Validation of cardiac image-derived input functions for functional PET quantification.

PURPOSE: Functional PET (fPET) is a novel technique for studying dynamic changes in brain metabolism and neurotransmitter signaling. Accurate quantification of fPET relies on measuring the arterial input function (AIF), traditionally achieved through invasive arterial blood sampling. While non-invasive image-derived input functions (IDIF) offer an alternative, they suffer from limited spatial resolution and field of view. To overcome these issues, we developed and validated a scan protocol for brain fPET utilizing cardiac IDIF, aiming to mitigate known IDIF limitations. METHODS: Twenty healthy individuals underwent fPET/MR scans using [18F]FDG or 6-[18F]FDOPA, utilizing bed motion shuttling to capture cardiac IDIF and brain task-induced changes. Arterial and venous blood sampling was used to validate IDIFs. Participants performed a monetary incentive delay task. IDIFs from various blood pools and composites estimated from a linear fit over all IDIF blood pools (3VOI) and further supplemented with venous blood samples (3VOIVB) were compared to the AIF. Quantitative task-specific images from both tracers were compared to assess the performance of each input function to the gold standard. RESULTS: For both radiotracer cohorts, moderate to high agreement (r: 0.60-0.89) between IDIFs and AIF for both radiotracer cohorts was observed, with further improvement (r: 0.87-0.93) for composite IDIFs (3VOI and 3VOIVB). Both methods showed equivalent quantitative values and high agreement (r: 0.975-0.998) with AIF-derived measurements. CONCLUSION: Our proposed protocol enables accurate non-invasive estimation of the input function with full quantification of task-specific changes, addressing the limitations of IDIF for brain imaging by sampling larger blood pools over the thorax. These advancements increase applicability to any PET scanner and clinical research setting by reducing experimental complexity and increasing patient comfort.

Endocrinology application of molecular imaging: current role of PET/CT.

BACKGROUND: In recent years, nuclear medicine imaging methods have proven to be of paramount importance in a wide variety of diseases, particularly in oncology, where they are crucial for assessing the extent of disease when conventional methods fall short. Moreover, nuclear imaging modalities are able to better characterize lesions using target agents related to specific pathways (e.g. glucose metabolism, cellular proliferation, amino acid transport, lipid metabolism, specific receptor ligands). The clinical presentation of endocrine diseases encompasses a broad spectrum of sign and symptoms. Moreover, endocrine tumors show varying degrees of aggressiveness from well differentiated and indolent to highly aggressive cancers, respectively. RATIONALE: With the application of new medicinal radio-compounds and increasingly advanced tomographic imaging technology, the utility of Positron Emission Tomography/Computed Tomography (PET/CT) in the field of endocrine diseases is expanding. AIM: This review aims to analyze and summarize the primary indications of PET/CT, providing a practical approach for clinicians. A comprehensive literature search on PubMed was conducted to provide an updated overview of the available evidence regarding the use of PET/CT in endocrinology. Within this review, we will discuss the applications of PET/CT, compare different radiopharmaceuticals and highlight the uptake mechanism, excluding neuroendocrine carcinomas from discussion. CONCLUSIONS: PET/CT is a valuable tool in diagnosing and managing endocrine disorders due to its capacity to furnish both functional and anatomical information, facilitate early lesion detection, guide treatment decisions, and monitor treatment response. Its non-invasive nature and precision make it an integral component of modern endocrine healthcare. This review aims to provide physicians with a clear perspective on the role of PET/CT imaging, discussing its emerging opportunities and appropriateness of use in endocrinological diseases.

Automation of Copper-Mediated 18F-Fluorination of Aryl Pinacol Boronates Using 4-Dimethylaminopyridinium Triflate.

Currently, the copper-mediated radiofluorination of aryl pinacol boronates (arylBPin) using the commercially available, air-stable Cu(OTf)2Py4 catalyst is one of the most efficient synthesis approaches, greatly facilitating access to a range of radiotracers, including drug-like molecules with nonactivated aryl scaffolds. Further adjustment of this methodology, in particular, the [18F]fluoride recovery step for the routine preparation of radiotracers, has been the focus of recent research. In our recent study, an organic solution of 4-dimethylaminopyridinium trifluoromethanesulfonate (DMAPOTf) was found to be an efficient PTC for eluting radionuclides retained on the weak anion exchange cartridge, Oasis WAX 1cc, employing the inverse sorption-elution protocol. Notably, the following Cu-mediated radiofluorination of arylBPin precursors in the presence of the Cu(OTf)2(Py)4 catalyst can be performed with high efficiency in the same solvent, bypassing not only the conventional azeotropic drying procedure but any solvent replacement. In the current study, we aimed to translate this methodology, originally developed for remote-controlled operation with manual interventions, into the automated synthesis module on the TRACERlab automation platform. The adjustment of the reagent amounts and solvents allowed for high efficiency in the radiofluorination of a series of model arylBPin substrates on the TRACERlab FXFE Pro synthesis module, which was adapted for nucleophilic radiofluorinations. The practical applicability of the developed radiofluorination approach with DMAPOTf elution was demonstrated in the automated synthesis of 6-L-[18F]FDOPA. The radiotracer was obtained with an activity yield (AY; isolated, not decay-corrected) of 5.2 ± 0.5% (n = 3), with a synthesis time of ca. 70 min on the TRACERlab FX N Pro automation platform. The obtained AY was comparable with one reported by others (6 ± 1%) using the same boronate precursor, while a slightly higher AY of 6-L-[18F]FDOPA (14.5 ± 0.5%) was achieved in our previous work using commercially available Bu4NOTf as the PTC.

