Dynamic PET-CT Research Articles

P15.13.B DEVELOPMENT OF [18F]AG-120 AS AN IMAGING AGENT FOR THE DETECTION OF THE MUTANT ISOCITRATE DEHYDROGENASE 1 IN GLIOMA BY PET

Abstract BACKGROUND Gliomas are highly invasive and infiltrative solid tumors that present significant clinical challenges in terms of achieving complete surgical resection. These tumors often harbor mutated isocitrate dehydrogenase enzymes (mIDH), making them attractive theranostic targets. Therefore, accurately assessing mIDH status is essential for effective patient management. Currently, the presence of mIDH1 is determined either by invasive biopsy or indirectly by measuring the mIDH-derived oncometabolite 2-hydroxyglutarate (2-HG) using magnetic resonance spectroscopy (MRS). The availability of mIDH-targeted radioligands would allow for PET neuroimaging to detect the mIDH1 protein directly and non-invasively. MATERIAL AND METHODS The study involved obtaining 18F-labeled AG-120 (Ivosidenib), an FDA-approved small molecule inhibitor of mIDH, by Cu-mediated radiofluorination of a corresponding diastereomerically pure stannyl precursor. The researchers studied the internalization of [18F]AG-120 in vitro in U251 human glioblastoma cells stably transfected with IDH1 or IDH1R132H. Brain uptake and metabolism of [18F]AG-120 were investigated in healthy CD-1 mice by dynamic PET-MR imaging and radio-chromatographic analyses of plasma and brain tissue. Dynamic PET-CT imaging studies were performed in nude rats bearing U251-IDH1 or U251-IDH1R132H glioblastoma. RESULTS The (S,S)-enantiomer of [18F]AG-120 was successfully prepared, and the procedure was implemented into a remotely-controlled radiosynthesis module. A considerably higher uptake of activity was observed in U251-IDH1R132H cells compared to U251-IDH1 cells (0.422 vs. 0.014% applied activity/μg protein after 120 min incubation). The percentage of non-metabolized [18F]AG-120 in the mouse 30 min post i.v. injection was 85% in plasma and 91% in the brain, respectively. Dynamic PET studies showed limited blood-brain barrier permeation of [18F]AG-120 (SUV < 0.1 within the first 5 min post i.v. injection), which could be significantly increased by inhibiting the p-glycoprotein 1 with cyclosporine A. PET studies with glioblastoma rats indicated slightly higher tumor-to-blood ratios in IDH1R132H-tumors compared to IDH1-tumors (~1.7 vs. ~1.3 at 40-60 min p.i.). CONCLUSION For the first time, pure (S,S)-[18F]AG-120 has been synthesized. In addition, GMP-compliant production is facilitated by the established automated radiosynthesis. Despite limited BBB permeation, [18F]AG-120 shows target-specific internalization in vitro and high metabolic stability in vivo. Furthermore, the slightly higher accumulation of [18F]AG-120 in IDH1R132H-glioblastoma compared to IDH1-glioblastoma in vivo encourages further evaluation of mIDH inhibitors for the noninvasive detection of IDH1R132H in glioma by PET. SUPPORT European-Regional-Development-Fund ERDF and Sächsische-Aufbaubank SAB (#100364142).

Diagnostic Value of Dynamic 18F-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography (18F-FDG PET-CT) in Cervical Lymph Node Metastasis of Nasopharyngeal Cancer.

