European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma.

PURPOSE: Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results. METHODS: Guidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals. CONCLUSION: Since the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (68Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (123I)/iodine-131 (131I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.

EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma.

PURPOSE: Radionuclide imaging of phaeochromocytomas (PCCs) and paragangliomas (PGLs) involves various functional imaging techniques and approaches for accurate diagnosis, staging and tumour characterization. The purpose of the present guidelines is to assist nuclear medicine practitioners in performing, interpreting and reporting the results of the currently available SPECT and PET imaging approaches. These guidelines are intended to present information specifically adapted to European practice. METHODS: Guidelines from related fields, issued by the European Association of Nuclear Medicine and the Society of Nuclear Medicine, were taken into consideration and are partially integrated within this text. The same was applied to the relevant literature, and the final result was discussed with leading experts involved in the management of patients with PCC/PGL. The information provided should be viewed in the context of local conditions, laws and regulations. CONCLUSION: Although several radionuclide imaging modalities are considered herein, considerable focus is given to PET imaging which offers high sensitivity targeted molecular imaging approaches.

Population pharmacokinetics analysis of mycophenolic acid in adult kidney transplant patients with chronic graft dysfunction.

The aim of this study is to develop a population pharmacokinetic model for total and free mycophenolic acid (MPA) in adult kidney transplant patients with chronic graft dysfunction to understand the contribution of potentially relevant covariates to the inter- and the intraindividual variability of MPA in these patients. Twenty patients received mycophenolate mofetil orally up to 1 g twice daily were enrolled in this prospective pharmacokinetic study. Two hundred twenty-nine total and 257 free concentration-time points were determined using reversed-phase high-performance liquid chromatography/ultraviolet at 21 days and 6 months after initiation of mycophenolate mofetil therapy. Data were analyzed using nonlinear mixed effects modeling. A two-compartment model, with zero-order input and first-order elimination from the central compartment, which combined total and free concentration, was selected. Intersubject variability (ISV) was estimated on the clearance, central volume of distribution, and intercompartmental clearance. Only body weight (WT, kg), occasion, and albumin concentration (mg/L) were kept as covariates in the final model. The population pharmacokinetic parameters were: clearance, 0.27 x WT (L/h) on Day 21 and 0.233 x WT (L/h) at 6 months (ISV, 51%; interoccasion variability, 47%); central distribution volume, 47.6 L (ISV, 31%); intercompartmental clearance, 33.1 L/h (ISV, 128%); peripheral distribution volume, 724 L; duration of infusion, 0.64 (hours), and binding capacity, 0.0012 L/mg. The multiple regression analysis between free and total MPA concentration led to the following model: free MPA concentration (mg/L) = 0.31 + 0.02 total MPA concentration (mg/L) - 0.007 albumin (g/L). The large inter- and intravariability of MPA raises questions about the value of the use of therapeutic monitoring and limited sampling strategies as currently practiced. Moreover, none of the data presented here could justify measurement of free concentration for therapeutic drug monitoring.

Sevoflurane preconditioning against focal cerebral ischemia: inhibition of apoptosis in the face of transient improvement of neurological outcome.

BACKGROUND: Preconditioning the brain with volatile anesthetics seems to be a viable option for reducing ischemic cerebral injury. However, it is uncertain whether this preconditioning effect extends over a longer period of time. The purpose of this study was to determine if sevoflurane preconditioning offers durable neuroprotection against cerebral ischemia. METHODS: Rats (Sprague-Dawley) were randomly allocated to two groups: nonpreconditioned control group (n = 44) and preconditioned group (n = 45) exposed to 2.7 vol% sevoflurane (45 min) 60 min before surgery. Animals in both groups were anesthetized with 3.0 vol% sevoflurane and subjected to transient middle cerebral artery occlusion. After 60 min of awake focal ischemia, the filament was removed. Functional neurologic outcome (range 0-18; 0 = no deficit), cerebral infarct size (Nissl staining), and apoptosis (Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling; cleaved caspase-3 staining) were evaluated at 3, 7, and 14 days after ischemia. RESULTS: Sevoflurane preconditioning significantly improved functional outcome and reduced infarct volume (109 +/- 43 vs. 148 +/- 56 mm(3)) 3 days after ischemia compared to the control group. However, after 7- and 14-day recovery periods, no significant differences were observed between groups. The number of apoptotic cells was significantly lower in the preconditioned group than in the control group after 3- and 7-day recovery periods. Fourteen days after ischemia, no differences were observed between groups. CONCLUSION: In this model of transient focal cerebral ischemia, sevoflurane preconditioning induced effective but transient neuroprotective effects. Sevoflurane preconditioning also decreased ischemia-induced apoptosis in a more sustained way because it was observed up to 7 days after injury.

Early anesthetic preconditioning in mixed cortical neuronal-glial cell cultures subjected to oxygen-glucose deprivation: the role of adenosine triphosphate dependent potassium channels and reactive oxygen species in sevoflurane-induced neuroprotection.

