Scutellaria baicalensis, and it has been reported to take part in the regulation of adipocyte function. All these highlighted the potential of baicalin in the regulation of fat accumulation and obesity. Yet the impact of baicalin on thermogenic function of adipocytes remains to be deciphered. OBJECTIVE: This study aims to explore the anti-obesity effects of baicalin. MATERIALS & METHODS: The level of mRNA was detected by qRT-PCR and the protein expression level was examined by western blot. H&E staining was used for the observation of the structure of adipose tissue. Serum triglyceride and insulin levels were detected by commercial test kits. RESULTS: Our data demonstrated that baicalin up-regulates the expression of UCP1 and PGC1a in a dose-dependent manner in vitro. Baicalin also increases ERK phosphorylation, and the increased expression of UCP1 and PGC1a in adipocytes could be inhibited by an ERK inhibitor, U0126. Moreover, dietary baicalin ameliorates high fat diet (HFD)-induced obesity without affecting food intake. In addition, dietary baicalin inhibits adipocyte hypertrophy and enhances thermogenic gene program in sWAT and intrascapular brown adipose tissue (iBAT) in vivo. DISCUSSION & CONCLUSION: Baicalin prevents HFD-induced obesity partially through promoting adipocyte thermogenesis. Baicalin may be a promising compound against human obesity and related metabolic diseases.

Performance Evaluation of the uEXPLORER Total-Body PET/CT Scanner Based on NEMA NU 2-2018 with Additional Tests to Characterize PET Scanners with a Long Axial Field of View.

The world's first total-body PET scanner with an axial field of view (AFOV) of 194 cm is now in clinical and research use at our institution. The uEXPLORER PET/CT system is the first commercially available total-body PET scanner. Here we present a detailed physical characterization of this scanner based on National Electrical Manufacturers Association (NEMA) NU 2-2018 along with a new set of measurements devised to appropriately characterize the total-body AFOV. Methods: Sensitivity, count-rate performance, time-of-flight resolution, spatial resolution, and image quality were evaluated following the NEMA NU 2-2018 protocol. Additional measurements of sensitivity and count-rate capabilities more representative of total-body imaging were performed using extended-geometry phantoms based on the world-average human height (∼165 cm). Lastly, image quality throughout the long AFOV was assessed with the NEMA image quality (IQ) phantom imaged at 5 axial positions and over a range of expected total-body PET imaging conditions (low dose, delayed imaging, short scan duration). Results: Our performance evaluation demonstrated that the scanner provides a very high sensitivity of 174 kcps/MBq, a count-rate performance with a peak noise-equivalent count rate of approximately 2 Mcps for total-body imaging, and good spatial resolution capabilities for human imaging (≤3.0 mm in full width at half maximum near the center of the AFOV). Excellent IQ, excellent contrast recovery, and low noise properties were illustrated across the AFOV in both NEMA IQ phantom evaluations and human imaging examples. Conclusion: In addition to standard NEMA NU 2-2018 characterization, a new set of measurements based on extending NEMA NU 2-2018 phantoms and experiments was devised to characterize the physical performance of the first total-body PET system. The rationale for these extended measurements was evident from differences in sensitivity, count-rate-activity relationships, and noise-equivalent count-rate limits imposed by differences in dead time and randoms fraction between the NEMA NU 2 70-cm phantoms and the more representative total-body imaging phantoms. Overall, the uEXPLORER PET system provides ultra-high sensitivity that supports excellent spatial resolution and IQ throughout the field of view in both phantom and human imaging.

Total-Body Quantitative Parametric Imaging of Early Kinetics of 18F-FDG.

