Search

Purpose: Radiation therapy (RT) exerts its anti-tumour efficacy by inducing direct damage to cancer cells but also through modification of the tumour microenvironment (TME) by inducing immunogenic antitumor response. Conversely, RT also promotes an immunosuppressive TME notably through the recruitment of regulatory T cells (Tregs). Glycoprotein A repetitions predominant (GARP), a transmembrane protein highly expressed by activated Tregs, plays a key role in the activation of TGF-β and thus promotes the immunosuppressive action of Tregs. The development of a theranostic approach targeting GARP combining imaging and targeted radionuclide therapy (TRT) was carried out., Methods: A preclinical model of 4T1 triple negative breast tumour-bearing BALB/c mice was used to show that GARP expression is increased after external beam radiation in the TME of our cancer model. We generated a theranostic probe through the bioconjugation of the chelating agent DOTAGA onto an anti-GARP monoclonal antibody. The bioconjugation with DOTAGA allows the radiolabelling of the DOTAGA-GARP conjugate with both Indium-111 for SPECT imaging and Lutetium-177 for TRT purposes., Results: We demonstrate that GARP expression is increased following RT in vivo and can be specifically detected and quantified using in vivo SPECT imaging with [ 111 In]In-DOTAGA-GARP. In addition, 177 Lu-DOTAGA-GARP limits tumour growth in our cancer model., Conclusion: This theranostic strategy may allow for the personalization of cancer treatments by early detection of activated Tregs infiltration following RT and identification of patients likely to respond to Tregs-targeted therapy via TRT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Objective . We introduce a versatile methodology for the accurate modelling of PET imaging systems via Monte Carlo simulations, using the Geant4 application for tomographic emission (GATE) platform. Accurate Monte Carlo modelling involves the incorporation of a complete analytical signal processing chain, called the digitizer in GATE, to emulate the different count rates encountered in actual positron emission tomography (PET) systems. Approach . The proposed approach consists of two steps: (1) modelling the digitizer to replicate the detection chain of real systems, covering all available parameters, whether publicly accessible or supplied by manufacturers; (2) estimating the remaining parameters, i.e. background noise level, detection efficiency, and pile-up, using optimisation techniques based on experimental single and prompt event rates. We show that this two-step optimisation reproduces the other experimental count rates (true, scatter, and random), without the need for additional adjustments. This method has been applied and validated with experimental data derived from the NEMA count losses test for three state-of-the-art SiPM-based time-of-flight (TOF)-PET systems: Philips Vereos, Siemens Biograph Vision 600 and GE Discovery MI 4-ring. Main results . The results show good agreement between experiments and simulations for the three PET systems, with absolute relative discrepancies below 3%, 6%, 6%, 7% and 12% for prompt, random, true, scatter and noise equivalent count rates, respectively, within the 0-10 kBq·ml -1 activity concentration range typically observed in whole-body 18 F scans. Significance . Overall, the proposed digitizer optimisation method was shown to be effective in reproducing count rates and NECR for three of the latest generation SiPM-based TOF-PET imaging systems. The proposed methodology could be applied to other PET scanners., (Creative Commons Attribution license.)

Background: The aim of this study is to investigate the added value of combining tumour blood flow (BF) and metabolism parameters, including texture features, with clinical parameters to predict, at baseline, the pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in patients with newly diagnosed breast cancer (BC)., Methods: One hundred and twenty-eight BC patients underwent a 18 F-FDG PET/CT before any treatment. Tumour BF and metabolism parameters were extracted from first-pass dynamic and delayed PET images, respectively. Standard and texture features were extracted from BF and metabolic images. Prediction of pCR was performed using logistic regression, random forest and support vector classification algorithms. Models were built using clinical (C), clinical and metabolic (C+M) and clinical, metabolic and tumour BF (C+M+BF) information combined. Algorithms were trained on 80% of the dataset and tested on the remaining 20%. Univariate and multivariate features selections were carried out on the training dataset. A total of 50 shuffle splits were performed. The analysis was carried out on the whole dataset (HER2 and Triple Negative (TN)), and separately in HER2 (N=76) and TN (N=52) tumours., Results: In the whole dataset, the highest classification performances were observed for C+M models, significantly (p-value<0.01) higher than C models and better than C+M+BF models (mean balanced accuracy of 0.66, 0.61, and 0.64 respectively). For HER2 tumours, equal performances were noted for C and C+M models, with performances higher than C+M+BF models (mean balanced accuracy of 0.64, and 0.61 respectively). Regarding TN tumours, the best classification results were reported for C+M models, with better performances than C and C+M+BF models but not significantly (mean balanced accuracy of 0.65, 0.63, and 0.62 respectively)., Conclusion: Baseline clinical data combined with global and texture tumour metabolism parameters assessed by 18 F-FDG PET/CT provide a better prediction of pCR after NAC in patients with BC compared to clinical parameters alone for TN, and HER2 and TN tumours together. In contrast, adding BF parameters to the models did not improve prediction, regardless of the tumour subgroup analysed., (© 2024. The Author(s).)

In medical imaging, accurate segmentation is crucial to improving diagnosis, treatment, or both. However, navigating the multitude of available architectures for automatic segmentation can be overwhelming, making it challenging to determine the appropriate type of architecture and tune the most crucial parameters during dataset optimisation. To address this problem, we examined and refined seven distinct architectures for segmenting the liver, as well as liver tumours, with a restricted training collection of 60 3D contrast-enhanced magnetic resonance images (CE-MRI) from the ATLAS dataset. Included in these architectures are convolutional neural networks (CNNs), transformers, and hybrid CNN/transformer architectures. Bayesian search techniques were used for hyperparameter tuning to hasten convergence to the optimal parameter mixes while also minimising the number of trained models. It was unexpected that hybrid models, which typically exhibit superior performance on larger datasets, would exhibit comparable performance to CNNs. The optimisation of parameters contributed to better segmentations, resulting in an average increase of 1.7% and 5.0% in liver and tumour segmentation Dice coefficients, respectively. In conclusion, the findings of this study indicate that hybrid CNN/transformer architectures may serve as a practical substitute for CNNs even in small datasets. This underscores the significance of hyperparameter optimisation., (© 2024. The Author(s).)

Background: We propose a comprehensive evaluation of a Discovery MI 4-ring (DMI) model, using a Monte Carlo simulator (GATE) and a clinical reconstruction software package (PET toolbox). The following performance characteristics were compared with actual measurements according to NEMA NU 2-2018 guidelines: system sensitivity, count losses and scatter fraction (SF), coincidence time resolution (CTR), spatial resolution (SR), and image quality (IQ). For SR and IQ tests, reconstruction of time-of-flight (TOF) simulated data was performed using the manufacturer's reconstruction software., Results: Simulated prompt, random, true, scatter and noise equivalent count rates closely matched the experimental rates with maximum relative differences of 1.6%, 5.3%, 7.8%, 6.6%, and 16.5%, respectively, in a clinical range of less than 10 kBq/mL. A 3.6% maximum relative difference was found between experimental and simulated sensitivities. The simulated spatial resolution was better than the experimental one. Simulated image quality metrics were relatively close to the experimental results., Conclusions: The current model is able to reproduce the behaviour of the DMI count rates in the clinical range and generate clinical-like images with a reasonable match in terms of contrast and noise., (© 2024. The Author(s).)

