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Ronald Boellaard

r.boellaard@vumc.nl
Present occupation:
Associate professor, Head of the (clinical) physics section, Dept. of Nuclear Medicine & PET Research, VU University Medical Centre, Amsterdam, The Netherlands

Journal articles

2009
 
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M A Kropholler, R Boellaard, E H Elzinga, C J van der Laken, K Maruyama, R W Kloet, A E Voskuyl, B A C Dijkmans, A A Lammertsma (2009)  Quantification of (R)-[11C]PK11195 binding in rheumatoid arthritis.   Eur J Nucl Med Mol Imaging 36: 4. 624-631 Apr  
Abstract: PURPOSE: Rheumatoid arthritis (RA) involves migration of macrophages into inflamed areas. (R)-[(11)C]PK11195 binds to peripheral benzodiazepine receptors, expressed on macrophages, and may be used to quantify inflammation using positron emission tomography (PET). This study evaluated methods for the quantification of (R)-[(11)C]PK11195 binding in the knee joints of RA patients. METHODS: Data from six patients with RA were analysed. Dynamic PET scans were acquired in 3-D mode following (R)-[(11)C]PK11195 injection. During scanning arterial radioactivity concentrations were measured to determine the plasma (R)-[(11)C]PK11195 concentrations. Data were analysed using irreversible and reversible one-tissue and two-tissue compartment models and input functions with various types of metabolite correction. Model preferences according to the Akaike information criterion (AIC) and correlations between measures were evaluated. Correlations between distribution volume (V(d)) and standardized uptake values (SUV) were evaluated. RESULTS: AIC indicated optimal performance for a one-tissue reversible compartment model including blood volume. High correlations were observed between V(d) obtained using different input functions (R(2)=0.80-1.00) and between V(d) obtained with one- and two-tissue reversible compartment models (R(2)=0.75-0.94). A high correlation was observed between optimal V(d) and SUV after injection (R(2)=0.73). CONCLUSION: (R)-[(11)C]PK11195 kinetics in the knee were best described by a reversible single-tissue compartment model including blood volume. Applying metabolite corrections did not increase sensitivity. Due to the high correlation with V(d), SUV is a practical alternative for clinical use.
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Tolboom, van der Flier, Yaqub, Boellaard, Verwey, Blankenstein, Windhorst, Scheltens, Lammertsma, van Berckel (2009)  Relationship of Cerebrospinal Fluid Markers to 11C-PiB and 18F-FDDNP Binding.   J Nucl Med Aug  
Abstract: The purpose of this study was to investigate the potential relationships between cerebrospinal fluid (CSF) measurements of beta-amyloid-1-42 (Abeta1-42) and total tau to (11)C-Pittsburgh compound B ((11)C-PiB) and 2-(1-{6-[(2-(18)F-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile ((18)F-FDDNP) binding as measured using PET. METHODS: A total of 37 subjects were included, consisting of 15 patients with Alzheimer disease (AD), 12 patients with mild cognitive impairment, and 10 healthy controls. All subjects underwent a lumbar puncture and PET using both (11)C-PiB and (18)F-FDDNP. For both PET tracers, parametric images of binding potential were generated. Potential associations of CSF levels of Abeta1-42 and tau with (11)C-PiB and (18)F-FDDNP binding were assessed using Pearson correlation coefficients and linear regression analyses. RESULTS: For both global (11)C-PiB and (18)F-FDDNP binding, significant correlations with CSF levels of Abeta1-42 (r = -0.72 and -0.37, respectively) and tau (r = 0.58 and 0.56, respectively) were found across groups (all P < 0.001, except P < 0.05 for correlation between (18)F-FDDNP and Abeta1-42). Linear regression analyses showed that, adjusted for regional volume, age, sex, and diagnosis, global (11)C-PiB uptake had an inverse association with Abeta1-42 CSF levels (standardized beta = -0.50, P < 0.001), whereas there was a positive association between global (18)F-FDDNP binding and tau CSF levels (standardized beta = 0.62, P < 0.01). CONCLUSION: The good agreement between these 2 different types of biomarkers (i.e., CSF and PET) provides converging evidence for their validity. The inverse association between (11)C-PiB and CSF tau Abeta1-42 confirms that (11)C-PiB measures amyloid load in the brain. The positive association between (18)F-FDDNP and CSF tau suggests that at least part of the specific signal of (18)F-FDDNP in AD patients is due to tangle formation.
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Floris H P van Velden, Reina W Kloet, Bart N M van Berckel, Adriaan A Lammertsma, Ronald Boellaard (2009)  Accuracy of 3-dimensional reconstruction algorithms for the high-resolution research tomograph.   J Nucl Med 50: 1. 72-80 Jan  
Abstract: The high-resolution research tomograph (HRRT) is a dedicated human brain PET scanner. At present, iterative reconstruction methods are preferred for reconstructing HRRT studies. However, these iterative reconstruction algorithms show bias in short-duration frames. New algorithms such as the shifted Poisson ordered-subsets expectation maximization (SP-OSEM) and ordered-subsets weighted least squares (OSWLS) showed promising results in bias reduction, compared with the recommended ordinary Poisson OSEM (OP-OSEM). The goal of this study was to evaluate quantitative accuracy of these iterative reconstruction algorithms, compared with 3-dimensional filtered backprojection (3D-FBP). METHODS: The 3 above-mentioned 3D iterative reconstruction methods were implemented for the HRRT. To evaluate the various 3D iterative reconstruction techniques quantitatively, several phantom studies and a human brain study (n=5) were performed. RESULTS: OSWLS showed a low and almost linearly increasing coefficient of variation (SD over average activity concentration), with decreasing noise-equivalent count rates. In decay studies, OSWLS showed good agreement with the 3D-FBP gray matter (GM)-to-white matter (WM) contrast ratio (<4%), and OP-OSEM and SP-OSEM showed agreement within 6% and 7%, respectively. For various frame durations, both SP-OSEM and OP-OSEM showed the fewest errors in GM-to-WM contrast ratios, varying 75% between different noise-equivalent count rates; this variability was much higher for other iterative methods (>92%). 3D-FBP showed the least variability (34%). Visually, OSWLS hardly showed any artifacts in parametric images and showed good agreement with 3D-FBP data for parametric images, especially in the case of reference-tissue kinetic methods (slope, 1.02; Pearson correlation coefficient, 0.99). CONCLUSION: OP-OSEM, SP-OSEM, and OSWLS showed good performance for phantom studies. In addition, OSWLS showed better results for parametric analysis of clinical studies and is therefore recommended for quantitative HRRT brain PET studies.
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Adrianus J de Langen, Bianca Klabbers, Mark Lubberink, Ronald Boellaard, Marieke D Spreeuwenberg, Ben J Slotman, Remco de Bree, Egbert F Smit, Otto S Hoekstra, Adriaan A Lammertsma (2009)  Reproducibility of quantitative 18F-3'-deoxy-3'-fluorothymidine measurements using positron emission tomography.   Eur J Nucl Med Mol Imaging 36: 3. 389-395 Mar  
Abstract: PURPOSE: Positron emission tomography (PET) using (18)F-3'-deoxy-3'-fluorothymidine ([(18)F]FLT) allows noninvasive monitoring of tumour proliferation. For serial imaging in individual patients, good reproducibility is essential. The purpose of the present study was to evaluate the reproducibility of quantitative [(18)F]FLT measurements. METHODS: Nine patients with non-small-cell lung cancer (NSCLC) and six with head-and-neck cancer (HNC) underwent [(18)F]FLT PET twice within 7 days prior to therapy. The maximum pixel value (SUV(max)) and a threshold defined volume (SUV(41%)) were defined for all delineated lesions. The plasma to tumour transfer constant (K(i)) was estimated using both Patlak graphical analysis and nonlinear regression (NLR). NLR was also used to estimate k(3), which, at least in theory, selectively reflects thymidine kinase 1 activity. The level of agreement between test and retest values was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: All primary tumours and >90% of clinically suspected locoregional metastases could be delineated. In total, 24 lesions were defined. NLR-derived K(i), Patlak-derived K(i), SUV(41%) and SUV(max) showed excellent reproducibility with ICCs of 0.92, 0.95, 0.98 and 0.93, and SDs of 16%, 12%, 7% and 11%, respectively. Reproducibility was poor for k(3) with an ICC of 0.43 and SD of 38%. CONCLUSION: Quantitative [(18)F]FLT measurements are reproducible in both NSCLC and HNC patients. When monitoring response in individual patients, changes of more than 15% in SUV(41%), 20-25% in SUV(max) and Patlak-derived K(i), and 32% in NLR3k-derived K(i) are likely to represent treatment effects.