BACKGROUND: The purpose of the present study, on mixed cortical neuronal-glial cell cultures subjected to transient oxygen-glucose deprivation (OGD) was: i) to compare the neuroprotection afforded by sevoflurane added either before (preconditioning) or during (direct neuroprotection) the OGD and ii) to explore the possible involvement of adenosine triphosphate-sensitive potassium (KATP) channels and intracellular reactive oxygen species (ROS) levels in the mechanism of the early preconditioning effect of sevoflurane. METHODS: Mature mixed cortical neuronal-glial cell cultures were exposed to 90-min OGD in an anaerobic chamber followed by reoxygenation. Sevoflurane (0.03-3.4 mM) was randomly administered for 90 min and discontinued 60 min before OGD (early preconditioning) or during the 90-min OGD (direct neuroprotection). Cell death was quantified 24 h after the OGD by lactate dehydrogenase release into the bathing medium. Intracellular ROS generation was assessed at the end of sevoflurane preconditioning using 2',7'-dichlorofluorescin diacetate. RESULTS: Sevoflurane preconditioning elicited a potent threshold-dependent neuroprotective effect at concentrations higher than 0.07 mM and sevoflurane added during OGD elicited a dose dependent neuroprotective effect. Blockers of KATP channels (glibenclamide 0.3 microM and 5 hydroxydecanoic acid 50 microM), or ROS-scavengers (N-2-mercaptopropionyl glycine 100 microM and N-acetylcysteine 50 microM), although they did not affect cell viability, counteracted the neuroprotection produced by early sevoflurane preconditioning. Sevoflurane exposure during preconditioning induced a significant increase in ROS levels which was prevented by both ROS scavengers and blockers of KATP channels. CONCLUSION: Early sevoflurane preconditioning induced a threshold-dependent protection of mixed cortical neuronal-glial cell cultures against OGD by mechanisms that seem to involve opening KATP channels, thereby leading to generation of ROS.

Sevoflurane protects rat mixed cerebrocortical neuronal-glial cell cultures against transient oxygen-glucose deprivation: involvement of glutamate uptake and reactive oxygen species.

BACKGROUND: The purpose of this study was to clarify the role of glutamate and reactive oxygen species in sevoflurane-mediated neuroprotection on an in vitro model of ischemia-reoxygenation. METHODS: Mature mixed cerebrocortical neuronal-glial cell cultures, treated or not with increasing concentrations of sevoflurane, were exposed to 90 min combined oxygen-glucose deprivation (OGD) in an anaerobic chamber followed by reoxygenation. Cell death was quantified by lactate dehydrogenase release into the media and cell viability by reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium by mitochondrial succinate dehydrogenase. Extracellular concentrations of glutamate and glutamate uptake were assessed at the end of the ischemic injury by high-performance liquid chromatography and incorporation of L-[H]glutamate into cells, respectively. Free radical generation in cells was assessed 6 h after OGD during the reoxygenation period using 2',7'-dichlorofluorescin diacetate, which reacts with intracellular radicals to be converted to its fluorescent product, 2',7'-dichlorofluorescin, in cell cytosol. RESULTS: Twenty-four hours after OGD, sevoflurane, in a concentration-dependent manner, significantly reduced lactate dehydrogenase release and increased cell viability. At the end of OGD, sevoflurane was able to reduce the OGD-induced decrease in glutamate uptake. This effect was impaired in the presence of threo-3-methyl glutamate, a specific inhibitor of the glial transporter GLT1. Sevoflurane counteracted the increase in extracellular level of glutamate during OGD and the generation of reactive oxygen species during reoxygenation. CONCLUSION: Sevoflurane had a neuroprotective effect in this in vitro model of ischemia-reoxygenation. This beneficial effect may be explained, at least in part, by sevoflurane-induced antiexcitotoxic properties during OGD, probably depending on GLT1, and by sevoflurane-induced decrease of reactive oxygen species generation during reoxygenation.

Neuroprotective effects of propofol in a model of ischemic cortical cell cultures: role of glutamate and its transporters.

BACKGROUND: During cerebral ischemia, excess of glutamate release and dysfunction of its high affinity transport induce an accumulation of extracellular glutamate, which plays an important role in neuronal death. The authors studied the relationship among propofol neuroprotection, glutamate extracellular concentrations, and glutamate transporter activity in a model of ischemic cortical cell cultures. METHODS: Thirteen-day-old primary cortical neuronal-glial cultures were exposed to a 90-min combined oxygen-glucose deprivation (OGD) in an anaerobic chamber, followed by reoxygenation. Propofol was added only during the OGD period, and its effect was compared to that of the N-methyl-d-aspartate receptor antagonist dizocilpine (MK-801). Twenty-four hours after the injury, cell death was quantified by lactate dehydrogenase release and cell viability by reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT). Extracellular concentrations of glutamate in culture supernatants and glutamate uptake were performed at the end of OGD period by high-performance liquid chromatography and incorporation of l-[3H]glutamate into cells, respectively. RESULTS: At clinically relevant concentrations (0.05-10 microm), propofol offered protection equivalent to that of MK-801. It significantly reduced lactate dehydrogenase release and increased the reduction of MTT. At the end of the ischemic injury, propofol was able to reverse the OGD-induced increase in glutamate extracellular concentrations and decrease of glutamate uptake. The inhibition of the glial GLT1 transporter by 3-methyl-glutamate did not further modify the effect of propofol on glutamate uptake, suggesting that GLT1 was not the major target of propofol. CONCLUSION: Propofol showed a neuroprotective effect in this in vitro model of OGD, which was apparently mediated by a GLT1-independent restoration of the glutamate uptake impaired during the injury.