Daniela D'Ambrosio

Cerenkov radiation allows in vivo optical imaging of positron emitting radiotracers.

In this paper, we showed that Cerenkov radiation (CR) escaping from the surface of small living animals injected with (18)F-FDG can be detected with optical imaging techniques. (18)F decays by emitting positrons with a maximum energy of 0.635 MeV; such positrons, when travelling into tissues faster than the speed of light in the same medium, are responsible of CR emission. A detailed model of the CR spectrum considering the positron energy spectrum was developed in order to quantify the amount of light emission. The results presented in this work were obtained using a commercial optical imager equipped with charged coupled detectors (CCD). Our data open the door to optical imaging (OI) in vivo of the glucose metabolism, at least in pre-clinical research. We found that the heart and bladder can be clearly identified in the animal body reflecting the accumulation of the (18)F-FDG. Moreover, we describe two different methods based on the spectral analysis of the CR that can be used to estimate the depth of the source inside the animal. We conclude that (18)F-FDG can be employed as it is as a bimodal tracer for positron emission tomography (PET) and OI techniques. Our results are encouraging, suggesting that it could be possible to apply the proposed approach not only to beta(+) but also to pure beta(-) emitters.

Combined optical and single photon emission imaging: preliminary results.

In vivo optical imaging instruments are generally devoted to the acquisition of light coming from fluorescence or bioluminescence processes. Recently, an instrument was conceived with radioisotopic detection capabilities (Kodak in Vivo Multispectral System F) based on the conversion of x-rays from the phosphorus screen. The goal of this work is to demonstrate that an optical imager (IVIS 200, Xenogen Corp., Alameda, USA), designed for in vivo acquisitions of small animals in bioluminescent and fluorescent modalities, can even be employed to detect signals due to radioactive tracers. Our system is based on scintillator crystals for the conversion of high-energy rays and a collimator. No hardware modifications are required. Crystals alone permit the acquisition of photons coming from an in vivo 20 g nude mouse injected with a solution of methyl diphosphonate technetium 99 metastable (Tc99m-MDP). With scintillator crystals and collimators, a set of measurements aimed to fully characterize the system resolution was carried out. More precisely, system point spread function and modulation transfer function were measured at different source depths. Results show that system resolution is always better than 1.3 mm when the source depth is less than 10 mm. The resolution of the images obtained with radioactive tracers is comparable with the resolution achievable with dedicated techniques. Moreover, it is possible to detect both optical and nuclear tracers or bi-modal tracers with only one instrument.

Restaging clear cell renal carcinoma with 18F-FDG PET/CT.

Aim The aim of our retrospective study was to assess the usefulness of 18F-FDG PET/CT in the restaging of clear cell renal cell carcinoma (RCC) patients. Patients and Methods Sixty-nine patients (median age = 62 years; range = 36–86 years) affected by clear cell RCC (TNM at staging: T1, 42 patients; T2, 13 patients; T3, 11 patients; T4, 3 patients; Fuhrman grade: G2, 47 patients; G3, 20 patients; G4, 2 patients) underwent whole-body 18F-FDG PET/CT to restage the disease after nephrectomy for clinical or radiological suspicion of metastases. Areas of abnormal uptake at PET/CT were classified, taking the liver uptake as reference, as follows: 1 = faint uptake, lower than liver; 2 = moderate uptake, equal to liver; and 3 = high uptake, higher than liver. Validation of 18F-FDG PET/CT results was established by (1) biopsy (23 patients) and (2) other imaging modalities (addressed BS; c.e.CT; MRI; 18F-fluoride PET/CT; subsequent 18F-FDG PET/CT), and/or clinical and radiological follow-up of 12 months (46 patients). Results 18F-FDG PET/CT was positive in 42 patients and negative in 27 patients. Sixteen patients presented single lesions and 26 patients presented multiple localizations of the disease. On a patient basis, 40 patients resulted true positive, 2 patient false positive, 23 patients true negative, and 4 patients false negative. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 90%, 92%, 91%, 95%, and 85%, respectively. On a lesion basis, PET/CT detected 114 areas of abnormal uptake in 42 positive patients of which 112 resulted to be true positive. FDG uptake of the true positive lesions resulted to be high in 83 cases, moderate in 17 lesions, and finally faint in 12 lesions. Conclusions 18F-FDG PET/CT demonstrated a good sensitivity in the restaging of clear cell RCC. Most of the lesions showed intense activity. According to our results, it seems that the use of 18F-FDG PET/CT in the restaging of RCC is feasible because the number of false-negative cases is limited.

