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.

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.

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.

Ultra-low-dose CT reconstructed with the artificial intelligence iterative reconstruction algorithm (AIIR) in 18F-FDG total-body PET/CT examination: a preliminary study.

PURPOSE: To investigate the feasibility of ultra-low-dose CT (ULDCT) reconstructed with the artificial intelligence iterative reconstruction (AIIR) algorithm in total-body PET/CT imaging. METHODS: The study included both the phantom and clinical parts. An anthropomorphic phantom underwent CT imaging with ULDCT (10mAs) and standard-dose CT (SDCT) (120mAs), respectively. ULDCT was reconstructed with AIIR and hybrid iterative reconstruction (HIR) (expressed as ULDCT-AIIRphantom and ULDCT-HIRphantom), respectively, and SDCT was reconstructed with HIR (SDCT-HIRphantom) as control. In the clinical part, 52 patients with malignant tumors underwent the total-body PET/CT scan. ULDCT with AIIR (ULDCT-AIIR) and HIR (ULDCT-HIR), respectively, was reconstructed for PET attenuation correction, followed by the SDCT reconstructed with HIR (SDCT-HIR) for anatomical location. PET/CT images' quality was qualitatively assessed by two readers. The CTmean, as well as the CT standard deviation (CTsd), SUVmax, SUVmean, and the SUV standard deviation (SUVsd), was recorded. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated and compared. RESULTS: The image quality of ULDCT-HIRphantom was inferior to the SDCT-HIRphantom, but no significant difference was found between the ULDCT-AIIRphantom and SDCT-HIRphantom. The subjective score of ULDCT-AIIR in the neck, chest and lower limb was equivalent to that of SDCT-HIR. Besides the brain and lower limb, the change rates of CTmean in thyroid, neck muscle, lung, mediastinum, back muscle, liver, lumbar muscle, first lumbar spine and sigmoid colon were -2.15, -1.52, 0.66, 2.97, 0.23, 8.91, 0.06, -4.29 and 8.78%, respectively, while all CTsd of ULDCT-AIIR was lower than that of SDCT-HIR. Except for the brain, the CNR of ULDCT-AIIR was the same as the SDCT-HIR, but the SNR was higher. The change rates of SUVmax, SUVmean and SUVsd were within [Formula: see text] 3% in all ROIs. For the lesions, the SUVmax, SUVsd and TBR showed no significant difference between PET-AIIR and PET-HIR. CONCLUSION: The SDCT-HIR could not be replaced by the ULDCT-AIIR at date, but the AIIR algorithm decreased the image noise and increased the SNR, which can be implemented under special circumstances in PET/CT examination.

The feasibility of ultra-early and fast total­body [68 Ga]Ga-FAPI-04 PET/CT scan.

PURPOSE: [68 Ga]Ga-FAPI-04 PET/CT has been widely used in oncology patients. The patients need to lie still for 20-30 min during scan after waiting for 60 min post-tracer injection in traditional [68 Ga]Ga-FAPI-04 PET/CT scan. This is difficult for some patients who are intolerant to prolonged horizontal positioning and waiting time. Therefore, we evaluated the diagnostic value of the images obtained in ultra-early and fast scan (5-min p.i., 30-s acquisition time) by the total-body [68 Ga]Ga-FAPI-04 PET/CT and to investigate whether they could meet the requirements of clinical diagnosis. METHODS: Total-body [68 Ga]Ga-FAPI-04 PET/CT was conducted in 12 patients at the Renji Hospital. Patients underwent PET with two acquisitions: 5-min p.i. and 30-s acquisition time (ultra-early and fast imaging) and 60-min p.i. and 300-s acquisition time (traditional imaging). Mean [68 Ga]Ga-FAPI-04 injection dose was 1.85 MBq/kg. RESULTS: Forty-four lesions were detected in 12 patients on traditional imaging. All the 44 lesions on conventional imaging could also detected by ultra-early and fast imaging. For all the 12 patients, the tumor stage did not change, as same lesions were visible for every case in both images. There was no statistically significant difference in SUVmax of lesions between ultra-early and fast imaging and traditional imaging (12.5 ± 8.7 vs 13.7 ± 8.5, P = 0.528). Background bloodpool (4.0 ± 0.6 vs 0.9 ± 0.2, P < 0.001)and liver (2.5 ± 0.7 vs 1.0 ± 0.5, P < 0.001)at traditional imaging showed a significant decrease in SUVmean compared to ultra-early and fast imaging. CONCLUSIONS: Ultra-early and fast imaging versus traditional [68 Ga]Ga-FAPI-04 imaging resulted in equivalent tumor detection and lesion uptake. Ultra-early and fast total-body [68 Ga]Ga-FAPI-04 PET/CT scan could meet clinical diagnostic requirements for patients with poor tolerant to prolonged horizontal positioning and waiting time.