Slowing of EEG waves correlates with striatal [18 F]fluorodopa PET/CT uptake and executive dysfunction in Parkinson's disease.

Parkinson's disease (PD) research on specific neuroimaging and neurophysiological biomarkers revealing executive dysfunction mechanisms is limited, necessitating validation. Thus, our study aimed to assess associations between electroencephalographic power spectral density (PSD-EEG), striatal [18 F]Fluorodopa uptake and neuropsychological executive function (EF) testing parameters in PD, while also estimating their diagnostic accuracy. We compared resting PSD-EEG, striatal [18 F]Fluorodopa uptake ratios based on positron emission computed tomography ([18 F]FDOPA PET/CT) and neuropsychological EF tests outcomes [Trail Making Test (TMT) and Stroop Test (ST)] between PD patients and healthy controls (HCO) and then calculated correlations among these measures separately for each group. Additionally, we estimated PD diagnostic accuracy of the PSD-EEG and [18 F]FDOPA PET/CT parameters. In PD patients, we observed the following: (i) slower EEG waves, reflected in increased power of the EEG theta and lower-alpha bands in frontal lobe areas; (ii) reduced [18 F]FDOPA PET/CT uptake in the putaminal and caudate nuclei, along with a decreased putamen-to-caudate ratio ([18 F]FDOPA PET/CT PCR); and (iii) longer performance times evident in nearly all EF tests' parameters. Slower EEG waves correlated negatively with [18 F]FDOPA PET/CT PCR and positively with most of the EF test parameters. Furthermore, we found negative correlations between [18 F]FDOPA PET/CT PCR and certain EF measures related to ST. [18 F]FDOPA PET/CT ratios and several PSD-EEG parameters, particularly those from the prefrontal cortex, demonstrated clinically reasonable diagnostic accuracy for PD. In conclusion, EEG waves slowing in the frontal lobe were correlated with striatal dopaminergic deficiency and impaired executive function in mild PD patients and showed promise as a biomarker of PD-related executive dysfunction.

Added value of [18F]FDOPA PET to the management of high-grade glioma patients after their initial treatment: a prospective multicentre study.

BACKGROUND: Diagnostic value of 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine ([18F]FDOPA) PET in patients with suspected recurrent gliomas is recognised. We conducted a multicentre prospective study to assess its added value in the practical management of patients suspected of recurrence of high grade gliomas (HGG). METHODS: Patients with a proven HGG (WHO grade III and IV) were referred to the multidisciplinary neuro-oncology board (MNOB) during their follow-up after initial standard of care treatment and when MRI findings were not fully conclusive. Each case was discussed in 2 steps. For step 1, a diagnosis and a management proposal were made only based on the clinical and the MRI data. For step 2, the same process was repeated taking the [18F]FDOPA PET results into consideration. A level of confidence for the decisions was assigned to each step. Changes in diagnosis and management induced by [18F]FDOPA PET information were measured. When unchanged, the difference in the confidence of the decisions were assessed. The diagnostic performances of each step were measured. RESULTS: 107 patients underwent a total of 138 MNOB assessments. The proposed diagnosis changed between step 1 and step 2 in 37 cases (26.8%) and the proposed management changed in 31 cases (22.5%). When the management did not change, the confidence in the MNOB final decision was increased in 87 cases (81.3%). Step 1 had a sensitivity, specificity and accuracy of 83%, 58% and 66% and step 2, 86%, 64% and 71% respectively. CONCLUSION: [18F]FDOPA PET adds significant information for the follow-up of HGG patients in clinical practice. When MRI findings are not straightforward, it can change the management for more than 20% of the patients and increases the confidence level of the multidisciplinary board decisions.

Differentiating high-grade glioma progression from treatment-related changes with dynamic [18F]FDOPA PET: a multicentric study.