Dynamic 18F-FDG PET-CT scanning can accurately quantify 18F-FDG uptake and has been successfully applied in diagnosing and evaluating therapeutic effects in various malignant tumors. There is no conclusion as to whether it can accurately distinguish benign and malignant lymph nodes in nasopharyngeal cancer. The main purpose of this study is to reveal the diagnostic value of dynamic PET-CT in cervical lymph node metastasis of nasopharyngeal cancer through analysis. We first searched for cervical lymph nodes interested in static PET-CT, measured their SUV-Max values, and found the corresponding lymph nodes in magnetic resonance images before and after treatment. The valid or invalid groups were included according to the changes in lymph node size before and after treatment. If the change in the product of the maximum diameter and maximum vertical transverse diameter of the lymph node before and after treatment was greater than or equal to 50%, they would be included in the valid group. If the change was less than 50%, they would be included in the invalid group. Their Ki values were measured on dynamic PET-CT and compared under different conditions. Then, we conducted a correlation analysis between various factors and Ki values. Finally, diagnostic tests were conducted to compare the sensitivity and specificity of Ki and SUV-Max. We included 67 cervical lymph nodes from different regions of 51 nasopharyngeal cancer patients and divided them into valid and invalid groups based on changes before treatment. The valid group included 50 lymph nodes, while the invalid group included 17. There wer significant differences (p < 0.001) between the valid and the invalid groups in SUV-Max, Ki-Mean, and Ki-Max values. When the SUV-Max was ≤4.5, there was no significant difference in the Ki-Mean and Ki-Max between the two groups (p > 0.05). When the SUV-Max was ≤4.5 and pre-treatment lymph nodes were <1.0 cm, the valid group had significantly higher Ki-Mean (0.00910) and Ki-Maximum (0.01004) values than the invalid group (Ki-Mean = 0.00716, Ki-Max = 0.00767) (p < 0.05). When the SUV-Max was ≤4.5, the pre-treatment lymph nodes < 1.0 cm, and the EBV DNA replication normal, Ki-Mean (0.01060) and Ki-Max (0.01149) in the valid group were still significantly higher than the invalid group (Ki-Mean = 0.00670, Ki-Max = 0.00719) (p < 0.05). The correlation analysis between different factors (SUV-Max, T-stage, normal EB virus DNA replication, age, and pre-treatment lymph node < 1.0 cm) and the Ki value showed that SUV-Max and a pre-treatment lymph node < 1.0 cm were related to Ki-Mean and Ki-Max. Diagnostic testing was conducted; the AUC value of the SUV-Max value was 0.8259 (95% confidence interval: 0.7296-0.9222), the AUC value of the Ki-Mean was 0.8759 (95% confidence interval: 0.7950-0.9567), and the AUC value of the Ki-Max was 0.8859 (95% confidence interval: 0.8089-0.9629). After comparison, it was found that there was no significant difference in AUC values between Ki-Mean and SUV-Max (p = 0.220 > 0.05), and there was also no significant difference in AUC values between Ki max and SUV-Max (p = 0.159 > 0.05). By calculating the Youden index, we identified the optimal cut-off value. It was found that the sensitivity of SUV-Max was 100% and the specificity was 66%, the sensitivity of Ki-Mean was 100% and the specificity was 70%, and the sensitivity of Ki-Max was 100% and the specificity was 72%. After Chi-Square analysis, it was found that there was no significant difference in specificity between Ki-Mean and SUV-Max (p = 0.712), and there was also no significant difference in specificity between Ki-Max and SUV-Max (p = 0.755). Dynamic PET-CT has shown a significant diagnostic value in diagnosing cervical lymph node metastasis of nasopharyngeal cancer, especially for the small SUV value, and lymph nodes do not meet the metastasis criteria before treatment, and EBV DNA replication is normal. Although the diagnostic accuracy, sensitivity, and specificity of dynamic PET-CT were not significantly different from traditional static PET-CT, the dynamic PET-CT had a more accurate tendency.

Role of dynamic and parametric whole-body FDG PET/CT imaging in molecular characterization of primary breast cancer: a single institution experience.

The aim of this pilot study was to assess the role of dynamic whole-body PET and parametric imaging in the biological characterization of primary breast cancer. In total 24 histologically proven primary breast cancer lesions in 21 consecutive patients were retrospectively analyzed. Each patient underwent 18F-fluoro-deoxyglucose whole-body dynamic PET-CT before any treatment. Dynamic PET images were acquired in the list mode for a total duration of 70 min. The reconstructed parametric imaging generated Patlak plot-based 'Slope' and 'Intercept' images, from which parametric indices ki and DV were obtained. The standard uptake value (SUV) metric was also obtained by summing the last few frames of the dynamic study. ki, distribution volume (DV) and SUV were correlated with the histological tumor grade, biomarkers [hormone receptors and human epidermal growth factor receptor 2 (HER-2) neu expression] and molecular subtypes (A, B and C) as well as with tumor size, regional nodal metastases and distant metastases. The mean ki was found to be significantly higher in grade III than II lesions (P = 0.005), HER-2 neu positive status (P = 0.04) and molecular subtype B (P = 0.04) as well as in greater than T1 lesions(P = 0.0003 and P = 0.04, respectively) and node-positive lesions (P = 0.009). Though mean ki was not found to be significant for the hormone receptors status (P = 0.08), it showed the best correlation compared to the other parameters (P = 0.8 for DV and P = 0.1 for SUV). Spearman's correlation test, area under the curve (AUC) and mismatch percentage also revealed ki to predict tumor grade (AUC, 0.95; r = 0.7; P = 0.0001), HER-2 neu status and molecular subtypes (AUC, 0.81; r = 0.49 and P = 0.01) along with the hormone receptors status (AUC, 0.83; r = 0.32; P = 0.1). The mean DV failed to show any association with any of the biological or anatomical staging parameters. Though ki was found to be comparable to that of SUV in almost all the assessed parameters, it appeared to be better for predicting hormone receptors status even though both parameters were not statistically significant. Our initial observation in a small cohort of breast cancer patients suggests that ki is promising in stratifying primary breast cancer lesions according to the tumor grade and biological characteristics.

TG-Net: Combining transformer and GAN for nasopharyngeal carcinoma tumor segmentation based on total-body uEXPLORER PET/CT scanner

Nasopharyngeal carcinoma (NPC) is a malignant tumor, and the main treatment is radiotherapy. Accurate delineation of the target tumor is essential for radiotherapy of NPC. NPC tumors are small in size and vary widely in shape and structure, making it a time-consuming and laborious task for even experienced radiologists to manually outline tumors. However, the segmentation performance of current deep learning models is not satisfactory, mainly manifested by poor segmentation boundaries. To solve this problem, this paper proposes a segmentation method for nasopharyngeal carcinoma based on dynamic PET-CT image data, whose input data include CT, PET, and parametric images (Ki images). This method uses a generative adversarial network with a modified UNet integrated with a Transformer as the generator (TG-Net) to achieve automatic segmentation of NPC on combined CT-PET-Ki images. In the coding stage, TG-Net uses moving windows to replace traditional pooling operations to obtain patches of different sizes, which can reduce information loss in the coding process. Moreover, the introduction of Transformer can make the network learn more representative features and improve the discriminant ability of the model, especially for tumor boundaries. Finally, the results of fivefold cross validation with an average Dice similarity coefficient score of 0.9135 show that our method has good segmentation performance. Comparative experiments also show that our network structure is superior to the most advanced methods in the segmentation of NPC. In addition, this work is the first to use Ki images to assist tumor segmentation. We also demonstrated the usefulness of adding Ki images to aid in tumor segmentation.