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Matthijs G Bossong, Bart N M van Berckel, Ronald Boellaard, Lineke Zuurman, Robert C Schuit, Albert D Windhorst, Joop M A van Gerven, Nick F Ramsey, Adriaan A Lammertsma, René S Kahn (2009)  Delta 9-tetrahydrocannabinol induces dopamine release in the human striatum.   Neuropsychopharmacology 34: 3. 759-766 Feb  
Abstract: The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that Delta 9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D(2)/D(3) receptor tracer [(11)C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [(11)C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia.
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Abraham Rijbroek, Ronald Boellaard, Erik G J Vermeulen, Adriaan A Lammertsma, Jan A Rauwerda (2009)  Hemodynamic changes in ipsi- and contralateral cerebral arterial territories after carotid endarterectomy using positron emission tomography.   Surg Neurol 71: 6. 668-76, discussion 676 Jun  
Abstract: BACKGROUND: The purpose of this study was to characterize ipsi- and contralateral cerebral hemodynamics before and after CEA. METHODS: Cerebral blood flow, CBV, and MVTT were measured in 10 patients before and after CEA using PET. Absolute and relative values of these parameters were calculated bilaterally for the entire arterial territories and hemispheres. RESULTS: For all territories in both hemispheres, the mean absolute postoperative CBF was significantly increased compared with preoperative CBF (P < .05). Only in MCA was this increase higher in the ipsilateral than in the contralateral hemisphere (P = .02). Cerebral blood volume was unaffected, whereas MVTT decreased in ipsilateral MCA (P = .05). CONCLUSIONS: The present findings suggest that, on the first day after CEA, absolute CBF is increased in all arterial territories on both ipsi- and contralateral sides, but that there are only minor changes in the relative distribution, whereas the CBV was unaffected.
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A Rijbroek, R Boellaard, E M Vriens, A A Lammertsma, J A Rauwerda (2009)  Comparison of transcranial Doppler ultrasonography and positron emission tomography using a three-dimensional template of the middle cerebral artery.   Neurol Res 31: 1. 52-59 Feb  
Abstract: OBJECTIVE: Transcranial Doppler (TCD) measures blood flow velocities (BFV) and is an indirect method of assessing cerebral blood flow (CBF). Positron emission tomography (PET) is a direct method to measure CBF. This study evaluates the correlations between TCD and PET findings Methods: Nine patients with a symptomatic carotid artery stenosis, who underwent CEA, were studied pre- and post-operatively on the ipsi- and contralateral sides. Measurements of the BFV, CO(2) reactivity, CBF, cerebral blood volume (CBV) and mean vascular transit time (MVTT) were performed using a three-dimensional volume of interest (VOI) for the middle cerebral artery (MCA). RESULTS: CBF in the MCA region, as measured with PET, shows a good correlation with BFV, as measured with TCD, with similar pattern for total, gray and white matter MCA territory (Pearson's correlation coefficients: 0.751, 0.748 and 0.748, respectively). This correlation was found in the pre-operative as well as the post-operative state. No association could be demonstrated between CO(2) reactivity and CBV or (Pearson's correlation coefficients: 0.051 and 0.166, respectively). CONCLUSION: With PET, it is possible to create three-dimensional VOI of arterial territories. CBF measured in these VOI seems to correlate with BFV before and after CEA on ipsi- and contralateral sides, while CBV shows no association with pre-operative CO(2) reactivity.
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Nelleke Tolboom, Maqsood Yaqub, Wiesje M van der Flier, Ronald Boellaard, Gert Luurtsema, Albert D Windhorst, Frederik Barkhof, Philip Scheltens, Adriaan A Lammertsma, Bart N M van Berckel (2009)  Detection of Alzheimer pathology in vivo using both 11C-PIB and 18F-FDDNP PET.   J Nucl Med 50: 2. 191-197 Feb  
Abstract: 11C-Pittsburgh Compound-B (11C-PIB) and 18F-(2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) (18F-FDDNP) have been developed as PET tracers for in vivo imaging of pathology in Alzheimer's disease (AD). The purpose of this study was to directly compare these tracers in patients with AD, patients with mild cognitive impairment (MCI), and healthy controls. METHODS: Paired 11C-PIB and 18F-FDDNP scans were acquired in 14 patients with AD, 11 patients with amnestic MCI, and 13 controls. For both tracers, parametric images of binding potential (BPND) were generated. Global cortical BPND was assessed using ANOVA. In addition, regional patterns of BPND were compared between diagnostic groups using ANOVA for repeated measures. RESULTS: Global cortical BPND of 11C-PIB showed higher binding in patients with AD than in controls and patients with MCI. 18F-FDDNP uptake was higher in patients with AD than in controls, but MCI could not be distinguished from AD or from controls. Global BPND values of both tracers were moderately correlated (r=0.45; P=0.005). In MCI, BPND of 11C-PIB showed a bimodal distribution, whereas values for 18F-FDDNP were more widespread, with more MCI patients demonstrating increased uptake. Regional 11C-PIB binding showed different patterns across diagnostic groups, as AD patients showed an overall increase in binding, with the lowest binding in the medial temporal lobe. With 18F-FDDNP, patterns were similar across diagnostic groups. For all groups, highest values were observed in the medial temporal lobe. CONCLUSION: Differences in BPND between patients with AD, patients with MCI, and controls were more pronounced for 11C-PIB. The difference in regional binding, the moderate correlation, and the discrepant findings in MCI suggest that they measure related, but different, characteristics of the disease.
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Jurgen E M Mourik, Mark Lubberink, Alie Schuitemaker, Nelleke Tolboom, Bart N M van Berckel, Adriaan A Lammertsma, Ronald Boellaard (2009)  Image-derived input functions for PET brain studies.   Eur J Nucl Med Mol Imaging 36: 3. 463-471 Mar  
Abstract: PURPOSE: To assess the robustness of a previously introduced method to obtain accurate image-derived input functions (IDIF) for three other tracers. METHODS: Dynamic PET and online blood data of five repeat [(11)C]PIB (Pittsburgh Compound-B) ([(11)C]PIB), six repeat (R)-[(11)C]verapamil, and ten single (R)-[(11)C]PK11195 studies were used. IDIFs were extracted from partial volume corrected scans using the four hottest pixels per plane method. Results obtained with IDIFs were compared with those using standard online measured arterial input functions (BSIF). IDIFs were used both with and without calibration based on manual blood samples. RESULTS: For (R)-[(11)C]verapamil, accurate IDIFs were obtained using noncalibrated IDIFs (slope 0.96+/-0.17; R (2) 0.92+/-0.07). However, calibration was necessary to obtain IDIFs comparable to the BSIF for both [(11)C]PIB (slope 1.04+/-0.05; R (2) 1.00+/-0.01) and (R)-[(11)C]PK11195 (slope 0.96+/-0.05; R (2) 0.99+/-0.01). The need for calibration may be explained by the sticking property of both tracers, indicating that BSIF may be affected by sticking and therefore may be unreliable. CONCLUSION: The present study shows that a previously proposed method to extract IDIFs is suitable for analysing [(11)C]PIB, (R)-[(11)C]verapamil and (R)-[(11)C]PK11195 studies, thereby obviating the need for online arterial sampling.