Parametric imaging has been shown to provide better quantitation physiologically than SUV imaging in PET. With the increased sensitivity from a recently developed total-body PET scanner, whole-body scans with higher temporal resolution become possible for dynamic analysis and parametric imaging. In this paper, we focus on deriving the parameter k1 using compartmental modeling and on developing a method to acquire whole-body 18F-FDG PET parametric images using only the first 90 s of the postinjection scan data with the total-body PET system. Methods: Dynamic projections were acquired with a time interval of 1 s for the first 30 s and a time interval of 2 s for the following minute. Image-derived input functions were acquired from the reconstructed dynamic sequences in the ascending aorta. A 1-tissue-compartment model with 4 parameters (k1, k2, blood fraction, and delay time) was used. A maximum-likelihood-based estimation method was developed with the 1-tissue-compartment model solution. The accuracy of the acquired parameters was compared with the ones estimated using a 2-tissue-compartment irreversible model with 1-h-long data. Results: All 4 parametric images were successfully calculated using data from 2 volunteers. By comparing the time-activity curves acquired from the volumes of interest, we showed that the parameters estimated using our method were able to predict the time-activity curves of the early dynamics of 18F-FDG in different organs. The delay-time effects for different organs were also clearly visible in the reconstructed delay-time image with delay variations of as large as 40 s. The estimated parameters using both 90-s data and 1-h data agreed well for k1 and blood fraction, whereas a large difference in k2 was found between the 90-s and 1-h data, suggesting k2 cannot be reliably estimated from the 90-s scan. Conclusion: We have shown that with total-body PET and the increased sensitivity, it is possible to estimate parametric images based on the very early dynamics after 18F-FDG injection. The estimated k1 might potentially be used clinically as an indicator for identifying abnormalities.

Total-Body Dynamic Reconstruction and Parametric Imaging on the uEXPLORER.

The world's first 194-cm-long total-body PET/CT scanner (uEXPLORER) has been built by the EXPLORER Consortium to offer a transformative platform for human molecular imaging in clinical research and health care. Its total-body coverage and ultra-high sensitivity provide opportunities for more accurate tracer kinetic analysis in studies of physiology, biochemistry, and pharmacology. The objective of this study was to demonstrate the capability of total-body parametric imaging and to quantify the improvement in image quality and kinetic parameter estimation by direct and kernel reconstruction of the uEXPLORER data. Methods: We developed quantitative parametric image reconstruction methods for kinetic analysis and used them to analyze the first human dynamic total-body PET study. A healthy female subject was recruited, and a 1-h dynamic scan was acquired during and after an intravenous injection of 256 MBq of 18F-FDG. Dynamic data were reconstructed using a 3-dimensional time-of-flight list-mode ordered-subsets expectation maximization (OSEM) algorithm and a kernel-based algorithm with all quantitative corrections implemented in the forward model. The Patlak graphical model was used to analyze the 18F-FDG kinetics in the whole body. The input function was extracted from a region over the descending aorta. For comparison, indirect Patlak analysis from reconstructed frames and direct reconstruction of parametric images from the list-mode data were obtained for the last 30 min of data. Results: Images reconstructed by OSEM showed good quality with low noise, even for the 1-s frames. The image quality was further improved using the kernel method. Total-body Patlak parametric images were obtained using either indirect estimation or direct reconstruction. The direct reconstruction method improved the parametric image quality, having a better contrast-versus-noise tradeoff than the indirect method, with a 2- to 3-fold variance reduction. The kernel-based indirect Patlak method offered image quality similar to the direct Patlak method, with less computation time and faster convergence. Conclusion: This study demonstrated the capability of total-body parametric imaging using the uEXPLORER. Furthermore, the results showed the benefits of kernel-regularized reconstruction and direct parametric reconstruction. Both can achieve superior image quality for tracer kinetic studies compared with the conventional indirect OSEM for total-body imaging.

First Human Imaging Studies with the EXPLORER Total-Body PET Scanner.