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.

Respiratory-gated PET imaging with reduced acquisition time for suspect malignancies: the first experience in application of total-body PET/CT.

OBJECTIVES: This study aimed to investigate the performance of respiratory-gating imaging with reduced acquisition time using the total-body positron emission tomography/computed tomography (PET/CT) scanner. METHODS: Imaging data of 71 patients with suspect malignancies who underwent total-body 2-[18F]-fluoro-2-deoxy-D-glucose PET/CT for 15 min with respiration recorded were analyzed. For each examination, four reconstructions were performed: Ungated-15, using all coincidences; Ungated-5, using data of the first 5 min; Gated-15 using all coincidences but with respiratory gating; and Gated-6 using data of the first 6 min with respiratory gating. Lesions were quantified and image quality was evaluated; both were compared between the four image sets. RESULTS: A total of 390 lesions were found in the thorax and upper abdomen. Lesion detectability was significantly higher in gated-15 (97.2%) than in ungated-15 (93.6%, p = 0.001) and ungated-5 (92.3%, p = 0.001), but comparable to Gated-6 (95.9%, p = 0.993). A total of 131 lesions were selected for quantitative analyses. Lesions in Gated-15 presented significantly larger standardized uptake values, tumor-to-liver ratio, and tumor-to-blood ratio, but smaller metabolic tumor volume, compared to those in Ungated-15 and Ungated-5 (all p < 0.001). These differences were more obvious in small lesions and in lesions from sites other than mediastinum/retroperitoneum. However, these indices were not significantly different between Gated-15 and Gated-6. Higher, but acceptable, image noise was identified in gated images than in ungated images. CONCLUSIONS: Respiratory-gating imaging with reduced scanning time using the total-body PET/CT scanner is superior to ungated imaging and can be used in the clinic. KEY POINTS: • In PET imaging, respiratory gating can improve lesion presentation and detectability but requires longer imaging time. • This single-center study showed that the total-body PET scanner allows respiratory-gated imaging with reduced and clinically acceptable scanning time.

Myocardium-specific Isca1 knockout causes iron metabolism disorder and myocardial oncosis in rat.

AIMS: Multiple mitochondrial dysfunction (MMD) can lead to complex damage of mitochondrial structure and function, which then lead to the serious damage of various metabolic pathways including cerebral abnormalities. However, the effects of MMD on heart, a highly mitochondria-dependent tissue, are still unclear. In this study, we use iron-sulfur cluster assembly 1 (Isca1), which has been shown to cause MMD syndromes type 5 (MMDS5), to verify the above scientific question. MAIN METHODS: We generated myocardium-specific Isca1 knockout rat (Isca1flox/flox/α-MHC-Cre) using CRISPR-Cas9 technology. Echocardiography, magnetic resonance imaging (MRI), histopathological examinations and molecular markers detection demonstrated phenotypic characteristics of our model. Immunoprecipitation, immunofluorescence co-location, mitochondrial activity, ATP generation and iron ions detection were used to verify the molecular mechanism. KEY FINDINGS: This study was the first to verify the effects of Isca1 deficiency on cardiac development in vivo, that is cardiomyocytes suffer from mitochondria damage and iron metabolism disorder, which leads to myocardial oncosis and eventually heart failure and body death in rat. Furthermore, forward and reverse validation experiments demonstrated that six-transmembrane epithelial antigen of prostate 3 (STEAP3), a new interacting molecule for ISCA1, plays an important role in iron metabolism and energy generation impairment induced by ISCA1 deficiency. SIGNIFICANCE: This result provides theoretical basis for understanding of MMDS pathogenesis, especially on heart development and the pathological process of heart diseases, and finally provides new clues for searching clinical therapeutic targets of MMDS.