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Saskia P A Wolfensberger, Bart N M van Berckel, Anu J Airaksinen, Kaoru Maruyama, Mark Lubberink, Ronald Boellaard, William D H Carey, Wieb Reddingius, Dick J Veltman, Albert D Windhorst, Josée E Leysen, Adriaan A Lammertsma (2009)  First evaluation of [11C]R116301 as an in vivo tracer of NK1 receptors in man.   Mol Imaging Biol 11: 4. 241-245 Jul/Aug  
Abstract: PURPOSE: NK1 receptors have been implicated in various neuropsychiatric and other disorders. R116301 is a selective NK1 receptor antagonist. In this pilot study, [(11)C]R116301 was evaluated as a potential positron emission tomography (PET) ligand for the NK1 receptor. PROCEDURES: Two dynamic PET studies were performed in three normal volunteers before and after a blocking dose of aprepitant. Data were analyzed using striatum to cerebellum standardized uptake value (SUV) ratios. RESULTS: Baseline SUV ratios at 60-90 min after injection ranged from 1.22 to 1.70. Following aprepitant administration, this specific signal was completely blocked. Aprepitant administration did not significantly affect uptake in cerebellum, confirming the absence of NK1 receptors in cerebellum. CONCLUSION: These preliminary results indicate that [(11)C]R116301 has potential as a radioligand for in vivo assessment of NK1 receptors in the human brain.
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Mourik, Lubberink, van Velden, Lammertsma, Boellaard (2009)  Off-line motion correction methods for multi-frame PET data.   Eur J Nucl Med Mol Imaging Jul  
Abstract: PURPOSE: Patient motion during PET acquisition may affect measured time-activity curves, thereby reducing accuracy of tracer kinetic analyses. The aim of the present study was to evaluate different off-line frame-by-frame methods to correct patient motion, which is of particular interest when no optical motion tracking system is available or when older data sets have to be reanalysed. METHODS: Four different motion correction methods were evaluated. In the first method attenuation-corrected frames were realigned with the summed image of the first 3 min. The second method was identical, except that non-attenuation-corrected images were used. In the third and fourth methods non-attenuation-corrected images were realigned with standard and cupped transmission images, respectively. Two simulation studies were performed, based on [(11)C]flumazenil and (R)-[(11)C]PK11195 data sets, respectively. For both simulation studies different types (rotational, translational) and degrees of motion were added. Simulated PET scans were corrected for motion using all correction methods. The optimal method derived from these simulation studies was used to evaluate two (one with and one without visible movement) clinical data sets of [(11)C]flumazenil, (R)-[(11)C]PK11195 and [(11)C]PIB. For these clinical data sets, the volume of distribution (V(T)) was derived using Logan analysis and values were compared before and after motion correction. RESULTS: For both [(11)C]flumazenil and (R)-[(11)C]PK11195 simulation studies, optimal results were obtained when realignment was based on non-attenuation-corrected images. For the clinical data sets motion disappeared visually after motion correction. Regional differences of up to 433% in V(T) before and after motion correction were found for scans with visible movement. On the other hand, when no visual motion was present in the original data set, overall differences in V(T) before and after motion correction were <1.5 +/- 1.3%. CONCLUSION: Frame-by-frame motion correction using non-attenuation-corrected images improves the accuracy of tracer kinetic analysis compared to non-motion-corrected data.
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Yaqub, Tolboom, van Berckel, Scheltens, Lammertsma, Boellaard (2009)  Simplified parametric methods for [(18)F]FDDNP studies.   Neuroimage Jul  
Abstract: The purpose of the present study was to evaluate the performance of various parametric methods for quantification of [(18)F]FDDNP studies. All parametric methods tested were based on the use of a reference tissue and they were compared with the simplified reference tissue model (SRTM), as previously it has been shown that SRTM is the method of choice for analysing [(18)F]FDDNP studies, even when an arterial plasma input function is available. The following parametric methods were evaluated: receptor parametric mapping (basis function implementation of SRTM; with and without fixing the reference tissue efflux rate constant k'(2)), reference Logan and several multi-linear reference tissue methods (again with and without fixing k'(2)). Simulations were used to assess the effects of variation in relative flow (R(1)), fractional blood volume (V(b)) and binding potential (BP(ND)) on precision and accuracy of estimated BP(ND). For clinical data, best performance was obtained using receptor parametric mapping (RPM2) and one of the multi-linear reference tissue models (MRTM2), with k'(2) being fixed in both methods. These models showed good correlation with SRTM, their BP(ND) results were less affected by noise and images showed good contrast. Furthermore, in simulations, RPM2 and MRTM2 provided the most accurate and precise BP(ND) estimates. RPM2 and MRTM2 are the methods of choice for parametric analysis of [(18)F]FDDNP studies.
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Ronald Boellaard (2009)  Standards for PET image acquisition and quantitative data analysis.   J Nucl Med 50 Suppl 1: 11S-20S May  
Abstract: Quantitative (18)F-FDG PET is increasingly being recognized as an important tool for diagnosis, determination of prognosis, and response monitoring in oncology. However, PET quantification with, for example, standardized uptake values (SUVs) is affected by many technical and physiologic factors. As a result, some of the variations in the literature on SUV-based patient outcomes are explained by differences in (18)F-FDG PET study methods. Various technical and clinical studies have been performed to understand the factors affecting PET quantification. On the basis of the results of those studies, several recommendations and guidelines have been proposed with the aims of improving the image quality and the quantitative accuracy of (18)F-FDG PET studies. In this contribution, an overview of recommendations and guidelines for quantitative (18)F-FDG PET studies in oncology is provided. Special attention is given to the rationale underlying certain recommendations and to some of the differences in various guidelines.
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Tolboom, Yaqub, Boellaard, Luurtsema, Windhorst, Scheltens, Lammertsma, van Berckel (2009)  Test-retest variability of quantitative [(11)C]PIB studies in Alzheimer's disease.   Eur J Nucl Med Mol Imaging Apr  
Abstract: PURPOSE: The aim of this study was to assess the test-retest variability of [(11)C]PIB studies in patients with Alzheimer's disease (AD) and healthy controls using several tracer kinetic models and to assess the suitability of the cerebellum as reference tissue. METHODS: [(11)C]PIB studies with arterial sampling were performed in eight AD patients and eight healthy controls. Retest scans were performed in six controls and six AD patients. Data were analysed using plasma input and reference tissue models, together with simple ratios. RESULTS: Test-retest variability was best ( approximately 3%) for SRTM2, a parametric method based on the simplified reference tissue model. Highest values ( approximately 10%) were found for plasma input models. Cerebellar V(T) values did not differ significantly between AD and controls. CONCLUSION: Parametric SRTM2 with the cerebellum as reference tissue is the method of choice for quantitative analysis of [(11)C]PIB PET studies.
