FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo

This study aimed to test whether [18F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg−1 per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses ⩾5 mg kg−1 per day (tumour volume treated vs control (T/C): 51% for 5 mg kg−1 per day and 57% for 15 mg kg−1 per day). Correspondingly, doses ⩾5 mg kg−1 per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg−1 per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg−1 per day and 52% for 15 mg kg−1 per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials

Molecular imaging in oncology: the acceptance of PET/CT and the emergence of MR/PET imaging

In the last decade, PET-only systems have been phased out and replaced with PET-CT systems. This merger of a functional and anatomical imaging modality turned out to be extremely useful in clinical practice. Currently, PET-CT is a major diagnostic tool in oncology. At the dawn of the merger of MRI and PET, another breakthrough in clinical imaging is expected. The combination of these imaging modalities is challenging, but has particular features such as imaging biological processes at the same time in specific body locations

Elevated [11C]-D-Deprenyl Uptake in Chronic Whiplash Associated Disorder Suggests Persistent Musculoskeletal Inflammation

There are few diagnostic tools for chronic musculoskeletal pain as structural imaging methods seldom reveal pathological alterations. This is especially true for Whiplash Associated Disorder, for which physical signs of persistent injuries to the neck have yet to be established. Here, we sought to visualize inflammatory processes in the neck region by means Positron Emission Tomography using the tracer 11C-D-deprenyl, a potential marker for inflammation. Twenty-two patients with enduring pain after a rear impact car accident (Whiplash Associated Disorder grade II) and 14 healthy controls were investigated. Patients displayed significantly elevated tracer uptake in the neck, particularly in regions around the spineous process of the second cervical vertebra. This suggests that whiplash patients have signs of local persistent peripheral tissue inflammation, which may potentially serve as a diagnostic biomarker. The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that 11C-D-deprenyl is a promising tracer for these purposes

Early Detection of Erlotinib Treatment Response in NSCLC by 3′-Deoxy-3′-[18F]-Fluoro-L-Thymidine ([18F]FLT) Positron Emission Tomography (PET)

Background: Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking. Methodology/Principal Findings: We performed a systematic comparison of 3′-Deoxy-3′-[$^{18}F$]-fluoro-L-thymidine ([$^{18}F$]FLT) and 2-[$^{18}F$]-fluoro-2-deoxy-D-glucose ([$^{18}F$]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [$^{18}F$]FLT uptake after only two days of treatment, [$^{18}F$]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [$^{18}F$]FLT PET but not [$^{18}F$]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [$^{18}F$]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [$^{18}F$]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR. Conclusions: [$^{18}F$]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [$^{18}F$]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC

[18F]FDG-6-P as a novel in vivo tool for imaging staphylococcal infections

Background Management of infection is a major clinical problem. Staphylococcus aureus is a Gram-positive bacterium which colonises approximately one third of the adult human population. Staphylococcal infections can be life-threatening and are frequently complicated by multi-antibiotic resistant strains including methicillin-resistant S. aureus (MRSA). Fluorodeoxyglucose ([18F]FDG) imaging has been used to identify infection sites; however, it is unable to distinguish between sterile inflammation and bacterial load. We have modified [18F]FDG by phosphorylation, producing [18F]FDG-6-P to facilitate specific uptake and accumulation by S. aureus through hexose phosphate transporters, which are not present in mammalian cell membranes. This approach leads to the specific uptake of the radiopharmaceutical into the bacteria and not the sites of sterile inflammation. Methods [18F]FDG-6-P was synthesised from [18F]FDG. Yield, purity and stability were confirmed by RP-HPLC and iTLC. The specificity of [18F]FDG-6-P for the bacterial universal hexose phosphate transporter (UHPT) was confirmed with S. aureus and mammalian cell assays in vitro. Whole body biodistribution and accumulation of [18F]FDG-6-P at the sites of bioluminescent staphylococcal infection were established in a murine foreign body infection model. Results In vitro validation assays demonstrated that [18F]FDG-6-P was stable and specifically transported into S. aureus but not mammalian cells. [18F]FDG-6-P was elevated at the sites of S. aureus infection in vivo compared to uninfected controls; however, the increase in signal was not significant and unexpectedly, the whole-body biodistribution of [18F]FDG-6-P was similar to that of [18F]FDG. Conclusions Despite conclusive in vitro validation, [18F]FDG-6-P did not behave as predicted in vivo. However at the site of known infection, [18F]FDG-6-P levels were elevated compared with uninfected controls, providing a higher signal-to-noise ratio. The bacterial UHPT can transport hexose phosphates other than glucose, and therefore alternative sugars may show differential biodistribution and provide a means for specific bacterial detection

