ImmunoPET imaging of Trop2 in patients with solid tumours.

Accurately predicting and selecting patients who can benefit from targeted or immunotherapy is crucial for precision therapy. Trophoblast cell surface antigen 2 (Trop2) has been extensively investigated as a pan-cancer biomarker expressed in various tumours and plays a crucial role in tumorigenesis through multiple signalling pathways. Our laboratory successfully developed two 68Ga-labelled nanobody tracers that can rapidly and specifically target Trop2. Of the two tracers, [68Ga]Ga-NOTA-T4, demonstrated excellent pharmacokinetics in preclinical mouse models and a beagle dog. Moreover, [68Ga]Ga-NOTA-T4 immuno-positron emission tomography (immunoPET) allowed noninvasive visualisation of Trop2 heterogeneous and differential expression in preclinical solid tumour models and ten patients with solid tumours. [68Ga]Ga-NOTA-T4 immunoPET could facilitate clinical decision-making through patient stratification and response monitoring during Trop2-targeted therapies.

Effects of deep brain stimulation on dopamine D2 receptor binding in patients with treatment-refractory depression.

BACKGROUND: Depression is a chronic psychiatric disorder related to diminished dopaminergic neurotransmission. Deep brain stimulation (DBS) has shown effectiveness in treating patients with treatment-refractory depression (TRD). This study aimed to evaluate the effect of DBS on dopamine D2 receptor binding in patients with TRD. METHODS: Six patients with TRD were treated with bed nucleus of the stria terminalis (BNST)-nucleus accumbens (NAc) DBS were recruited. Ultra-high sensitivity [11C]raclopride dynamic total-body positron emission tomography (PET) imaging was used to assess the brain D2 receptor binding. Each patient underwent a [11C]raclopride PET scan for 60-min under DBS OFF and DBS ON, respectively. A simplified reference tissue model was used to generate parametric images of binding potential (BPND) with the cerebellum as reference tissue. RESULTS: Depression and anxiety symptoms improved after 3-6 months of DBS treatment. Compared with two-day-nonstimulated conditions, one-day BNST-NAc DBS decreased [11C]raclopride BPND in the amygdala (15.9 %, p < 0.01), caudate nucleus (15.4 %, p < 0.0001) and substantia nigra (10.8 %, p < 0.01). LIMITATIONS: This study was limited to the small sample size and lack of a healthy control group. CONCLUSIONS: Chronic BNST-NAc DBS improved depression and anxiety symptoms, and short-term stimulation decreased D2 receptor binding in the amygdala, caudate nucleus, and substantia nigra. The findings suggest that DBS relieves depression and anxiety symptoms possibly by regulating the dopaminergic system.

The superior detection rate of total-body [68Ga]Ga-PSMA-11 PET/CT compared to short axial field-of-view [68Ga]Ga-PSMA-11 PET/CT for early recurrent prostate cancer patients with PSA < 0.2 ng/mL after radical prostatectomy.

BACKGROUND AND PURPOSE: [68Ga]Ga-PSMA PET imaging has been extensively utilized for the detection of biochemical recurrence (BCR) in prostate cancer. However, the detection rate declines to merely 10-40% when PSA levels are < 0.2 ng/mL employing short axial field-of-view (SAFOV) PET. Prior studies exhibited superior detection rates with total-body [68Ga]Ga-PSMA-11 PET compared to SAFOV [68Ga]Ga-PSMA-11 PET in BCR patients with PSA > 0.2 ng/mL. Nevertheless, the diagnostic utility of total-body [68Ga]Ga-PSMA-11 PET for BCR patients when PSA is < 0.2 ng/mL remains unclear. This study aimed to assess whether total-body [68Ga]Ga-PSMA-11 PET/CT could improve the detection rate compared to SAFOV [68Ga]Ga-PSMA-11 PET/CT in BCR patients with PSA < 0.2 ng/mL. METHODS: Eighty BCR patients with PSA < 0.2 ng/mL underwent total-body [68Ga]Ga-PSMA-11 PET/CT. These patients were matched by baseline qualities to another 80 patients who received SAFOV [68Ga]Ga-PSMA-11 PET/CT. The detection rates of total-body [68Ga]Ga-PSMA-11 PET/CT and SAFOV [68Ga]Ga-PSMA-11 PET/CT were compared utilizing a chi-square test and stratified analysis. Image quality of total-body [68Ga]Ga-PSMA PET/CT and SAFOV [68Ga]Ga-PSMA-11 PET/CT was assessed based on subjective scoring and objective parameters. The objective parameters measured were SUVmax, SUVmean, standard deviation (SD) of SUV, and signal-to-noise ratio (SNR) of liver and gluteus maximus. RESULTS: The image quality of total-body [68Ga]Ga-PSMA PET/CT was superior to that of SAFOV [68Ga]Ga-PSMA-11 PET/CT in both early and delayed scans. The detection rate of total-body [68Ga]Ga-PSMA PET/CT for BCR patients with PSA < 0.2 ng/mL was significantly higher than that of SAFOV [68Ga]Ga-PSMA-11 PET/CT (73.75% vs. 43.75%, P < 0.001). Total-body [68Ga]Ga-PSMA PET/CT resulted in noteworthy modifications to the treatment regimen when contrasted with SAFOV [68Ga]Ga-PSMA-11 PET/CT. CONCLUSIONS: In BCR patients with PSA < 0.2 ng/mL, total-body [68Ga]Ga-PSMA-11 PET/CT not only demonstrated a significantly higher detection rate compared to SAFOV [68Ga]Ga-PSMA-11 PET/CT but also led to significant alterations in treatment regimens.

