Influence of Different Measurement Methods of Arterial Input Function on Quantitative Dynamic Contrast-Enhanced MRI Parameters in Head and Neck Cancer.

BACKGROUND: Head and neck cancer (HNC) is the sixth most prevalent cancer worldwide. Dynamic contrast-enhanced MRI (DCE-MRI) helps in diagnosis and prognosis. Quantitative DCE-MRI requires an arterial input function (AIF), which affects the values of pharmacokinetic parameters (PKP). PURPOSE: To evaluate influence of four individual AIF measurement methods on quantitative DCE-MRI parameters values (Ktrans , ve , kep , and vp ), for HNC and muscle. STUDY TYPE: Prospective. POPULATION: A total of 34 HNC patients (23 males, 11 females, age range 24-91) FIELD STRENGTH/SEQUENCE: A 3 T; 3D SPGR gradient echo sequence with partial saturation of inflowing spins. ASSESSMENT: Four AIF methods were applied: automatic AIF (AIFa) with up to 50 voxels selected from the whole FOV, manual AIF (AIFm) with four voxels selected from the internal carotid artery, both conditions without (Mc-) or with (Mc+) motion correction. Comparison endpoints were peak AIF values, PKP values in tumor and muscle, and tumor/muscle PKP ratios. STATISTICAL TESTS: Nonparametric Friedman test for multiple comparisons. Nonparametric Wilcoxon test, without and with Benjamini Hochberg correction, for pairwise comparison of AIF peak values and PKP values for tumor, muscle and tumor/muscle ratio, P value ≤ 0.05 was considered statistically significant. RESULTS: Peak AIF values differed significantly for all AIF methods, with mean AIFmMc+ peaks being up to 66.4% higher than those for AIFaMc+. Almost all PKP values were significantly higher for AIFa in both, tumor and muscle, up to 76% for mean Ktrans values. Motion correction effect was smaller. Considering tumor/muscle parameter ratios, most differences were not significant (0.068 ≤ Wilcoxon P value ≤ 0.8). DATA CONCLUSION: We observed important differences in PKP values when using either AIFa or AIFm, consequently choice of a standardized AIF method is mandatory for DCE-MRI on HNC. From the study findings, AIFm and inflow compensation are recommended. The use of the tumor/muscle PKP ratio should be of interest for multicenter studies. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Diffusion-weighted Imaging Voxelwise-matched Analyses of Lung Cancer at 3.0-T PET/MRI: Reverse Phase Encoding Approach for Echo-planar Imaging Distortion Correction.

Background PET/MRI has drawn increasing interest in thoracic oncology due to the simultaneous acquisition of PET and MRI data. Geometric distortions related to diffusion-weighted imaging (DWI) limit the evaluation of voxelwise multimodal analyses. Purpose To assess the effectiveness of reverse phase encoding in correcting DWI geometric distortion for multimodal PET/MRI voxelwise lung tumor analyses. Materials and Methods In this prospective study, reverse phase encoding method was implemented with 3.0-T PET/MRI to correct geometric distortions related to DWI. The method was validated in dedicated phantom and then applied to 12 consecutive patients (mean age, 66 years ± 13 [standard deviation]; 10 men) suspected of having lung cancer who underwent fluorodeoxyglucose PET/MRI between October 2018 and April 2019. The effects on DWI-related image matching and apparent diffusion coefficient (ADC) regional map computation were assessed. Consequences on multimodal PET/MRI voxelwise lung tumor analyses were evaluated. Spearman correlation coefficients (rs) between the standardized uptake value (SUV) and ADC data corrected for distortion were computed from optimal realigned DWI PET data, along with bootstrap confidence intervals. Results Phantom results showed that in highly distorted areas, correcting the distortion significantly reduced the mean error against the ground truth (-25% ± 10.6 to -18.4% ± 12.6; P < .001) and the number of voxels with more than 20% error (from 85.3% to 31.4%). In the 12 patients, the coregistration of multimodal PET/MRI tumor data was improved by using the reverse phase encoding method (0.4%-44%). In all tumors, voxelwise correlations (rs) between ADC and SUV revealed null or weak monotonic relationships (mean rs of 0.016 ± 0.24 with none above 0.5). Conclusion Reverse phase encoding is a simple-to-implement method for improved diffusion-weighted multimodal PET/MRI voxelwise-matched analyses in lung cancer. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Colletti in this issue.