Purpose: The aim of this study was (a) to optimise the 99m Tc-SPECT reconstruction parameters for the pre-treatment dosimetry of 90 Y-selective internal radiation therapy (SIRT) and (b) to compare the accuracy of clinical dosimetry methods with full Monte-Carlo dosimetry (fMCD) performed with Gate., Methods: To optimise the reconstruction parameters, two hundred reconstructions with different parameters were performed on a NEMA phantom, varying the number of iterations, subsets, and post-filtering. The accuracy of the dosimetric methods was then investigated using an anthropomorphic phantom. Absorbed dose maps were generated using (1) the Partition Model (PM), (2) the Dose Voxel Kernel (DVK) convolution, and (3) the Local Deposition Method (LDM) with known activity restricted to the whole phantom (WP) or to the liver and lungs (LL). The dose to the lungs was calculated using the "multiple DVK" and "multiple LDM" methods., Results: Optimal OSEM reconstruction parameters were found to depend on object size and dosimetric criterion chosen (D mean or DVH-derived metric). The D mean of all three dosimetric methods was close (≤ 10%) to the D mean of fMCD simulations when considering large segmented volumes (whole liver, normal liver). In contrast, the D mean to the small volume (∅=31) was systemically underestimated (12%-25%). For lungs, the "multiple DVK" and "multiple LDM" methods yielded a D mean within 20% for the WP method and within 10% for the LL method., Conclusions: All three methods showed a substantial degradation of the dose-volume histograms (DVHs) compared to fMCD simulations. The DVK and LDM methods performed almost equally well, with the "multiple DVK" method being more accurate in the lungs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

The availability of preclinical simultaneous PET/MR imaging systems has been increasing in recent years. Therefore, this technique is progressively moving from the hands of pure physicists towards those of scientists more involved in pharmacology and biology. Unfortunately, these combined scanners can be prone to artefacts and deviation of their characteristics under the influence of external factors or mutual interference between subsystems. This may compromise the image quality as well as the quantitative aspects of PET and MR data. Hence, quality assurance is crucial to avoid loss of animals and experiments. A possible risk to the acceptance of quality control by preclinical teams is that the complexity and duration of this quality control are increased by the addition of MR and PET tests. To avoid this issue, we have selected over the past 5 years, simple tests that can be easily and quickly performed each day before starting an animal PET/MR acquisition. These tests can be performed by the person in charge of the experiment even if this person has a limited expertise in instrumentation and performance evaluation. In addition to these daily tests, other tests are suggested for an advanced system follow-up at a lower frequency. In the present paper, the proposed tests are sorted by periodicity from daily to annual. Besides, we have selected test materials that are available at moderate cost either commercially or through 3D printing., (© 2022. The Author(s).)

Purpose: A strategy for management of radioactive waste associated with 177 Lu-dotatate (Lutathera®) treatments was established in our institution, based on predicted storage times of 3-5 years extrapolated from the results of a 2-year measurement study. The aim of this work was to validate this strategy by identifying contaminants and confirming disposal based on the clearance level twice-the-background was within expected time frames., Methods: We conducted a prospective series of measurements of radioactive waste associated with the first 65 treatments administered. Sequential measurements of the first 45 vials used were performed on a dose calibrator to identify contaminants. Exposure rates in contact were monitored with a dose ratemeter on a 6-monthly basis for all waste stored: 46 empty vials, 19 vials partially used and 61 biohazard containers., Results: Initial median activity of the first vials used was 118 MBq [4-4188 MBq]. For each vial, the decay curve of activity obtained was adjusted to a bi-exponential model. The major component, representing 99.7% of the activity, has a median half-life of 6.6 days [5.7-7.2 days] corresponding to 177 Lu. The second, representing only 0.3% of the activity and having a median half-life of 152 days [104-205 days] corresponding to 177m Lu, determines necessary storage times. Partially used vials can be disposed of after 5 years, other waste after 3 years. Compliance with the regulatory clearance level is achieved within expected time frames., Conclusion: Although only present as traces, 177m Lu associated with the direct production route results in major radioactive waste disposal issues for hospitals. Availability of radiopharmaceuticals without impurities appears to be crucial for an expanding use of targeted radionuclide therapy., (© 2023. The Author(s).)

Purpose: Assessment of tumour blood flow (BF) heterogeneity using first-pass FDG PET/CT and textural feature (TF) analysis is an innovative concept. We aim to explore the relationship between BF heterogeneity measured with different TFs calculation methods and the response to neoadjuvant chemotherapy (NAC) in patients with newly diagnosed breast cancer (BC)., Methods: One hundred and twenty-five patients were enrolled. Dynamic first-pass and delayed FDG PET/CT scans were performed before NAC. Nine TFs were calculated from perfusion and metabolic PET images using relative (RR) or absolute (AR) rescaling strategies with two textural matrix calculation methods. Patients were classified according to presence or absence of a pathologic complete response (pCR) after NAC. The relationship between BF texture features and conventional features were analysed using spearman correlations. The TFs' differences between pCR and non-pCR groups were evaluated using Mann-Whitney tests and descriptive factorial discriminant analysis (FDA)., Results: Relation between tumour BF-based TFs and global BF parameters were globally similar to those observed for tumour metabolism. None of the TFs was significantly different between pCR and non-pCR groups in the Mann-Whitney analysis, after Benjamini-Hochberg correction. Using a RR led to better discriminations between responders and non-responders in the FDA analysis. The best results were obtained by combining all the PET features, including BF ones., Conclusion: A better differentiation of patients reaching a pCR was observed using a RR. Moreover, BF heterogeneity might bring a useful information when combined with metabolic PET parameters to predict the pCR after neoadjuvant chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Background: During anthracycline treatment of cancer, there is a lack for biomarkers of cardiotoxicity besides the cardiac dysfunction. The objective of the present study was to compare [ 18 F]FDG and [ 123 I]MIBG (metaiodobenzylguanidine) in a longitudinal study in a doxorubicin-induced cardiotoxicity rat model., Methods: Male Wistar Han rats were intravenously administered 3 times at 10 days' interval with saline or doxorubicin (5 mg/kg). [ 123 I]MIBG SPECT/CT (single photon emission computed tomography-computed tomography) and simultaneous [ 18 F]FDG PET (positron emission tomography)/7 Tesla cardiac MR (magnetic resonance) imaging acquisitions were performed at 24 h interval before first doxorubicin / saline injection and every 2 weeks during 6 weeks. At 6 weeks, the heart tissue was collected for histomorphometry measurements., Results: At week 4, left ventricle (LV) end-diastolic volume was significantly reduced in the doxorubicin group. At week 6, the decreased LV end-diastolic volume was maintained, and LV end-systolic volume was increased resulting in a significant reduction of LV ejection fraction (47 ± 6% vs. 70 ± 3%). At weeks 4 and 6, but not at week 2, myocardial [ 18 F]FDG uptake was decreased compared with the control group (respectively, 4.2 ± 0.5%ID/g and 9.2 ± 0.8%ID/g at week 6). Moreover, [ 18 F]FDG cardiac uptake correlated with cardiac function impairment. In contrast, from week 2, a significant decrease of myocardial [ 123 I]MIBG heart to mediastinum ratio was detected in the doxorubicin group and was maintained at weeks 4 and 6 with a 45.6% decrease at week 6., Conclusion: This longitudinal study precises that after doxorubicin treatment, cardiac [ 123 I]MIBG uptake is significantly reduced as early as 2 weeks followed by the decrease of the LV end-diastolic volume and [ 18 F]FDG uptake at 4 weeks and finally by the increase of LV end-systolic volume and decrease of LV ejection fraction at 6 weeks. Cardiac innervation imaging should thus be considered as an early key feature of anthracycline cardiac toxicity., (© 2021. The Author(s).)