In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer is the fourth leading cause of tumour death in the western world. However, appropriate tumour models are scarce. Here we present a syngeneic murine pancreatic cancer model using 7 Tesla MRI and evaluate its clinical relevance and applicability.</p> <p>Methods</p> <p>6606PDA murine pancreatic cancer cells were orthotopically injected into the pancreatic head. Liver metastases were induced through splenic injection. Animals were analyzed by MRI three and five weeks following injection. Tumours were detected using T2-weighted high resolution sequences. Tumour volumes were determined by callipers and MRI. Liver metastases were analyzed using gadolinium-EOB-DTPA and T1-weighted 3D-Flash sequences. Tumour blood flow was measured using low molecular gadobutrol and high molecular gadolinium-DTPA.</p> <p>Results</p> <p>MRI handling and applicability was similar to human systems, resolution as low as 0.1 mm. After 5 weeks tumour volumes differed significantly (p < 0.01) when comparing calliper measurments (n = 5, mean 1065 mm³+/-243 mm³) with MRI (mean 918 mm³+/-193 mm³) with MRI being more precise. Histology (n = 5) confirmed MRI tumour measurements (mean size MRI 38.5 mm²+/-22.8 mm²versus 32.6 mm²+/-22.6 mm²(histology), p < 0,0004) with differences due to fixation and processing of specimens. After splenic injection all mice developed liver metastases with a mean of 8 metastases and a mean volume of 173.8 mm³+/-56.7 mm³after 5 weeks. Lymphnodes were also easily identified. Tumour accumulation of gadobutrol was significantly (p < 0.05) higher than gadolinium-DTPA. All imaging experiments could be done repeatedly to comply with the 3R-principle thus reducing the number of experimental animals.</p> <p>Conclusions</p> <p>This model permits monitoring of tumour growth and metastasis formation in longitudinal non-invasive high-resolution MR studies including using contrast agents comparable to human pancreatic cancer. This multidisciplinary environment enables radiologists, surgeons and physicians to further improve translational research and therapies of pancreatic cancer.</p

Relationship Between [18F]FDOPA PET Uptake, Apparent Diffusion Coefficient (ADC), and Proliferation Rate in Recurrent Malignant Gliomas

Purpose: Diffusion magnetic resonance imaging (MRI) and 6-[18F]fluoro-l-dopa ([18F]FDOPA) positron emission tomography (PET) are used to interrogate malignant tumor microenvironment. It remains unclear whether there is a relationship between [18F]FDOPA uptake, diffusion MRI estimates of apparent diffusion coefficient (ADC), and mitotic activity in the context of recurrent malignant gliomas, where the tumor may be confounded by the effects of therapy. The purpose of the current study is to determine whether there is a correlation between these imaging techniques and mitotic activity in malignant gliomas.Procedures: We retrospectively examined 29 patients with recurrent malignant gliomas who underwent structural MRI, diffusion MRI, and [18F]FDOPA PET prior to surgical resection. Qualitative associations were noted, and quantitative voxel-wise and median measurement correlations between [18F]FDOPA PET, ADC, and mitotic index were performed.Results: Areas of high [18F]FDOPA uptake exhibited low ADC and areas of hyperintensity T2/fluid-attenuated inversion recovery (FLAIR) with low [18F]FDOPA uptake exhibited high ADC. There was a significant inverse voxel-wise correlation between [18F]FDOPA and ADC for all patients. Median [18F]FDOPA uptake and median ADC also showed a significant inverse correlation. Median [18F]FDOPA uptake was positively correlated, and median ADC was inversely correlated with mitotic index from resected tumor tissue.Conclusions: A significant association may exist between [18F]FDOPA uptake, diffusion MRI, and mitotic activity in recurrent malignant gliomas