Rapid Contour-based Segmentation for 18F-FDG PET Imaging of Lung Tumors by Using ITK-SNAP: Comparison to Expert-based Segmentation.

Purpose To assess the performance of the ITK-SNAP software for fluorodeoxyglucose (FDG) positron emission tomography (PET) segmentation of complex-shaped lung tumors compared with an optimized, expert-based manual reference standard. Materials and Methods Seventy-six FDG PET images of thoracic lesions were retrospectively segmented by using ITK-SNAP software. Each tumor was manually segmented by six raters to generate an optimized reference standard by using the simultaneous truth and performance level estimate algorithm. Four raters segmented 76 FDG PET images of lung tumors twice by using ITK-SNAP active contour algorithm. Accuracy of ITK-SNAP procedure was assessed by using Dice coefficient and Hausdorff metric. Interrater and intrarater reliability were estimated by using intraclass correlation coefficients of output volumes. Finally, the ITK-SNAP procedure was compared with currently recommended PET tumor delineation methods on the basis of thresholding at 41% volume of interest (VOI; VOI41) and 50% VOI (VOI50) of the tumor's maximal metabolism intensity. Results Accuracy estimates for the ITK-SNAP procedure indicated a Dice coefficient of 0.83 (95% confidence interval: 0.77, 0.89) and a Hausdorff distance of 12.6 mm (95% confidence interval: 9.82, 15.32). Interrater reliability was an intraclass correlation coefficient of 0.94 (95% confidence interval: 0.91, 0.96). The intrarater reliabilities were intraclass correlation coefficients above 0.97. Finally, VOI41 and VOI50 accuracy metrics were as follows: Dice coefficient, 0.48 (95% confidence interval: 0.44, 0.51) and 0.34 (95% confidence interval: 0.30, 0.38), respectively, and Hausdorff distance, 25.6 mm (95% confidence interval: 21.7, 31.4) and 31.3 mm (95% confidence interval: 26.8, 38.4), respectively. Conclusion ITK-SNAP is accurate and reliable for active-contour-based segmentation of heterogeneous thoracic PET tumors. ITK-SNAP surpassed the recommended PET methods compared with ground truth manual segmentation.

18F-FDG PET in drug-resistant epilepsy due to focal cortical dysplasia type 2: additional value of electroclinical data and coregistration with MRI.

PURPOSE: To assess the localizing value of 18F-FDG PET in patients operated on for drug-resistant epilepsy due to focal cortical dysplasia type 2 (FCD2). METHODS: We analysed 18F-FDG PET scans from 103 consecutive patients (52 males, 7-65 years old) with histologically proven FCD2. PET and MRI data were first reviewed by visual analysis blinded to clinical information and FCD2 location. The additional value of electroclinical data and PET/MRI coregistration was assessed by comparison with pathological results and surgical outcomes. RESULTS: Visual analysis of PET scans showed focal or regional hypometabolism corresponding to the FCD2 in 45 patients (44%), but the findings were doubtful or misleading in 37 patients and negative in 21. When considering electroclinical data, positive localization was obtained in 73 patients, and this increased to 85 (83%) after coregistration of PET and MRI data. Under the same conditions, MRI was positive in 61 patients (59%), doubtful in 15 and negative in 27. The additional value of PET was predominant in patients negative or doubtful on MRI, localizing the FCD2 in 35 patients (83%). Interobserver agreement correlated with the grade of hypometabolism: it was good in patients with mild to severe hypometabolism (82-95%), but moderate in those with subtle/doubtful hypometabolism (45%). The main factors influencing positive PET localization were the grade of hypometabolism and the size of the FCD2 (P < 0.0001). Misleading location (nine patients) was associated with a small FCD2 in the mesial frontal and central regions. Following limited cortical resection mainly located in extratemporal areas (mean follow-up 5.6 years), a seizure-free outcome was achieved in 94% of patients, including Engel's class IA in 72%. CONCLUSION: In this series, 18F-FDG PET contributed to the localization of FCD2 in 83% of patients. This high localizing value was obtained by integration of electroclinical data and PET/MRI coregistration. This approach may help improve the surgical outcome in extratemporal epilepsy, even in patients negative on MRI.