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Floris H P van Velden, Reina W Kloet, Bart N M van Berckel, Fred L Buijs, Gert Luurtsema, Adriaan A Lammertsma, Ronald Boellaard (2009)  HRRT versus HR+ human brain PET studies: an interscanner test-retest study.   J Nucl Med 50: 5. 693-702 May  
Abstract: The high-resolution research tomograph (HRRT) is a dedicated human brain PET scanner. The purpose of this study was to compare the quantitative accuracy of the HRRT with that of the clinical HR+ PET scanner and to assess effects of differences in spatial resolution between both scanners ( approximately 2.7 mm and approximately 7.0 mm for HRRT and HR+, respectively). METHODS: Paired (11)C-flumazenil scans of 7 healthy volunteers were assessed. For each volunteer, dynamic scans (including arterial sampling) were acquired on both scanners on the same day, thereby minimizing intersubject variability. Volume of distribution was generated using Logan plot analysis with plasma input. In addition, other plasma input, reference tissue (with pons as the reference tissue input), and parametric methods were included in the interscanner comparison. RESULTS: Logan volume-of-distribution analysis of HRRT data showed higher values than that of HR+ data (slope with the intercept fixed at the origin of 1.14 +/- 0.10 to 1.19 +/- 0.10, depending on the HRRT reconstruction method used). Smoothing HRRT reconstructions with a 6-mm full width at half maximum gaussian kernel reduced this slope toward the line of identity (1.04 +/- 0.11 to 1.07 +/- 0.11), retaining good correlation between HR+ and HRRT data (r, approximately 0.98). Similar trends were observed for other plasma input, reference tissue, and parametric methods. However, after reference matching the reference tissue models showed lower HRRT kinetic parameter values than HR+ values (slope with fixed intercept, 0.90 +/- 0.10 to 0.94 +/- 0.13). CONCLUSION: Higher values of pharmacokinetic parameter values, obtained from HRRT versus HR+ PET studies, indicate improved HRRT PET quantification primarily due to a reduction in partial-volume effects.
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Maqsood Yaqub, Ronald Boellaard, Bart N M van Berckel, Nelleke Tolboom, Gert Luurtsema, Anke A Dijkstra, Mark Lubberink, Albert D Windhorst, Philip Scheltens, Adriaan A Lammertsma (2009)  Evaluation of tracer kinetic models for analysis of [18F]FDDNP studies.   Mol Imaging Biol 11: 5. 322-333 Sep/Oct  
Abstract: PURPOSE: Different pharmacokinetic methods for [18F]FDDNP studies were evaluated using both simulations and clinical data. PROCEDURES: Methods included two-tissue reversible plasma (2T4k), simplified reference tissue input (SRTM), and a modified 2T4k models. The latter included an additional compartment for metabolites (2T1M). For plasma input models, binding potential, BP(ND), was obtained both directly (=k (3)/k (4)) and indirectly (using volume of distribution ratios). RESULTS: For clinical data, 2T1M was preferred over 2T4k according to Akaike criterion. Indirect BP(ND) using 2T1M correlated better with SRTM then direct BP(ND). Fairly constant volume of distribution of metabolites was found across brain and across subjects, which was strongly related to bias in BP(ND) obtained from SRTM as seen in simulations. Furthermore, in simulations, SRTM showed constant bias with best precision if metabolites entered brain. CONCLUSIONS: SRTM is the method of choice for quantitative analysis of [18F]FDDNP even if it is unclear whether labeled metabolites enter the brain.
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Floris H P van Velden, Reina W Kloet, Bart N M van Berckel, Carla F M Molthoff, Hugo W A M de Jong, Adriaan A Lammertsma, Ronald Boellaard (2008)  Impact of attenuation correction strategies on the quantification of High Resolution Research Tomograph PET studies.   Phys Med Biol 53: 1. 99-118 Jan  
Abstract: In this study, the quantitative accuracy of different attenuation correction strategies presently available for the High Resolution Research Tomograph (HRRT) was investigated. These attenuation correction methods differ in reconstruction and processing (segmentation) algorithms used for generating a micro-image from measured 2D transmission scans, an intermediate step in the generation of 3D attenuation correction factors. Available methods are maximum-a-posteriori reconstruction (MAP-TR), unweighted OSEM (UW-OSEM) and NEC-TR, which transforms sinogram values back to their noise equivalent counts (NEC) to restore Poisson distribution. All methods can be applied with or without micro-image segmentation. However, for MAP-TR a micro-histogram is a prior during reconstruction. All possible strategies were evaluated using phantoms of various sizes, simulating preclinical and clinical situations. Furthermore, effects of emission contamination of the transmission scan on the accuracy of various attenuation correction strategies were studied. Finally, the accuracy of various attenuation corrections strategies and its relative impact on the reconstructed activity concentration (AC) were evaluated using small animal and human brain studies. For small structures, MAP-TR with human brain priors showed smaller differences in micro-values for transmission scans with and without emission contamination (<8%) than the other methods (<26%). In addition, it showed best agreement with true AC (deviation <4.5%). A specific prior designed to take into account the presence of small animal fixation devices only very slightly improved AC precision to 4.3%. All methods scaled micro-values of a large homogeneous phantom to within 4% of the water peak, but MAP-TR provided most accurate AC after reconstruction. However, for clinical data MAP-TR using the default prior settings overestimated the thickness of the skull, resulting in overestimations of micro-values in regions near the skull and thus in incorrect AC for cortical regions. Using NEC-TR with segmentation or MAP-TR with an adjusted human brain prior showed less overestimation in both skull thickness and AC for these structures and are therefore the recommended methods for human brain studies.
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A Rijbroek, R Boellaard, E M Vriens, A A Lammertsma, J A Rauwerda (2008)  Peroperative neuromonitoring during carotid endarterectomy in relation to preoperative positron emission tomography findings.   Eur J Vasc Endovasc Surg 35: 6. 652-660 Jun  
Abstract: OBJECTIVES: To compare stump pressure (SP), transcranial Doppler (TCD), electroencephalography (EEG) and selective shunting during carotid endarterectomy (CEA) with preoperative positron emission tomography (PET) parameters. MATERIALS AND METHODS: Preoperative PET measurements and peroperative neuromonitoring were performed in ten patients undergoing CEA for symptomatic carotid artery disease. PET parameters measured were cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral oxygen metabolism (CMRO(2)), cerebral blood volume (CBV), mean vascular transit time (MVTT) and cerebral perfusion pressure (CPP). Results of these measurements in ipsilateral medial cerebral artery (MCA), ipsilateral hemisphere and total cerebrum were compared with absolute mean SP, mean SP<40mmHg, TCD, EEG changes and selective shunting. RESULTS: None of the PET parameters showed any significant correlations with peroperative neuromonitoring findings. There were only trends for correlations of CBF and MVTT with TCD changes and of CPP and CMRO(2) with selective shunting. CONCLUSIONS: Preoperative PET examinations are not useful for predicting the need for shunting during CEA.
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Floris H P van Velden, Reina W Kloet, Bart N M van Berckel, Saskia P A Wolfensberger, Adriaan A Lammertsma, Ronald Boellaard (2008)  Comparison of 3D-OP-OSEM and 3D-FBP reconstruction algorithms for High-Resolution Research Tomograph studies: effects of randoms estimation methods.   Phys Med Biol 53: 12. 3217-3230 Jun  
Abstract: The High-Resolution Research Tomograph (HRRT) is a dedicated human brain positron emission tomography (PET) scanner. Recently, a 3D filtered backprojection (3D-FBP) reconstruction method has been implemented to reduce bias in short duration frames, currently observed in 3D ordinary Poisson OSEM (3D-OP-OSEM) reconstructions. Further improvements might be expected using a new method of variance reduction on randoms (VRR) based on coincidence histograms instead of using the delayed window technique (DW) to estimate randoms. The goal of this study was to evaluate VRR in combination with 3D-OP-OSEM and 3D-FBP reconstruction techniques. To this end, several phantom studies and a human brain study were performed. For most phantom studies, 3D-OP-OSEM showed higher accuracy of observed activity concentrations with VRR than with DW. However, both positive and negative deviations in reconstructed activity concentrations and large biases of grey to white matter contrast ratio (up to 88%) were still observed as a function of scan statistics. Moreover 3D-OP-OSEM+VRR also showed bias up to 64% in clinical data, i.e. in some pharmacokinetic parameters as compared with those obtained with 3D-FBP+VRR. In the case of 3D-FBP, VRR showed similar results as DW for both phantom and clinical data, except that VRR showed a better standard deviation of 6-10%. Therefore, VRR should be used to correct for randoms in HRRT PET studies.
