Lise Borgwardt

Molecular Pathology in Vulnerable Carotid Plaques: Correlation with (18)-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)

OBJECTIVES Atherosclerosis is recognised as an inflammatory disease, and new diagnostic tools are warranted to evaluate plaque inflammatory activity and risk of cardiovascular events. We investigated [18]-fluorodeoxyglucose (FDG) uptake in vulnerable carotid plaques visualised by positron emission tomography (PET). Uptake was correlated to quantitative gene expression of known markers of inflammation and plaque vulnerability. METHODS Ten patients with recent transient ischaemic attack and carotid artery stenosis (>50%) underwent combined FDG-PET and computed tomography angiography (CTA) the day before carotid endarterectomy. Plaque mRNA expression of the inflammatory cytokine interleukin 18 (IL-18), the macrophage-specific marker CD68 and the two proteinases, Cathepsin K and matrix metalloproteinase 9 (MMP-9), were quantified using real-time quantitative polymerase chain reaction. RESULTS Consistent up-regulation of CD68 (3.8-fold+/-0.9; mean+/-standard error), Cathepsin K (2.1-fold+/-0.5), MMP-9 (122-fold+/-65) and IL-18 (3.4-fold+/-0.7) were found in the plaques, compared to reference-artery specimens. The FDG uptake by plaques was strongly correlated with CD68 gene expression (r=0.71, P=0.02). Any correlations with Cathepsin K, MMP-9 or IL-18 gene expression were weaker. CONCLUSIONS FDG-PET uptake in carotid plaques is correlated to gene expression of CD68 and other molecular markers of inflammation and vulnerability.

Increased fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) uptake in childhood CNS tumors is correlated with malignancy grade : A study with FDG positron emission tomography/magnetic resonance imaging coregistration and image fusion

PURPOSE Positron emission tomography (PET) has been used in grading of CNS tumors in adults, whereas studies of children have been limited. PATIENTS AND METHODS Nineteen boys and 19 girls (median age, 8 years) with primary CNS tumors were studied prospectively by fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) PET with (n = 16) or without (n = 22) H(2)(15)O-PET before therapy. Image processing included coregistration to magnetic resonance imaging (MRI) in all patients. The FDG uptake in tumors was semiquantitatively calculated by a region-of-interest-based tumor hotspot/brain index. Eight tumors without histologic confirmation were classified as WHO grade 1 based on location, MRI, and clinical course (22 to 42 months). Results Four grade 4 tumors had a mean index of 4.27 +/- 0.5, four grade 3 tumors had a mean index of 2.47 +/- 1.07, 10 grade 2 tumors had a mean index of 1.34 +/- 0.73, and eight of 12 grade 1 tumors had a mean index of -0.31 +/- 0.59. Eight patients with no histologic confirmation had a mean index of 1.04. For these 34 tumors, FDG uptake was positively correlated with malignancy grading (n = 34; r = 0.72; P < .01), as for the 26 histologically classified tumors (n = 26; r = 0.89; P < .01). The choroid plexus papilloma (n = 1) and the pilocytic astrocytomas (n = 3) had a mean index of 3.26 (n = 38; r = 0.57; P < .01). H(2)(15)O-uptake showed no correlation with malignancy. Digitally performed PET/MRI coregistration increased information on tumor characterization in 90% of cases. CONCLUSION FDG PET of the brain with MRI coregistration can be used to obtain a more specific diagnosis with respect to malignancy grading. Improved PET/MRI imaging of the benign hypermetabolic tumors is needed to optimize clinical use.

PET/MRI in cancer patients: first experiences and vision from Copenhagen

Combined PET/MRI systems are now commercially available and are expected to change the medical imaging field by providing combined anato-metabolic image information. We believe this will be of particular relevance in imaging of cancer patients. At the Department of Clinical Physiology, Nuclear Medicine & PET at Rigshospitalet in Copenhagen we installed an integrated PET/MRI in December 2011. Here, we describe our first clinical PET/MR cases and discuss some of the areas within oncology where we envision promising future application of integrated PET/MR imaging in clinical routine. Cases described include brain tumors, pediatric oncology as well as lung, abdominal and pelvic cancer. In general the cases show that PET/MRI performs well in all these types of cancer when compared to PET/CT. However, future large-scale clinical studies are needed to establish when to use PET/MRI. We envision that PET/MRI in oncology will prove to become a valuable addition to PET/CT in diagnosing, tailoring and monitoring cancer therapy in selected patient populations.

Practical use and implementation of PET in children in a hospital PET centre

Children are not just small adults—they differ in their psychology, normal physiology and pathophysiology, and various aspects should be considered when planning a positron emission tomography (PET) scan in a child. PET in children is a growing area, and this article describes the practical use and implementation of PET in children in a hospital PET centre. It is intended to be of use to nuclear medicine departments implementing or starting to implement PET scans in children. Topics covered are: dealing with children, dosimetry, organisation within the department and relations with other departments, preparation of the child (provision of information to the child and parents and the fasting procedure), the imaging procedure (resting, tracer injection, positioning, sedation and bladder emptying) and pitfalls in the interpretation of PET scans in children, including experiences with telemedicine.