Correction to: 18F-FDG PET in drug-resistant epilepsy due to focal cortical dysplasia type 2: additional value of electroclinical data and coregistration with MRI.

The original version of this article has added numbers in the text which are unnecessary. Correct line should be: "We also performed PET/MRI based surgical resections in an increasing number of MRI negative/ doubtful cases with favourable outcome."

Intracellular metabolites in the primate brain are primarily localized in long fibers rather than in cell bodies, as shown by diffusion-weighted magnetic resonance spectroscopy.

Due to their pure intracellular compartmentation, the translational diffusion of brain metabolites in vivo depends on the intracellular environment, including viscosity, molecular crowding and subcellular structures. However, as the diffusion time is increased, metabolites have enough time to significantly encounter cell boundaries, so that cell size and geometry are expected to strongly determine metabolite diffusion path. In the present work, diffusion-weighted nuclear magnetic resonance spectroscopy was used to investigate brain metabolite diffusion in vivo, at long and ultra-long diffusion times (from ~80 ms to more than 1 s), in a voxel with equal proportions of white and grey matter in macaque monkeys. No dramatic dependence of the ADC on the diffusion time was observed, suggesting that metabolites' apparent diffusion is largely unrestricted over these time-scales. In an attempt to explain this stability and relate it to plausible cell geometries, data were analyzed with two simple geometrical models describing diffusion either in fibers such as axons, dendrites and astrocytic processes, or in closed cell bodies. Results support the idea that DW-MRS is sensitive to cell shape, and that a vast fraction of brain metabolites is diffusing in long fibers rather than being confined in cell bodies.

Brain 18 F-FDG PET reveals cortico-subcortical hypermetabolic dysfunction in juvenile neuropsychiatric systemic lupus erythematosus.

BACKGROUND: In juvenile systemic lupus erythematosus (j-SLE) with neuropsychiatric (NP) symptoms, there is a lack of diagnostic biomarkers. Thus, we study whether PET-FDG may identify any metabolic dysfunction in j-NPSLE. METHODS: A total of 19 18FDG-PET exams were consecutively performed using PET-MRI system in 11 non-sedated patients presenting with j-NPSLE (11-18y) for less than 18 months (m) and without any significant lesion at MRI. Psychiatric symptoms were scored from 0 (none) to 3 (severe) at PET time. PET images were visually analyzed and voxel-based analyses of cerebral glucose metabolism were performed using statistical parametric mapping (spm) with an age-matched control group, at threshold set > 50 voxels using both p < 0.001 uncorrected (unc.) and p < 0.05 corrected family wise error (FWE). RESULTS: Patients exhibited mainly psychiatric symptoms, with diffuse inflammatory j-NPSLE. First PET (n = 11) was performed at a mean of 15y of age, second/third PET (n = 7/n = 1) 6 to 19 m later. PET individual analysis detected focal bilateral anomalies in 13/19 exams visually but 19/19 using spm (unc.), mostly hypermetabolic areas (18/19). A total of 15% of hypermetabolic areas identified by spm had been missed visually. PET group analysis (n = 19) did not identify any hypometabolic area, but a large bilateral cortico-subcortical hypermetabolic pattern including, by statistical decreasing order (unc.), thalamus, subthalamic brainstem, cerebellum (vermis and cortex), basal ganglia, visual, temporal and frontal cortices. Mostly the subcortical hypermetabolism survived to FWE analysis, being most intense and extensive (51% of total volume) in thalamus and subthalamus brainstem. Hypermetabolism was strictly subcortical in the most severe NP subgroup (n = 8, scores 2-3) whereas it also extended to cerebral cortex, mostly visual, in the less severe subgroup (n = 11, scores 0-1), but difference was not significant. Longitudinal visual analysis was inconclusive due to clinical heterogeneity. CONCLUSIONS: j-NPSLE patients showed a robust bilateral cortico-subcortical hypermetabolic network, focused subcortically, particularly in thalamus, proportionally to psychiatric features severity. Further studies with larger, but homogeneous, cohorts are needed to determine the sensitivity and specificity of this dysfunctional pattern as a potential biomarker in diffuse inflammatory j-NPSLE with normal brain MRI.

Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging.

Astrocytes and microglia become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. It is widely considered that TSPO PET signal reveals reactive microglia, although a few studies suggested a potential contribution of reactive astrocytes. Because astrocytes and microglia play very different roles, it is crucial to determine whether reactive astrocytes can also overexpress TSPO and yield to a detectable TSPO PET signal in vivo. We used a model of selective astrocyte activation through lentiviral gene transfer of the cytokine ciliary neurotrophic factor (CNTF) into the rat striatum, in the absence of neurodegeneration. CNTF induced an extensive activation of astrocytes, which overexpressed GFAP and become hypertrophic, whereas microglia displayed minimal increase in reactive markers. Two TSPO radioligands, [(18)F]DPA-714 [N,N-diethyl-2-(2-(4-(2-[(18)F]fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide] and [(11)C]SSR180575 (7-chloro-N,N-dimethyl-5-[(11)C]methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide), showed a significant binding in the lenti-CNTF-injected striatum that was saturated and displaced by PK11195 [N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)-isoquinoline-3-carboxamide]. The volume of radioligand binding matched the GFAP immunopositive volume. TSPO mRNA levels were significantly increased, and TSPO protein was overexpressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microglia.

Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology.

Mutations in SQSTM1 encoding the sequestosome 1/p62 protein have recently been identified in familial and sporadic cases of amyotrophic lateral sclerosis (ALS). p62 is a component of the ubiquitin inclusions detected in degenerating neurons in ALS patients. We sequenced SQSTM1 in 90 French patients with familial ALS (FALS) and 74 autopsied ALS cases with sporadic ALS (SALS). We identified, at the heterozygote state, one missense c.1175C>T, p.Pro392Leu (exon 8) in one of our FALS and one substitution in intron 7 (the c.1165+1G>A, previously called IVS7+1 G-A, A390X) affecting the exon 7 splicing site in one SALS. These mutations that are located in the ubiquitin-associated domain (UBA domain) of the p62 protein have already been described in Paget's disease and ALS patients carrying these mutations had both concomitant Paget's disease. However, we also identified two novel missense mutations in two SALS: the c.259A>G, p.Met87Val in exon 2 and the c.304A>G, p.Lys102Glu in exon 3. These mutations that were not detected in 360 control subjects are possibly pathogenic. Neuropathology analysis of three patients carrying SQSTM1 variants revealed the presence of large round p62 inclusions in motor neurons, and immunoblot analysis showed an increased p62 and TDP-43 protein levels in the spinal cord. Our results confirm that SQSTM1 gene mutations could be the cause or genetic susceptibility factor of ALS in some patients.

Relevance of 18F-DOPA visual and semi-quantitative PET metrics for the diagnostic of Parkinson disease in clinical practice: a machine learning-based inference study.

PURPOSE: To decipher the relevance of visual and semi-quantitative 6-fluoro-(18F)-L-DOPA (18F-DOPA) interpretation methods for the diagnostic of idiopathic Parkinson disease (IPD) in hybrid positron emission tomography (PET) and magnetic resonance imaging. MATERIAL AND METHODS: A total of 110 consecutive patients (48 IPD and 62 controls) with 11 months of median clinical follow-up (reference standard) were included. A composite visual assessment from five independent nuclear imaging readers, together with striatal standard uptake value (SUV) to occipital SUV ratio, striatal gradients and putamen asymmetry-based semi-quantitative PET metrics automatically extracted used to train machine learning models to classify IPD versus controls. Using a ratio of 70/30 for training and testing sets, respectively, five classification models-k-NN, LogRegression, support vector machine, random forest and gradient boosting-were trained by using 100 times repeated nested cross-validation procedures. From the best model on average, the contribution of PET parameters was deciphered using the Shapley additive explanations method (SHAP). Cross-validated receiver operating characteristic curves (cv-ROC) of the most contributive PET parameters were finally estimated and compared. RESULTS: The best machine learning model (k-NN) provided final cv-ROC of 0.81. According to SHAP analyses, visual PET metric was the most important contributor to the model overall performance, followed by the minimum between left and right striatal to occipital SUV ratio. The 10-time cv-ROC curves of visual, min SUVr or both showed quite similar performance (mean area under the ROC of 0.81, 0.81 and 0.79, respectively, for visual, min SUVr or both). CONCLUSION: Visual expert analysis remains the most relevant parameter to predict IPD diagnosis at 11 months of median clinical follow-up in 18F-FDOPA. The min SUV ratio appears interesting in the perspective of simple semi-automated diagnostic workflows.