Introduction: The aim of this study was to evaluate the impact of the contouring methods on dose metrics and their predictive value on tumor control and survival, in both situations of pre-treatment and post-treatment dosimetry, for patients with advanced HCC treated with SIRT., Methods: Forty-eight patients who underwent SIRT between 2012 and 2020 were retrospectively included in this study. Target volumes were delineated using two methods: MRI-based contours manually drawn by a radiologist and then registered on SPECT/CT and PET/CT via deformable registration (Pre-C MRI and Post-C MRI ), 99m Tc-MAA-SPECT and 90 Y-microspheres-PET 10% threshold contouring (Pre-C SPECT and Post-C PET ). The mean absorbed dose (Dm) and the minimal absorbed dose delivered to 70% of the tumor volume (D70) were evaluated with both contouring methods; the tumor-to-normal liver uptake ratio (TNR) was evaluated with MRI-based contours only. Tumor response was assessed using the mRECIST criteria on the follow-up MRIs., Results: No significant differences were found for Dm and TNR between pre- and post-treatment. TNR evaluated with radiologic contours (Pre-C MRI and Post-C MRI ) were predictive of tumor control at 6 months on pre- and post-treatment dosimetry (OR 5.9 and 7.1, respectively; p = 0.02 and 0.01). All dose metrics determined with both methods were predictive of overall survival (OS) on pre-treatment dosimetry, but only Dm with MRI-based contours was predictive of OS on post-treatment images with a median of 23 months for patients with a supramedian Dm versus 14 months for the others (p = 0.04)., Conclusion: In advanced HCC treated with SIRT, Dm and TNR determined with radiologic contours were predictive of tumor control and OS. This study shows that a rigorous clinical workflow (radiologic contours + registration on scintigraphic images) is feasible and should be prospectively considered for improving therapeutic strategy.

Liver tumors are common and may be unamenable to surgery or ablative treatments. Consequently, other treatments have been devised. To assess the safety and efficacy of transarterial radioembolization (TARE) with Yttrium-90 for hepatocellular carcinoma (HCC), liver-dominant hepatic colorectal cancer metastases (mCRC), and cholangiocarcinoma (CCA), performed according to current recommendations, we conducted a single-center retrospective study in 70 patients treated with TARE (HCC, n = 44; mCRC, n = 20; CCA, n = 6). Safety and toxicity were assessed using the National Cancer Institute Common Terminology Criteria. Treatment response was evaluated every 3 months on imaging studies using Response Evaluation Criteria in Solid Tumors (RECIST) or mRECIST criteria. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. The median delivered dose was 1.6 GBq, with SIR-Spheres ® or TheraSphere ® microspheres. TARE-related grade 3 adverse events affected 17.1% of patients. Median follow-up was 32.1 months. Median progression-free survival was 5.6 months and median overall time from TARE to death was 16.1 months and was significantly shorter in men. Progression-free survival was significantly longer in women (HR, 0.49; 95%CI, 0.26-0.90; p = 0.031). Risk of death or progression increased with the number of systemic chemotherapy lines. TARE can be safe and effective in patients with intermediate- or advanced-stage HCC, CCA, or mCRC refractory or intolerant to appropriate treatments.

We present the design and performance of a new compact preclinical system combining positron emission tomography (PET) and magnetic resonance imaging (MRI) for simultaneous scans. The PET contains sixteen SiPM-based detector heads arranged in two octagons and covers an axial field of view (FOV) of 102.5 mm. Depth of interaction effects and detector's temperature variations are compensated by the system. The PET is integrated in a dry magnet operating at 7 T. PET and MRI characteristics were assessed complying with international standards and interferences between both subsystems during simultaneous scans were addressed. For the rat size phantom, the peak noise equivalent count rates (NECR) were 96.4 kcps at 30.2 MBq and 132.3 kcps at 28.4 MBq respectively with and without RF coil. For mouse, the peak NECR was 300.0 kcps at 34.5 MBq and 426.9 kcps at 34.3 MBq respectively with and without coil. At the axial centre of the FOV, spatial resolutions expressed as full width at half maximum / full width at tenth maximum (FWHM/FWTM) ranged from 1.69/3.19 mm to 2.39/4.87 mm. The peak absolute sensitivity obtained with a 250-750 keV energy window was 7.5% with coil and 7.9% without coil. Spill over ratios of the NEMA NU4-2008 image quality (NEMA-IQ) phantom ranged from 0.25 to 0.96 and the percentage of non-uniformity was 5.7%. The image count versus activity was linear up to 40 MBq. The principal magnetic field variation was 0.03 ppm/mm over 40 mm. The qualitative and quantitative aspects of data were preserved during simultaneous scans.

This 37-year-old woman was diagnosed with breast cancer during pregnancy. After multidisciplinary meeting, she was referred to our department for an FDG PET/CT for staging, and chemotherapy with weekly infusion of paclitaxel was initiated before childbirth. We estimated the fetal dose from the PET/CT procedure, and our results show that, if deemed necessary, this examination can reasonably be performed during pregnancy. The patient gave birth vaginally at term to an apparently healthy girl.

Purpose: The aim of this prospective study is to analyze the global tumor blood flow (BF) and its heterogeneity in newly diagnosed breast cancer (BC) according to tumor biological characteristics and molecular subtypes. These perfusion parameters were compared to those classically derived from metabolic studies to investigate links between perfusion and metabolism., Methods: Two hundred seventeen newly diagnosed BC patients underwent a 18 F-FDG PET/CT exam before any treatment. A 2-min dynamic acquisition, centered on the chest, was performed immediately after intravenous injection of 3 MBq/kg of 18 F-FDG, followed by a two-step static acquisition 90 min later. Tumor BF was calculated (in ml/min/g) using a single compartment kinetic model. In addition to standard PET parameters, texture features (TF) describing the heterogeneity of tumor perfusion and metabolism were extracted. Patients were divided into three groups: Luminal (HR+/HER2-), HER2 (HER2+), and TN (HR-/HER2-). Global and TF parameters of BF and metabolism were compared in different groups of patients according to tumor biological characteristics., Results: Tumors with lymph node involvement showed a higher perfusion, whereas no significant differences in SUV&#95;max or SUV&#95;mean were reported. TN tumors had a higher metabolic activity than HER2 and luminal tumors but no significant differences in global BF values were noted. HER2 tumors exhibited a larger tumor heterogeneity of both perfusion and metabolism compared to luminal and TN tumors. Heterogeneity of perfusion appeared well correlated to that of metabolism., Conclusions: The study of breast cancer perfusion shows a higher BF in large tumors and in tumors with lymph node involvement, not paralleled by similar modifications in tumor global metabolism. In addition, the observed correlation between the perfusion heterogeneity and the metabolism heterogeneity suggests that tumor perfusion and consequently the process of tumor angiogenesis might be involved in the metabolism heterogeneity previously shown in BC.