Within the EXPLORER Consortium, the construction of the world's first total-body PET/CT scanner has recently been completed. The 194-cm axial field of view of the EXPLORER PET/CT scanner is sufficient to cover, for the first time, the entire human adult body in a single acquisition in more than 99% of the population and allows total-body pharmacokinetic studies with frame durations as short as 1 s. The large increase in sensitivity arising from total-body coverage as well as increased solid angle for detection at any point within the body allows whole-body 18F-FDG PET studies to be acquired with unprecedented count density, improving the signal-to-noise ratio of the resulting images. Alternatively, the sensitivity gain can be used to acquire diagnostic PET images with very small amounts of activity in the field of view (25 MBq, 0.7 mCi or less), with very short acquisition times (∼1 min or less) or at later time points after the tracer's administration. We report here on the first human imaging studies on the EXPLORER scanner using a range of different protocols that provide initial evidence in support of these claims. These case studies provide the foundation for future carefully controlled trials to quantitatively evaluate the improvements possible through total-body PET imaging.

A Novel Data-Driven Cardiac Gating Signal Extraction Method for PET.

Compared to external device based approaches, a data-driven gating technique in PET imaging is advantageous as it does not require additional hardware or procedure. Currently, data-driven cardiac gating is less studied than respiratory gating. The aim of this paper is to develop a robust data-driven cardiac gating approach for clinical application. First, the central location of the heart is obtained from the corresponding CT image. A cylinder-shaped volume of interest (VOI) centered at the central location of the heart is used to confine cardiac signal calculation. The cardiac signal modeling the expansion/contraction of the heart is calculated using the second order moment of the tracer distribution in the VOI in the projection domain. The signal-to-noise ratio (SNR) of the cardiac motion signal is defined as the energy of the cardiac frequency components over the energy of other non-cardiac frequencies. The optimal cardiac signal with maximal SNR is obtained through an iterative optimization of signal extraction parameters. To validate our method, simulations of different scan parameters including tracer uptake and noise level were generated from the 4D XCAT phantom. Quantitative evaluation was achieved by comparing the extracted signal with the truth in the simulation study. Our method was also applied to 19 patients with high myocardium uptake and compared with the conventional center-of-mass based data-driven method. The simulation study suggests that two major limiting factors in the performance of our method are the myocardium/body uptake ratio and the count rate of the whole field of view. High accuracy of the detected signal was observed with myocardium/body uptake ratio > 7 and count rate > 100 counts/ms. Cardiac peak frequencies were successfully detected in all 19 patients using our method, while the conventional method obtained peaks in only 12 data sets. Our method was also visually validated by gated reconstructions. In summary, we have developed a novel dedicated data-driven cardiac gating method for PET by tracking the contraction/expansion of the heart during the scan. Quantitative evaluation using simulations and qualitative validation with clinical datasets both demonstrate that our method is a robust alternative to the device-based method with a high success rate.

Joint activity and attenuation estimation for PET with TOF data and single events.

Maximum likelihood reconstruction of activity and attenuation (MLAA) for PET data with time-of-flight (TOF) information can determine the activity distribution up to a scale, and the attenuation map Radon transform up to a related constant. Prior knowledge is widely used for the determination of the constant. However, prior knowledge could be inaccurate due to patient variation and may result in quantitation errors. Our goal is to develop a method that can determine the scale and the related constant in the TOF-MLAA algorithm to obtain quantitatively accurate activity and attenuation maps. Our idea is to utilize the single events which have depth dependent attenuation factors, contrary to coincidence events. We show that in a 2D case, with the combination of TOF information and single events, a unique solution of attenuation and activity can be achieved. A three-step iterative image reconstruction algorithm is developed. In each iteration, the activity distribution is first updated using the MLEM approach with TOF PET data; the attenuation map is then updated using MLTR with non-TOF data; finally, both activity distribution and attenuation map are updated using a scale estimated from single events. Noisy and noise-free projection data are generated for 2D XCAT phantoms through analytical simulation. Both scatter information and randoms information are assumed to be known. The proposed method and the conventional TOF-MLAA algorithm are used to reconstruct the simulated data. Conventional MLEM method with known attenuation map is implemented for comparison as well. Normalized root mean square error (NRMSE) and optimal constant are defined for the quantitative analysis of reconstructed images. Our proposed image reconstruction method achieves ~1% NRMSE for the activity map and ~5% NRMSE for the attenuation map with a correct scale after 150 iterations for noise-free data. Results of noisy simulations are consistent with noise-free data. In summary, we have proposed to use the single events for constant determination in TOF-MLAA algorithm to obtain a unique solution of attenuation map and activity distribution without prior information. Future work will be dedicated to the extension of our method to the 3D situation.