Intelligent ultrafast total-body PET for sedation-free pediatric [18F]FDG imaging.

PURPOSE: This study aims to develop deep learning techniques on total-body PET to bolster the feasibility of sedation-free pediatric PET imaging. METHODS: A deformable 3D U-Net was developed based on 245 adult subjects with standard total-body PET imaging for the quality enhancement of simulated rapid imaging. The developed method was first tested on 16 children receiving total-body [18F]FDG PET scans with standard 300-s acquisition time with sedation. Sixteen rapid scans (acquisition time about 3 s, 6 s, 15 s, 30 s, and 75 s) were retrospectively simulated by selecting the reconstruction time window. In the end, the developed methodology was prospectively tested on five children without sedation to prove the routine feasibility. RESULTS: The approach significantly improved the subjective image quality and lesion conspicuity in abdominal and pelvic regions of the generated 6-s data. In the first test set, the proposed method enhanced the objective image quality metrics of 6-s data, such as PSNR (from 29.13 to 37.09, p < 0.01) and SSIM (from 0.906 to 0.921, p < 0.01). Furthermore, the errors of mean standardized uptake values (SUVmean) for lesions between 300-s data and 6-s data were reduced from 12.9 to 4.1% (p < 0.01), and the errors of max SUV (SUVmax) were reduced from 17.4 to 6.2% (p < 0.01). In the prospective test, radiologists reached a high degree of consistency on the clinical feasibility of the enhanced PET images. CONCLUSION: The proposed method can effectively enhance the image quality of total-body PET scanning with ultrafast acquisition time, leading to meeting clinical diagnostic requirements of lesion detectability and quantification in abdominal and pelvic regions. It has much potential to solve the dilemma of the use of sedation and long acquisition time that influence the health of pediatric patients.

Exploring the nigrostriatal and digestive interplays in Parkinson's disease using dynamic total-body [11C]CFT PET/CT.

PURPOSE: Dynamic total-body imaging enables new perspectives to investigate the potential relationship between the central and peripheral regions. Employing uEXPLORER dynamic [11C]CFT PET/CT imaging with voxel-wise simplified reference tissue model (SRTM) kinetic modeling and semi-quantitative measures, we explored how the correlation pattern between nigrostriatal and digestive regions differed between the healthy participants as controls (HC) and patients with Parkinson's disease (PD). METHODS: Eleven participants (six HCs and five PDs) underwent 75-min dynamic [11C]CFT scans on a total-body PET/CT scanner (uEXPLORER, United Imaging Healthcare) were retrospectively enrolled. Time activity curves for four nigrostriatal nuclei (caudate, putamen, pallidum, and substantia nigra) and three digestive organs (pancreas, stomach, and duodenum) were obtained. Total-body parametric images of relative transporter rate constant (R1) and distribution volume ratio (DVR) were generated using the SRTM with occipital lobe as the reference tissue and a linear regression with spatial-constraint algorithm. Standardized uptake value ratio (SUVR) at early (1-3 min, SUVREP) and late (60-75 min, SUVRLP) phases were calculated as the semi-quantitative substitutes for R1 and DVR, respectively. RESULTS: Significant differences in estimates between the HC and PD groups were identified in DVR and SUVRLP of putamen (DVR: 4.82 ± 1.58 vs. 2.58 ± 0.53; SUVRLP: 4.65 ± 1.36 vs. 2.84 ± 0.67; for HC and PD, respectively, both p < 0.05) and SUVREP of stomach (1.12 ± 0.27 vs. 2.27 ± 0.65 for HC and PD, respectively; p < 0.01). In the HC group, negative correlations were observed between stomach and substantia nigra in both the R1 and SUVREP values (r=-0.83, p < 0.05 for R1; r=-0.94, p < 0.01 for SUVREP). Positive correlations were identified between pancreas and putamen in both DVR and SUVRLP values (r = 0.94, p < 0.01 for DVR; r = 1.00, p < 0.001 for SUVRLP). By contrast, in the PD group, no correlations were found between the aforementioned target nigrostriatal and digestive areas. CONCLUSIONS: The parametric images of R1 and DVR generated from the SRTM model, along with SUVREP and SUVRLP, were proposed to quantify dynamic total-body [11C]CFT PET/CT in HC and PD groups. The distinction in correlation patterns of nigrostriatal and digestive regions between HC and PD groups identified by R1 and DVR, or SUVRs, may provide new insights into the disease mechanism.

Genome-wide detection of selection signatures in Jianli pigs reveals novel cis-regulatory haplotype in EDNRB associated with two-end black coat color.