Potential of [11C]UCB-J as a PET tracer for islets of Langerhans

Biomarkers for the measurement of islets of Langerhans could help elucidate the etiology of diabetes. Synaptic vesicle glycoprotein 2 A (SV2A) is a potential marker reported to be localized in the endocrine pancreas. [11C]UCB-J is a novel positron emission tomography (PET) radiotracer that binds to SV2A and was previously evaluated as a synaptic marker in the central nervous system. Here, we evaluated whether [11C]UCB-J could be utilized as a PET tracer for the islets of Langerhans in the pancreas by targeting SV2A. The mRNA transcription of SV2A was evaluated in human isolated islets of Langerhans and exocrine tissue. In vitro autoradiography was performed on pancreas and brain sections from rats and pigs, and consecutive sections were immunostained for insulin. Sprague–Dawley rats were examined with PET-MRI and ex vivo autoradiography at baseline and with administration of levetiracetam (LEV). Similarly, pigs were examined with dynamic PET-CT over the pancreas and brain after administration of [11C]UCB-J at baseline and after pretreatment with LEV. In vivo radioligand binding was assessed using a one-compartment tissue model. The mRNA expression of SV2A was nearly 7 times higher in endocrine tissue than in exocrine tissue (p < 0.01). In vitro autoradiography displayed focal binding of [11C]UCB-J in the pancreas of rats and pigs, but the binding pattern did not overlap with the insulin-positive areas or with ex vivo autoradiography. In rats, pancreas binding was higher than that in negative control tissues but could not be blocked by LEV. In pigs, the pancreas and brain exhibited accumulation of [11C]UCB-J above the negative control tissue spleen. While brain binding could be blocked by pretreatment with LEV, a similar effect was not observed in the pancreas. Transcription data indicate SV2A to be a valid target for imaging islets of Langerhans, but [11C]UCB-J does not appear to have sufficient sensitivity for this application.

Dynamic 11C-Methionine PET-CT: Prognostic Factors for Disease Progression and Survival in Patients with Suspected Glioma Recurrence.

Simple SummaryRecurrence after initial treatments is an expected event in glioma patients, particularly for high-grade glioma, with a median progression-free survival of 8–11 weeks. The prognostic evaluation of disease is a crucial step in the planning of therapeutic strategies, in both the primary and recurrence stages of disease. The aim of our retrospective study was to assess the prognostic value of 11C-methionine PET-CT dynamic and semiquantitative parameters in patients with suspected glioma recurrence at MR, in terms of progression-free survival and overall survival. In a population of sixty-seven consecutive patients, both static and kinetic analyses provided parameters (i.e., tumour-to-background ratio and SUVmax associated with time-to-peak, respectively) able to predict both progression-free and overall survival in the whole population and in the high-grade glioma subgroup of patients. Dynamic 11C-methionine PET-CT can be a useful diagnostic tool, in patients with suspicion of glioma recurrence, able to produce significant prognostic indices.Purpose: The prognostic evaluation of glioma recurrence patients is important in the therapeutic management. We investigated the prognostic value of 11C-methionine PET-CT (MET-PET) dynamic and semiquantitative parameters in patients with suspected glioma recurrence. Methods: Sixty-seven consecutive patients who underwent MET-PET for suspected glioma recurrence at MR were retrospectively included. Twenty-one patients underwent static MET-PET; 46/67 underwent dynamic MET-PET. In all patients, SUVmax, SUVmean and tumour-to-background ratio (T/B) were calculated. From dynamic acquisition, the shape and slope of time-activity curves, time-to-peak and its SUVmax (SUVmaxTTP) were extrapolated. The prognostic value of PET parameters on progression-free (PFS) and overall survival (OS) was evaluated using Kaplan–Meier survival estimates and Cox regression. Results: The overall median follow-up was 19 months from MET-PET. Recurrence patients (38/67) had higher SUVmax (p = 0.001), SUVmean (p = 0.002) and T/B (p < 0.001); deceased patients (16/67) showed higher SUVmax (p = 0.03), SUVmean (p = 0.03) and T/B (p = 0.006). All static parameters were associated with PFS (all p < 0.001); T/B was associated with OS (p = 0.031). Regarding kinetic analyses, recurrence (27/46) and deceased (14/46) patients had higher SUVmaxTTP (p = 0.02, p = 0.01, respectively). SUVmaxTTP was the only dynamic parameter associated with PFS (p = 0.02) and OS (p = 0.006). At univariate analysis, SUVmax, SUVmean, T/B and SUVmaxTTP were predictive for PFS (all p < 0.05); SUVmaxTTP was predictive for OS (p = 0.02). At multivariate analysis, SUVmaxTTP remained significant for PFS (p = 0.03). Conclusion: Semiquantitative parameters and SUVmaxTTP were associated with clinical outcomes in patients with suspected glioma recurrence. Dynamic PET-CT acquisition, with static and kinetic parameters, can be a valuable non-invasive prognostic marker, identifying patients with worse prognosis who require personalised therapy.