OBJECTIVES: Diagnostic accuracy of amino-acid PET for distinguishing progression from treatment-related changes (TRC) is currently based on single-center non-homogeneous glioma populations. Our study assesses the diagnostic value of static and dynamic [18F]FDOPA PET acquisitions to differentiate between high-grade glioma (HGG) recurrence and TRC in a large cohort sourced from two independent nuclear medicine centers. METHODS: We retrospectively identified 106 patients with suspected glioma recurrences (WHO GIII, n = 38; GIV, n = 68; IDH-mutant, n = 35, IDH-wildtype, n = 71). Patients underwent dynamic [18F]FDOPA PET/CT (n = 83) or PET/MRI (n = 23), and static tumor-to-background ratios (TBRs), metabolic tumor volumes and dynamic parameters (time to peak and slope) were determined. The final diagnosis was either defined by histopathology or a clinical-radiological follow-up at 6 months. Optimal [18F]FDOPA PET parameter cut-offs were obtained by receiver operating characteristic analysis. Predictive factors and clinical parameters were assessed using univariate and multivariate Cox regression survival analyses. RESULTS: Surgery or the clinical-radiological 6-month follow-up identified 71 progressions and 35 treatment-related changes. TBRmean, with a threshold of 1.8, best-differentiated glioma recurrence/progression from post-treatment changes in the whole population (sensitivity 82%, specificity 71%, p < 0.0001) whereas curve slope was only significantly different in IDH-mutant HGGs (n = 25). In survival analyses, MTV was a clinical independent predictor of progression-free and overall survival on the multivariate analysis (p ≤ 0.01). A curve slope > -0.12/h was an independent predictor for longer PFS in IDH-mutant HGGs CONCLUSION: Our multicentric study confirms the high accuracy of [18F]FDOPA PET to differentiate recurrent malignant gliomas from TRC and emphasizes the diagnostic and prognostic value of dynamic acquisitions for IDH-mutant HGGs. KEY POINTS: • The diagnostic accuracy of dynamic amino-acid PET, for distinguishing progression from treatment-related changes, is currently based on single-center non-homogeneous glioma populations. • This multicentric study confirms the high accuracy of static [18F]FDOPA PET images for differentiating progression from treatment-related changes in a homogeneous population of high-grade gliomas and highlights the diagnostic and prognostic value of dynamic acquisitions for IDH-mutant high-grade gliomas. • Dynamic acquisitions should be performed in IDH-mutant glioma patients to provide valuable information for the differential diagnosis of recurrence and treatment-related changes.

Comparative analysis of striatal [18 F]FDOPA uptake in a partial lesion model of Parkinson's disease in rats: Ratio method versus graphical model.

Animal models of Parkinson's disease are useful to evaluate new treatments and to elucidate the etiology of the disease. Hence, it is necessary to have methods that allow quantification of their effectiveness. [18 F]FDOPA-PET (FDOPA-PET) imaging is outstanding for this purpose because of its capacity to measure changes in the dopaminergic pathway noninvasively and in vivo. Nevertheless, PET acquisition and quantification is time-consuming making it necessary to find faster ways to quantify FDOPA-PET data. This study evaluated Male Wistar rats by FDOPA, before and after being partially injured with 6-OHDA unilaterally. MicroPET scans with a duration of 120 min were acquired and Patlak reference plots were created to estimate the influx constant Kc in the striatum using the full dynamic scan data. Additionally, simple striatal-to-cerebral ratios (SCR) of short static acquisitions were computed and compared with the Kc values. Good correlation (r > 0.70) was obtained between Kc and SCR, acquired between 80-120 min after FDOPA administration with frames of 10 or 20 min and both methods were able to separate the FDOPA-uptake of healthy controls from that of the PD model (SCR -28%, Kc -71%). The present study concludes that Kc and SCR can be trustfully used to discriminate partially lesioned rats from healthy controls.

Assessment of myocardial sympathetic innervation with 18F-FDOPA-PET/CT in patients with autonomic dysfunction: feasibility study in IPD patients.

BACKGROUND: Dysfunction and denervation of myocardial nor-adrenergic sympathetic neurons has been documented in IPD patients with dysautonomia. The aim of this study was to evaluate the feasibility of single tracer imaging of myocardial sympathetic and cerebral striatal involvement in these patients. METHODS: Twenty-two controls (mean-age 59.09 ± 12.39 years, 15 men) with no clinical autonomic-dysfunction and normal striatal-uptake in 18F-FDOPA-PET/CT; and 28 patients (mean-age 58.18 ± 8.25 years, 18 men) with autonomic-dysfunction (in Autonomic Function Tests) and striatal dopaminergic-dysfunction were enrolled. Both cardiac-PET/CT (40 minutes post IV-injection of 185-259MBq 18F-FDOPA) and Brain-PET/CT (60 minutes post-IV) were acquired in same session. ROIs were drawn over the entire left ventricular myocardium, individual walls and mediastinum for quantification. Patients and controls were followed-up for 26.93 ± 5.43 months and 37.91 ± 8.63 months, respectively. RESULTS: Striatal and myocardial-parameters were significantly lower in patients compared to controls; with Myocardium/mediastinal ratio (MwMR) yielding the area-under-the-curve of .941 (P < .001). MwMR correlated negatively with the drop in systolic blood pressure (SBP) during AFTs {Pearson-coefficient (-).565, P = .002}. Mean MwMR in patients with abnormal-AFTs was significantly lower than patients with borderline-AFTs (1.39 ± .12 vs 1.55 ± .10; P = .002). 9/20 patients with abnormal-AFTs showed functional worsening during follow-up, compared to 2/8 with borderline-AFTs. CONCLUSION: Single tracer, single session imaging of striatal and cardiac sympathetic dysfunction in patients with advanced IPD is feasible with use of 18F-FDOPA. Significantly reduced 18F-FDOPA uptake is seen in the myocardium of the IPD patients with sympathetic dysfunction.

