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PurposeDiverse 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.MethodsGuidelines 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.ConclusionSince 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.

Due to its ideal physical properties, fluorine-18 turns out to be a key radionuclide for positron emission tomography (PET) imaging, for both preclinical and clinical applications. However, usual biomolecules radiofluorination procedures require the formation of covalent bonds with fluorinated prosthetic groups. This drawback makes radiofluorination impractical for routine radiolabeling, gallium-68 appearing to be much more convenient for the labeling of chelator-bearing PET probes. In response to this limitation, a recent expansion of the 18F chemical toolbox gave aluminum [18F]fluoride chemistry a real prominence since the late 2000s. This approach is based on the formation of an [18F][AlF]2+ cation, complexed with a 9-membered cyclic chelator such as NOTA, NODA or their analogs. Allowing a one-step radiofluorination in an aqueous medium, this technique combines fluorine-18 and non-covalent radiolabeling with the advantage of being very easy to implement. Since its first reports, [18F]AlF radiolabeling approach has been applied to a wide variety of potential PET imaging vectors, whether of peptidic, proteic, or small molecule structure. Most of these [18F]AlF-labeled tracers showed promising preclinical results and have reached the clinical evaluation stage for some of them. The aim of this report is to provide a comprehensive overview of [18F]AlF labeling applications through a description of the various [18F]AlF-labeled conjugates, from their radiosynthesis to their evaluation as PET imaging agents.

Bioimaging plays an important role in cancer diagnosis and treatment. However, imaging sensitivity and specificity still constitute key challenges. Nanotechnology-based imaging is particularly promising for overcoming these limitations because nanosized imaging agents can specifically home in on tumors via the \"enhanced permeation and retention\" (EPR) effect, thus resulting in enhanced imaging sensitivity and specificity. Here, we report an original nano-system for positron emission tomography (PET) imaging based on an amphiphilic dendrimer, which bears multiple PET reporting units at the terminals. This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective PET imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this nanosystem demonstrates superior imaging sensitivity and specificity, with up to 14-fold increased PET signal ratios compared with the clinical gold reference 2-fluorodeoxyglucose ([ 18 F]FDG). Most importantly , this dendrimer system can detect imaging-refractory low-glucose-uptake tumors that are otherwise undetectable using [ 18 F]FDG. In addition, it is endowed with an excellent safety profile and favorable pharmacokinetics for PET imaging. Consequently , this dendrimer nanosystem constitutes an effective and promising approach for cancer imaging. Our study also demonstrates that nanotechnology based on self-assembling den-drimers provides a fresh perspective for biomedical imaging and cancer diagnosis.

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.

Mesothelin (MSLN) is overexpressed in a wide variety of cancers with few therapeutic options and has recently emerged as an attractive target for cancer therapy, with a large number of approaches currently under preclinical and clinical investigation. In this respect, developing mesothelin specific tracers as molecular companion tools for predicting patient eligibility, monitoring then response to mesothelin-targeting therapies, and tracking the evolution of the disease or for real-time visualisation of tumours during surgery is of growing importance. Methods We generated by phage display a nanobody (Nb S1) and used enzymatic approaches were used to site-directed conjugate Nb S1 with either ATTO 647N fluorochrome or NODAGA chelator for fluorescence and positron emission tomography imaging (PET) respectively. Results We demonstrated that Nb S1 displays a high apparent affinity and specificity for human mesothelin and demonstrated that the binding, although located in the membrane distal domain of mesothelin, is not impeded by the presence of MUC16, the only known ligand of mesothelin, nor by the therapeutic antibody amatuximab. In vivo experiments showed that both ATTO 647N and [ 68 Ga]Ga-NODAGA-S1 rapidly and specifically accumulated in mesothelin positive tumours compared to mesothelin negative tumours or irrelevant Nb with a high tumour/background ratio. The ex vivo biodistribution profile analysis also confirmed a significantly higher uptake of Nb S1 in MSLN-positive tumours than in MSLN low tumours. Conclusion We demonstrated for the first time the use of an anti-MSLN nanobody as PET radiotracer for same day imaging of MSLN + tumours, targeting an epitope compatible with the monitoring of amatuximab-based therapies and current SS1-derived-drug conjugates.