A novel trifunctional imaging probe containing a chelator of radiometal for PET, a NIR heptamethine cyanine dye, and a bioconjugatable handle, has been grafted onto AGuIX® nanoparticles via a Michael addition reaction. The resulting functionalized nanoparticles have been fully characterized, radiolabelled with 64 Cu, and evaluated in a mice TSA tumor model using multimodal (PET/MRI/optical) imaging., Competing Interests: FD is scientific advisor and shareholder of Chematech. FL and OT have to disclose the patent WO2011/135101. This patent protects the AGuIX® NPs described in this publication. FL and OT are employees from NH TherAguix that is developing the AGuIX® NPs and possess shares of this company., (This journal is © The Royal Society of Chemistry.)

The combination of two imaging probes on the same biomolecule gives access to targeted bimodal imaging agents that can provide more accurate diagnosis, complementary information, or that may be used in different applications, such as nuclear imaging and fluorescence guided surgery. In this study, we demonstrate that dichlorotetrazine, a small, commercially available compound, can be used as a modular platform to easily assemble various imaging probes. Doubly labeled tetrazines can then be conjugated to a protein through a biorthogonal IEDDA reaction. A series of difunctionalized tetrazine compounds containing various chelating agents and fluorescent dyes was synthesized. As a proof of concept, one of these bimodal probes was conjugated to trastuzumab, previously modified with a constrained alkyne group, and the resulting dual-labeled antibody was evaluated in a mouse model, bearing a HER2-positive tumor. A significant uptake into tumor tissues was observed in vivo, by both SPECT-CT and fluorescence imaging, and confirmed ex vivo in biodistribution studies.

Superparamagnetic iron oxide nanoparticles were developed as positron emission tomography (PET) and magnetic resonance imaging (MRI) bimodal imaging agents. These nanoparticles (NPs), with a specific nanoflower morphology, were first synthesized and simultaneously functionalized with 3,4-dihydroxy-l-phenylalanine (LDOPA) under continuous hydrothermal conditions. The resulting NPs exhibited a low hydrodynamic size of 90 ± 2 nm. The functional groups of LDOPA (-NH 2 and -COOH) were successfully used for the grafting of molecules of interest in a second step. The nanostructures were modified by poly(ethylene glycol) (PEG) and a new macrocyclic chelator MANOTA for further 64 Cu radiolabeling for PET imaging. The functionalized NPs showed promising bimodal (PET and MRI) imaging capability with high r 2 and r 2 * ( T 2 and T 2 * relaxivities) values and good stability. They were mainly uptaken from liver and kidneys. No cytotoxicity effect was observed. These NPs appear as a good candidate for bimodal tracers in PET/MRI., Competing Interests: The authors declare no competing financial interest.

Background: Debio 1143, a potent orally available SMAC mimetic, targets inhibitors of apoptosis proteins (IAPs) members and is currently in clinical trials. In this study, nuclear imaging evaluated the effects of Debio 1143 on tumor cell death and metabolism in a triple-negative breast cancer (TNBC) cell line (MDA-MB-231)-based animal model., Methods: Apoptosis induced by Debio 1143 was assessed by FACS (caspase-3, annexin 5 (A5)), binding of 99m Tc-HYNIC-Annexin V, and a cell proliferation assay. 99m Tc-HYNIC-Annexin V SPECT and [ 18 F]-FDG PET were also performed in mice xenografted with MDA-MB-231 cells., Results: Debio 1143 induced early apoptosis both in vitro and in vivo 6 h after treatment. Debio 1143 inhibited tumor growth, which was associated with a decreased tumor [ 18 F]-FDG uptake when measured during treatment., Conclusions: This imaging study combining SPECT and PET showed the early proapoptotic effects of Debio 1143 resulting in a robust antitumor activity in a preclinical TNBC model. These imaging biomarkers represent valuable noninvasive tools for translational and clinical research in TNBC.

Purpose: This study aimed to investigate theranostic strategies in colorectal and skin cancer based on fragments of cetuximab, an anti-EGFR mAb, labeled with radionuclide with imaging and therapeutic properties, 111 In and 177 Lu, respectively., Methods: We designed F(ab') 2 -fragments of cetuximab radiolabeled with 111 In and 177 Lu. 111 In-F(ab') 2 -cetuximab tumor targeting and biodistribution were evaluated by SPECT in BalbC nude mice bearing primary colorectal tumors. The efficacy of 111 In-F(ab') 2 -cetuximab to assess therapy efficacy was performed on BalbC nude mice bearing colorectal tumors receiving 17-DMAG, an HSP90 inhibitor. Therapeutic efficacy of the radioimmunotherapy based on 177 Lu-F(ab') 2 -cetuximab was evaluated in SWISS nude mice bearing A431 tumors., Results: Radiolabeling procedure did not change F(ab') 2 -cetuximab and cetuximab immunoreactivity nor affinity for HER1 in vitro. 111 In-DOTAGA-F(ab') 2 -cetuximab exhibited a peak tumor uptake at 24 h post-injection and showed a high tumor specificity determined by a significant decrease in tumor uptake after the addition of an excess of unlabeled-DOTAGA-F(ab') 2 -cetuximab. SPECT imaging of 111 In-DOTAGA-F(ab') 2 -cetuximab allowed an accurate evaluation of tumor growth and successfully predicted the decrease in tumor growth induced by 17-DMAG. Finally, 177 Lu-DOTAGA-F(ab') 2 -cetuximab radioimmunotherapy showed a significant reduction of tumor growth at 4 and 8 MBq doses., Conclusions: 111 In-DOTAGA-F(ab') 2 -cetuximab is a reliable and stable tool for specific in vivo tumor targeting and is suitable for therapy efficacy assessment. 177 Lu-DOTAGA-F(ab') 2 -cetuximab is an interesting theranostic tool allowing therapy and imaging.

Multimodal nanoprobes are highly demanded for biomedical imaging applications to enhance the reliability of the diagnostic results. Among different types of nano-objects, ultrasmall silica gadolinium nanoparticle (SiGdNP) appears as a safe, effective, and versatile platform for this purpose. In this study, a new method to functionalize SiGdNP based on silane chemistry has been reported. Two types of chelating silanes (APTES-DOTAGA and APTES-NODAGA) have been synthesized and grafted on SiGdNP by a simple one-step protocol. This functionalization strategy requires no other reactants or catalyzers and does not compromise the ultrasmall size of the particles. NODAGA-functionalized particle has been labeled with 64 Cu isotope and injected intravenously to mice bearing TS/A carcinoma tumor for biodistribution study to demonstrate its potential as a bimodal MRI/PET imaging agent. A fully integrated MRI/PET system was used to simultaneously monitor the distribution of the particle. The results showed that the functionalized particle maintained properties of a renal clearable NP which could rapidly escape through kidneys and had low retention in other organs, especially liver, even though its accumulation in the tumor was modest.