Sporadic Primary Pheochromocytoma: A Prospective Intraindividual Comparison of Six Imaging Tests (CT, MRI, and PET/CT Using 68Ga-DOTATATE, FDG, 18F-FDOPA, and 18F-FDA).

BACKGROUND. Recent professional society guidelines for radionuclide imaging of sporadic pheochromocytoma (PHEO) recommend 18F-fluorodihydroxyphenylala-nine (18F-FDOPA) as the radiotracer of choice, deeming 68Ga-DOTATATE and FDG to be second- and third-line agents, respectively. An additional agent, 18F-fluorodopamine (18F-FDA), remains experimental for PHEO detection. A paucity of research has performed head-to-head comparison among these agents. OBJECTIVE. The purpose of this study was to perform an intraindividual comparison of 68Ga-DOTATATE PET/CT, FDG PET/CT, 18F-FDOPA PET/CT, 18F-FDA PET/CT, CT, and MRI in visualization of sporadic primary PHEO. METHODS. This prospective study enrolled patients referred with clinical suspicion for sporadic PHEO. Patients were scheduled for 68Ga-DOTATATE PET/CT, FDG PET/CT, 18F-FDOPA PET/CT, 18F-FDA PET/CT, whole-body staging CT (portal venous phase), and MRI within a 3-month period. PET/CT examinations were reviewed by two nuclear medicine physicians, and CT and MRI were reviewed by two radiologists; differences were resolved by consensus. Readers scored lesions in terms of confidence in diagnosis of PHEO (1-5 scale; 4-5 considered positive for PHEO). Lesion-to-liver SUVmax was computed using both readers' measurements. Interreader agreement was assessed using intraclass correlation coefficients (ICCs) for SUVmax. Analysis included only patients with histologically confirmed PHEO on resection. RESULTS. The analysis included 14 patients (eight women, six men; mean age, 52.4 ± 16.8 [SD] years) with PHEO. Both 68Ga-DOTATATE PET/CT and FDG PET/CT were completed in all 14 patients, 18F-FDOPA PET/CT in 11, 18F-FDA PET/CT in 7, CT in 12, and MRI in 12. Mean conspicuity score for PHEO was 5.0 ± 0.0 for 18F-FDOPA PET/CT, 4.7 ± 0.5 for MRI, 4.6 ± 0.8 for 18F-FDA PET/CT, 4.4 ± 1.0 for 68Ga-DOTATATE PET/CT, 4.3 ± 1.0 for CT, and 4.1 ± 1.5 for FDG PET/CT. The positivity rate for PHEO was 100.0% (11/11) for 18F-FDOPA PET/CT, 100.0% (12/12) for MRI, 85.7% (6/7) for 18F-FDA PET/CT, 78.6% (11/14) for FDG PET/CT, 78.6% (11/14) for 68Ga-DOTATATE PET/CT, and 66.7% (8/12) for CT. Lesion-to-liver SUVmax was 10.5 for 18F-FDOPA versus 3.0-4.2 for the other tracers. Interreader agreement across modalities ranged from 85.7% to 100.0% for lesion positivity with ICCs of 0.55-1.00 for SUVmax measurements. CONCLUSION. Findings from this small intraindividual comparative study support 18F-FDOPA PET/CT as a preferred first-line imaging modality in evaluation of sporadic PHEO. CLINICAL IMPACT. This study provides data supporting current guidelines for imaging evaluation of suspected PHEO. TRIAL REGISTRATION. ClinicalTrials.gov NCT00004847.

Intraindividual comparison of 18 F-FDOPA and 68 Ga-DOTATOC PET/CT detection rate for metastatic assessment in patients with ileal neuroendocrine tumours.

INTRODUCTION: In patients with ileal neuroendocrine tumours (ileal NETs), head-to-head evaluation of diagnostic performances of 68 Ga-DOTA-peptides and 18 F-fluorodihydroxyphenylalanine (18 F-FDOPA) positron emission tomography/computed tomography (PET/CT) has been performed in only few small patients' cohorts. The aim of this retrospective study was to compare 68 Ga-DOTATOC and 18 F-FDOPA PET/CT for metastatic disease assessment in a homogeneous large series of patients with well-differentiated ileal NETs. METHODS: All patients with ileal NETs who underwent both 18 F-FDOPA and 68 Ga-DOTATOC PET/CT within a 3-month period and no therapeutic change between the two studies were retrospectively included. The detection rates of both modalities were calculated using per-patient, per-region and per-lesion analyses. RESULTS: Forty one patients with ileal NETs were evaluated. 18 F-FDOPA and 68 Ga-DOTATOC showed similar detection rates according to per-patient (97% for both) and per-region analyses (94% for 18 F-FDOPA vs 88% for 68 Ga-DOTATOC, P = .35). For a total of 605 positive lesions, 458 (76%) were detected by both modalities, 122 (20%) exclusively by 18 F-FDOPA PET/CT, and 25 (4%) by 68 Ga-DOTATOC PET/CT only. In a per-lesion analysis, 18 F-FDOPA PET/CT performed better than 68 Ga-DOTATOC PET/CT (overall detection rates of 96% vs 80%; P < .001). 18 F-FDOPA PET/CT detected significantly more metastases than 68 Ga-DOTATOC PET/CT in the liver, peritoneum, abdominal and supra-diaphragmatic lymph nodes. CONCLUSION: 18 F-FDOPA PET/CT seems not inferior than 68 Ga-DOTATOC PET/CT for the delineation of metastatic spread of ileal NETs. Therefore, according to local expertise and technical availability, 18 F-FDOPA should be considered as a valid clinical diagnostic option for exhaustive metastatic assessment in patients with ileal NETs. Obviously, 68 Ga-DOTATOC PET/CT remains mandatory for PRRT assessment. Further comparative studies are needed to determine the optimal approach in various clinical scenarios such as preoperative staging and primary tumour detection.