Application of PET Imaging in the Brain Regions of the Emotional Control Loop in Patients with Generalized Anxiety Disorder.

Objective This study uses PET imaging to observe the uptake and metabolism of 18F-fluorodeoxyglucose (18F-FDG) in the multibrain areas of the emotional control loop in patients with generalized anxiety disorder (GAD) and investigate the brain of GAD patient's functional abnormality mechanism. Methods The thesis clinically collected 20 GAD patients and 20 healthy subjects. Dynamic PET-CT scans were used. At the same time, 18F-FDG whole-brain uptake and metabolism data were collected. Image fusion and semiquantitative analysis were used to measure emotional control loops. The maximum standard uptake value (SUVmax) and dynamic uptake and metabolic changes of 11 time points in the brain area at 150 min were measured. Results Compared with the healthy control group, the peak uptake of the bilateral prefrontal cortex and the average uptake rate before the peak in GAD patients were significantly reduced (P < 0.05), and the average metabolic rate after the peak was significantly increased (P < 0.05). The peak uptake of the left striatum and the left hippocampus, the average uptake rate before the peak, and the average metabolic rate after the peak were all significantly reduced (P < 0.05); There were no obvious changes in the three indexes of the right striatum and the right hippocampus. Conclusion There are 18F-FDG uptake and metabolic disorders in multiple brain areas of the affective control loop of GAD patients. The abnormal peak and rate of uptake may be related to the pathogenesis of GAD.

Pharmacokinetic studies of [68\xa0Ga]Ga-PSMA-11 in patients with biochemical recurrence of prostate cancer: detection, differences in temporal distribution and kinetic modelling by tissue type

Purpose[68 Ga]Ga-PSMA-11 is a promising radiopharmaceutical for detecting tumour lesions in prostate cancer, but knowledge of the pharmacokinetics is limited. Dynamic PET-CT was performed to investigate the tumour detection and differences in temporal distribution, as well as in kinetic modelling of [68 Ga]Ga-PSMA-11 by tissue type.MethodsDynamic PET-CT over the lower abdomen and static whole-body PET-CT 80–90 min p.i. from 142 patients with biochemical recurrence were retrospectively analysed. Detection rates were compared to PSA levels. Average time-activity curves were calculated from tumour lesions and normal tissue. A three-compartment model and non-compartment model were used to calculate tumour kinetics.ResultsOverall detection rate was 70.42%, and in patients with PSA > 0.4 ng/mL 76.67%. All tumour lesions presented the steepest standardised uptake value (SUV) incline in the first 7–8 min before decreasing to different degrees. Normal tissue presented with a low uptake, except for the bladder, which accumulated activity the steepest 15–16 min. p.i.. While all tumour lesions continuously increased, bone metastases showed the steepest decline, resulting in a significantly lower SUV than lymph node metastases (60 and 80–90 min). Transport rate from the blood and tracer binding and internalisation rate were lower in bone metastases. Heterogeneity (fractal dimension) and vascular density were significantly lower in bone metastases.ConclusionEven at low PSA between 0.51 and 0.99 ng/mL, detection rate was 57%. Dynamic imaging showed a time window in the first 10 min where tumour uptake is high, but no bladder activity is measured, aiding accuracy in distinction of local recurrence. Kinetic modelling provided additional information for tumour characterisation by tissue type.

Longitudinal evaluation of a novel BChE PET tracer as an early in vivo biomarker in the brain of a mouse model for Alzheimer disease.

Purpose: The increase in butyrylcholinesterase (BChE) activity in the brain of Alzheimer disease (AD) patients and animal models of AD position this enzyme as a potential biomarker of the disease. However, the information on the ability of BChE to serve as AD biomarker is contradicting, also due to scarce longitudinal studies of BChE activity abundance. Here, we report 11C-labeling, in vivo stability, biodistribution, and longitudinal study on BChE abundance in the brains of control and 5xFAD (AD model) animals, using a potent BChE selective inhibitor, [11C]4, and positron emission tomography (PET) in combination with computerised tomography (CT). We correlate the results with in vivo amyloid beta (Aβ) deposition, longitudinally assessed by [18F]florbetaben-PET imaging.Methods: [11C]4 was radiolabelled through 11C-methylation. Metabolism studies were performed on blood and brain samples of female wild type (WT) mice. Biodistribution studies were performed in female WT mice using dynamic PET-CT imaging. Specific binding was demonstrated by ex vivo and in vivo PET imaging blocking studies in female WT and 5xFAD mice at the age of 7 months. Longitudinal PET imaging of BChE was conducted in female 5xFAD mice at 4, 6, 8, 10 and 12 months of age and compared to age-matched control animals. Additionally, Aβ plaque distribution was assessed in the same mice using [18F]florbetaben at the ages of 2, 5, 7 and 11 months. The results were validated by ex vivo staining of BChE at 4, 8, and 12 months and Aβ at 12 months on brain samples.Results: [11C]4 was produced in sufficient radiochemical yield and molar activity for the use in PET imaging. Metabolism and biodistribution studies confirmed sufficient stability in vivo, the ability of [11C]4 to cross the blood brain barrier (BBB) and rapid washout from the brain. Blocking studies confirmed specificity of the binding. Longitudinal PET studies showed increased levels of BChE in the cerebral cortex, hippocampus, striatum, thalamus, cerebellum and brain stem in aged AD mice compared to WT littermates. [18F]Florbetaben-PET imaging showed similar trend of Aβ plaques accumulation in the cerebral cortex and the hippocampus of AD animals as the one observed for BChE at ages 4 to 8 months. Contrarily to the results obtained by ex vivo staining, lower abundance of BChE was observed in vivo at 10 and 12 months than at 8 months of age.Conclusions: The BChE inhibitor [11C]4 crosses the BBB and is quickly washed out of the brain of WT mice. Comparison between AD and WT mice shows accumulation of the radiotracer in the AD-affected areas of the brain over time during the early disease progression. The results correspond well with Aβ accumulation, suggesting that BChE is a promising early biomarker for incipient AD.