Attenuation Correction for Small Animal PET Images: A Comparison of Two Methods

In order to extract quantitative parameters from PET images, several physical effects such as photon attenuation, scatter, and partial volume must be taken into account. The main objectives of this work were the evaluation of photon attenuation in small animals and the implementation of two attenuation correction methods based on X-rays CT and segmentation of emission images. The accuracy of the first method with respect to the beam hardening effect was investigated by using Monte Carlo simulations. Mouse- and rat-sized phantoms were acquired in order to evaluate attenuation correction in terms of counts increment and recovery of uniform activity concentration. Both methods were applied to mice and rat images acquired with several radiotracers such as18F-FDG, 11C-acetate, 68Ga-chloride, and 18F-NaF. The accuracy of the proposed methods was evaluated in heart and tumour tissues using 18F-FDG images and in liver, kidney, and spinal column tissues using 11C-acetate, 68Ga-chloride, and 18F-NaF images, respectively. In vivo results from animal studies show that, except for bone scans, differences between the proposed methods were about 10% in rats and 3% in mice. In conclusion, both methods provide equivalent results; however, the segmentation-based approach has several advantages being less time consuming and simple to implement.

Feasibility of Carbidopa Premedication in Pediatric Patients: A Pilot Study

AIM To verify the potential role and feasibility of carbidopa premedication in pediatric patients undergoing ¹⁸F-DOPA (Fluorine-18 fluorodihydroxyphenylalanine) PET scanning. MATERIALS AND METHODS For this limited study, 5 patients (M:F=3:2; mean age 4.8 years) with a positive history for neuroblastoma who had been referred to our institution for instrumental monitoring during clinical follow-up were enrolled. In all cases, two consecutive ¹⁸F-DOPA PET scans, the first without carbidopa and the second with carbidopa premedication, were scheduled: patients received 4 MBq/kg of radiotracer and a dose of 2 mg/kg of carbidopa. Dedicated VOIs were drawn on the basal ganglia, pancreas, liver, and renal cortex. These regions were semiquantitatively analyzed at both the first and at the second ¹⁸F-DOPA scan, and mean SUV(max) values were compared using the t-test. RESULTS On a visual basis, a clear reduction in the abdominal accumulation of (18)F-DOPA was observed in all cases after carbidopa premedication. This reduction related both to the biliary structures and the excretory system, and was accompanied by a generalized increase in soft tissue uptake. The semiquantitative analysis documented an absolute increase in SUV(max) after carbidopa premedication in the basal ganglia (3.4±1.3 vs. 2.1±0.8) and liver parenchyma (2.2±0.5 vs. 1.5±0.5), whereas SUV(max) decreased in the renal cortex (1.7±0.8 vs. 3.7±1.0) and the pancreas (2.3±0.6 vs. 3.5±0.5). The changes in SUV(max) were statistically significant for the pancreas and liver parenchyma (p=0.022 and 0.045, respectively), but not for the basal ganglia and renal cortex (p=0.143 and 0.15, respectively). CONCLUSIONS Carbidopa premedication in the pediatric population appears feasible and seems to influence ¹⁸F-DOPA distribution in the liver and pancreas in a manner similar to that reported in adults. Larger series are however needed to properly define the clinical role of carbidopa premedication in children.

Small animal PET for the evaluation of an animal model of genital infection

Background:  [18F]‐FDG is a widely used tracer for the non‐invasive evaluation of hypermetabolic processes like cancer and inflammation. However, [18F]‐FDG is considered inaccurate for the diagnosis of urinary tract and genital infections because of its urinary excretion. Since the 1970s, Gallium scintigraphy is a well established test that has been used for the evaluation of inflammation and infection in human patients.

Accurate modeling of a DOI capable small animal PET scanner using GATE

In this work we developed a Monte Carlo (MC) model of the Sedecal Argus pre-clinical PET scanner, using GATE (Geant4 Application for Tomographic Emission). This is a dual-ring scanner which features DOI compensation by means of two layers of detector crystals (LYSO and GSO). Geometry of detectors and sources, pulses readout and selection of coincidence events were modeled with GATE, while a separate code was developed in order to emulate the processing of digitized data (for example, customized time windows and data flow saturation), the final binning of the lines of response and to reproduce the data output format of the scanners acquisition software. Validation of the model was performed by modeling several phantoms used in experimental measurements, in order to compare the results of the simulations. Spatial resolution, sensitivity, scatter fraction, count rates and NECR were tested. Moreover, the NEMA NU-4 phantom was modeled in order to check for the image quality yielded by the model. Noise, contrast of cold and hot regions and recovery coefficient were calculated and compared using images of the NEMA phantom acquired with our scanner. The energy spectrum of coincidence events due to the small amount of (176)Lu in LYSO crystals, which was suitably included in our model, was also compared with experimental measurements. Spatial resolution, sensitivity and scatter fraction showed an agreement within 7%. Comparison of the count rates curves resulted satisfactory, being the values within the uncertainties, in the range of activities practically used in research scans. Analysis of the NEMA phantom images also showed a good agreement between simulated and acquired data, within 9% for all the tested parameters. This work shows that basic MC modeling of this kind of system is possible using GATE as a base platform; extension through suitably written customized code allows for an adequate level of accuracy in the results. Our careful validation against experimental data confirms that the developed simulation setup is a useful tool for a wide range of research applications.