Identify glioma recurrence and treatment effects with triple-tracer PET/CT.

BACKGROUND: Differential diagnosis of tumour recurrence (TuR) from treatment effects (TrE), mostly induced by radiotherapy and chemotherapy, is still difficult by using conventional computed tomography (CT) or magnetic resonance (MR) imaging. We have investigated the diagnostic performance of PET/CT with 3 tracers, 13N-NH3, 18F-FDOPA, and 18F-FDG, to identify TuR and TrE in glioma patients following treatment. METHODS: Forty-three patients with MR-suspected recurrent glioma were included. The maximum and mean standardized uptake values (SUVmax and SUVmean) of the lesion and the lesion-to-normal grey-matter cortex uptake (L/G) ratio were obtained from each tracer PET/CT. TuR or TrE was determined by histopathology or clinical MR follow-up for at least 6 months. RESULTS: In this cohort, 34 patients were confirmed to have TuR, and 9 patients met the diagnostic standard of TrE. The SUVmax and SUVmean of 13N-NH3 and 18F-FDOPA PET/CT at TuR lesions were significantly higher compared with normal brain tissue (13N-NH3 0.696 ± 0.558, 0.625 ± 0.507 vs 0.486 ± 0.413; 18F-FDOPA 0.455 ± 0.518, 0.415 ± 0.477 vs 0.194 ± 0.203; both P < 0.01), but there was no significant difference in 18F-FDG (6.918 ± 3.190, 6.016 ± 2.807 vs 6.356 ± 3.104, P = 0.290 and 0.493). L/G ratios of 13N-NH3 and 18F-FDOPA were significantly higher in TuR than in TrE group (13N-NH3, 1.573 ± 0.099 vs 1.025 ± 0.128, P = 0.008; 18F-FDOPA, 2.729 ± 0.131 vs 1.514 ± 0.141, P < 0.001). The sensitivity, specificity and AUC (area under the curve) by ROC (receiver operating characteristic) analysis were 57.7%, 100% and 0.803, for 13N-NH3; 84.6%, 100% and 0.938, for 18F-FDOPA; and 80.8%, 100%, and 0.952, for the combination, respectively. CONCLUSION: Our results suggest that although multiple tracer PET/CT may improve differential diagnosis efficacy, for glioma TuR from TrE, 18F-FDOPA PET-CT is the most reliable. The combination of 18F-FDOPA and 13N-NH3 does not increase the diagnostic efficiency, while 18F-FDG is not worthy for differential diagnosis of glioma TuR and TrE.

Solid pseudopapillary tumour should be part of differential diagnosis of focal pancreatic lesions with increased 18 F-FDOPA uptake.

OBJECTIVE: To assess the specificity of increased 18 F-dihydroxyphenylalanine (18 F-FDOPA) uptake in patients who underwent PET/CT for suspicion of isolated pancreatic neuroendocrine tumour (pNET). False-positive results mimicking a pNET have been investigated. MATERIAL AND METHODS: Carbidopa-assisted 18 F-FDOPA PET/CT scans performed in patients with suspicion of localized pNET were retrieved. Only patients with a definitive diagnosis were retrospectively included. When available, the histopathological result after pancreatic surgery was the gold standard. In other cases, the diagnosis was based on endoscopic ultrasonography (EUS)/cytology and/or on concordant imaging results of at least two of the following: contrast-enhanced computed tomography (CE-CT), magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS). RESULTS: Forty-four among 731 patients were selected. Among these, 36 patients (82%) were surgically treated, revealing pNET (n = 28), solid pseudopapillary tumour (SPT) (n = 4), adenocarcinoma (n = 2), serous cystadenomas (n = 1) and solitary fibrous tumour (n = 1) cases. An additional three cases of pNET were diagnosed by EUS/cytology. In the remaining five patients, a consensus was reached on follow-up imaging results: pNET (n = 1), serous cystadenoma (n = 2) and undetermined/no pNET (n = 2). Both specificity and negative predictive value of 18 F-FDOPA PET/CT for localized pNET were 67%. Surprisingly, all four false-positive results were SPTs showing intense 18 F-FDOPA uptake and negative SRS. There was no significant difference in 18 F-FDOPA uptake intensity between PET-positive pNETs and SPTs. CONCLUSION: 18 F-FDOPA PET/CT is not specific for pNET in patients with localized pancreatic lesions. SPT could mimic pNET and should be part of differential diagnosis in such a clinical situation. If these results are confirmed in a broader population, the imaging pattern 18 F-FDOPA PET-positive/SRS-negative lesions might be considered as the imaging phenotype of SPT.