Prognostic value of subventricular zone involvement in relation to tumor volumes defined by fused MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET imaging in glioblastoma multiforme

BackgroundSubventricular zone (SVZ) involvement is associated with a dismal prognosis in patients with glioblastoma multiforme (GBM). Dual-time point (dtp) O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET/CT (PET) may be a time- and cost-effective alternative to dynamic FET PET, but its prognostic value, particularly with respect to SVZ involvement, is unknown.MethodsThirty-five patients had two scans 5–15 and 50–60 min after i.v. FET injection to define tumor volumes and SVZ involvement before starting radiotherapy. Associations between clinical progression markers, MRI- and dtp FET PET-based tumor volumes, or SVZ involvement and progression-free (PFS) and overall survival (OS) were assessed in univariable and multivariable analyses.ResultsThe extent of resection was not related to outcomes. Albeit non-significant, dtp FET PET detected more SVZ infiltration than MRI (60% vs. 51%, p = 0.25) and was significantly associated with poor survival (p < 0.03), but PET-T1-Gad volumes were larger in this group (p < 0.002). Survival was shorter in patients with larger MRI tumor volumes, larger PET tumor volumes, and worse Karnofsky performance status (KPS), with fused PET-T1-Gad and KPS significant in multivariable analysis (p < 0.03). Uptake kinetics was not associated with treatment outcomes.ConclusionsFET PET-based tumor volumes may be useful for predicting worse prognosis glioblastoma. Although the presence of SVZ infiltration is linked to higher PET/MRI-based tumor volumes, the independent value of dtp FET PET parameters and SVZ infiltration as prognostic markers pre-irradiation has not been confirmed.

Partial-volume correction in dynamic PET-CT: effect on tumor kinetic parameter estimation and validation of simplified metrics

BackgroundPartial-volume effects generally result in an underestimation of tumor tracer uptake on PET-CT for small lesions, necessitating partial-volume correction (PVC) for accurate quantification. However, investigation of PVC in dynamic oncological PET studies to date is scarce. The aim of this study was to investigate PVC’s impact on tumor kinetic parameter estimation from dynamic PET-CT acquisitions and subsequent validation of simplified semi-quantitative metrics. Ten patients with EGFR-mutated non-small cell lung cancer underwent dynamic 18F-fluorothymidine PET-CT before, 7 days after, and 28 days after commencing treatment with a tyrosine kinase inhibitor. Parametric PVC was applied using iterative deconvolution without and with highly constrained backprojection (HYPR) denoising, respectively. Using an image-derived input function with venous parent plasma calibration, we estimated full kinetic parameters VT, K1, and k3/k4 (BPND) using a reversible two-tissue compartment model, and simplified metrics (SUV and tumor-to-blood ratio) at 50–60 min post-injection.ResultsPVC had a non-linear effect on measured activity concentrations per timeframe. PVC significantly changed each kinetic parameter, with a median increase in VT of 11.8% (up to 25.1%) and 10.8% (up to 21.7%) without and with HYPR, respectively. Relative changes in kinetic parameter estimates vs. simplified metrics after applying PVC were poorly correlated (correlations 0.36–0.62; p < 0.01). PVC increased correlations between simplified metrics and VT from 0.82 and 0.81 (p < 0.01) to 0.90 and 0.88 (p < 0.01) for SUV and TBR, respectively, albeit non-significantly. PVC also increased correlations between treatment-induced changes in simplified metrics vs. VT at 7 (SUV) and 28 (SUV and TBR) days after treatment start non-significantly. Delineation on partial-volume corrected PET images resulted in a median decrease in metabolic tumor volume of 14.3% (IQR − 22.1 to − 7.5%), and increased the effect of PVC on kinetic parameter estimates.ConclusionPVC has a significant impact on tumor kinetic parameter estimation from dynamic PET-CT data, which differs from its effect on simplified metrics. However, it affected validation of these simplified metrics both as single measurements and as biomarkers of treatment response only to a small extent. Future dynamic PET studies should preferably incorporate PVC.Trial registrationDutch Trial Register, NTR3557.