Local and distant response to intratumoral immunotherapy assessed by immunoPET in mice.

BACKGROUND: Despite the promising efficacy of immune checkpoint blockers (ICB), tumor resistance and immune-related adverse events hinder their success in cancer treatment. To address these challenges, intratumoral delivery of immunotherapies has emerged as a potential solution, aiming to mitigate side effects through reduced systemic exposure while increasing effectiveness by enhancing local bioavailability. However, a comprehensive understanding of the local and systemic distribution of ICBs following intratumoral administration, as well as their impact on distant tumors, remains crucial for optimizing their therapeutic potential.To comprehensively investigate the distribution patterns following the intratumoral and intravenous administration of radiolabeled anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and to assess its corresponding efficacy in both injected and non-injected tumors, we conducted an immunoPET imaging study. METHODS: CT26 and MC38 syngeneic colorectal tumor cells were implanted subcutaneously on both flanks of Balb/c and C57Bl/6 mice, respectively. Hamster anti-mouse CTLA-4 antibody (9H10) labeled with zirconium-89 ([89Zr]9H10) was intratumorally or intravenously administered. Whole-body distribution of the antibody was monitored by immunoPET imaging (n=12 CT26 Balb/c mice, n=10 MC38 C57Bl/6 mice). Tumorous responses to injected doses (1-10 mg/kg) were correlated with specific uptake of [89Zr]9H10 (n=24). Impacts on the tumor microenvironment were assessed by immunofluorescence and flow cytometry. RESULTS: Half of the dose was cleared into the blood 1 hour after intratumoral administration. Despite this, 7 days post-injection, 6-8% of the dose remained in the intratumoral-injected tumors. CT26 tumors with prolonged ICB exposure demonstrated complete responses. Seven days post-injection, the contralateral non-injected tumor uptake of the ICB was comparable to the one achieved through intravenous administration (7.5±1.7% ID.cm-3 and 7.6±2.1% ID.cm-3, respectively) at the same dose in the CT26 model. This observation was confirmed in the MC38 model. Consistent intratumoral pharmacodynamic effects were observed in both intratumoral and intravenous treatment groups, as evidenced by a notable increase in CD8+T cells within the CT26 tumors following treatment. CONCLUSIONS: ImmunoPET-derived pharmacokinetics supports intratumoral injection of ICBs to decrease systemic exposure while maintaining efficacy compared with intravenous. Intratumoral-ICBs lead to high local drug exposure while maintaining significant therapeutic exposure in non-injected tumors. This immunoPET approach is applicable for clinical practice to support evidence-based drug development.

Head-to-Head Comparison Between Rabbit Sign and EANM/SNMMI Criteria for the 18F-DOPA Visual Assessment of Parkinsonian Syndromes in PET/MRI: A Multiple Expert-Based and Blinded Controlled Study.