Integration of dynamic parameters in the analysis of 18F-FDopa PET imaging improves the prediction of molecular features of gliomas.

PURPOSE: 18F-FDopa PET imaging of gliomas is routinely interpreted with standardized uptake value (SUV)-derived indices. This study aimed to determine the added value of dynamic 18F-FDopa PET parameters for predicting the molecular features of newly diagnosed gliomas. METHODS: We retrospectively included 58 patients having undergone an 18F-FDopa PET for establishing the initial diagnosis of gliomas, whose molecular features were additionally characterized according to the WHO 2016 classification. Dynamic parameters, involving time-to-peak (TTP) values and curve slopes, were tested for the prediction of glioma types in addition to current static parameters, i.e., tumor-to-normal brain or tumor-to-striatum SUV ratios and metabolic tumor volume (MTV). RESULTS: There were 21 IDH mutant without 1p/19q co-deletion (IDH+/1p19q-) gliomas, 16 IDH mutants with 1p/19q co-deletion (IDH+/1p19q+) gliomas, and 21 IDH wildtype (IDH-) gliomas. Dynamic parameters enabled differentiating the gliomas according to these molecular features, whereas static parameters did not. In particular, a longer TTP was the single best independent predictor for identifying (1) IDH mutation status (area under the curve (AUC) of 0.789, global accuracy of 74% for the criterion of a TTP ≥ 5.4 min) and (2) 1p/19q co-deletion status (AUC of 0.679, global accuracy of 69% for the criterion of a TTP ≥ 6.9 min). Moreover, the TTP from IDH- gliomas was significantly shorter than those from both IDH+/1p19q- and IDH+/1p19q+ (p ≤ 0.007). CONCLUSION: Prediction of the molecular features of newly diagnosed gliomas with 18F-FDopa PET and especially of the presence or not of an IDH mutation, may be obtained with dynamic but not with current static uptake parameters.

Rate of change in maximum 18F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas.

PURPOSE: To examine whether the rate of change in maximum 18F-FDOPA PET uptake and the rate of change in non-enhancing tumor volume could predict malignant transformation and residual overall survival (OS) in low grade glioma (LGG) patients who received serial 18F-FDOPA PET and MRI scans. METHODS: 27 LGG patients with ≥ 2 18F-FDOPA PET and MRI scans between 2003 and 2016 were included. The rate of change in FLAIR volume (uL/day) and maximum normalized 18F-FDOPA specific uptake value (nSUVmax/month), were compared between histological and molecular subtypes. General linear models (GLMs) were used to integrate clinical information with MR-PET measurements to predict malignant transformation. Cox univariate and multivariable regression analyses were performed to identify imaging and clinical risk factors related to OS. RESULTS: A GLM using patient age, treatment, the rate of change in FLAIR and 18F-FDOPA nSUVmax could predict malignant transformation with > 67% sensitivity and specificity (AUC = 0.7556, P = 0.0248). A significant association was observed between OS and continuous rates of change in PET uptake (HR = 1.0212, P = 0.0034). Cox multivariable analysis confirmed that continuous measures of the rate of change in PET uptake was an independent predictor of OS (HR = 1.0242, P = 0.0033); however, stratification of patients based on increasing or decreasing rate of change in FLAIR (HR = 2.220, P = 0.025), PET uptake (HR = 2.148, P = 0.0311), or both FLAIR and PET (HR = 2.354, P = 0.0135) predicted OS. CONCLUSIONS: The change in maximum normalized 18F-FDOPA PET uptake, with or without clinical information and rate of change in tumor volume, may be useful for predicting the risk of malignant transformation and estimating residual survival in patients with LGG.

MGMT Promoter Methylation and IDH1 Mutations Do Not Affect [18F]FDOPA Uptake in Primary Brain Tumors.

The aim of our study was to investigate the effects of methylation of O6-methylguanine-DNA methyltransferase promoter (MGMTp) and isocitrate dehydrogenase 1 (IDH 1) mutations on amino acid metabolism evaluated with 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine ([18F] FDOPA) positron emission tomography/computed tomography (PET/CT). Seventy-two patients with primary brain tumors were enrolled in the study (33 women and 39 men; mean age 44 ± 12 years old). All of them were subjected to PET/CT examination after surgical treatment. Of them, 29 (40.3%) were affected by grade II glioma and 43 (59.7%) by grade III. PET/CT was scored as positive or negative and standardized uptake value ratio (SUVr) was calculated as the ratio between SUVmax of the lesion vs that of the background. Statistical analysis was performed with the Mann-Whitney U test. Methylation of MGMTp was detectable in 61 out of the 72 patients examinated. Mean SUVr in patients without methylation of MGMTp was 1.44 ± 0,38 vs. 1.35 ± 0.48 of patients with methylation (p = 0.15). Data on IDH1 mutations were available for 43 subjects; of them, 31 are IDH-mutant. Mean SUVr was 1.38 ± 0.51 in patients IDH mutant and 1.46 ± 0.56 in patients IDH wild type. MGMTp methylation and IDH1 mutations do not affect [18F] FDOPA uptake in primary brain tumors and therefore cannot be assessed or predicted by radiopharmaceutical uptake parameters.