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Paul Knaapen, Tjeerd Germans, Paolo G Camici, Ornella E Rimoldi, Folkert J ten Cate, Jurrien M ten Berg, Pieter A Dijkmans, Ronald Boellaard, Willem G van Dockum, Marco J W Götte, Jos W R Twisk, Albert C van Rossum, Adriaan A Lammertsma, Frans C Visser (2008)  Determinants of coronary microvascular dysfunction in symptomatic hypertrophic cardiomyopathy.   Am J Physiol Heart Circ Physiol 294: 2. H986-H993 Feb  
Abstract: Impaired hyperemic myocardial blood flow (MBF) in hypertrophic cardiomyopathy (HCM), despite normal epicardial coronary arteries, results in microvascular dysfunction. The aim of the present study was to determine the relative contribution of extravascular compressive forces to microvascular dysfunction in HCM. Eighteen patients with symptomatic HCM and normal coronary arteries and 10 age-matched healthy volunteers were studied with PET to quantify resting and hyperemic MBF at a subendocardial and subepicardial level. In HCM patients, MRI was performed to determine left ventricular (LV) mass index (LVMI) and volumes, echocardiography to assess diastolic perfusion time, heart catheterization to measure LV outflow tract gradient (LVOTG) and LV pressures, and serum NH(2)-terminal pro-brain natriuretic peptide (NT-proBNP) as a biochemical marker of LV wall stress. Hyperemic MBF was blunted in HCM vs. controls (2.26 +/- 0.97 vs. 2.93 +/- 0.64 ml min(-1) g(-1), P < 0.05). In contrast to controls (1.38 +/- 0.15 to 1.25 +/- 0.19, P = not significant), the endocardial-to-epicardial MBF ratio decreased significantly in HCM during hyperemia (1.20 +/- 0.11 to 0.88 +/- 0.18, P < 0.01). This pattern was similar for hypertrophied septum and lateral wall. Hyperemic MBF was inversely correlated with LVOTG, NT-proBNP, left atrial volume index, and LVMI (all P < 0.01). Multivariate regression analysis, however, revealed that only LVMI and NT-proBNP were independently related to hyperemic MBF, with greater impact at the subendocardial myocardial layer. Hyperemic MBF is more severely impaired at the subendocardial level in HCM patients. The level of impairment is related to markers of increased hemodynamic LV loading conditions and LV mass. These observations suggest that, in addition to reduced capillary density caused by hypertrophy, extravascular compressive forces contribute to microvascular dysfunction in HCM patients.
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E Geuze, B N M van Berckel, A A Lammertsma, R Boellaard, C S de Kloet, E Vermetten, H G M Westenberg (2008)  Reduced GABAA benzodiazepine receptor binding in veterans with post-traumatic stress disorder.   Mol Psychiatry 13: 1. 74-83, 3 Jan  
Abstract: Gamma-aminobutyric acid (GABA(A)) receptors are thought to play an important role in modulating the central nervous system in response to stress. Animal data have shown alterations in the GABA(A) receptor complex by uncontrollable stressors. SPECT imaging with benzodiazepine ligands showed lower distribution volumes of the benzodiazepine-GABA(A) receptor in the prefrontal cortex of patients with post-traumatic stress disorder (PTSD) in one, but not in another study. The objective of the present study was to assess differences in the benzodiazepine-GABA(A) receptor complex in veterans with and without PTSD using [(11)C]flumazenil and positron emission tomography (PET). Nine drug naive male Dutch veterans with deployment related PTSD and seven male Dutch veterans without PTSD were recruited, and matched for age, region and year of deployment. Each subject received a [(11)C]flumazenil PET scan and a structural magnetic resonance imaging scan. Dynamic 3D PET scans with a total duration of 60 min were acquired, and binding in template based and manually defined regions of interest (ROI) was quantified using validated plasma input and reference tissue models. In addition, parametric binding potential images were compared on a voxel-by-voxel basis using statistical parametric mapping (SPM2). ROI analyses using both template based and manual ROIs showed significantly reduced [(11)C]flumazenil binding in PTSD subjects throughout the cortex, hippocampus and thalamus. SPM analysis confirmed these results. The observed global reduction of [(11)C]flumazenil binding in patients with PTSD provides circumstantial evidence for the role of the benzodiazepine-GABA(A) receptor in the pathophysiology of PTSD and is consistent with previous animal research and clinical psychopharmacological studies.
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Bart N van Berckel, Matthijs G Bossong, Ronald Boellaard, Reina Kloet, Alie Schuitemaker, Esther Caspers, Gert Luurtsema, Albert D Windhorst, Wiepke Cahn, Adriaan A Lammertsma, René S Kahn (2008)  Microglia activation in recent-onset schizophrenia: a quantitative (R)-[11C]PK11195 positron emission tomography study.   Biol Psychiatry 64: 9. 820-822 Nov  
Abstract: BACKGROUND: Schizophrenia is a brain disease involving progressive loss of gray matter of unknown cause. Most likely, this loss reflects neuronal damage, which should, in turn, be accompanied by microglia activation. Microglia activation can be quantified in vivo using (R)-[(11)C]PK11195 and positron emission tomography (PET). The purpose of this study was to investigate whether microglia activation occurs in patients with recent-onset schizophrenia. METHODS: Ten patients with recent-onset schizophrenia and 10 age-matched healthy control subjects were included. A fully quantitative (R)-[(11)C]PK11195 PET scan was performed on all subjects, including arterial sampling to generate a metabolite-corrected input curve. RESULTS: Compared with control subjects, binding potential of (R)-[(11)C]PK11195 in total gray matter was increased in patients with schizophrenia. There were no differences in other PET parameters. CONCLUSIONS: Activated microglia are present in schizophrenia patients within the first 5 years of disease onset. This suggests that, in this period, neuronal injury is present and that neuronal damage may be involved in the loss of gray matter associated with this disease. Microglia may form a novel target for neuroprotective therapies in schizophrenia.
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Ursula M H Klumpers, Dick J Veltman, Ronald Boellaard, Emile F Comans, Cassandra Zuketto, Maqsood Yaqub, Jurgen E M Mourik, Mark Lubberink, Witte J G Hoogendijk, Adriaan A Lammertsma (2008)  Comparison of plasma input and reference tissue models for analysing [(11)C]flumazenil studies.   J Cereb Blood Flow Metab 28: 3. 579-587 Mar  
Abstract: A single-tissue compartment model with plasma input is the established method for analysing [(11)C]flumazenil ([(11)C]FMZ) studies. However, arterial cannulation and measurement of metabolites are time-consuming. Therefore, a reference tissue approach is appealing, but this approach has not been fully validated for [(11)C]FMZ. Dynamic [(11)C]FMZ positron emission tomography scans with arterial blood sampling were performed in nine drug-free depressive patients and eight healthy subjects. Regions of interest were defined on co-registered magnetic resonance imaging scans and projected onto dynamic [(11)C]FMZ images. Using a Hill-type metabolite function, single (1T) and reversible two-tissue (2T) compartmental models were compared. Simplified reference tissue model (SRTM) and full reference tissue model (FRTM) were investigated using both pons and (centrum semiovale) white matter as reference tissue. The 2T model provided the best fit in 59% of cases. Two-tissue V(T) values were on average 1.6% higher than 1T V(T) values. Owing to the higher rejection rate of 2T fits (7.3%), the 1T model was selected as plasma input method of choice. SRTM was superior to FRTM, irrespective whether pons or white matter was used as reference tissue. BP(ND) values obtained with SRTM correlated strongly with 1T V(T) (r=0.998 and 0.995 for pons and white matter, respectively). Use of white matter as reference tissue resulted in 5.5% rejected fits, primarily in areas with intermediate receptor density. No fits were rejected using pons as reference tissue. Pons produced 23% higher BP(ND) values than white matter. In conclusion, for most clinical studies, SRTM with pons as reference tissue can be used for quantifying [(11)C]FMZ binding.