BACKGROUND: Jianli pig, a renowned indigenous breed in China, has the characteristics of a two-end black (TEB) coat color, excellent meat quality, strong adaptability and increased prolificacy. However, there is limited information available regarding the genetic diversity, population structure and genomic regions under selection of Jianli pig. On the other hand, the genetic mechanism of TEB coat color has remained largely unknown. RESULTS: In this study, the whole genome resequencing of 30 Jianli pigs within a context of 153 individuals representing 13 diverse breeds was performed. The population structure analysis revealed that Jianli pigs have close genetic relationships with the Tongcheng pig breed, their geographical neighbors. Three methods (observed heterozygosity, expected heterozygosity, and runs of homozygosity) implied a relatively high level of genetic diversity and, a low inbreeding coefficient in Jianli compared with other pigs. We used Fst and XP-EHH to detect the selection signatures in Jianli pigs compared with Asian wild boar. A total of 451 candidate genes influencing meat quality (CREBBP, ADCY9, EEPD1 and HDAC9), reproduction (ESR1 and FANCA), and coat color (EDNRB, MITF and MC1R), were detected by gene annotation analysis. Finally, to fine-map the genomic region for the two-end black (TEB) coat color phenotype in Jianli pigs, we performed three signature selection methods between the TEB coat color and no-TEB coat color pig breeds. The current study, further confirmed that the EDNRB gene is a candidate gene for TEB color phenotype found in Chinese pigs, including Jinhua pigs, and the haplotype harboring 25 SNPs in the EDNRB gene may promote the formation of TEB coat color. Further ATAC-seq and luciferase reporter assays of these regions suggest that the 25-SNPs region was a strong candidate causative mutation that regulates the TEB coat color phenotype by altering enhancer function. CONCLUSION: Our results advanced the understanding of the genetic mechanism behind artificial selection, and provided further resources for the protection and breeding improvement of Jianli pigs.

Clinical Efficacy, Analgesic Efficacy, and Effects of Cocktail Analgesic Regimens in Patients Undergoing Total Knee Arthroplasty: A Systematic Review and Meta-Analysis.

Objective: Multimodal cocktail analgesic injection (CAI) is widely used as an adjunct pain-reliever in the postoperative phase of patients undergoing total knee arthroplasty (TKA) due to intense postoperative pain accompanying the procedure leading to complications, thereby extending hospital stays. The aim of this study is to establish the clinical efficacy and effects of utilizing CAI regimens during the TKA procedure and the corresponding postoperative patient outcomes. Methods: A database search for pertinent articles literature search was performed in Embase, PubMed, Cochrane Library, Web of Science, and MEDLINE databases. RevMan version 5.4 was used to perform a meta-analysis on the included studies. Results: Data screening and selection produced 15 relevant articles that met the eligibility criteria of this study. The meta-analysis revealed insignificant difference between cocktail injected and control groups in VAS postoperative pain scores both at rest and during activity (OR 0.79, 95% CI 0.59 to 1.05; I2 = 0%; P = .93) and (OR 0.79, 95% CI 0.57 to 1.10; I2 = 0%; P = .75), respectively. Similarly, there was insignificant differences in postoperative knee flexion ROM, postoperative narcotic consumption, and length of stays between the two groups, (OR 1.20, 95% CI 1.03 to 1.40; P = .53), (OR 0.62, 95% CI 0.36 to 1.07; P = .09), and (OR 0.45, 95% CI 0.29 to 0.70; P = .21), respectively. However, the postoperative complications reveal statistical significance between the cocktail injected and the control group (OR 0.45, 95% CI 0.29 to 0.70; P = .004). Conclusion: It is concluded that CAI can play a crucial role in minimizing post-operative complications for patients undergoing TKA.

Comparison of parametric imaging and SUV imaging with [68 Ga]Ga-PSMA-11 using dynamic total-body PET/CT in prostate cancer.

PURPOSE: Standardized uptake value (SUV) has been prevalently used to measure [68 Ga]Ga-PSMA-11 activity in prostate cancer, but it is susceptible to multiple factors. Parametric imaging allows for absolute quantification of tracer uptake and provides a better diagnostic accuracy that is crucial for lesion detection. However, the clinical significance of total-body parametric imaging of [68 Ga]Ga-PSMA-11 remains to be fully assessed. Therefore, the aim of our study is to delve into the diagnostic implications of total-body parametric imaging of [68 Ga]Ga-PSMA-11 PET/CT for patients with prostate cancer. METHODS: Twenty prostate cancer patients were included and underwent a dynamic total-body [68 Ga]Ga-PSMA-11 PET/CT scan. An irreversible two-tissue compartment model (2T3k) was fitted for each tissue time-to-activity curve, and the net influx rate (Ki) was obtained. The image quality and semi-quantitative analysis of lesion-to-background ratio (LBR), signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were compared between parametric images and SUV images. RESULTS: Kinetic modeling using 2T3k demonstrated favorable model fitting in both normal organs and lesions. All of the lesions detected on SUV images (55-60 min) could be detected on Ki images. The correlation between Ki, SUVmean, and SUVmax in both normal organs and pathological lesions was found to be positive and statistically significant. Conversely, a moderate positive correlations were found between Ki and K1 (R = 0.69, P < 0.001; R = 0.61, P < 0.001) and Ki and k3 (R = 0.69, P < 0.001; R = 0.62, P < 0.001), in normal organs and pathological lesions, respectively. Visual assessment in Ki images showed less image noise and higher lesions conspicuity compared to SUV images. Ki image-derived LBR, SNR, and CBR of pathological lesions including primary tumors (PTs), lymph node metastases (LNMs) and bone metastases (BMs), exhibited remarkably higher folds (1.4-3.6 folds) compared to those derived from SUV of corresponding lesions. CONCLUSIONS: Total-body parametric imaging of [68 Ga]Ga-PSMA-11 enhanced lesion contrast and improved lesion detectability compared to SUV images. This may potentially serve as an imaging biomarker and theranostic tool for precise diagnosis and treatment evaluation in prostate cancer patients.

Assessing dynamic metabolic heterogeneity in prostate cancer patients via total-body [68Ga]Ga-PSMA-11 PET/CT imaging: quantitative analysis of [68Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs.