PET images deliver functional data, whereas MRI images provide anatomical information. Merging the complementary information from these two modalities is helpful in oncology. Alignment of PET/MRI images requires the use of multi-modal registration methods. Most of existing PET/MRI registration methods have been developed for humans and few works have been performed for small animal images. We proposed an automatic tool allowing PET/MRI registration for pre-clinical study based on a two-level hierarchical approach. First, we applied a non-linear intensity transformation to the PET volume to enhance. The global deformation is modeled by an affine transformation initialized by a principal component analysis. A free-form deformation based on B-splines is then used to describe local deformations. Normalized mutual information is used as voxel-based similarity measure. To validate our method, CT images acquired simultaneously with the PET on tumor-bearing mice were used. Results showed that the proposed algorithm outperformed affine and deformable registration techniques without PET intensity transformation with an average error of 0.72 ± 0.44 mm. The optimization time was reduced by 23% due to the introduction of robust initialization. In this paper, an automatic deformable PET-MRI registration algorithm for small animals is detailed and validated. Graphical abstract ᅟ.

Aim: Evaluate response and predict prognosis of patients with newly diagnosed metastatic breast cancer treated with first line systemic therapy using European Organization for Research and Treatment of Cancer (EORTC) criteria and PET Response Criteria in solid Tumours (PERCIST)., Methods: From December 2006 to August 2013, 57 women with newly diagnosed metastatic breast cancer were retrospectively evaluated. FDG-PET/CT was performed within one month before treatment and repeated after at least 3 cycles of treatment. Metabolic response evaluation was evaluated by two readers according to both EORTC criteria and PERCIST, classifying the patients into 4 response groups: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD)., Results: With EORTC criteria, 22 patients had CMR, 17 PMR, 6 SMD and 12 PMD. With PERCIST, 20 patients had CMR, 15 PMR, 10 SMD and 12 PMD. There was agreement between EORTC and PERCIST in 84% of the patients. By log-rank analysis, metabolic response evaluated with both EORTC criteria and PERCIST was able to predict overall survival (p = 0.028 and 0.002 respectively). CMR patient group had longer median OS than patients in the combined PMR+SMD+PMD group (60 vs 26 months both with EORTC and PERCIST; p = 0.009 and 0.006 respectively). By multivariate analysis, CMR either with EORTC or PERCIST remained an independent predictor of survival., Conclusion: Metabolic response evaluation with EORTC criteria and PERCIST gave similar prognostic stratification for metastatic breast cancer treated with a first line of systemic therapy., Competing Interests: The authors have declared that no competing interests exist.

We evaluated the performance characteristics of a prototype preclinical PET scanner available as an easy clippable assembly that can dock to an MRI system. The single ring version of the PET system consists of eight detectors, each of which comprises a 12  ×  12 silicon photomultipliers (SiPMs) array coupled with a dual layer of offset scintillation crystals to measure depth of interaction. The crystal arrays have 29  ×  29 (30  ×  30 for the outer layer) 4 mm long LYSO crystals (6 mm for the outer layer). The ring diameter is 119.2 mm and the axial field of view is 50.4 mm. The NEMA NU 4-2008 protocol was followed for studying the PET performance. Temperature stability of SiPMs was also investigated. The peak system absolute sensitivity was 4.70% with an energy window of 250-750 keV. The spatial resolution was 1.28/1.88/1.85 mm FWHM (radial/tangential/axial) at a distance of 5 mm from the center. Peak noise equivalent counting rate and scatter fraction for mouse phantom were 61.9 kcps at 14.9 MBq and 21.0%, respectively. The uniformity was 6.3% and the spill-over ratios in the images of the water-and air-filled chambers were 0.07 and 0.17, respectively. Recovery coefficients ranged from 0.13 to 0.96. Change in sensitivity as a function of ambient temperature was 0.3%/°C. These first results indicate excellent spatial resolution performance for use with animal studies. Moreover, the clippable assembly can be upgraded to accept a second ring of SiPMs modules, leading to improved sensitivity and axial coverage.

Improved bifunctional chelating agents (BFC) are required for copper-64 radiolabelling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific imaging agents. Four different bifunctional chelating agents (BFC) were evaluated for Fab (Fragment antigen binding) conjugation and radiolabelling with copper-64. Two DOTA- (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and two NOTA- (1,4,7-triazacyclononane-1,4,7-triacetic acid) derivatives bearing a p-benzyl-isothiocyanate group were conjugated to Fab-trastuzumab - which targets the HER2/neu receptor - and the average number of chelators attached ranged from 2.4 to 4.3 macrocycles per Fab. Labelling of the immunoconjugate with copper-64 was achieved in high radiochemical yields after 45 min at 37 °C, and the radiochemical purity of each 64 Cu-BFC-Fab-trastuzumab reached 97% after purification. The affinity of each 64 Cu-BFC-Fab-trastuzumab ranged between 10 and 50 nM as evaluated by in vitro saturation assays using the HCC1954 breast cancer cell line. PET-MR imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumours were clearly visualized on PET images at 4 and 24 hours post-injection. The tumour uptake of 64 Cu-BFC-Fab-trastuzumab reached 8.9 to 12.8% ID g -1 24 hours post-injection and significant differences in non-specific liver uptake were observed depending on the BFC conjugated, the lowest being observed with MANOTA. These results show that MANOTA is a valuable tool for copper-64 radiolabelling.