Glioblastoma (GBM), an incurable primary brain tumor, typically requires surgical intervention followed by chemoradiation; however, recurrences remain fatal. Our previous work demonstrated that a nanomedicine hydrogel (GemC 12 -LNC) delays recurrence when administered post-surgery. However, tumor debulking also triggers time-dependent immune reactions that promote recurrence at the resection cavity borders. We hypothesized that combining the hydrogel with an immunomodulatory drug could enhance therapeutic outcomes. A thorough characterization of the post-surgical microenvironment (SMe) is crucial to guide combinatorial approaches. In this study, we performed cellular resolution imaging, flow cytometry and spatial hyperplexed immunofluorescence imaging to characterize the SMe in a syngeneic mouse model of tumor resection. Owing to our dynamic approach, we observed transient opening of the blood–brain barrier (BBB) during the first week after surgery. BBB permeability post-surgery was also confirmed in GBM patients. In our murine model, we also observed changes in immune cell morphology and spatial location post-surgery over time in resected animals as well as the accumulation of reactive microglia and anti-inflammatory macrophages in recurrences compared to unresected tumors since the first steps of recurrence growth. Therefore we investigated whether starting a systemic treatment with the SMAC mimetic small molecule (GDC-0152) directly after surgery would be beneficial for enhancing microglial anti-tumoral activity and decreasing the number of anti-inflammatory macrophages around the GemC 12 -LNC hydrogel-loaded tumor cavity. The immunomodulatory effects of this drug combination was firstly shown in patient-derived tumoroids. Its efficacy was confirmed in vivo by survival analysis and correlated with reversal of the immune profile as well as delayed tumor recurrence. This comprehensive study identified critical time frames and immune cellular targets within the SMe, aiding in the rational design of combination therapies to delay recurrence onset. Our findings suggest that post-surgical systemic injection of GDC-0152 in combination with GemC 12 -LNC local treatment is a promising and innovative approach for managing GBM recurrence, with potential for future translation to human patient. Graphical Abstract

Cardiovascular complications observed in chronic kidney disease (CKD) are associated with aryl hydrocarbon receptor (AhR) activation by tryptophan-derived uremic toxins—mainly indoxyl sulfate (IS). AhR is a ligand-activated transcription factor originally characterized as a receptor of xenobiotics involved in detoxification. The aim of this study was to determine the role of AhR in a CKD mouse model based on an adenine diet. Wild-type (WT) and AhR−/− mice were fed by alternating an adenine-enriched diet and a regular diet for 6 weeks. Our results showed an increased mortality rate of AhR−/− males. AhR−/− females survived and developed a less severe renal insufficiency that WT mice, reflected by urea, creatinine, and IS measurement in serum. The protective effect was related to a decrease of pro-inflammatory and pro-fibrotic gene expression, an attenuation of tubular injury, and a decrease of 2,8-dihydroxyadenine crystal deposition in the kidneys of AhR−/− mice. These mice expressed low levels of xanthine dehydrogenase, which oxidizes adenine into 2,8-dihydroxyadenine, and low levels of the IS metabolism enzymes. In conclusion, the CKD model of adenine diet is not suitable for AhR knockout mice when studying the role of this transcription factor in cardiovascular complications, as observed in human CKD.