Nucleophilic Synthesis of 6-l-[18F]FDOPA. Is Copper-Mediated Radiofluorination the Answer?

Positron emission tomography employing 6-l-[18F]fluoro-3,4-dihydroxyphenylalanine (6-l-[18F]FDOPA) is currently a highly relevant clinical tool for detection of gliomas, neuroendocrine tumors and evaluation of Parkinson's disease progression. Yet, the deficiencies of electrophilic synthesis of 6-l-[18F]FDOPA hold back its wider use. To fulfill growing clinical demands for this radiotracer, novel synthetic strategies via direct nucleophilic 18F-radiloabeling starting from multi-Curie amounts of [18F]fluoride, have been recently introduced. In particular, Cu-mediated radiofluorination of arylpinacol boronates and arylstannanes show significant promise for introduction into clinical practice. In this short review these current developments will be discussed with a focus on their applicability to automation.

Exploring the link between tumour metabolism and succinate dehydrogenase deficiency: A 18 F-FDOPA PET/CT study in head and neck paragangliomas.

OBJECTIVES: Nuclear imaging findings by virtue of phenotyping disease heavily depend on genetic background, metabolites, cell membrane specific targets and signalling pathways. PPGL related to succinate dehydrogenase subunits mutations (SDHx mutations) are less differentiated than other subgroups and therefore may lack to concentrate 18 F-FDOPA, a precursor of catecholamines biosynthesis. However, this 18 F-FDOPA negative phenotype has been reported mostly in SDHx-PPGL of sympathetic origin, suggesting that both genotype status and location (from sympathetic vs parasympathetic paraganglia; adrenal vs extra-adrenal) could influence 18 F-FDOPA uptake. The aim of this study was to test if SDHx drives 18 F-FDOPA uptake in presence of normal epinephrine/norepinephrine concentrations. DESIGN: Retrospective study PATIENTS: A cohort of 86 head and neck PPGL patients (including three metastatic) with normal metanephrines underwent 18 F-FDOPA PET/CT. The relationships between 18 F-FDOPA uptake and tumour genotype were evaluated. RESULTS: In nonmetastatic HNPGL (50 non-SDHx/33 SDHx), no significant difference was observed between these two groups for SUVmax (P = .256), SUVmean (P = .188), MTV 42% (P = .596) and total lesion uptake (P = .144). Metastatic HNPGL also had high elevated uptake values. CONCLUSIONS: Our results suggest that SDH deficiency or metastatic behaviour have no influence on 18 F-FDOPA uptake in HNPGL probably due to their very-well differentiation status, even at metastatic stage. The potential prognosticator value of 18 F-FDOPA uptake would need to be further explored in the setting of metastatic PPGL of sympathetic origin.

Early 18F-FDOPA PET/CT imaging after carbidopa premedication as a valuable diagnostic option in patients with insulinoma.

PURPOSE: Data on the diagnostic value of 18F-FDOPA PET/CT in patients with insulinoma are limited and are focused on small patient populations explored using different PET/CT protocols and the inconsistent use of carbidopa premedication. The aim of this study was to improve the current knowledge about the diagnostic value of 18F-FDOPA PET/CT combined with oral carbidopa premedication and early pancreatic imaging for tumour localization in patients with insulinoma-related hyperinsulinaemic hypoglycaemia (HH). The relationships among 18F-FDOPA quantitative uptake parameters, insulin secretion and tumour pathological features were also investigated. METHODS: Of 34 patients with suspicion of insulinoma-related HH examined by dual time-point carbidopa-assisted 18F-FDOPA PET/CT, 24 with histologically proven insulinoma were retrospectively included. One patient underwent two PET/CT examinations for relapsing insulinoma after surgical excision. Thus, 25 preoperative 18F-FDOPA PET/CT studies were finally retained and analysed. All studies were performed under carbidopa premedication (200 mg orally, 1-2 h prior to tracer injection). The PET/CT acquisition protocol included an early acquisition (5 min after 18F-FDOPA injection) over the upper abdomen and a delayed whole-body acquisition starting 20-30 min later. The cytological and/or histopathological diagnosis of insulinoma was the diagnostic standard of truth. RESULTS: 18F-FDOPA PET/CT localized insulinoma in 21 of the 25 studies, leading to a primary lesion detection rate of 84%. Four lesions (19%) were detected only on early acquisitions. The false-negative tumour detection rates were, respectively, 22% and 12.5% in patients receiving and not receiving treatment for hypoglycaemic symptoms at the time of PET/CT. In benign insulinomas, the early maximum standardized uptake value (SUVmax) was significantly higher than the delayed SUVmax. Compared to the 21 benign lesions, four malignant insulinomas showed significantly higher 18F-FDOPA uptake. Lesion size, fasting-end insulin and C-peptide levels correlated with tumour 18F-FDOPA uptake, dopaminergic tumour volume and metabolic burden. CONCLUSION: The present study showed that 18F-FDOPA PET/CT combined with carbidopa premedication and early pancreatic acquisitions is a valuable diagnostic option in patients with insulinoma when GLP1R-based imaging is not available. The results also provide new insights into the relationships between tumour secretion and imaging phenotype in insulinomas.