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Jurgen E M Mourik, Mark Lubberink, Ursula M H Klumpers, Emile F Comans, Adriaan A Lammertsma, Ronald Boellaard (2008)  Partial volume corrected image derived input functions for dynamic PET brain studies: methodology and validation for [11C]flumazenil.   Neuroimage 39: 3. 1041-1050 Feb  
Abstract: Extraction of arterial input functions from dynamic brain scans may obviate the need for arterial sampling and would increase the clinical applicability of quantitative PET studies. The aim of the present study was to evaluate applicability and accuracy of image derived input functions (IDIFs) following reconstruction based partial volume correction (PVC). Settings for the PVC ordered subset expectation maximization (PVC-OSEM) reconstruction algorithm were varied. In addition, different methods for defining arterial regions of interest (ROI) in order to extract IDIFs were evaluated. [(11)C]flumazenil data of 10 subjects were used in the present study. Results obtained with IDIFs were compared with those using standard on-line measured arterial input functions. These included areas under the curve (AUC) for peak (1-2 min) and tail (2-60 min), volume of distribution (V(T)) obtained using Logan analysis, and V(T) and K(1) obtained with a basis function implementation of a single tissue compartment model. Best results were obtained with PVC-OSEM using 4 iterations and 16 subsets. Based on (11)C point source measurements, a 4.5 mm FWHM (full width at half maximum) resolution kernel was used to correct for partial volume effects. A ROI consisting of the four hottest pixels per plane (over the carotid arteries) was the best method to extract IDIFs. Excellent peak AUC ratios (0.99+/-0.09) between IDIF and blood sampler input function (BSIF) were found. Furthermore, extracted IDIFs provided V(T) and K(1) values that were very similar to those obtained using BSIFs. The proposed method appears to be suitable for analysing [(11)C]flumazenil data without the need for online arterial sampling.
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Marinke Westerterp, Gerrit W Sloof, Otto S Hoekstra, Fiebo J W Ten Kate, Gerrit A Meijer, Johannes B Reitsma, Ronald Boellaard, J Jan B van Lanschot, Carla F M Molthoff (2008)  18FDG uptake in oesophageal adenocarcinoma: linking biology and outcome.   J Cancer Res Clin Oncol 134: 2. 227-236 Feb  
Abstract: PURPOSE: Variable uptake of 18FDG has been noticed in positron emission tomography (PET) studies of patients with oesophageal adenocarcinoma. The aim of the present study was to investigate biological parameters involved in 18FDG uptake in oesophageal adenocarcinoma for selection of patients with increased 18FDG uptake and prediction of prognostic value of 18FDG PET. PATIENTS AND METHODS: Preoperative PET scans were performed in 26 patients with histologically proven oesophageal adenocarcinoma. 18FDG uptake was semiquantitatively measured by SUV(BSAg. )Tumour sections were stained by immunohistochemistry for angiogenic markers (VEGF, CD31), glucose transporter-1 (Glut-1), hexokinase (HK) isoforms, for proliferation marker (Ki67), for macrophage marker (CD68) and for apoptosis marker (cleaved caspase-3). Cell densities, differentiation grade, degree of necrosis and mucus, T-stage and tumour size were assessed. In addition follow-up was analysed. RESULTS: No association was found between 18FDG uptake and angiogenic markers. In contrast, a significant correlation was found between 18FDG uptake and Glut-1 expression. No correlations were found between 18FDG uptake and HK isoforms, Ki67 or cleaved caspase-3. Also, no correlations were found between 18FDG uptake and cell density, differentiation grade, CD68, mucus and necrosis. However, there was a significant correlation between 18FDG uptake and tumour size and between 18FDG uptake and tumour recurrence. CONCLUSIONS: Glut-1 expression and tumour size seem parameters associated with 18FDG uptake in patients with biopsy proven oesophageal adenocarcinoma, and may be used to select oesophageal cancer patients in whom 18FDG-PET is of diagnostic value and may predict disease outcome.
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J M T Omloo, G W Sloof, R Boellaard, O S Hoekstra, P L Jager, H M van Dullemen, P Fockens, J T M Plukker, J J B van Lanschot (2008)  Importance of fluorodeoxyglucose-positron emission tomography (FDG-PET) and endoscopic ultrasonography parameters in predicting survival following surgery for esophageal cancer.   Endoscopy 40: 6. 464-471 Jun  
Abstract: BACKGROUND AND STUDY AIMS: To assess the prognostic importance of standardized uptake value (SUV) for 18F-fluorodeoxyglucose (FDG) at positron emission tomography (PET) and of EUS parameters, in esophageal cancer patients primarily treated by surgery. PATIENTS AND METHODS: Between October 2002 and August 2004 a prospective cohort study involved 125 patients, with histologically proven cancer of the esophagus, without evidence of distant metastases or locally irresectable disease based on extensive preoperative work-up, and fit to undergo major surgery. Follow-up was complete until October 2006, ensuring a minimal potential follow-up of 25 months. RESULTS: The median SUV was 0.27 (interquartile range 0.13 - 0.45), and was used as cutoff value between high (n = 62) and low (n = 63) SUV. Patients with a high SUV had a significantly worse disease-specific survival compared with patients with a low SUV (P = 0.04). Tumor location (P = 0.005), EUS T stage (P < 0.001), EUS N stage (P = 0.006) and clinical stage (P < 0.006) were also associated with disease-specific survival. However, in multivariate analysis only EUS T stage appeared to be of independent prognostic significance (P = 0.007). CONCLUSION: In esophageal cancer patients, EUS T stage, EUS N stage, location and SUV of the primary tumor are pretreatment factors that are associated with disease-specific survival. However, only EUS T stage is an independent prognostic factor.
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Adrianus J de Langen, Mark Lubberink, Ronald Boellaard, Marieke D Spreeuwenberg, Egbert F Smit, Otto S Hoekstra, Adriaan A Lammertsma (2008)  Reproducibility of tumor perfusion measurements using 15O-labeled water and PET.   J Nucl Med 49: 11. 1763-1768 Nov  
Abstract: PET and 15O-labeled water (H215O) can be used to noninvasively monitor tumor perfusion. This allows evaluation of the direct target of antiangiogenic drugs, that is, tumor vasculature. Because these drugs often result in consolidation rather than regression of the tumor mass, a change in perfusion might be a more sensitive way to evaluate response than are indirect size measures on a CT scan. However, to use the technique for serial imaging of individual patients, good reproducibility is essential. The purpose of the present study was to evaluate the reproducibility of quantitative H215O measurements. METHODS: Nine patients with non-small-cell lung cancer (NSCLC) were scanned twice within 7 d and before any therapy. All H215O scans were followed by an 18F-fluorothymidine scan to allow for adequate volume-of-interest (VOI) definition. VOIs were defined using a 3-dimensional threshold technique. Tumor perfusion and the volume of distribution (VT) were obtained using a 1-tissue-compartment model including an arterial blood volume component and an image-derived input function. The level of agreement between test and retest values was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman analyses. Possible dependency on absolute values and lesion size was assessed by linear regression. RESULTS: All primary tumors and more than 90% of clinically suspected locoregional metastases could be delineated. In total, 14 lesions in 9 patients were analyzed. Tumor perfusion showed excellent reproducibility, with an ICC of 0.95 and SD of 9%. The VT was only moderately reproducible, with an ICC of 0.52 and SD of 16%. No dependency was found on absolute values of perfusion (P = 0.14) and VT (P = 0.15). In addition, tumor volume did not influence the reproducibility of perfusion (P = 0.46) and VT (P = 0.25). CONCLUSION: Quantitative measurements of tumor perfusion using H215O and PET are reproducible in NSCLC. When patients are repeatedly being scanned during therapy, changes of more than 18% in tumor perfusion and 32% in VT (>1.96 x SD) are likely to represent treatment effects.