Background Several lipid metabolites in cerebrospinal fluid are correlated with poor outcomes in aneurysmal subarachnoid haemorrhage. Most of these metabolites bind to ubiquitous thromboxane–prostaglandin (TP) receptors, causing vasoconstriction and inflammation. Here, we evaluated terutroban (TBN), a specific TP receptor antagonist, for the prevention of post-haemorrhage blood-brain barrier disruption, neuronal apoptosis and delayed cerebral hypoperfusion. Methods The rat double subarachnoid haemorrhage model was produced by twice injecting (days 1 and 2) autologous blood into the cisterna magna. Seventy-eight male Sprague-Dawley rats were assigned to experimental groups. Rats exposed to subarachnoid haemorrhage were allocated to no treatment (SAH group) or TBN treatment by gastric gavage during the first 5 days after haemorrhage (SAH+TBN group). Control rats received artificial cerebrospinal fluid injections (CSF group). Sham-operated rats with or without TBN administration were also studied. Body weight and Garcia neurological scores were assessed on day 2 and day 5. We used nanoscale single-photon emission computed tomography (nanoSPECT) to measure brain uptake of three radiolabelled agents: 99m Technetium-diethylenetriaminepentacetate ( 99m Tc-DTPA), which indicated blood-brain barrier permeability on day 3, 99m Technetium-annexin V-128 ( 99m Tc-Anx-V128), which indicated apoptosis on day 4, and 99m Technetium-hexamethylpropyleneamineoxime ( 99m Tc-HMPAO), which indicated cerebral perfusion on day 5. Basilar artery narrowing was verified histologically, and cerebral TP receptor agonists were quantified. Results 99m Tc-DTPA uptake unveiled blood-brain barrier disruption in the SAH group. TBN mitigated this disruption in the brainstem area. 99m Tc-Anx-V128 uptake was increased in the SAH group and TBN diminished this effect in the cerebellum. 99m Tc-HMPAO uptake revealed a global decreased perfusion on day 5 in the SAH group that was significantly counteracted by TBN. TBN also mitigated basilar artery vasoconstriction, neurological deficits (on day 2), body weight loss (on day 5) and cerebral production of vasoconstrictors such as Thromboxane B2 and Prostaglandin F2α. Conclusions Based on in vivo nanoscale imaging, we demonstrated that TBN protected against blood-brain barrier disruption, exerted an anti-apoptotic effect and improved cerebral perfusion. Thus, TP receptor antagonists showed promising results in treating post-haemorrhage neurovascular events.

Neonatal hypoxic‐ischemic encephalopathy (NHIE) is a dramatic perinatal complication, associated with poor neurological prognosis despite neuroprotection by therapeutic hypothermia, in the absence of an available curative therapy. We evaluated and compared ready‐to‐use human umbilical cord blood cells (HUCBC) and bankable but allogeneic endothelial progenitors (ECFC) as cell therapy candidate for NHIE. We compared benefits of HUCBC and ECFC transplantation 48 hours after injury in male rat NHIE model, based on the Rice‐Vannucci approach. Based on behavioral tests, immune‐histological assessment and metabolic imaging of brain perfusion using single photon emission computed tomography (SPECT), HUCBC, or ECFC administration provided equally early and sustained functional benefits, up to 8 weeks after injury. These results were associated with total normalization of injured hemisphere cerebral blood flow assessed by SPECT/CT imaging. In conclusion, even if ECFC represent an efficient candidate, HUCBC autologous criteria and easier availability make them the ideal candidate for hypoxic‐ischemic cell therapy. Stem Cells Translational Medicine 2017;6:1987–1996 Neonatal hypoxic ischemic encephalopathy is a dramatic perinatal complication and to date no curative therapy available has been validated. Based on behavioral tests, immune‐histological assessment and metabolic imaging of brain perfusion using single photon emission computed tomography, we report in this work that transplantation of both human umbilical cord blood cells and endothelial progenitors provided equally early and sustained functional benefits, up to adulthood.

BackgroundGastroparesis (GP) is a prevalent sensorimotor disorder characterized by delayed gastric emptying without mechanical obstruction, posing significant diagnostic challenges. Gastric emptying scintigraphy (GES) is the gold standard for diagnosing GP. However, its accuracy can be compromised by many medications that affect gastric motility. This study evaluates the impact of medication reconciliation on the diagnostic accuracy of GES.ResultsA significant proportion of patients (75%) were on medications known to affect gastric motility. Recommendations for medication adjustments were communicated, with 30% non-adherence. Adjustments in GES interpretations were necessary for 20% of patients following comprehensive medication reviews. The involvement of radiopharmacists facilitated accurate diagnostic conclusions, underscoring the critical role of medication reconciliation in GES accuracy.ConclusionMedication reconciliation enhanced the accuracy of GES in diagnosing gastroparesis, emphasizing the need to integrate clinical pharmacy practices into nuclear medicine. This interdisciplinary approach not only improves diagnostic accuracy but also enhances patient safety, advocating for the adoption of such practices in the management of gastroparesis.