Purpose: To compare the diagnostic performance of 18 F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT), multiparametric prostate magnetic resonance imaging (mpMRI), and a combination of both techniques for the detection of local recurrence of prostate cancer initially treated by radiation therapy., Methods and Materials: This was a retrospective, single-institution study of 32 patients with suspected prostate cancer recurrence who underwent both FCH-PET/CT and 3T mpMRI within 3 months of one another for the detection of recurrence. All included patients had to be cleared for metastatic recurrence. The reference procedure was systematic 3-dimensional (3D)-transperineal prostate biopsy for the final assessment of local recurrence. Both imaging modalities were analyzed by 2 experienced readers blinded to clinical data. The analysis was made per-patient and per-segment using a 4-segment model., Results: The median prostate-specific antigen value at the time of imaging was 2.92 ng/mL. The mean prostate-specific antigen doubling time was 14 months. Of the 32 patients, 31 had a positive 3D-transperineal mapping biopsy for a local relapse. On a patient-based analysis, the detection rate was 71% (22 of 31) for mpMRI and 74% (23 of 31) for FCH-PET/CT. On a segment-based analysis, the sensitivity and specificity were, respectively, 32% and 87% for mpMRI, 34% and 87% for FCH-PET/CT, and 43% and 83% for the combined analysis of both techniques. Accuracy was 64%, 65%, and 66%, respectively. The interobserver agreement was κ = 0.92 for FCH-PET/CT and κ = 0.74 for mpMRI., Conclusions: Both mpMRI and FCH-PET/CT show limited sensitivity but good specificity for the detection of local cancer recurrence after radiation therapy, when compared with 3D-transperineal mapping biopsy. Prostate biopsy still seems to be mandatory to diagnose local relapse and select patients who could benefit from local salvage therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Previous studies have suggested that early changes in blood flow (BF) in response to neoadjuvant chemotherapy and evaluated with 15 O-water are a surrogate biomarker of outcome in women with breast cancer. This study investigates, in the triple-negative breast cancer subtype, the prognostic relevance of tumor BF changes (ΔBF) in response to chemotherapy, assessed using a short dynamic 18 F-FDG PET acquisition., Methods: Forty-six consecutive women with triple-negative breast cancer and an indication for neoadjuvant chemotherapy were prospectively included. Women benefited from a baseline 18 F-FDG PET examination with a 2-min chest-centered dynamic acquisition, started at the time of 18 F-FDG injection. Breast tumor perfusion was calculated from this short dynamic image using a first-pass model. This dynamic PET acquisition was repeated after the first cycle of chemotherapy to measure early ΔBF. Delayed static PET acquisitions were also performed (90 min after 18 F-FDG injection) to measure changes in tumor glucose metabolism (ΔSUV max ). The association between tumor BF, clinicopathologic characteristics, and patients' overall survival (OS) was evaluated., Results: Median baseline tumor BF was 21 mL/min/100 g (range, 6-46 mL/min/100 g) and did not significantly differ according to tumor size, Scarf-Bloom-Richardson grade, or Ki-67 expression. Median tumor ∆BF was -30%, with highly scattered values (range, -93% to +118%). A weak correlation was observed between ΔBF and ∆SUV max (r = +0.40, P = 0.01). The median follow-up was 30 mo (range, 6-73 mo). Eight women developed recurrent disease, 7 of whom died. Low OS was associated with menopausal history (P = 0.03), persistent or increased tumor vascularization on the interim PET (ΔBF cutoff = -30%; P = 0.03), non-breast-conserving surgery (P = 0.04), and the absence of a pathologic complete response (pCR) (P = 0.01). ΔBF and pCR provided incremental prognostic stratification: 3-y OS was 100% in pCR women, 87% in no-pCR women but achieving an early tumor BF response, and only 48% in no-pCR/no-BF-response women (ΔBF cutoff = -30%, P < 0.001)., Conclusion: This study suggests the clinical usefulness of an early user- and patient-friendly 2-min dynamic acquisition to monitor breast tumor ΔBF to neoadjuvant chemotherapy using 18 F-FDG PET/CT. Monitoring tumor perfusion and angiogenesis response to treatment seems to be a promising target for PET tracers., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

A new generation of monomolecular imaging probes (MOMIP) based on a distyryl-BODIPY (BODIPY=boron-dipyrromethene) coupled with three DOTA macrocycles has been prepared (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The MOMIP presents good fluorescence properties and is very stable in serum. The bimodal probe was conjugated to trastuzumab, and an optical in vivo study showed high accumulation of the imaging agent at the tumor site. (111) In radiometallation of the bioconjugate was performed in high radiochemical yield, highlighting the potential of this new BODIPY-chelators derivative as a bimodal imaging probe., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aim: To investigate the respective influence of software tool and total metabolic tumor volume (TMTV0) calculation method on prognostic stratification of baseline 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography ([18F]FDG-PET) in newly diagnosed Hodgkin lymphoma (HL)., Methods: 59 patients with newly diagnosed HL were retrospectively included. [18F]FDG-PET was performed before any treatment. Four sets of TMTV0 were calculated with Beth Israel (BI) software: based on an absolute threshold selecting voxel with standardized uptake value (SUV) >2.5 (TMTV02.5), applying a per-lesion threshold of 41% of the SUV max (TMTV041) and using a per-patient adapted threshold based on SUV max of the liver (>125% and >140% of SUV max of the liver background; TMTV0125 and TMTV0140). TMTV041 was also determined with commercial software for comparison of software tools. ROC curves were used to determine the optimal threshold for each TMTV0 to predict treatment failure., Results: Median follow-up was 39 months. There was an excellent correlation between TMTV041 determined with BI and with the commercial software (r = 0.96, p<0.0001). The median TMTV0 value for TMTV041, TMTV02.5, TMTV0125 and TMTV0140 were respectively 160 (used as reference), 210 ([28;154] p = 0.005), 183 ([-4;114] p = 0.06) and 143 ml ([-58;64] p = 0.9). The respective optimal TMTV0 threshold and area under curve (AUC) for prediction of progression free survival (PFS) were respectively: 313 ml and 0.70, 432 ml and 0.68, 450 ml and 0.68, 330 ml and 0.68. There was no significant difference between ROC curves. High TMTV0 value was predictive of poor PFS in all methodologies: 4-years PFS was 83% vs 42% (p = 0.006) for TMTV02.5, 83% vs 41% (p = 0.003) for TMTV041, 85% vs 40% (p<0.001) for TMTV0125 and 83% vs 42% (p = 0.004) for TMTV0140., Conclusion: In newly diagnosed HL, baseline metabolic tumor volume values were significantly influenced by the choice of the method used for determination of volume. However, no significant differences were found in term of prognosis.