Adrenal tracer uptake by 18F-FDOPA PET/CT in patients with pheochromocytoma and controls.

CONTEXT: 18F-FDOPA PET/CT accurately localizes pheochromocytoma in patients with an established biochemical diagnosis. However, cut-off 18F-FDOPA levels of standardized uptake values (SUVmax) for both normal adrenal glands and pheochromocytoma are lacking. OBJECTIVE: Objectives of this study were to determine (1) reference maximum standardized uptake values (SUVmax) for normal adrenal 18F-DOPA tracer uptake and (2) the optimal diagnostic approach for pheochromocytoma localization by using 18F-DOPA SUVmax across a series of cut-off points: the affected adrenal gland (inter-individual analysis), the difference in SUVmax between the affected adrenal gland and the contralateral normal adrenal gland (intra-individual analysis), or a combination of these two. PATIENTS AND METHODS: All patients with histologically confirmed pheochromocytoma diagnosed at our center between November 2009 and December 2017 were retrospectively analysed. Only those patients who underwent an 18F-FDOPA PET/CT-scan for localization purposes before adrenalectomy were included for further analysis. The control group consisted of patients who underwent 18F-FDOPA PET/CT for other indications and who had no genetic susceptibility for developing a pheochromocytoma. SUVmax of the volume of interest surrounding the adrenal glands was determined on EARL reconstructed images. Receiver operating characteristic (ROC) analysis was performed for adrenal gland SUVmax and intra-individual difference in SUVmax between affected and normal adrenal gland. In addition, binary logistic regression was performed for ROC analysis of the combined parameters. RESULTS: In total, 47 histologically confirmed pheochromocytomas were diagnosed in 45 patients, and 245 disease control patients were identified. In the control group, no statistical differences between the SUVmax of left and right adrenal glands were observed, and uptake values in both adrenal glands correlated significantly with each other (r = 0.865, p < 0.001). Median (range) adrenal gland SUVmax in pheochromocytomas and in the control group was 12 (2.6-50) and 2.9 (1.1-6.6), respectively (p < 0.001). ROC analysis revealed 93% sensitivity and 85% specificity at an SUVmax cut-off value of 4.1 (area under the curve (AUC) = 0.951), and 93% sensitivity and 96% specificity at an intra-individual SUVmax difference between the affected and normal adrenal gland of 1.0 (AUC = 0.992). The combination of both variables increased the AUC to 0.995. CONCLUSIONS: 18F-FDOPA PET/CT distinguishes pheochromocytoma from normal adrenal glands with the highest diagnostic accuracy when combining the SUVmax of the affected adrenal gland with the difference in SUVmax between affected and normal adrenal gland.

Diagnostic and grading accuracy of 18F-FDOPA PET and PET/CT in patients with gliomas: a systematic review and meta-analysis.

BACKGROUND: Positron emission tomography (PET) and PET/computed tomography (PET/CT) imaging with 3,4-dihydroxy-6-[18F] fluoro-L-phenylalanine (18F-FDOPA) has been used in the evaluation of gliomas. We performed a meta-analysis to obtain the diagnostic and grading accuracy of 18F-FDOPA PET and PET/CT in patients with gliomas. METHODS: PubMed, Embase, Cochrane Library and Web of Science were searched through 13 May 2019. We included studies reporting the diagnostic performance of 18F-FDOPA PET or PET/CT in glioma patients. Pooled sensitivity, specificity, and area under the summary receiver operating characteristic (SROC) curve were calculated from eligible studies on a per-lesion basis. RESULTS: Eventually, 19 studies were included. Across 13 studies (370 patients) for glioma diagnosis, the pooled sensitivity and specificity of 18F-FDOPA PET and PET/CT were 0.90 (95%CI: 0.86-0.93) and 0.75 (95%CI: 0.65-0.83). Across 7 studies (219 patients) for glioma grading, 18F-FDOPA PET and PET/CT showed a pooled sensitivity of 0.88 (95%CI: 0.81-0.93) and a pooled specificity of 0.73 (95%CI: 0.64-0.81). CONCLUSIONS: 18F-FDOPA PET and PET/CT demonstrated good performance for diagnosing gliomas and differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs). Further studies implementing standardized PET protocols and investigating the grading parameters are needed.