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Conny J van der Laken, Ernst H Elzinga, Mark A Kropholler, Carla F M Molthoff, Joost W van der Heijden, Kaoru Maruyama, Ronald Boellaard, Ben A C Dijkmans, Adriaan A Lammertsma, Alexandre E Voskuyl (2008)  Noninvasive imaging of macrophages in rheumatoid synovitis using 11C-(R)-PK11195 and positron emission tomography.   Arthritis Rheum 58: 11. 3350-3355 Nov  
Abstract: OBJECTIVE: Noninvasive imaging by positron emission tomography (PET) of macrophages in inflamed joints of patients with rheumatoid arthritis (RA) may allow early detection of disease activity. We undertook this study to investigate whether rheumatoid synovitis can be visualized by PET using the tracer 11C-(R)-PK11195, which binds to peripheral benzodiazepine receptors (PBRs) on macrophages. METHODS: Knee joints of 11 RA patients with active arthritis of at least 1 knee joint were imaged with 11C-(R)-PK11195 PET. Tissue uptake of 11C-(R)-PK11195 was quantified. PET was followed by arthroscopy of the most inflamed knee joint of each RA patient. Synovial tissue samples were subjected to immunohistochemical staining. RESULTS: 11C-(R)-PK11195 uptake on the PET scans was significantly higher in severely inflamed joints than in joints with moderate or mild signs of inflammation. In addition, tracer uptake in contralateral uninflamed knee joints of RA patients was significantly higher than in uninflamed joints of control patients without inflammatory joint disease, suggesting the presence of subclinical disease activity. PET tracer uptake in joints correlated significantly with PBR staining in the sublining of synovial tissue. PBR staining correlated significantly with CD68 staining of macrophages. CONCLUSION: 11C-(R)-PK11195 PET imaging allows noninvasive in vivo imaging of macrophages in rheumatoid synovitis and possibly even in subclinical synovitis. Noninvasive visualization of macrophages may be useful both for detecting early synovitis and for monitoring synovitis activity during treatment.
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Maqsood Yaqub, Nelleke Tolboom, Ronald Boellaard, Bart N M van Berckel, Erica W van Tilburg, Gert Luurtsema, Philip Scheltens, Adriaan A Lammertsma (2008)  Simplified parametric methods for [11C]PIB studies.   Neuroimage 42: 1. 76-86 Aug  
Abstract: The purpose of the present study was to evaluate the performance of various parametric reference tissue models for quantification of [11C]PIB studies. Several models with and without fixing the reference tissue efflux rate constant (k'(2)) were investigated using both simulations and clinical data. The following parametric methods were evaluated: receptor parametric mapping (basis function implementation of the simplified reference tissue model with and without fixed k'(2)), reference Logan, and several multi-linear reference tissue methods (again with and without fixed k'(2)). In addition, standardised uptake value ratios with cerebellum (SUV(r)) were evaluated. Simulations were used to assess the effects of variation in flow (R(1)), fractional blood volume (V(b)) and binding potential (BP(ND)) itself on precision and accuracy of parametric BP(ND). For clinical studies, most parametric methods showed comparable performance, with poorest results for SUV(r). Best performance was obtained for receptor parametric mapping (RPM2) and one of the multi-linear reference tissue models (MRTM2), both with fixed k'(2): BP(ND) outcome was less affected by noise and the images showed better contrast than other tested methods. RPM2 and MRTM2 also provided best accuracy and precision in the simulation studies and are therefore the methods of choice for parametric analysis of clinical [11C]PIB studies.
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Maqsood Yaqub, Ronald Boellaard, Alie Schuitemaker, Bart N M van Berckel, Adriaan A Lammertsmae (2008)  Impact of wavelet based denoising of [11C](R)-PK11195 time activity curves on accuracy and precision of kinetic analysis.   Med Phys 35: 11. 5069-5078 Nov  
Abstract: The purpose of the present study was to investigate the use of various wavelets based techniques for denoising of [11C](R)-PK11195 time activity curves (TACs) in order to improve accuracy and precision of PET kinetic parameters, such as volume of distribution (V(T)) and distribution volume ratio with reference region (DVR). Simulated and clinical TACs were filtered using two different categories of wavelet filters: (1) wave shrinking thresholds using a constant or a newly developed time varying threshold and (2) "statistical" filters, which filter extreme wavelet coefficients using a set of "calibration" TACs. PET pharmacokinetic parameters were estimated using linear models (plasma Logan and reference Logan analyses). For simulated noisy TACs, optimized wavelet based filters improved the residual sum of squared errors with the original noise free TACs. Furthermore, both clinical results and simulations were in agreement. Plasma Logan V(T) values increased after filtering, but no differences were seen in reference Logan DVR values. This increase in plasma Logan V(T) suggests a reduction of noise induced bias by wavelet based denoising, as was seen in the simulations. Wavelet denoising of TACs for [11C](R)-PK11195 PET studies is therefore useful when parametric Logan based V(T) is the parameter of interest.
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Jurgen E M Mourik, Floris H P van Velden, Mark Lubberink, Reina W Kloet, Bart N M van Berckel, Adriaan A Lammertsma, Ronald Boellaard (2008)  Image derived input functions for dynamic High Resolution Research Tomograph PET brain studies.   Neuroimage 43: 4. 676-686 Dec  
Abstract: The High Resolution Research Tomograph (HRRT) is a dedicated human brain positron emission tomography (PET) scanner. The aim of the present study was to validate the use of image derived input functions (IDIF) as an alternative for arterial sampling for HRRT human brain studies. To this end, IDIFs were extracted from 3D ordinary Poisson ordered subsets expectation maximization (OP-OSEM) and reconstruction based partial volume corrected (PVC) OP-OSEM images. IDIFs, either derived directly from regions of interest or further calibrated using manual samples taken during scans, were evaluated for dynamic [(11)C]flumazenil data (n=6). Results obtained with IDIFs were compared with those obtained using blood sampler input functions (BSIF). These comparisons included areas under the curve (AUC) for peak (0-3.3 min) and tail (3.3-55.0 min). In addition, slope, intercept and Pearson's correlation coefficient of tracer kinetic analysis results based on IDIF and BSIF were calculated for each subject. Good peak AUC ratios (0.83+/-0.21) between IDIF and BSIF were found for calibrated IDIFs extracted from OP-OSEM images. This combination of IDIFs and images also provided good slope values (1.07+/-0.11). Improved resolution, as obtained with PVC OP-OSEM, changed AUC ratios to 1.14+/-0.35 and, for tracer kinetic analysis, slopes changed to 0.95+/-0.13. For all reconstructions, non-calibrated IDIFs gave poorer results (>61+/-34% higher slopes) compared with calibrated IDIFs. The results of this study indicate that the use of IDIFs, extracted from OP-OSEM or PVC OP-OSEM images, is feasible for dynamic HRRT data, thereby obviating the need for online arterial sampling.