When to image carotid plaque inflammation with FDG PET/CT.

ObjectiveQuantification of 18-fluorodeoxyglucose (FDG) uptake in inflamed high-risk carotid atherosclerotic plaques is challenged by the spatial resolution of positron emission tomography (PET) and luminal blood activity. Late acquisition protocols have been used to overcome these challenges to enhance the contrast between the plaque and blood-pool FDG activity. However, for prospective studies the late acquisition is inconvenient for the patient and staff, and most retrospective studies of plaque uptake use data from early acquisition protocols. The objective was to evaluate changes in the quantification methods of FDG uptake in carotid artery plaques between early and late PET scans. MethodsFDG uptake 1 and 3 h after tracer injection was compared in 19 carotid artery plaques. The average plaque maximum standardized uptake value (SUVmax) and a target to background ratio (TBR), using venous blood-pool activity as background, were evaluated at the two time points. These methods have been shown earlier to quantitate the degree of inflammation in late hour scans. ResultsA good individual plaque FDG uptake consistency was found between the two time points for SUVmax, r2=0.86. In contrast, the ratio method did not conserve the results between the two time points: TBR r2=0.34. For both methods, absolute values changed over time. TBR values generally increased as blood pool activity decreased, whereas the individual plaque SUVmax values showed both increases and decreases over time. ConclusionIdentification of carotid plaque inflammation with PET can be performed 1 h after FDG injection using SUVmax for plaque FDG uptake quantification.

Paediatric doses—a critical appraisal of the EANM paediatric dosage card

In the May 2007 issue of the European Journal of Nuclear Medicine and Molecular Imaging, two very important papers concerning paediatric nuclear medicine were published: an editorial “PET/CT in paediatrics: it is time to increase its use” [1] and “The new EANM paediatric dosage card” [2]. In the excellent editorial by Isabel Roca and co-workers, it was recommended that the use of PET/CT for diagnostic purposes in children should be increased. We fully support this statement: based on our experience gained from performing approximately 100 PET scans per year in children, and the use of paediatric PET since 1991, it is our impression that the added value from PET/CT is even more pronounced in children than in adults [3]. The new dosage card suggested by the EANM Dosimetry and Paediatrics groups [2] represents a major step forward. It utilises much of the existing knowledge about the dosimetry for different radiopharmaceuticals to estimate the activity that can be given to children at different weights whilst maintaining the same effective dose as given to adults. We acknowledge the large uncertainty of all these calculated values. The ICRP [4, 5] accounts for neither the normal age-dependent biodistribution nor the diseasedependent differences among patients. Compared with the large effort that has been put into the calculation of the new weight-dependent doses, however, the suggested minimum values are still not based on sound scientific argument [2]. In the text they are described as “determined based upon considerations concerning the limitations of conventional gamma cameras and PET scanners in terms of image quality, as described by Jacobs et al.” [2, 6]. In reference [6], however, the considerations mainly consist of referring the problem to be “addressed by a working party ...”. With the newly recommended minimum doses for PET [2], examinations of neonatal patients will result in very high effective doses and thereby either entail considerable risk or simply be impossible to perform according to the recommendations owing to ethical considerations. We are, of course, not the first to point out that minimum values may not be necessary in all cases. Smith and Gordon [7], in their paper on radiopharmaceutical schedules in children, applied some theoretical scaling arguments. Børch et al. [8] showed, although for a special instrument, that in HMPAO brain imaging in neonates, linear scaling (4 MBq/kg) without a minimum may apply. Also for FDG, Ruotsalainen et al. [9] performed imaging and effective dose estimation in neonates with a fixed activity per weight down to 1.8 kg. It should also be noted that the EANM guidelines for Brain Imaging using [F]FDG (http://www. eanm.org) do apply a minimum limit, but of 10 MBq rather than the 70 MBq proposed in [2]. The images we present here (Figs. 1, 2) clearly show that PET images of sufficient quality can be obtained with an amount of activity that is considerably less than that suggested as the “minimum” in the new dosage card [2]. Why is that? In the paper by Jacobs et al. [6], ”image quality” is inferred solely from “count rate”. Given the influence of this choice on the recommendations, it is important to note that little reflection has been given to this subject. Below, we explain how, in our opinion, the authors are making a number of mistakes, and how these result in over-dosing (particularly in PET) of the smallest children, for whom the original aim of protection has the greatest importance. Eur J Nucl Med Mol Imaging (2007) 34:1713–1718 DOI 10.1007/s00259-007-0508-0

Fourteen-year-old girl with endobronchial carcinoid tumour presenting with asthma and lobar emphysema.

Introduction:  Bronchial carcinoid tumours seldom occur in children, and represent a rare cause of pulmonary obstruction. Because of low clinical suspicion and the variable ways of presentation, diagnosis may be delayed.