PURPOSE: This study aimed to quantitatively assess [68Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs in prostate cancer using the total-body [68Ga]Ga-PSMA-11 PET/CT and to characterize the dynamic metabolic heterogeneity of prostate cancer. METHODS: Dynamic total-body [68Ga]Ga-PSMA-11 PET/CT scans were performed on ten prostate cancer patients. Manual delineation of volume-of-interests (VOIs) was performed on multiple normal organs displaying high [68Ga]Ga-PSMA-11 uptake, as well as pathological lesions. Time-to-activity curves (TACs) were generated, and the four compartment models including one-tissue compartmental model (1T1k), reversible one-tissue compartmental model (1T2k), irreversible two-tissue compartment model (2T3k) and reversible two-tissue compartmental model (2T4k) were fitted to each tissue TAC. Various rate constants, including K1 (forward transport rate from plasma to the reversible compartment), k2 (reverse transport rate from the reversible compartment to plasma), k3 (tracer binding on the PSMA-receptor and its internalization), k4 (the externalization rate of the tracer) and Ki (net influx rate), were obtained. The selection of the optimal model for describing the uptake of both lesions and normal organs was determined using the Akaike information criteria (AIC). Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values for differentiating physiological and pathological [68Ga]Ga-PSMA-11 uptake. RESULTS: Both 1T1k and 1T2k models showed relatively high AIC values compared to the 2T3k and 2T4k models in both pathological lesions and normal organs. The kinetic behavior of pathological lesions was better described by the 2T3k model compared to the 2T4k model, while the normal organs were better described by the 2T4k model. Significant variations in kinetic metrics, such as K1, k2, and k3, and Ki, were observed among normal organs with high [68Ga]Ga-PSMA-11 uptake and pathological lesions. The high Ki value in normal organs was primarily determined by elevated K1 and low k3, rather than k2. Conversely, the high Ki value in pathological lesions, ranking second to the kidney and similar to salivary glands and spleen, was predominantly determined by the highest k3 value. Notably, k3 exhibited the highest performance in distinguishing between physiological and pathological [68Ga]Ga-PSMA-11 uptake, with an area under the curve (AUC) of 0.844 (95% CI, 0.773-0.915), sensitivity of 82.9%, and specificity of 74.1%. The k3 values showed better performance than SUVmean (AUC, 0.659), SUVmax (AUC, 0.637), and other kinetic parameter including K1 (AUC, 0.604), k2 (AUC, 0.634), and Ki (AUC, 0.651). CONCLUSIONS: Significant discrepancies in kinetic metrics were detected between pathological lesions and normal organs, despite their shared high uptake of [68Ga]Ga-PSMA-11. Notably, the k3 value exhibits a noteworthy capability to distinguish between pathological lesions and normal organs with elevated [68Ga]Ga-PSMA-11 uptake. This discovery implies that k3 holds promise as a prospective imaging biomarker for distinguishing between pathologic and non-specific [68Ga]Ga-PSMA-11 uptake in patients with prostate cancer.

Total-body PET/CT with half-dose [68 Ga]Ga-PSMA-11 for biochemical recurrent prostate cancer: comparable diagnostic value to short axial field-of-view PET/CT with full-dose [68 Ga]Ga-PSMA-11.

PURPOSE: The objective of this study was to evaluate the diagnostic performance and image quality of total-body positron emission tomography/computed tomography (PET/CT) imaging using a half-dose of [68 Ga]Ga-prostate specific membrane antigen ([68 Ga]Ga-PSMA) radiotracer, compared to conventional short axial field-of-view PET/CT imaging using a full dose of [68 Ga]Ga-PSMA. METHODS: This retrospective study enrolled 52 patients with biochemical recurrent (BCR) prostate cancer after radical prostatectomy who underwent total-body PET/CT with a half-dose (0.9-1.1 MBq/kg) of [68 Ga]Ga-PSMA. These patients were matched by baseline characteristics to another 52 BCR patients after prostatectomy who underwent conventional PET/CT with a full dose (1.8-2.2 MBq/kg) of [68 Ga]Ga-PSMA. The half-dose group was further divided into 5-min (G5) and 2-min (G2) acquisition subgroups. Image quality was assessed through subjective analysis using a 5-point scale and objective measurements of standard uptake value maximum (SUVmax), standard uptake value mean (SUVmean), background variation (BV) of the liver, blood pool, and parotid glands. Additionally, SUVmax and tumor-to-background ratio (TBR) were calculated for lesions. RESULTS: No significant difference in subjective image quality was found between the G2 and full-dose groups (p > 0.05). PET/CT image quality was significantly higher for the G5 versus G2 (p < 0.001) and full-dose groups (p < 0.001). TBR did not differ between the G2 and full-dose groups (4.23 ± 5.21 vs 4.22 ± 3.97, p = 0.99). Liver BV was significantly lower for G2 versus full-dose groups (0.16 ± 0.03 vs 0.20 ± 0.05, p < 0.001). CONCLUSIONS: Total-body PET/CT with a half-dose [68 Ga]Ga-PSMA yields image quality superior or comparable to that of conventional PET/CT. The utilization of total-body [68 Ga]Ga-PSMA PET/CT meets the diagnostic demands of BCR patients, particularly those who exhibit reduced tolerance to prolonged horizontal positioning and scan durations, while simultaneously reducing radiation exposure for the subjects.

Feasibility of acquisitions using total-body PET/CT with a half-dose [68Ga]Ga-FAPI-04 activity in oncology patients.