PURPOSE: The aim of this study was to compare the diagnostic performance of the rabbit visual pattern versus the one endorsed by the EANM/SNMMI for the diagnosis of parkinsonian syndromes in PET/MRI. PATIENTS AND METHODS: The 18F-DOPA PET images of 129 consecutive patients (65 Park+ and 64 controls) with 1 year of clinical follow-up were reviewed independently by 5 experienced readers on the same imaging workstation, blinded to the final clinical diagnosis. Two visual methods were assessed independently, with several days to months of interval: the criteria endorsed by EANM/SNMMI and the "rabbit" shape of the striate assessed on 3D MIP images. The sensitivities, specificities, likelihood ratios, and predictive values of the 2 diagnostic tests were estimated simultaneously by using the "comparison of 2 binary diagnostic tests to a paired design" method. RESULTS: The estimated 95% confidence interval (CI) of sensitivities and specificities ranged from 49.4% to 76.5% and from 83.2% to 97.7%, respectively. The 95% CI estimates of positive and negative likelihood ratios ranged from 3.8 to 26.7 and from 0.26 to 0.56, respectively. The 95% CI estimates of the positive and negative predictive values ranged from 78.1% to 96.7% and from 60.3% to 81.4%, respectively. For all the parameters, no statistical difference was observed between the 2 methods (P > 0.05). The rabbit sign reduced the readers' discrepancies by 25%, while maintaining the same performance. CONCLUSIONS: The rabbit visual pattern appears at least comparable to the current EANM/SNMMI reference procedure for the assessment of parkinsonian syndromes in daily clinical practice, without the need of any image postprocessing. Further multicenter prospective studies would be of relevance to validate these findings.

A new sequence for single-shot diffusion-weighted NMR spectroscopy by the trace of the diffusion tensor.

Diffusion-weighted spectroscopy is a unique tool for exploring the intracellular microenvironment in vivo. In living systems, diffusion may be anisotropic, when biological membranes exhibit particular orientation patterns. In this work, a volume selective diffusion-weighted sequence is proposed, allowing single-shot measurement of the trace of the diffusion tensor, which does not depend on tissue anisotropy. With this sequence, the minimal echo time is only three times the diffusion time. In addition, cross-terms between diffusion gradients and other gradients are cancelled out. An adiabatic version, similar to localization by adiabatic selective refocusing sequence, is then derived, providing partial immunity against cross-terms. Proof of concept is performed ex vivo on chicken skeletal muscle by varying tissue orientation and intra-voxel shim. In vivo performance of the sequence is finally illustrated in a U87 glioblastoma mouse model, allowing the measurement of the trace apparent diffusion coefficient for six metabolites, including J-modulated metabolites. Although measurement performed along three separate orthogonal directions would bring similar accuracy on trace apparent diffusion coefficient under ideal conditions, the method described here should be useful for probing intimate properties of the cells with minimal experimental bias.

Multimodal neuroimaging provides a highly consistent picture of energy metabolism, validating 31P MRS for measuring brain ATP synthesis.

Neuroimaging methods have considerably developed over the last decades and offer various noninvasive approaches for measuring cerebral metabolic fluxes connected to energy metabolism, including PET and magnetic resonance spectroscopy (MRS). Among these methods, (31)P MRS has the particularity and advantage to directly measure cerebral ATP synthesis without injection of labeled precursor. However, this approach is methodologically challenging, and further validation studies are required to establish (31)P MRS as a robust method to measure brain energy synthesis. In the present study, we performed a multimodal imaging study based on the combination of 3 neuroimaging techniques, which allowed us to obtain an integrated picture of brain energy metabolism and, at the same time, to validate the saturation transfer (31)P MRS method as a quantitative measurement of brain ATP synthesis. A total of 29 imaging sessions were conducted to measure glucose consumption (CMRglc), TCA cycle flux (V(TCA)), and the rate of ATP synthesis (V(ATP)) in primate monkeys by using (18)F-FDG PET scan, indirect (13)C MRS, and saturation transfer (31)P MRS, respectively. These 3 complementary measurements were performed within the exact same area of the brain under identical physiological conditions, leading to: CMRglc = 0.27 +/- 0.07 micromol x g(-1) x min(-1), V(TCA) = 0.63 +/- 0.12 micromol x g(-1) x min(-1), and V(ATP) = 7.8 +/- 2.3 micromol x g(-1) x min(-1). The consistency of these 3 fluxes with literature and, more interestingly, one with each other, demonstrates the robustness of saturation transfer (31)P MRS for directly evaluating ATP synthesis in the living brain.

