Background. Abdominal aortic aneurysm (AAA) is a focal aortic dilatation progressing towards rupture. Non-invasive AAA-associated cell proliferation biomarkers are not yet established. We investigated the feasibility of the cell proliferation radiotracer, fluorine-18fluorothymidine ([ 18 F]FLT) with positron emission tomography/computed tomography (PET/ CT) in a progressive pre-clinical AAA model (angiotensin II, AngII infusion).

Anti-1-amino-3-18fluorine-fluorocyclobutane-1-carboxylic acid (18F-fluciclovine) positron emission tomography (PET) shows preferential glioma uptake but there is little data on how uptake correlates with post-contrast T1-weighted (Gd-T1) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) activity during adjuvant treatment. This pilot study aimed to compare 18F-fluciclovine PET, DCE-MRI and Gd-T1 in patients undergoing chemoradiotherapy for glioblastoma (GBM), and in a parallel pre-clinical GBM model, to investigate correlation between 18F-fluciclovine uptake, MRI findings, and tumour biology. 18F-fluciclovine-PET-computed tomography (PET-CT) and MRI including DCE-MRI were acquired before, during and after adjuvant chemoradiotherapy (60 Gy in 30 fractions with temozolomide) in GBM patients. MRI volumes were manually contoured; PET volumes were defined using semi-automatic thresholding. The similarity of the PET and DCE-MRI volumes outside the Gd-T1 volume boundary was measured using the Dice similarity coefficient (DSC). CT-2A tumour-bearing mice underwent MRI and 18F-fluciclovine PET-CT. Post-mortem mice brains underwent immunohistochemistry staining for ASCT2 (amino acid transporter), nestin (stemness) and Ki-67 (proliferation) to assess for biologically active tumour. 6 patients were recruited (GBM 1–6) and grouped according to overall survival (OS)—short survival (GBM-SS, median OS 249 days) and long survival (GBM-LS, median 903 days). For GBM-SS, PET tumour volumes were greater than DCE-MRI, in turn greater than Gd-T1. For GBM-LS, Gd-T1 and DCE-MRI were greater than PET. Tumour-specific 18F-fluciclovine uptake on pre-clinical PET-CT corresponded to immunostaining for Ki-67, nestin and ASCT2. Results suggest volumes of 18F-fluciclovine-PET activity beyond that depicted by DCE-MRI and Gd-T1 are associated with poorer prognosis in patients undergoing chemoradiotherapy for GBM. The pre-clinical model confirmed 18F-fluciclovine uptake reflected biologically active tumour.

Changes in composition of the intestinal microbiota are linked to the development of obesity and can lead to endothelial cell (EC) dysfunction. It is unknown whether EC can directly influence the microbiota. Insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) are critical for coupling nutritional status and cellular growth; IGF-1R is expressed in multiple cell types including EC. The role of ECIGF-1R in the response to nutritional obesity is unexplored. To examine this, we use gene-modified mice with EC-specific overexpression of human IGF-1R (hIGFREO) and their wild-type littermates. After high-fat feeding, hIGFREO weigh less, have reduced adiposity and have improved glucose tolerance. hIGFREO show an altered gene expression and altered microbial diversity in the gut, including a relative increase in the beneficial genus Akkermansia. The depletion of gut microbiota with broad-spectrum antibiotics induces a loss of the favourable metabolic differences seen in hIGFREO mice. We show that IGF-1R facilitates crosstalk between the EC and the gut wall; this crosstalk protects against diet-induced obesity, as a result of an altered gut microbiota.

The porcine pancreatic elastase (PPE) model is a common preclinical model of abdominal aortic aneurysms (AAA). Some notable characteristics of this model include the low aortic rupture rate, non-progressive disease course, and infra-renal AAA formation. Enhanced [18F]fluorothymidine ([18F]FLT) uptake on positron emission tomography/computed tomography (PET/CT) has previously been reported in the angiotensin II-induced murine model of AAA. Here, we report our preliminary findings of investigating [18F]FLT uptake in the PPE murine model of AAA. [18F]FLT uptake was found to be substantially increased in the abdominal areas recovering from the surgery, whilst it was not found to be significantly increased within the PPE-induced AAA, as confirmed using in vivo PET/CT and ex vivo whole-organ gamma counting (PPE, n = 7; controls, n = 3). This finding suggests that the [18F]FLT may not be an appropriate radiotracer for this specific AAA model, and further studies with larger sample sizes are warranted to elucidate the pathobiology contributing to the reduced uptake of [18F]FLT in this model.

BACKGROUND Glioblastoma multiforme (GBM) carries a poor prognosis, partly due to biological and anatomical heterogeneity. Although radiotherapy (RT) is effective, high doses damage surrounding healthy tissues. Multimodal imaging with Magnetic Resonance (MRI) and Positron Emission Tomography (PET) may represent a useful approach for identifying GBM heterogeneity and visualising metabolic tumour properties. PET radiotracer [18F]-fluciclovine is preferentially accumulated in gliomas compared to healthy brain tissue via the cellular transport systems, LAT1 and ASCT2. In this study the effect of fractionated RT using multimodal imaging including [18F]-fluciclovine uptake and immunohistochemistry (IHC) in a GBM preclinical model will be validated. MATERIAL AND METHODS Two C57BL/6J mice cohorts were injected intracranially (i.c.) with murine CT2A-luc cells and subsequently submitted to multiparametric MRI and [18F]-fluciclovine PET imaging during hemi-brain RT (3Gy on 2 days/each week) for maximum 25 days after i.c. injection. Brains were collected for IHC characterization including LAT1 and ASCT2 staining. RESULTS Preliminary data showed that both MRI and PET were effective modalities to track tumour growth in this model. PET data revealed up to greater than 3-fold increase in SUVmax from regions of interest around the tumour site compared to healthy brain tissue. Time activity curves showed a steady increase in tumour uptake over 90 minutes. MRI showed a 25% increase in T2 values in tumours relative to unaffected contralateral regions. Confirmation of treatment response through matched imaging and IHC are ongoing, from which changes in glioma cell biology as well as amino acid transporter protein levels will be analysed. CONCLUSION These preliminary results show that multimodal imaging presents novel data in the assessment of treatment response in this model and will permit parallel IHC analyses to better define GBM tumour heterogeneity aligned with imaging changes. These data will also inform an on-going clinical study using the same imaging modalities. Work at authors’ labs are supported by an Investigator initiated project from Blue Earth Diagnostics (AS, SCS) and a University of Leeds Biswas studentship (SCS, DS). Daniela Salvatore is also supported by a Scholarship provided by Molecular and Translational Medicine Doctorate School of University of Milan (Italy).