PET-MR Attenuation Correction in Dynamic Brain PET Using [11C]Cimbi-36: A Direct Comparison With PET-CT

PET-MR is increasingly used in a range of clinical indications, though its use for quantitative brain PET research has not been widely reported. To isolate and evaluate MR-based attenuation correction (MR-AC) effects on fitted PET kinetic model parameters, we used a previously reported atlas-based method to synthesize CTs from structural MR scans, substituted for the CTs acquired in a dynamic PET-CT study where [11C]Cimbi-36 was used to quantify 5-HT2 A receptor binding in the brain. The resulting small differences (<5%) in kinetic outcome measures using MR-AC compared to CT-AC were consistent with the observed differences between the MR-AC and CT attenuation maps and within the test-retest variability of the radioligand. This supports the use of MR-AC for quantitative PET imaging of the brain.

Reproducible quantification of cardiac sympathetic innervation using graphical modeling of carbon-11-meta-hydroxyephedrine kinetics with dynamic PET-CT imaging

BackgroundGraphical methods of radiotracer kinetic modeling in PET are ideal for parametric imaging and data quality assurance but can suffer from noise bias. This study compared the Logan and Multilinear Analysis-1 (MA1) graphical models to the standard one-tissue-compartment (1TC) model, including correction for partial-volume effects, in dynamic PET-CT studies of myocardial sympathetic innervation in the left ventricle (LV) using [11C]HED.MethodsTest and retest [11C]HED PET imaging (47 ± 22 days apart) was performed in 18 subjects with heart failure symptoms. Myocardial tissue volume of distribution (VT) was estimated using Logan and MA1 graphical methods and compared to the 1TC standard model values using intraclass correlation (ICC) and Bland-Altman analysis of the non-parametric reproducibility coefficient (NPC).ResultsA modeling start-time of t* = 5 min gave the best fit for both Logan and MA1 (R2 = 0.95) methods. Logan slightly underestimated VT relative to 1TC (p = 0.002), whereas MA1 did not (p = 0.96). Both the MA1 and Logan models exhibited good-to-excellent agreement with the 1TC (MA1-1TC ICC = 0.96; Logan-1TC ICC = 0.93) with no significant differences in NPC between the two comparisons (p = 0.92). All methods exhibited good-to-excellent test-retest repeatability with no significant differences in NPC (p = 0.57).ConclusionsLogan and MA1 models exhibited similar agreement and variability compared to the 1TC for modeling of [11C]HED kinetics. Using t* = 5 min and partial-volume correction produced accurate estimates of VT as an index of myocardial sympathetic innervation.

18F-Alanine Derivative Serves as an ASCT2 Marker for Cancer Imaging.

Amino acids derivative are well established molecular probes for diagnosis of a variety of cancer using positron emission tomography (PET). Recently, boramino acid (BAAs) was found as a prospective molecular platform for developing PET tracer. The objective of this study was to develop a 18F-labeled alanine derivative through displacing its carboxylate by trifluoroborate as a selective ASCT2 marker for cancer imaging. 18F-Ala-BF3 was first evaluated in healthy FVB/N mice in vivo, exhibiting rapid renal clearance with almost negligible uptake in stomach (1.53 ± 0.31%ID/g). Notable uptake was observed in thyroid (3.71 ± 0.49%ID/g, 40 min post injection), of which the uptake was significantly inhibited by co-injection with natural L-alanine. In addition, we further established 18F-Ala-BF3 on a human gastric cancer cell (BGC-823) xenografts bearing mouse model. Dynamic PET-CT scan revealed the optimal time window for tumor imaging, it was between 40 and 60 min post injection, when the BGC-823 xenografts uptake was 5.49 ± 1.47%ID/g ( n = 4), and the tumor-to-stomach, tumor-to-blood, tumor-to-muscle, and tumor-to-brain ratios were 3.27 ± 1.53, 3.80 ± 1.48, 3.47 ± 1.48, and 6.20 ± 1.47, respectively.

Synthesis, Chemical Characterization and Multiscale Biological Evaluation of a Dimeric-cRGD Peptide for Targeted Imaging of \u03b1V\u03b23 Integrin Activity

Cyclic peptides containing the Arg-Gly-Asp (RGD) sequence have been shown to specifically bind the angiogenesis biomarker αVβ3 integrin. We report the synthesis, chemical characterization, and biological evaluation of two novel dimeric cyclic RGD-based molecular probes for the targeted imaging of αVβ3 activity (a radiolabeled version, 64Cu-NOTA-PEG4-cRGD2, for PET imaging, and a fluorescent version, FITC-PEG4-cRGD2, for in vitro work). We investigated the performance of this probe at the receptor, cell, organ, and whole-body levels, including its use to detect diabetes associated impairment of ischemia-induced myocardial angiogenesis. Both versions of the probe were found to be stable, demonstrated fast receptor association constants, and showed high specificity for αVβ3 in HUVECs (Kd ~ 35 nM). Dynamic PET-CT imaging indicated rapid blood clearance via kidney filtration, and accumulation within αVβ3-positive infarcted myocardium. 64Cu-NOTA-PEG4-cRGD2 demonstrated a favorable biodistribution, slow washout, and excellent performance with respect to the quality of the PET-CT images obtained. Importantly, the ratio of probe uptake in infarcted heart tissue compared to normal tissue was significantly higher in non-diabetic rats than in diabetic ones. Overall, our probes are promising agents for non-invasive quantitative imaging of αVβ3 expression, both in vitro and in vivo.