BACKGROUND: [68Ga]Ga-FAPI-04 (gallium-68-labeled fibroblast activation protein inhibitor-04) PET/CT has been widely used in diagnosing malignant tumors. Total-body PET/CT has a long axial field of view and provides higher sensitivity compared to traditional PET/CT. However, whether the reduced injected dose of [68Ga]Ga-FAPI-04 could obtain qualified imaging has not been evaluated. PURPOSE: To explore the effect of half-dose [68Ga]Ga-FAPI-04 on image quality and tumor detectability in oncology patients. METHODS: A total of twenty-seven patients with tumors or clinically suspected tumors were included, and all patients were scanned with total-body PET/CT after an injected dose of 0.84-1.14 MBq/kg [68Ga]Ga-FAPI-04. All patients obtained superior image quality with 300 s original acquisition time. Images were reconstructed using 180 s, 120 s, 60 s, 40 s, 30 s, 20 s scanning duration by ordered subset expectation maximization algorithm. The subjective image quality of all patients in each time group was scored using 5-point Likert scale. Mediastinal blood pool, liver, spleen, and muscle were analyzed as background using semi-quantitative parameters maximum standardized uptake values (SUVmax), mean standardized uptake values (SUVmean), standard deviation (SD), and signal to noise ratio (SNR). The lesion detection rate, SUVmax, and tumor-to-background ratio (TBR) were calculated for tumors confirmed by pathology. RESULTS: The subjective image quality score decreased with the shortening of scanning time; however, both 180 s and 120 s images met the diagnostic requirements in terms of overall quality, lesion conspicuity, and image noise. The SUVmax of background increased with the reduction of scanning time, while the SUVmean was relatively stable. With the shortening of scanning time, the SD gradually increased, and the SNR gradually decreased, which was consistent with subjective image quality scores. In 180 s and 120 s images, all 11 primary lesions and 79 metastatic lesions were detected. The SUVmax of tumor focus showed an increasing trend as same as the background. Compared with 300 s, the TBR muscle had no statistical difference in 180 s and 120 s. CONCLUSIONS: Half-dose [68Ga]Ga-FAPI-04 in total-body PET/CT imaging can shorten the acquisition time to 120 s with acceptable subjective image quality and 100% tumor detection rate. Total-body PET/CT imaging with a half-dose [68Ga]Ga-FAPI-04 and reduced acquisition time can be used in radiation-sensitive and poor tolerant to prolong horizontal positioning and waiting time populations such as children and gravidas.

Biodistribution and radiation dosimetry of multiple tracers on total-body positron emission tomography/computed tomography.

Background: [18F]F-FDG, [68Ga]Ga-PSMA-11, and [68Ga]Ga-FAPI-04 have achieved good results in multiple clinical trials and clinical practice, but the imaging of these tracers is limited to traditional short-axis positron emission tomography/computed tomography (PET/CT). Therefore, we aimed to use total-body PET/CT dynamic scanning to describe whole-body biodistribution of these three tracers and to calculate more precise radiation doses. Methods: Total-body PET/CT (uExplorer, United Imaging Healthcare) dynamic scanning was performed on 54 patients, including 30 patients with [18F]F-FDG, 10 patients with [68Ga]Ga-PSMA-11, and 14 patients with [68Ga]Ga-FAPI-04. A 60-minute dynamic scanning of whole body was performed simultaneously after bedside bolus injection of the corresponding tracers. The dynamic sequence of 92 frames was quantitatively analyzed by the Pmod4.0 software. Whole body biodistribution was calculated as time-activity curves (TACs) describing dynamic uptake patterns in the subject's major organs, followed by calculation of tracer kinetics and cumulative organ activity. Finally, combined with the OLINDA/EXM software, effective doses of the different tracers and individual organ doses were calculated. Results: In a systematic TAC analysis of three tracers, we identified distinct biodistribution patterns in major organs. [68Ga]Ga-PSMA-11 showed a trend of rapid increasing and slow decreasing in liver, spleen, muscle, and bone. In the heart, stomach, brain, and lung, tracer decreased rapidly after rapid increasing. Similarly, tracer uptake in the kidney and urinary bladder increased gradually. [68Ga]Ga-FAPI-04 showed a rapid increasing and rapid decreasing trend in brain, lung, liver, spleen, bone, heart, kidney, and stomach. The mean effective dose of [68Ga]Ga-PSMA-11 was 1.47E-02 mSv/MBq, and the mean effective doses of [18F]F-FDG and [68Ga]Ga-FAPI-04 were comparable (2.52E-02 mSv/MBq and 2.23E-02 mSv/MBq). The mean effective dose of [18F]F-FDG was lower than that reported in the literature measured by previous short-axis PET, while both [68Ga]Ga-PSMA-11 and [68Ga]Ga-FAPI-04 had higher value than previously reported value. Conclusions: [18F]F-FDG, [68Ga]Ga-PSMA-11 and [68Ga]Ga-FAPI-04 have good biodistribution in human organs. Real-time high-sensitivity dynamic scanning with total-body PET/CT is a very effective way to accurately calculate biodistribution and effective dose of positron-labeled radiopharmaceuticals.

Improved [68Ga]Ga-PSMA-11 image qualities reconstructed by total variation regularized expectation maximization on total-body PET/CT.