Optimizing Immuno-PET Imaging of Tumor PD-L1 Expression: Pharmacokinetic, Biodistribution, and Dosimetric Comparisons of 89Zr-Labeled Anti-PD-L1 Antibody Formats.

PET imaging of programmed cell death ligand 1 (PD-L1) may help to noninvasively predict and monitor responses to anti-programmed cell death 1/anti-PD-L1 immunotherapies. In this study, we compared the imaging characteristics of 3 radioligands derived from the anti-PD-L1 IgG1 complement 4 (C4). In addition to the IgG C4, we produced a fragment antigen-binding (Fab) C4, as well as a double-mutant IgG C4 (H310A/H435Q) with minimal affinity for the murine neonatal Fc receptor. Methods: The pharmacokinetics, biodistribution, and dosimetry of the 3 89Zr-labeled C4 ligands were compared by longitudinal PET/CT imaging in nude mice bearing subcutaneous human non-small cell lung cancer xenografts with positive (H1975 model) or negative (A549 model) endogenous PD-L1 expression. Results: The C4 radioligands substantially accumulated in PD-L1-positive tumors but not in PD-L1-negative tumors or in blocked PD-L1-positive tumors, confirming their PD-L1-specific tumor targeting. 89Zr-Fab C4 and 89Zr-IgG C4 (H310A/H435Q) were rapidly eliminated compared with 89Zr-IgG C4. Consequently, maximal tumor-to-muscle ratios were obtained earlier, at 4 h after injection for 89Zr-Fab C4 (ratio, ∼6) and 24 h after injection for 89Zr-IgG C4 (H310A/H435Q) (ratio, ∼9), versus 48 h after injection for 89Zr-IgG C4 (ratio, ∼8). Background activity in nontumor tissues was low, except for high kidney retention of 89Zr-Fab C4 and persistent liver accumulation of 89Zr-IgG C4 (H310A/H435Q) compared with 89Zr-IgG C4. Dosimetry estimates suggested that the C4 radioligands would yield organ-absorbed doses tolerable for repeated clinical PET imaging studies. Conclusion: This study highlights the potential of designing radioligands with shorter pharmacokinetics for PD-L1 immuno-PET imaging in a preclinical model and encourages further clinical translation of such radioligands.

[11C]glyburide PET imaging for quantitative determination of the importance of Organic Anion-Transporting Polypeptide transporter function in the human liver and whole-body.

Organic Anion-Transporting Polypeptides (OATPs) are known to control the liver uptake of many drugs. Non-hepatic expression of OATPs has been reported although functional importance for whole-body pharmacokinetics (WBPK) remains unknown. Glyburide is a well described substrate of several hepatic and non-hepatic OATPs. Dynamic whole-body positron emission tomography (DWB-PET) with [11C]glyburide was performed in humans for determination of the importance of OATPs for liver uptake and WBPK. Seven healthy male subjects (24.7 ± 3.2 years) underwent [11C]glyburide PET scan with concomitant blood sampling. All subjects underwent baseline [11C]glyburide PET scan. Five subjects underwent a subsequent [11C]glyburide PET scan after infusion of the potent OATP inhibitor rifampicin (9 mg/kg i.v.). The transfer constant (kuptake) of [11C]glyburide from blood to the liver was estimated using the integration plot method. The tissue exposure of [11C]glyburide was described by the area under the time-activity curve (AUC) and corresponding tissue/blood ratio (AUCR). [11C]glyburide was barely metabolized in both the baseline and rifampicin conditions. Parent (unmetabolized) [11C]glyburide accounted for > 90 % of the plasma radioactivity. Excellent correlation was found between radioactive counting in arterial blood samples and in the image-derived input function, in both the baseline and rifampicin conditions (R2 = 97.9 %, p < 0.01). [11C]glyburide predominantly accumulated in the liver. Rifampicin decreased liver kuptake by 77.3 ± 7.3 %, which increased exposure in blood, kidneys, spleen, myocardium and brain (p < 0.05). No significant change in AUCR was observed except in the liver (p < 0.01). [11C]glyburide benefits from metabolic stability and high sensitivity to OATP inhibition which enables quantitative determination of OATP function. DWB-PET suggests negligible role for non-hepatic OATPs in controlling the tissue distribution of [11C]glyburide.