Abstract A24: Integration of tumor metabolomics, cancer genome sequencing and dynamic functional imaging to assess the metabolic effects of metformin in breast cancer

Abstract There is great interest in the effects on cancer metabolism of the diabetes drug, metformin and its potential as a cancer treatment. Despite intense investigation it is still not clear as to its metabolic effects on primary human cancer in vivo. 41 patients with primary breast cancer were recruited to a ‘window of opportunity study’ prior to neoadjuvant chemotherapy. Before and after 2 weeks of metformin, dynamic 18F-FDG PET-CT scans were carried out, breast core biopsies of the primary tumour taken for RNASeq, metabolomics and immunohistochemistry analysis and host serum metabolic markers assessed. Metabolomic mass spectrometry analysis revealed an increase in the ADP/ATP and AMP/ATP ratio (fold change 8.6 and 24.9, respectively, p = 0.07 and p = 0.14) after metformin treatment. RNA sequencing of the first 21 paired samples showed upregulation of many genes encoding components of complex 1, and the TCA cycle, glutaminolysis, and glycolysis pathways. Several genes encoding for glucose and glutamine transport were amongst those most consistently upregulated, including GLUT1, SLC38A1 and SLC7A5 (all p&amp;lt;0.0001). Dynamic PET-CT analysis of the first 17 paired scans demonstrated a trend toward a decrease in the variable K2 post-metformin (an estimate of 18F-FDG efflux from tumour intracellular pool back to blood), but with much variability between paired scans (0.70±0.11 vs 0.51±0.05 (p=0.14)). There was a decrease in serum C-peptide (0.56±0.04nmol/L vs 0.48±0.02nmol/L, pre- and post-metformin, p=0.003) consistent with reduced host insulin secretion. This is the first study in the clinical setting to show that metformin can cause an energy stress in cancer cells. The effect on mRNA expression was compatible with direct mitochondrial effects on the cancer cell leading to upregulation of the glutaminolysis and glycolysis pathways. The decrease in efflux of radiolabelled glucose may indicate retention of glucose possibly secondary to changes in blood glucose availability. We expect this study will help define biomarker development and future treatment strategies for metformin, in particular potential combination therapy. Note: This abstract was not presented at the conference. Citation Format: Simon R. Lord, Nilay Patel, D. Liu, J. Fenwick, C. Frezza, S. Henriques da Costa, E. Gaude, Q. Zhang, M. Wakelam, F. Gleeson, S. Haider, F. Buffa, A. L. Harris. Integration of tumor metabolomics, cancer genome sequencing and dynamic functional imaging to assess the metabolic effects of metformin in breast cancer [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A24.

Prognostic Value of (18)F-FDG PET-CT in Nasopharyngeal Carcinoma: Is Dynamic Scanning Helpful?

Objectives. To evaluate the differences in prognostic values of static and dynamic PET-CT in nasopharyngeal carcinoma (NPC). Material and Methods. Forty-five patients who had static scan were recruited. Sixteen had dynamic scan. The primary lesions were delineated from standardized uptake value (SUV) maps from static scan and K i maps from dynamic scan. The average follow-up lasted for 34 months. The patients who died or those with recurrence/residual disease were considered “poor outcome”; otherwise they were considered “good outcome.” Fisher's exact test and ROC analysis were used to evaluate the prognostic value of various factors. Results. Tumor volume thresholded by 40% of maximal SUV (VOLSUV40) significantly predicted treatment outcome (p = 0.024) in the whole cohort. In 16 patients with dynamic scan, all parameters by dynamic scan were insignificant in predicting the outcome. The combination of maximal SUV, maximal K i, VOLSUV40, and VOLKi37 (the tumor volume thresholded by 37% maximal K i) achieved the highest predicting accuracy for treatment outcome with sensitivity, specificity, and accuracy of 100% in these 16 patients; however this improvement compared to VOLSUV40 was insignificant. Conclusion. Tumor volume from static scan is useful in NPC prognosis. However, the role of dynamic scanning was not justified in this small cohort.

Preliminary evaluation of different biomaterials for defect healing in an experimental osteoporotic rat model with dynamic PET-CT (dPET-CT) using F-18-Sodium Fluoride (NaF)

The aim of the current study was to measure and compare the effect of calcium phosphate cement (CPC) and CPC enriched with strontium (SrCPC) for the healing of osteoporotic bone defects in the rat femur using 18F-Sodium Fluoride dPET-CT. Methods: Osteoporosis was induced by ovariectomy and a calcium restricted diet. After three months, rats were operated to create a 4mm defect in the distal metaphyseal femur with internal fixation. 7 Rats have been treated either with CPC (Group 2) or with SrCPC (Group 3) for bone replacement and defect healing. Furthermore, a control group of 7 rats without any biomaterial (Group 1) was used for reference. 18 weeks after osteoporosis induction and 6 weeks following femoral surgery, dPET-CT studies scan were performed with 18F-Sodium Fluoride. SUVs and a 2-tissue compartmental learning-machine model (K1-k4, VB, influx) were used for quantitative analysis. Results: VB, reflecting the fractional blood volume and k3, reflecting the formation of fluoroapatite were the most sensitive parameters for the characterisation of healing process and revealed the best differentiation for the control group and the CPC group (Group 2) as well as for the CPC with strontium carbonate group (Group 3) (p<0.05). VB was decreased by the order of Group1, Group 2 and Group3, while k3 was increased by the same order. Therefore, the data direct to a decreased fractional blood volume and increased fixation of fluoride in rats with these biomaterials. Conclusion: We found PET scanning using 18F-Sodium Fluoride to be a sensitive and useful method for evaluation of bone healing after replacement with CPC or SrCPC.