In molecular imaging, multimodal imaging agents can provide complementary information, for improving the accuracy of disease diagnosis or enhancing patient management. In particular, optical/nuclear imaging may find important preclinical and clinical applications. To simplify the preparation of dual-labeled imaging agents, we prepared versatile monomolecular multimodal imaging probe (MOMIP) platforms containing both a fluorescent dye (BODIPY) and a metal chelator (polyazamacrocycle). One of the MOMIP was conjugated to a cyclopeptide (i.e., octreotide) and radiolabeled with (111) In. In vitro and in vivo studies of the resulting bioconjugate were conducted, highlighting the potential of these BODIPY-based bimodal probes. This work also confirmed that the biovector and/or the bimodal probes must be chosen carefully, due to the impact of the MOMIP on the overall properties of the resulting imaging agent., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Micro-CT is considered to be a powerful tool to investigate various models of disease on anesthetized animals. In longitudinal studies, the radiation dose delivered by the micro-CT to the same animal is a major concern as it could potentially induce spurious effects in experimental results. Optically stimulated luminescence dosimeters (OSLDs) are a relatively new kind of detector used in radiation dosimetry for medical applications. The aim of this work was to assess the dose delivered by the CT component of a micro-SPECT (single-photon emission computed tomography)∕CT camera during a typical whole-body mouse study, using commercially available OSLDs based on Al2O3:C crystals., Methods: CTDI (computed tomography dose index) was measured in micro-CT with a properly calibrated pencil ionization chamber using a rat-like phantom (60 mm in diameter) and a mouse-like phantom (30 mm in diameter). OSLDs were checked for reproducibility and linearity in the range of doses delivered by the micro-CT. Dose measurements obtained with OSLDs were compared to those of the ionization chamber to correct for the radiation quality dependence of OSLDs in the low-kV range. Doses to tissue were then investigated in phantoms and cadavers. A 30 mm diameter phantom, specifically designed to insert OSLDs, was used to assess radiation dose over a typical whole-body mouse imaging study. Eighteen healthy female BALB∕c mice weighing 27.1 ± 0.8 g (1 SD) were euthanized for small animal measurements. OLSDs were placed externally or implanted internally in nine different locations by an experienced animal technician. Five commonly used micro-CT protocols were investigated., Results: CTDI measurements were between 78.0 ± 2.1 and 110.7 ± 3.0 mGy for the rat-like phantom and between 169.3 ± 4.6 and 203.6 ± 5.5 mGy for the mouse-like phantom. On average, the displayed CTDI at the operator console was underestimated by 1.19 for the rat-like phantom and 2.36 for the mouse-like phantom. OSLDs exhibited a reproducibility of 2.4% and good linearity was found between 60 and 450 mGy. The energy scaling factor was calculated to be between 1.80 ± 0.16 and 1.86 ± 0.16, depending on protocol used. In phantoms, mean doses to tissue over a whole-body CT examination were ranging from 186.4 ± 7.6 to 234.9 ± 7.1 mGy. In mice, mean doses to tissue in the mouse trunk (thorax, abdomen, pelvis, and flanks) were between 213.0 ± 17.0 and 251.2 ± 13.4 mGy. Skin doses (3 OSLDs) were much higher with average doses between 350.6 ± 25.3 and 432.5 ± 34.1 mGy. The dose delivered during a topogram was found to be below 10 mGy. Use of the multimouse bed of the system gave a significantly 20%-40% lower dose per animal (p < 0.05)., Conclusions: Absorbed doses in micro-CT were found to be relatively high. In micro-SPECT∕CT imaging, the micro-CT unit is mainly used to produce a localization frame. As a result, users should pay attention to adjustable CT parameters so as to minimize the radiation dose and avoid any adverse radiation effects which may interfere with biological parameters studied.

Improved bifunctional chelating agents (BFC) are required for indium-111 radiolabeling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific agents. 2,2',2"-(10-(2,6-Dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTAGA-anhydride) was evaluated for mAb conjugation and labeling with indium-111. The DOTA analogue was synthesized and conjugated to trastuzumab-which targets the HER2/neu receptor-in mild conditions (PBS pH 7.4, 25 °C, 30 min) and gave a mean degree of conjugation of 2.6 macrocycle per antibody. Labeling of this immunoconjugate with indium-111 was performed in 75% yield after 1 h at 37 °C, and the proportion of (111)In-DOTAGA-trastuzumab reached 97% after purification. The affinity of DOTAGA-trastuzumab was 5.5 ± 0.6 nM as evaluated by in vitro saturation assays using HCC1954 breast cancer cell line. SPECT/CT imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumors were clearly visualized on SPECT images at 24, 48, and 72 h postinjection. The tumor uptake of [(111)In-DOTAGA]-trastuzumab reached 65%ID/g 72 h postinjection. These results show that the DOTAGA BFC appears to be a valuable tool for biologics conjugation.

Unlabelled: The purpose of this study was to prospectively evaluate the relationship between tumor blood flow and glucose metabolism as evaluated by dynamic first-pass (18)F-FDG PET and by proliferation and endothelial pathologic markers in the setting of newly diagnosed breast cancer., Methods: Forty patients were prospectively included. Biopsy samples of each tumor were used to assess the Ki67 index of proliferation and immunostaining for CD34 (a panendothelial cell marker) and CD105 (a proliferation-related endothelial cell marker). All patients underwent (18)F-FDG PET/CT at least 1 wk after sample biopsy and before any treatment. A dynamic 2-min acquisition was performed immediately after intravenous injection of a 5 MBq/kg dose of (18)F-FDG; tumor blood flow was then calculated using a single-compartment kinetic model. A static acquisition was performed 90 min after injection for quantification of delayed (18)F-FDG tumor uptake (standardized uptake value maximal index [SUV(max)]), reflecting tumor metabolism., Results: Pathologic and PET/CT data were available for all patients. The SUV(max) measured on delayed PET images correlated strongly and positively with the expression of Ki67 (r = +0.69; P < 0.0001). In contrast, there was no significant correlation between SUV(max) and endothelial markers (CD34 and CD105). Tumor blood flow correlated positively with the expression of CD34 and CD105 (P = 0.016 and P = 0.007, respectively) and with the expression of Ki67 (P = 0.028). By logistic regression analysis, only expression of Ki67 remained an independent predictor of high (supramedian) SUV(max); CD105 score and histopathologic grade 3 were independently associated with a high (supramedian) tumor blood flow level., Conclusion: Tumor blood flow quantified by dynamic first-pass (18)F-FDG PET/CT is significantly associated with tumor angiogenesis as evaluated by immunohistochemistry in the setting of breast cancer, whereas tumor metabolism appears to be more associated with markers of proliferation. Thus, determination of tumor blood flow and metabolism with a single injection of (18)F-FDG could be an exciting alternative to more complex and less available techniques.

Purpose: We tested the impact of different values of the relaxation parameter lambda (lambda) on contrast and noise in line-of-response row-action maximum likelihood algorithm (LOR-RAMLA) in 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) imaging., Methods: Phantom studies were performed on a Gemini XL PET/CT scanner. The NEMA/IEC (National Electrical Manufacturers Association/International Electro technical Commission) torso phantom was used and acquisition data were reconstructed with lambda values ranging from 0.025 to 0.1. Quality of the reconstructed images was evaluated by contrast recovery coefficients and background variability values according to the NEMA NU 2-2001 procedures., Results: Contrast recovery coefficients and background variability increased significantly when lambda increased. The best noise-versus-resolution trade-off was obtained with lambda in the 0.04-0.06 range. For LOR-RAMLA reconstruction, the manufacturer allows a possible lambda choice from 0.025 to 0.1. We would not advise too small (0.025) or too large (0.1) lambda values which result in too smooth or too noisy images., Conclusion: We determined optimal lambda values in LOR-RAMLA on a Gemini XL PET/CT scanner. Caution is needed when using lambda values out of that range.