Pixel-based partial volume correction of small animal PET images using Point Spread Function system characterization: Evaluation of effects on cardiac output, perfusion and metabolic rate using parametric images

Physiologic parameters such as glucose metabolic rate (GMR), perfusion and cardiac output (CO) can be estimated by performing quantitative analysis using PET dynamic images. The measurement of the image derived arterial input function (IF) and the tissue time activity curve (TAC) can be affected by partial volume effect (PVE). Because of partial volume, the estimate of different physiological parameters can be severely biased. The main goal of this work was to evaluate the effects of an image reconstruction based partial volume correction (PVC) method of small animal PET images on metabolic rate and perfusion on a pixel-based analysis and on cardiac output. The proposed PVC method is based on Point Spread Function (PSF) modeling in the reconstruction scheme. Dynamic mouse heart images were created using the Moby phantom. IF and TAC were simulated for one and two compartmental models and different radiotracers in order to take into account the different positron range. Images were simulated using different sets of rate constants and different noise levels. In order to obtain an estimate of the probability distribution of each kinetic parameter from each pixel value, bootstrap resampling with replacement was applied. The coefficient of variation and the bias of the mean of the distribution with respect to the theoretical value were estimated. Pre and post-correction parametric images of GMR and perfusion and the relative errors show that the image reconstruction PVC reduces errors with respect to the theoretical values in each pixel. The percentage error of CO from uncorrected and corrected images with respect to the theoretical value was 13.5% and 2.3%, respectively, for 18F-FDG study. Regarding images acquired using 82Rb, CO estimate was equal to 34.6 % and 23.2 % for non PVC and PVC images, respectively. In conclusion, pixel based PVC allows to obtain a better measure of the radiotracer concentration in the heart and a more accurate estimation of the phisiological parameters.

RECONSTRUCTION OF DYNAMIC PET IMAGES USING ACCURATE SYSTEM POINT SPREAD FUNCTION MODELING: EFFECTS ON PARAMETRIC IMAGES

Quantitative analysis of positron emission tomography (PET) dynamic images allows to estimate physiological parameters such as glucose metabolic rate (GMR), perfusion, and cardiac output (CO). However, several physical effects such as photon attenuation, scatter and partial volume can reduce the accuracy of parameter estimation. The main goal of this work was to improve small animal PET image quality by introducing system point spread function (PSF) in the reconstruction scheme and to evaluate the effect of partial volume correction (PVC) on physiological parameter estimation. Images reconstructed respectively using constant and spatially variant (SV) PSFs and no PSF modeling was compared. The proposed algorithms were tested on simulated and real phantoms and mice images. Results show that the SV-PSF-based reconstruction method provides a significant contrast improvement of small animals PET cardiac images and, thus, the effects of PVC on physiological parameters were evaluated using such algorithm. Simulations show that the proposed PVC method reduces errors with respect to the true values for parametric images of GMR and perfusion. A reduction of CO percentage error with respect to the original value was also obtained using the SF-PSF approach. In conclusion, SV-PSF reconstruction method provides a more accurate estimation of several physiological parameters obtained from a dynamic PET scan.

Reply to 'Comments on "Cerenkov radiation allows in vivo optical imaging of positron emitting radiotracers"'.

In this reply, we address the criticisms by Drs Mitchell, Gill and Cherry (Mitchell et al 2010 Phys. Med. Biol. 55 L43–4) regarding our paper recently published in Physics Medicine and Biology (Spinelli et al 2010 Phys. Med. Biol. 55 483–95). In our paper we showed that it is possible to acquire Cerenkov radiation images of mice injected with 18F-FDG using an optical imaging device. We also showed two different approaches that can be used in order to estimate the depth of the Cerenkov radiation source inside the mouse. More precisely, we will discuss the criticisms regarding the proposed model of the Cerenkov radiation spectrum for positron emitters and the estimation methods of the radiation source depth by providing further experimental results.