Pilot Study of the Utility of the Synthetic PET Amino-Acid Radiotracer Anti-1-Amino-3-[18F]Fluorocyclobutane-1-Carboxylic Acid for the Noninvasive Imaging of Pulmonary Lesions

Anti-1-amino-3-[(18)F]fluorocyclobutane-1-carboxylic acid (anti-3-[(18)F]FACBC) is a synthetic amino acid positron emission tomography (PET) radiotracer with utility in detection of prostate carcinoma and brain tumors and has also been shown to have uptake in lung tumor cell lines. The purpose of this study is to determine the uptake characteristics of anti-3-[(18)F]FACBC in lung carcinoma and if this radiotracer may help characterize pulmonary lesions. Ten patients with pulmonary lesions scheduled for surgical resection or biopsy underwent 45-min dynamic PET-CT imaging of the thorax after IV injection of 214.6-384.8MBq of anti-3-[(18)F]FACBC. Anti-3-[(18)F]FACBC uptake was compared with that of routine 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) PET-CT scans of the same patient and validated with a combination of pathology, imaging and clinical follow-up. Immunohistochemistry for Ki-67 was performed on tissue samples. There were nine malignant (seven lung nodules and two mediastinal nodes), two inflammatory, and one carcinoid lesion ranging from 1 to 3.75cm. Mean(±SD) SUVmax of malignant lesions was 6.2(±2.6), 5.9(±2.7), 5.9(±3.4), and 5.7(±3.3), at 8, 16, 28, and 40min, respectively; while for inflammatory lesions at the same time points, 4.1(±0.6), 3.3(±0.9), 2.2(±0.03), and 2.3(±0.03), respectively. The carcinoid tumor had SUVmax of 2.8, 2.6, 1.5, and 0.9 at similar time points. Mean SUVmax of all malignant lesions was higher than that of inflammatory lesions for anti-3-[(18)F]FACBC, and was statistically significant at greater than 28min post-radiotracer infusion (p < 0.05). There was no significant correlation of anti-3-[(18)F]FACBC activity with Ki67, though there was a positive trend. There was a strong correlation between anti-3-[(18)F]FACBC and [(18)F]FDG uptake. Anti-3-[(18)F]FACBC uptake in malignant lesions is greater than in inflammatory lesions with a higher degree of separation of uptake on delayed imaging. More comprehensive study is required to determine the diagnostic performance of anti-3-[(18)F]FACBC in the characterization of pulmonary lesions.

Evaluation of New Bone Formation in Normal and Osteoporotic Rats with a 3-mm Femur Defect: Functional Assessment with Dynamic PET-CT (dPET-CT) Using 2-Deoxy-2-[18F]Fluoro-d-glucose (18F-FDG) and 18F-Fluoride

The aim of the current study was to assess the formation of new bone in a 3-mm created defect in the femur and its adjacent bone tissue in osteoporotic and normal animals. The assessment is based on bone remodeling and glucose metabolism in a rat model with a 3-mm created defct in the femur using (18)F-fluoride and 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) as tracers for dynamic PET-CT (dPET-CT). The (18)F-fluoride PET data were compared with those of (18)F-FDG. Osteoporosis was induced by ovariectomy and a calcium restricted diet in each rat (n = 7). Alternatively, a sham operation was performed in the control group (n = 8). After 3months, all rats were operated to create a 3-mm defect using an oscillating saw in the distal metaphyseal femur, which was internally fixed with a metal plate. Eighteen weeks after osteoporosis induction and 6weeks following femoral surgery, dPET-CT studies scan were performed with (18)F-FDG and (18)F-fluoride. Following PET data acquisition, standardized uptake values (SUVs) were calculated from the tracer concentration values. Then, a two-tissue compartmental learning-machine model was applied to the data for the calculation of the compartment parameters (K1-k4, VB, Ki). Furthermore, a non-compartmental model based on the fractal dimension was applied for quantitative analysis of both groups and both tracers. Finally, multivariate analysis was performed for the statistical analysis of the kinetic data. The values for K1 and Ki were higher in the osteoporotic rats than in the control group. Ki and K1 of (18)F-fluoride in the adjacent bone tissue differ significantly based on the Wilcoxon rank-sum test for the osteoporotic and control group (p < 0.05). The sensitivity and the negative predictive value (NPV) based on linear discriminant analysis was high with a value of 100% for both tracers and both evaluated regions (defect and adjacent bone tissue) when comparing control and osteoporotic rats. The overall accuracy with (18)F-FDG was generally higher than that with (18)F-fluoride for both evaluated regions for the control and osteoporotic rats based on a multiparameter evaluation. In this study, the changes in tracer kinetics accurately discriminated differences in the created defect in the femur and its adjacent bone tissue between osteoporotic and control rats.