PET imaging of immune checkpoint proteins in oncology.

Despite the remarkable clinical successes of immune checkpoint inhibitors (ICIs) in various advanced cancers, response is still limited to a subset of patients that generally exhibit tumoral expression of immune checkpoint (IC) proteins. Development of biomarkers assessing the expression of such ICs is therefore a major challenge nowadays to refine patient selection and improve therapeutic benefits. Positron emission tomography (PET) imaging using IC-targeted radiolabeled monoclonal antibodies (immunoPET) provides a non-invasive and whole-body visualization of in vivo IC biodistribution. As such, PET imaging of ICs may serve as a robust biomarker to predict and monitor responses to ICIs, complementing the existing immunohistochemical techniques. Besides monoclonal antibodies, other PET radioligand formats, ranging from antibody-derived fragments to small proteins, have gained increasing interest owing to their faster pharmacokinetics and enhanced imaging characteristics. We provide an overview of the various strategies investigated so far for PET imaging of ICs in preclinical and clinical studies, emphasizing their benefits and limitations. Moreover, we discuss various parameters to consider for designing optimized and best-suited PET radioligands.

Challenges and Perspectives of the Hybridization of PET with Functional MRI or Ultrasound for Neuroimaging.

Hybridization of positron emission tomography (PET) with other functional neuroimaging techniques such as functional magnetic resonance imaging (fMRI) or functional ultrasound (fUS) still raises technical and methodological challenges. Beyond the co-registration of anatomical images with functional data, development of hybrid imaging systems has paved the way for a large field of research based on the concept of bimodal functional neuroimaging such as PET/fMRI. In this framework, comparison of respective performances of brain PET and fUS suggests complementarity and great potential of hybrid PET/fUS for preclinical neuroimaging. Hybridization of functional neuroimaging techniques first offers opportunities to validate or improve measurement made by each modality. Future research may propose and validate hybrid parameters that quantitatively connect the brain molecular environment and the neuro-vascular coupling, which may improve our understanding of brain function in health and disease, with perspectives in neuroscience and neuropharmacology. In the coming years, cross-fertilization of neuroimaging communities and training of young researchers on multiple imaging modalities may foster the development of hybrid neuroimaging protocols that will take the full potential and the limitations of each modality into account.

18F-FDG PET/MR in focal epilepsy: A new step for improving the detection of epileptogenic lesions.

PURPOSE: Hybrid PET/MR is a promising tool in focal drug-resistant epilepsy, however the additional value for the detection of epileptogenic lesions and surgical decision-making remains to be established. METHODS: We retrospectively compared 18F-FDG PET/MR images with those obtained by a previous 18F-FDG PET co-registered with MRI (PET+MR) in 25 consecutive patients (16 females, 13-60 years) investigated for focal drug-resistant epilepsy. Visual analysis was performed by two readers blinded from imaging modalities, asked to assess the technical characteristics (co-registration, quality of images), the confidence in results, the location of PET abnormalities and the presence of a structural lesion on MRI. Clinical impact on surgical strategy and outcome was assessed independently. RESULTS: The location of epileptic focus was temporal in 9 patients and extra-temporal in 16 others. MRI was initially considered negative in 21 patients. PET stand-alone demonstrated metabolic abnormalities in 19 cases (76%), and the co-registration with MRI allowed the detection of 4 additional structural lesions. Compared to PET+MR, the PET/MR sensitivity was increased by 13% and new structural lesions (mainly focal cortical dysplasias) were detected in 6 patients (24%). Change of surgical decision-making was substantial for 10 patients (40%), consisting in avoiding invasive monitoring in 6 patients and modifying the planning in 4 others. Seizure-free outcome (follow-up>1 year) was obtained in 12/14 patients who underwent a cortical resection. CONCLUSION: Hybrid PET/MR may improve the detection of epileptogenic lesions, allowing to optimize the presurgical work-up and to increase the proportion of successful surgery even in the more complex cases.