Self-Gating: An Adaptive Center-of-Mass Approach for Respiratory Gating in PET.

The goal is to develop an adaptive center-of-mass (COM)-based approach for device-less respiratory gating of list-mode positron emission tomography (PET) data. Our method contains two steps. The first is to automatically extract an optimized respiratory motion signal from the list-mode data during acquisition. The respiratory motion signal was calculated by tracking the location of COM within a volume of interest (VOI). The signal prominence (SP) was calculated based on Fourier analysis of the signal. The VOI was adaptively optimized to maximize SP. The second step is to automatically correct signal-flipping effects. The sign of the signal was determined based on the assumption that the average patient spends more time during expiration than inspiration. To validate our methods, thirty-one 18F-FDG patient scans were included in this paper. An external device-based signal was used as the gold standard, and the correlation coefficient of the data-driven signal with the device-based signal was measured. Our method successfully extracted respiratory signal from 30 out of 31 datasets. The failure case was due to lack of uptake in the field of view. Moreover, our sign determination method obtained correct results for all scans excluding the failure case. Quantitatively, the proposed signal extraction approach achieved a median correlation of 0.85 with the device-based signal. Gated images using optimized data-driven signal showed improved lesion contrast over static image and were comparable to those using device-based signal. We presented a new data-driven method to automatically extract respiratory motion signal from list-mode PET data by optimizing VOI for COM calculation, as well as determine motion direction from signal asymmetry. Successful application of the proposed method on most clinical datasets and comparison with device-based signal suggests its potential of serving as an alternative to external respiratory monitors.

An image reconstruction method with a locally adaptive gating scheme for PET data.

In conventional gating approaches for positron emission tomography (PET), a single number of gates is predetermined for the whole field of view (FOV) regardless of spatially variant motion blurring effects, which compromises image quality by under-gating regions of large motion and over-gating static regions. To achieve the best resolution-noise trade-off for the whole FOV, we proposed a new approach that incorporates a spatially variant number of gates into gated image reconstruction. The first step was to estimate the motion amplitude of each spatial location. A preliminary set of gated image reconstructions was generated from the PET data. The spatially variant motion amplitudes were approximated based on the registration of 2D maximum intensity projections of the gated reconstructions as well as prior knowledge. Second, the spatially varying motion amplitudes were used to determine the optimal number of gates for each region. Finally, the adaptive gating image reconstruction algorithm that incorporates a gating transform function to model the spatially variant number of gates was applied to generate adaptively gated 4D images. Scans from large FOV systems were simulated using actual multi-bed patient data from a clinical scanner for evaluation purposes. Images reconstructed with the conventional gating scheme as well as static reconstruction were obtained for comparison with the results obtained using our new method. In areas with lower estimated motion amplitudes (such as the spine), the reconstructed images using the new approach showed reduced noise compared to images with conventional gated reconstructions and comparable quality with non-gated images. In areas with large estimated motion amplitudes, such as in the lung and liver, contrast and resolution of images using the new method and conventional gated-reconstructions were comparable, and both were higher than those of non-gated images. The results indicate that using a locally adaptive number of gates based on respiratory motion amplitude instead of a fixed number of gates can improve the statistics of gated PET images by optimizing the local noise-resolution trade-off.