Estimating GFR in children with 99mTc-DTPA renography: a comparison with single-sample 51Cr-EDTA clearance

Glomerular filtration rate (GFR) measurement by 51Cr‐ethylenediaminetetraacetic acid (EDTA) and blood sampling in children is usually cumbersome for the patient, parents and laboratory technicians. We have previously developed a method accurately estimating GFR in adults. The aim of the present study was to evaluate the accuracy of this non‐invasive method in children. We calculated GFR from 99mTc‐diethylene triamine pentaacetic acid (DTPA) renography and compared with 51Cr‐EDTA plasma clearance of 29 children between the age of 1 month and 12 years (mean 4·7 years). The correlation between 99mTc‐DTPA renography and 51Cr‐EDTA plasma clearance was for all children R = 0·96 (n = 29, P<0·0001), for children above 2 years of age R = 0·96 (n = 18, P<0·0001) and for children <2 years R = 0·84 (n = 11, P<0·001). We conclude that assessment of GFR from 99mTc‐DTPA renography is reliable and comparable to GFR calculated from 51Cr‐EDTA plasma clearance. Because our method is non‐invasive and only takes 21 min, it may be preferable in many cases where an assessment of renal function is needed in children especially when renography is performed anyhow.

First experiences from Copenhagen with paediatric single photon emission computed tomography/computed tomography.

ObjectiveThis study evaluates the diagnostic value of single photon emission computed tomographic (SPECT)/multislice computed tomographic (MSCT) fusion images compared with planar scintigraphy in children. MethodsFifteen children [eight girls, mean age 13 years (range 2–17 years)] who were examined in the SPECT/16-MSCT scanner at the Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet were included. The studies and clinical indications were eight 99mTc-hydroxymethane diphosphonate bone scintigraphies (three bone abnormalities, three osteomyelitis, two bone tumours), one bone scintigraphy combined with 111In-labelled leukocyte study (osteomyelitis), three 123I-meta-iodobenzylguanidine scintigraphies (neuroblastoma), three 111In-octreotide scintigraphies (two carcinoid tumours, one Langerhans cell histiocytosis) and one 99mTc-dimercaptosuccinic acid scintigraphy (suspected renal transplant infarction). At the evaluation of the planar scans, the decision to perform a SPECT/16-MSCT scan was taken. A specialist in nuclear medicine read the SPECT scans and the CT scans were, if performed as high resolution or when in doubt, read by the specialist in radiology, followed by a simultaneous reading. We categorized the additional information gained from the SPECT/MSCT scan into three groups: (i) structural information gained from the CT scan, (ii) additional nuclear medicine information gained from the SPECT scan and (iii) information used for biopsy guidance. Use of a CT scan of diagnostic quality was only allowed (n=1) after referral from the clinicians, and read in collaboration with the specialist in radiology. ResultsFourteen of the 15 planar scans gained additional structural information from SPECT/CT. Twelve of 15 planar scans gained additional nuclear medicine information. Six studies gained specific information for biopsy guidance. ConclusionSPECT/CT provided additional information in all cases. SPECT/CT in children seems to be a most valuable tool and it increases the certainty of the diagnostic work-up.

21. Increased FDG uptake in Childhood CNS Tumors is Associated with Tumor Malignancy.

Background: In adults PET scanning of CNS tumors with the tracer FDG (18F-flourodeoxyglucose) can provide information about the degree of malignancy, tumor extent, and dissemination. FDG PET can also be able to assess tumor response to therapy and to differentiate recurrence from necrosis. Although CNS tumors are the most common solid tumor in childhood, so far only few PET-studies have been reported. Pre-operative assessment of malignancy would facilitate surgical planning and the use of pre-operative chemotherapy.Materials and Methods: 21 children with CNS tumors were referred to clinical FDG PET prior to therapy (M/F = 12/9, median age: 9 (range 0-16)), (4 PNET/medulloblastomas; 1 gr. III ependymoma, 16 benign tumors)). Image processing included co-registration with MRI and image fusion. The FDG uptake in the tumors was ranked 0-5 by a hotspot/cortex-ratio by two observers independently. The FDG uptake in grey and white matter was used as reference for the grading system with FDG uptakes defined as 4 and 2 respectively.Results: 15 of 16 patients with tumors WHO gr. I-II had FDG-uptake of 1-2, and all 5 patients with tumors WHO gr. III-IV had FDG-uptake of 3-4. A WHO gr. I papilloma, known to have a high metabolism caused by high mitochondrial activity, had FDG uptake of 5. Except for this tumor, the FDG uptake was positively correlated with tumor malignancy. MRI/PET co-registration and image fusion increased the specificity of tumor location, as well as of tumor extent, and of heterogeneity (e.g., areas of necrosis).Conclusion: FDG PET with MRI/PET co-registration and image fusion could be an important adjunct in the diagnostic work up of pediatric CNS tumors, and could help define patients eligible for pre-operative chemotherapy.