Purpose: (99m)Tc-UBI 29-41 (UBI), an antimicrobial peptide, specifically targets bacteria. We tested the ability of UBI to discriminate between infected and uninfected prosthetic joints using a rabbit model previously validated., Methods: Left knee arthroplasty was performed on 20 New Zealand rabbits, then 10(7) cfu of S. aureus (n = 12) or sterile saline (n = 8) was injected into the joint. On days 9 and 20 after surgery, planar UBI scintigraphy was performed in six infected and four uninfected rabbits, 1 h and 4 h p.i. (150 MBq), on a gamma camera. Operated-to-normal knee activity ratio (ONKR) was calculated on each scintigram. Then, after sacrifice, tissue samples of both knees were counted in a gamma counter., Results: One rabbit injected with sterile saline had cutaneous infection at sacrifice and was excluded from analysis. ONKR was higher in infected than in uninfected animals 4 h p.i. 20 days after surgery: 1.75 +/- 0.48 vs 1.13 +/- 0.11, p = 0.04. From 1 h to 4 h p.i., ONKR increased in 9/12 infected and 0/7 uninfected animals. According to UBI uptake intensity and kinetics, scintigraphy was truly positive in all infected cases on day 9 and in four of six infected cases on day 20. It was truly negative in two of three sterile inflamed prosthetic knees on day 9, and in all cases on day 20. Biodistribution studies revealed increased UBI uptake in periprosthetic tissues in all animals 9 days after surgery, and only in infected animals on day 20., Conclusion: In this experimental study, (99m)Tc-UBI 29-41 scintigraphy permitted the early detection of acute prosthetic joint infection, and exclusion of infection in chronic sterile prosthetic joint inflammation.

Background: The mural thrombus of abdominal aortic aneurysms (AAA) is involved in aneurysm progression via several interdependent biological processes including platelet activation. 99mTc-annexin V (ANX) is a scintigraphic tracer that binds to phosphatidylserine exposed on activated platelets and apoptotic cells. Here, we evaluated the potential of ANX imaging to assess mural thrombus biological activity in an experimental AAA model. The clinical applicability was further tested ex vivo on human samples of excised AAA thrombi., Methods and Results: Experimental AAA was created by infusing elastase into infrarenal abdominal aorta in 17 rats, and 6 sham-operated rats were used as controls. Abdominal ANX scintigraphy was performed 2 weeks later followed by quantitative autoradiography and histological studies. Among the 13 rats which developed AAA, 11 displayed intense ANX uptake within AAA by scintigraphy. ANX uptake in the aneurysms on planar and single-photon emission computed tomography (SPECT) imaging was higher than that observed in infrarenal aorta of sham-operated controls (target/background ratio: 5.7+/-0.9 versus 1.33+/-0.21; P<0.005 for SPECT). Aneurysm-to-background activity ratios obtained by scintigraphy correlated with ANX activity in corresponding autoradiograms (R=0.69; P<0.02). This activity was located in the thrombus area where activated platelets and polymorphonuclear leukocytes accumulated. Similar patterns were also found in all of the 7 human AAA thrombi harvested during surgery., Conclusions: ANX imaging may assess mural thrombus renewal activity linked to permanent flowing blood interface.

Purpose: (99m)Tc-annexin V (ANX) allows scintigraphic detection of apoptotic cells via specific binding to exposed phosphatidylserine. In myocardial infarction, apoptosis of myocytes is variable and depends especially on the presence or absence of coronary reperfusion. In this study, ANX uptake in non-reperfused experimental myocardial infarcts was compared with uptake of a marker of myocyte necrosis ((111)In-antimyosin antibodies, AM) and an immunohistochemical marker of apoptosis (Apostain)., Methods: The left anterior coronary artery was ligated in 47 Wistar rats, which were then injected with ANX (n=20), AM (n=21) or both (n=6). Myocardial uptake of ANX and AM was determined at 2 h (n=14), 4 h (n=14) and 24 h (n=19) after coronary ligation (CL), by quantitative autoradiography with (n=23) or without (n=24) gamma imaging. Heart-to-lung ratios (HLRs) and infarct-to-remote myocardium activity ratios (INRs) were calculated on the scintigrams and autoradiograms respectively. Cardiac sections were stained with haematoxylin-eosin and Apostain. The above studies were repeated in 12 normal rats., Results: All rats with CL showed increased ANX and AM uptake in cardiac areas on scintigrams 24 h after CL, with HLRs higher than in controls: 3.1+/-0.6 versus 1.5+/-0.3 (p=0.001) for ANX and 1.99+/-0.44 versus 1.01+/-0.05 (p<0.0005) for AM. Autoradiography showed intense ANX and AM uptake in infarcts, with comparable topography and INRs at 2 h, 4 h and 24 h after CL (4.6+/-0.9 versus 5.0+/-1.8 at 24 h), while Apostain staining was very low (0.06+/-0.06% of cells)., Conclusion: In this model of persistent CL, we observed increased ANX uptake in injured myocardium, comparable in intensity, topography and kinetics to that of AM. There was only minimal Apostain staining in the same areas.

Unlabelled: 99mTc-Annexin-V (ANX), which allows in vivo detection of apoptotic cells, is potentially a promising noninvasive tool to diagnose myocarditis. To test this assumption, we compared the myocardial uptake of ANX (imaging and quantitative autoradiography) in experimental subacute myocarditis (Wistar Bonn/Kobori rats [WBN/Kob]) and in normal Wistar rats. WBN/Kob is an inbred strain of Wistar rat in which myocardial injury mimicking subacute catecholamine-induced myocarditis spontaneously develops (course duration, 18 mo). The apoptotic myocardial rates were determined by immunohistochemical studies., Methods: Fourteen WBN/Kob rats (8-10 mo old) and 12 control rats were injected with ANX (7.4 MBq/100 g). Ten-minute anterior planar thoracic images (matrix, 128 x 128) were obtained using a pinhole collimator, 1 and 4 h after injection. Heart-to-lung activity ratios were calculated on the scintigrams. Four hours after ANX injection, quantitative autoradiography of myocardial slices was performed, as well as histologic studies with hematoxylin-eosin and with a staining assay specific for apoptotic cells., Results: Heart-to-lung activity ratios were higher in WBN/Kob rats than in control rats on 4-h images (2.07 +/- 0.07 vs. 1.66 +/- 0.06, P = 0.0007). Autoradiographic studies showed moderate diffuse, homogeneous myocardial ANX uptake significantly higher in WBN/Kob rats than in control rats: 54 +/- 4 versus 37 +/- 3 counts/mm(2) (P < 0.007). The apoptotic rate, evaluated with an apoptotic cell-staining assay, was 0.51% +/- 0.14% of cells in WBN/Kob rats versus 0.0042% +/- 0.0008% in control rats (P < 0.008)., Conclusion: Compared with control rats, rats with subacute myocarditis mimicking catecholamine-induced myocarditis showed increased ANX myocardial uptake. This suggests a potential role for ANX imaging in the diagnosis of myocarditis.

In this study we investigate the possibility of using Auger electrons as a probing agent for the study of structures of nucleic acids. To this end, we present the distribution of breaks produced in strands of a DNA duplex and a triplex-forming oligonucleotide (TFO) carrying Auger emitting radionuclide 125I. The method of calculation includes use of a molecular model of plasmid DNA duplex with bound TFO carrying a labelled 125I at position C5 of a single deoxycytosine residue, a source of Auger spectra, Monte Carlo electron track structure and the ensuing chemistry codes, to simulate the distribution of breaks produced in both strands of a plasmid DNA. Frequencies of fragment length distributions were obtained for the TFO, the purine and the pyrimidine strands. The frequency of breaks in the purine strand showed good correlation with the published experimental results, while that for the pyrimidine strand is lower by a factor of 3. It is concluded that the true structure of triplex DNA may not be purely of B-form.