Background: Total variation regularized expectation maximization (TVREM) reconstruction algorithm on the image quality of gallium (68GA) prostate-specific membrane antigen-11 ([68Ga]Ga-PSMA-11) total-body positron emission tomography/computed tomography (PET/CT). Methods: Images of a phantom with small hot sphere inserts and the total-body PET/CT scans of 51 prostate cancer patients undergoing [68Ga]Ga-PSMA-11 were reconstructed using TVREM with 5 different penalization factors between 0.09 and 0.45 and for 20-, 40-, 60-, 120-, and 300-second acquisition, respectively. As a comparison, the same data were also reconstructed using the ordered subset expectation maximization (OSEM) with 3 iterations, 20 subsets, and 300 second acquisition. The contrast recovery coefficients (CRC) and background variability (BV) of the phantom, the tumor-to-background ratios (TBR), the contrast recovery (CR) ratio, the image noise of the liver, and maximum standard uptake value (SUVmax) of the lesions were calculated to evaluate the image quality. The clinical performance of the images was evaluated by 2 radiologists with a 5-point scale (1-poor, 5-excellent). Results: The TVREM reconstructions groups fwith 120 second acquisition and the penalization of 0.27 to 0.45 showed the best performance in terms of CR, TBR, image noise, and the gain of SUVmax compared to that obtained in the OSEM 300 second group. Even the image noise of the TVREM 120 second group with a penalization factor of 0.27 and 0.36 was comparable to the OSEM 300 second group; the lesions' SUVmax increased by 28% whereas the image noise decreased by 5% and 14%, respectively. The TVREM 120 second group with a penalization factor of 0.36 (5.00±0.00) had the highest qualitative score that equaled OSEM and TVREM for the 300 second (P>0.05) group. Conclusions: Our study has shown the potential of the TVREM reconstruction algorithm with optimized penalization factors to achieve comparable [68Ga]Ga-PSMA-11 total-body PET/CT image quality with a shorter acquisition time, compared with the conventional OSEM reconstruction algorithm.

Total-body [68 Ga]Ga-PSMA-11 PET/CT improves detection rate compared with conventional [68 Ga]Ga-PSMA-11 PET/CT in patients with biochemical recurrent prostate cancer.

PURPOSE: The purpose of this study was to assess whether total-body [68 Ga]Ga-PSMA-11 PET/CT could improve the detection rate compared with conventional [68 Ga]Ga-PSMA-11 PET/CT in patients with biochemical recurrent prostate cancer. METHODS: Two hundred biochemical recurrent prostate cancer patients with similar clinicopathological characteristics were included, of whom 100 patients underwent early total-body [68 Ga]Ga-PSMA-11 PET/CT and diuretic-delayed total-body [68 Ga]Ga-PSMA-11 PET/CT, and the other 100 patients received early conventional [68 Ga]Ga-PSMA-11 PET/CT and diuretic-delayed conventional [68 Ga]Ga-PSMA-11 PET/CT. The detection rates of total-body [68 Ga]Ga-PSMA-11 PET/CT and conventional [68 Ga]Ga-PSMA-11 PET/CT were compared using a chi-square test and stratified analysis. The image quality of total-body [68 Ga]Ga-PSMA PET/CT and conventional [68 Ga]Ga-PSMA-11 PET/CT was compared based on subjective scoring and objective parameters. Subjective scoring was conducted from background noise and lesion prominence using a 5-point scale. Objective parameters were evaluated by SUVmax, SUVmean, the standard deviation (SD) of SUV, and the signal-to-noise ratio (SNR) of liver and gluteus maximus. The SUVmax of the recurrent lesions was also measured. RESULTS: The liver SD of the total-body [68 Ga]Ga-PSMA-11 PET/CT was significantly lower than that of conventional [68 Ga]Ga-PSMA-11 PET/CT, the SNR was significantly higher than that of conventional [68 Ga]Ga-PSMA-11 PET/CT, and the subjective evaluation was significantly better than that of conventional [68 Ga]Ga-PSMA-11 PET/CT. The detection rate of total-body [68 Ga]Ga-PSMA PET/CT for biochemical recurrence of prostate cancer was significantly higher than that of conventional [68 Ga]Ga-PSMA-11 PET/CT (91.0% vs. 74.0%, P = 0.003). Total-body [68 Ga]Ga-PSMA-11 PET/CT had better detection efficiency for patients with a Gleason score ≤ 8 or PSA ≤ 2 ng/ml. The advantages of diuretic-delayed total-body [68 Ga]Ga-PSMA-11 PET/CT were more obvious. CONCLUSION: Total-body [68 Ga]Ga-PSMA-11 PET/CT could significantly improve the detection rate compared with conventional [68 Ga]Ga-PSMA-11 PET/CT in patients with biochemical recurrent prostate cancer.

Pilot study on 11C-CFT dynamic imaging using total-body PET/CT: biodistribution and radiation dosimetry in Parkinson's disease.