Polydopamine nanospheres with multiple quenching effect on TiO2/CdS:Mn for highly sensitive photoelectrochemical assay of tumor markers.

A photoelectrochemical (PEC) immunosensing strategy based on the multiple quenching of polydopamine nanoparticles (PDA NPs) to Mn2+-doped CdS-modified TiO2 nanoparticles (TiO2/CdS:Mn) was designed for the highly sensitive detection of carcinoembryonic antigen (CEA). The uniform PDA NPs possessed good dispersibility, good biocompatibility, and abundant functional groups for biomolecule assembly. They also had unique photophysical properties, with light absorption spanning the visible to infrared light range. When the immune-recognition brought the PDA NPs close to the TiO2/CdS:Mn interface, the PDA NPs competed with TiO2/CdS:Mn to absorb light, consumed photoelectrons generated in the TiO2/CdS:Mn, and hindered the access of electron donors to photoactive materials. The contribution from these aspects thus led to a significant decrease in photocurrent. Benefiting from the multiple quenching mechanism, the PEC immunosensor showed high sensitivity for CEA detection. Under optimal conditions, a low detection limit of 0.02 pg/mL and a wide linear relationship from 0.1 pg/mL to 100 ng/mL were obtained. The immunoassay showed good reproducibility and stability, and good selectivity and high accuracy in serum sample analysis. In this regard, PEC immunosensors may have great application potential for screening tumor markers and the prevention and monitoring of serious diseases.

A carboxylated graphene nanodisks/glucose oxidase nanotags and Mn:CdS/TiO2 matrix based dual signal amplification strategy for ultrasensitive photoelectrochemical detection of tumor markers.

Graphene nanodisks with good conductivity and plenty of edge sites were synthesized to load glucose oxidase (GRD-GOD) and coupled with a Mn2+ doped CdS quantum dot (QD) modified TiO2 electrode (CdS:Mn/TiO2) for a highly sensitive photoelectrochemical (PEC) immunoassay. The specific immune-recognition behaviour can bring the GRD-GOD labelled antigen into the antibody immobilized CdS:Mn/TiO2 interface and dramatically enhance the photocurrent response via a dual signal amplification strategy. First, graphene nanodisks with a strong electron transfer capacity can improve the conductivity of both the insulating protein layers and the CdS:Mn/TiO2 matrix, thus facilitating the regeneration of trapped carriers and hot electrons in the CdS:Mn QD films and enhancing the PEC performance. Second, graphene nanodisks introduce a great number of GOD molecules into a PEC detection process, which catalyze glucose to produce numerous molecules of H2O2. The latter act as sacrificial electron donors to scavenge photogenerated holes, retard the electron-hole recombination, and significantly improve the photo-to-electron conversion efficiency. Based on the dual signal amplification strategy and using a carcinoembryonic antigen as a model target, a highly sensitive PEC immunoassay was therefore developed with an extremely low limit of detection of 5.65 fg mL-1 and a rather wide linear range from 10 fg mL-1 to 1 ng mL-1. The immunoassay showed good reproducibility and stability, as well as good selectivity and high accuracy in serum sample analysis. In this regard, PEC immunosensors may have great application potential for the screening of tumor markers and the prevention and monitoring of serious diseases.