Objective: Total-body PET/CT equipment, uEXPLORER, is a newly developed imaging technology with a superior resolution, high sensitivity, and high signal-to-noise ratio, providing unique application advantages in the pharmacokinetic evaluation of positron tracers. While 11C-CFT PET/CT has been widely utilized in the early diagnosis of Parkinson's disease (PD), it is limited by the short half-life of the radionuclide and an incomplete understanding of its biological distribution in humans. This study aimed to use a total-body PET/CT dynamic scan with 11C-CFT imaging to describe the real-time internal biodistribution in PD patients and to obtain accurate radiation dosimetry. Methods: Six male subjects with suspected PD underwent dynamic 11C-CFT total-body PET/CT. Following a bedside intravenous bolus injection of 373.3 ± 71.56 MBq of 11C-CFT, PET acquisition was performed synchronously for 75 min with a maximum axial field of view (AFOV) of 194 cm. Time-activity curves (TACs) were generated by delineating volumes of interest (VOIs) of the sourced organs using PMOD software. Tracer kinetics and cumulative organ activities were calculated, and absorbed doses were calculated and estimated using the OLINDA/EXM software. Results: In the systemic TAC analysis of 11C-CFT, several unique types of distribution patterns were obtained among several major organs, including a "Fast-in Fast-out" pattern in the kidneys, lungs, spleen, and thyroid, a "Fast-in Slow-out" curve in the heart wall, a "Slow-in Slow-out" mode in the liver, a "Low-level extending" pattern in the whole brain and muscle, and a "Slow-in to plateau" trend in the striatum and bone. The effective dose of 11C-CFT was calculated to be 2.83E-03 mSv/MBq, which is only one-third of the literature value measured by the conventional method. Moreover, this dose is much lower compared to all other doses of DAT radioligands used in PET imaging. Conclusion: This study is a pioneering application of total-body PET/CT to 11C-CFT dynamic imaging. Our results confirmed that 11C-CFT has a favorable total body biodistribution, an extremely low internal radiation dose, and high imaging quality, making it suitable for reasonable PD diagnosis in patients requiring multiple follow-up examinations.

The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer.

Serving as targeting ligands, aptamers have shown promise in precision medicine. However, the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers' clinical translation. To bridge this gap, here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68 (68Ga) radiolabeled aptamers. The specificity and binding affinity of a radiolabeled aptamer, named 68Ga[Ga]-NOTA-SGC8, were maintained as proven in vitro. Further preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity, potential mutation risks, or genotoxicity at high dosage (40 mg/kg). Based on this result, a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles, as well as biosafety, of the radiolabeled SGC8 aptamer in the human body. Taking advantage of the cutting-edge total-body PET, the aptamers' distribution pattern in the human body was acquired in a dynamic fashion. This study revealed that radiolabeled aptamers are harmless to normal organs and most of them are accumulated in the kidney and cleared from the bladder via urine, which agrees with preclinical studies. Meanwhile, a physiologically based pharmacokinetic model of aptamer was developed, which could potentially predict therapeutic responses and plan personalized treatment strategies. This research studied the biosafety and dynamic pharmacokinetics of aptamers in the human body for the first time, as well as demonstrated the capability of novel molecular imaging fashion in drug development.

Improved accuracy of the biodistribution and internal radiation dosimetry of 13 N-ammonia using a total-body PET/CT scanner.

BACKGROUND: Conventional short-axis PET typically utilizes multi-bed multi-pass acquisition to produce quantitative whole-body dynamic images and cannot record all the uptake information simultaneously, resulting in errors when fitting the time-activity curves (TACs) and calculating radiation doses. PURPOSE: The aim of this study is to evaluate the 13 N-ammonia biodistribution and the internal radiation doses using a 194 cm long total-body PET/CT scanner (uEXPLORER), and make a comparison with the previous short-axis PET results. METHODS: Ten subjects (age 40-74 years) received 13 N-NH3 injection (418.1-670.81 MBq) and were under a dynamic scan for about 60 min with using a 3-dimensional whole-body protocol. ROIs were drawn visually on 11 major organs (brain, thyroid, gallbladder, heart wall, kidneys, liver, pancreas, spleen, lungs, bone marrow, and urinary bladder content) for each subject. TACs were generated using Pmod and the absorbed radiation doses were calculated using Olinda 2.2. To compare with the conventional PET/CT, five points were sampled on uEXPLORER's TACs to mimic the result of a short-axis PET/CT (15 cm axial FOV, consisted of 9 or 10 bed positions). Then the TACs were obtained using the multi-exponential fitting method, and the residence time and radiation dose were also calculated and compared with uEXPLORER. RESULTS: The highest absorbed organ doses were the pancreas, thyroid, spleen, heart wall, and kidneys for the male. For the female, the first five highest absorbed organ dose coefficients were the pancreas, heart wall, spleen, lungs, and kidneys. The lowest absorbed dose was found in red marrow both for male and female. The simulated short-axis PET can fit TACs well for the gradually-changed uptake organs but typically underestimated for the rapid-uptake organs during the first-10 min, resulting in errors in the calculated radiation dose. CONCLUSION: uEXPLORER PET/CT can measure 13 N-ammonia's TACs simultaneously in all organs of the whole body, which can provide more accurate biodistribution and radiation dose estimation compared with the conventional short-axis scanners.

Metabolic kinetic modeling of [11C]methionine based on total-body PET in multiple myeloma.

PURPOSE: Multiple myeloma (MM) is a malignant disease characterized by the secretion of monoclonal immunoglobulins and has a high demand for amino acids. [11C]methionine total-body PET is capable of noninvasive dynamic monitoring of radiotracer in vivo, thus providing a way to reveal the dynamic changes of myeloma metabolism. This study aims to analyze the metabolic process of [11C]methionine based on kinetic modeling, and to preliminary reveal its application value in MM. METHODS: Dynamic total-body [11C]methionine PET/CT was conducted with uEXPLORER in 12 subjects (9 MM patients and 3 controls). The tissue time activity curves (TACs) of organs and bone marrows were extracted. Model fitting of TACs was operated using PMOD Kinetic Modeling. After validation by Goodness of fit (GOF), the reversible two-tissue compartment model (2T4k) was used to further analysis. R software was used to analyze the correlation between kinetic parameters and clinical indicators. RESULTS: The 2T4k has passed the criterion of GOF and was used to fit the data of 0-20 minutes. The [11C]methionine net uptake rate (Ki) was significantly higher in the MM lesions than in the non-myeloma controls (control: 0.040±0.007 mL/g/min, MM: 0.171±0.108 mL/g/min, p=0.009). The Ki values were found to be correlated with M protein levels in MM patients. MM patients with t(4;14) translocations had an elevated k4 value compared with t(4;14) negative patients. CONCLUSION: MM lesions have a propensity for uptake of [11C]methionine. The serum levels of M protein are correlated with [11C]methionine uptake rate in myeloma. Metabolic classification based on the k4 value may be a promising strategy for risk stratification in MM.

First Total-Body Kinetic Modeling and Parametric Imaging of Dynamic 68Ga-FAPI-04 PET in Pancreatic and Gastric Cancer.

Fibroblast activation protein inhibitor (FAPI) is an ideal diagnostic and therapeutic target in malignant tumors. However, the knowledge of kinetic modeling and parametric imaging of 68Ga-FAPI is limited. Purpose: The purpose of this study was to explore the pharmacokinetics of 68Ga-FAPI-04 PET/CT in pancreatic cancer and gastric cancer and to conduct parametric imaging of dynamic total-body data compared with SUV imaging. Methods: Dynamic total-body 68Ga-FAPI-04 PET/CT was performed on 13 patients. The lesion time-activity curves were fitted by 3-compartment models and multigraphical models. The kinetics parameters derived from the 2-tissue reversible compartment model (2T4K) and multigraphical models were analyzed. Parametric [Formula: see text] imaging was generated using the 2T4K and Logan models, and their performances were evaluated compared with SUV images. Results: 2T4K had the lowest Akaike information criterion value, and its fitting curves matched excellently with the origin time-activity curves. Visual assessment revealed that the [Formula: see text](2T4K) images and [Formula: see text](Logan with spatial constraint [SC]) images both showed less image noise and higher lesion conspicuity compared with SUV images. Objective image quality assessment demonstrated that parametric [Formula: see text](2T4K) images and parametric [Formula: see text](Logan with SC) images had a 5.0-fold and 5.0-fold higher average signal-to-noise ratio and 3.6-fold and 4.1-fold higher average contrast-to-noise ratio compared with conventional SUV images, respectively. In addition, no significant differences in signal-to-noise ratio and contrast-to-noise of pathologic lesions were observed between parametric [Formula: see text](2T4K) images and parametric [Formula: see text](Logan with SC) images (all P > 0.05). Conclusions: The 2T4K model was the preferred compartment model. Total-body parametric imaging of 68Ga-FAPI-04 PET yielded superior quantification beyond SUV with enhanced lesion contrast, which may serve as a promising imaging method to make an early diagnosis, to better reflect tumor characterization, or to allow evaluation of treatment response. [Formula: see text](2T4K) images are comparable in image quality and consistent to [Formula: see text](Logan with SC) images in lesions conspicuity; however, [Formula: see text](Logan with SC) images presented an appealing alternative to [Formula: see text](2T4K) images because of their simplicity.

Tumor-to-blood ratio for assessment of fibroblast activation protein receptor density in pancreatic cancer using [68Ga]Ga-FAPI-04.

PURPOSE: [68Ga]Ga-FAPI PET/CT has been widely used in clinical diagnosis and radiopharmaceutical therapy. In this study, tumor-to-blood ratio (TBR) was evaluated as a powerful tool for semiquantitative assessment of [68Ga]Ga-FAPI-04 tumor uptake and as an effective index for tumors with high FAP expression in theranostics. METHODS: Nine patients with pancreatic cancer underwent a 60-min dynamic PET/CT scan by total-body PET/CT (with a long AFOV of 194 cm) after injection of [68Ga]Ga-FAPI-04. After dynamic PET/CT scan, three patients received chemotherapy and underwent the second dynamic scan to evaluate treatment response. Time-activity curves (TACs) were obtained by drawing regions of interest for primary pancreatic lesions and metastatic lesions. The lesion TACs were fitted using four compartment models by the software PMOD PKIN kinetic modeling. The preferred pharmacokinetic model for [68Ga]Ga-FAPI-04 was evaluated based on the Akaike information criterion. The correlations between simplified methods for quantification of [68Ga]Ga-FAPI-04 (SUVs; tumor-to-blood ratios [TBRs]) and the total distribution volume (Vt) estimates obtained from pharmacokinetic analysis were calculated. RESULTS: In total, 9 primary lesions and 25 metastatic lesions were evaluated. The reversible two-tissue compartment model (2TCM) was the most appropriate model among the four compartment models. The total distribution volume Vt values derived from 2TCM varied significantly in pathological lesions and background regions. A strong positive correlation was observed between TBRmean and Vt from the 2TCM model in pathological lesions (R2=0.92, P<0.001). The relative difference range for TBRmean was 2.1% compared to the reduction rate of Vt in the patients who were treated with chemotherapy. CONCLUSIONS: A strong positive correlation was observed between TBRmean and Vt for [68Ga]Ga-FAPI-04. TBRmean reflects FAP receptor density better than SUVmean and SUVmax, and would be the preferred measurement tool for semiquantitative assessment of [68Ga]Ga-FAPI-04 tumor uptake and as a means for evaluating treatment response.