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Floris H P van Velden, Reina W Kloet, Bart N M van Berckel, Carla F M Molthoff, Adriaan A Lammertsma, Ronald Boellaard (2008)  Gap filling strategies for 3-D-FBP reconstructions of High-Resolution Research Tomograph scans.   IEEE Trans Med Imaging 27: 7. 934-942  
Abstract: The High-Resolution Research Tomograph (HRRT) is a dedicated human brain positron emission tomography scanner. Currently available iterative reconstruction algorithms show bias due to nonnegativity constraints. Consequently, implementation of 3-D filtered backprojection (3-D-FBP) is of interest. To apply 3-D-FBP all missing data including those due to gaps between detector heads need to be estimated. The aim of this study was to evaluate various gap filling strategies for 3-D-FBP reconstructions of HRRT data, such as linear and bilinear interpolation or constraint Fourier space gap filling (confosp). Furthermore, missing planes were estimated using segment 0 image data only (noniterative) or by using reconstructed images based on all previous segments (iterative method). Use of bilinear interpolation showed worst correspondence between reconstructed and true activity concentration, especially for small structures. Moreover, phantom data indicated that use of linear interpolation resulted in artifacts in planes located near the edge of the field-of-view. Use of confosp did not show these artifacts. Iterative estimations of the missing planes for |segments| 0 improved image quality at the cost of more computation time. Therefore, use of confosp for filling sinogram gaps with both iterative and noniterative estimation of missing planes are recommended for quantitative 3-D-FBP of HRRT studies.
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Ronald Boellaard, Wim J G Oyen, Corneline J Hoekstra, Otto S Hoekstra, Eric P Visser, Antoon T Willemsen, Bertjan Arends, Fred J Verzijlbergen, Josee Zijlstra, Anne M Paans, Emile F I Comans, Jan Pruim (2008)  The Netherlands protocol for standardisation and quantification of FDG whole body PET studies in multi-centre trials.   Eur J Nucl Med Mol Imaging 35: 12. 2320-2333 Dec  
Abstract: INTRODUCTION: Several studies have shown the usefulness of positron emission tomography (PET) quantification using standardised uptake values (SUV) for diagnosis and staging, prognosis and response monitoring. Many factors affect SUV, such as patient preparation procedures, scan acquisition, image reconstruction and data analysis settings, and the variability in methodology across centres prohibits exchange of SUV data. Therefore, standardisation of 2-[(18)F] fluoro-2-deoxy-D-glucose (FDG) PET whole body procedures is required in multi-centre trials. METHODS: A protocol for standardisation of quantitative FDG whole body PET studies in the Netherlands (NL) was defined. This protocol is based on standardisation of: (1) patient preparation; (2) matching of scan statistics by prescribing dosage as function of patient weight, scan time per bed position, percentage of bed overlap and image acquisition mode (2D or 3D); (3) matching of image resolution by prescribing reconstruction settings for each type of scanner; (4) matching of data analysis procedure by defining volume of interest methods and SUV calculations and; (5) finally, a multi-centre QC procedure is defined using a 20-cm diameter phantom for verification of scanner calibration and the NEMA NU 2 2001 Image Quality phantom for verification of activity concentration recoveries (i.e., verification of image resolution and reconstruction convergence). DISCUSSION: This paper describes a protocol for standardization of quantitative FDG whole body multi-centre PET studies. CONCLUSION: The protocol was successfully implemented in the Netherlands and has been approved by the Netherlands Society of Nuclear Medicine.
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Mark van Heijl, Jikke Mt Omloo, Mark I van van Henegouwen, Olivier Rc Busch, Hugo W Tilanus, Patrick Mm Bossuyt, Otto S Hoekstra, Jaap Stoker, Maarten Ccm Hulshof, Ate van der Gaast, Grard Ap Nieuwenhuijzen, Han J Bonenkamp, John Thm Plukker, Ernst J Spillenaar Bilgen, Fibo Jw Ten Kate, Ronald Boellaard, Jan Pruim, Gerrit W Sloof, J Jan B van Lanschot (2008)  NEOadjuvant therapy monitoring with PET and CT in Esophageal Cancer (NEOPEC-trial).   BMC Med Phys 8: 07  
Abstract: ABSTRACT: BACKGROUND: Surgical resection is the preferred treatment of potentially curable esophageal cancer. To improve long term patient outcome, many institutes apply neoadjuvant chemoradiotherapy. In a large proportion of patients no response to chemoradiotherapy is achieved. These patients suffer from toxic and ineffective neoadjuvant treatment, while appropriate surgical therapy is delayed. For this reason a diagnostic test that allows for accurate prediction of tumor response early during chemoradiotherapy is of crucial importance. CT-scan and endoscopic ultrasound have limited accuracy in predicting histopathologic tumor response. Data suggest that metabolic changes in tumor tissue as measured by FDG-PET predict response better. This study aims to compare FDG-PET and CT-scan for the early prediction of non-response to preoperative chemoradiotherapy in patients with potentially curable esophageal cancer. METHODS/DESIGN: Prognostic accuracy study, embedded in a randomized multicenter Dutch trial comparing neoadjuvant chemoradiotherapy for 5 weeks followed by surgery versus surgery alone for esophageal cancer. This prognostic accuracy study is performed only in the neoadjuvant arm of the randomized trial. In 6 centers, 150 consecutive patients will be included over a 3 year period. FDG-PET and CT-scan will be performed before and 2 weeks after the start of the chemoradiotherapy. All patients complete the 5 weeks regimen of neoadjuvant chemoradiotherapy, regardless the test results. Pathological examination of the surgical resection specimen will be used as reference standard. Responders are defined as patients with < 10% viable residual tumor cells (Mandard-score).Difference in accuracy (area under ROC curve) and negative predictive value between FDG-PET and CT-scan are primary endpoints. Furthermore, an economic evaluation will be performed, comparing survival and costs associated with the use of FDG-PET (or CT-scan) to predict tumor response with survival and costs of neoadjuvant chemoradiotherapy without prediction of response (reference strategy). DISCUSSION: The NEOPEC-trial could be the first sufficiently powered study that helps justify implementation of FDG-PET for response-monitoring in patients with esophageal cancer in clinical practice. TRIAL REGISTRATION: ISRCTN45750457.
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Hugo W A M de Jong, Floris H P van Velden, Reina W Kloet, Fred L Buijs, Ronald Boellaard, Adriaan A Lammertsma (2007)  Performance evaluation of the ECAT HRRT: an LSO-LYSO double layer high resolution, high sensitivity scanner.   Phys Med Biol 52: 5. 1505-1526 Mar  
Abstract: The ECAT high resolution research tomograph (HRRT) is a dedicated brain and small animal PET scanner, with design features that enable high image spatial resolution combined with high sensitivity. The HRRT is the first commercially available scanner that utilizes a double layer of LSO/LYSO crystals to achieve photon detection with depth-of-interaction information. In this study, the performance of the commercial LSO/LYSO HRRT was characterized, using the NEMA protocol as a guideline. Besides measurement of spatial resolution, energy resolution, sensitivity, scatter fraction, count rate performance, correction for attenuation and scatter, hot spot recovery and image quality, a clinical evaluation was performed by means of a HR+/HRRT human brain comparison study. Point source resolution varied across the field of view from approximately 2.3 to 3.2 mm (FWHM) in the transaxial direction and from 2.5 to 3.4 mm in the axial direction. Absolute line-source sensitivity ranged from 2.5 to 3.3% and the NEMA-2001 scatter fraction equalled 45%. Maximum NECR was 45 kcps and 148 kcps according to the NEMA-2001 and 1994 protocols, respectively. Attenuation and scatter correction led to a volume uniformity of 6.3% and a system uniformity of 3.1%. Reconstructed values deviated up to 15 and 8% in regions with high and low densities, respectively, which can possibly be assigned to inaccuracies in scatter estimation. Hot spot recovery ranged from 60 to 94% for spheres with diameters of 1 to 2.2 cm. A high quantitative agreement was met between HR+ and HRRT clinical data. In conclusion, the ECAT HRRT has excellent resolution and sensitivity properties, which is a crucial advantage in many research studies.
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Maqsood Yaqub, Ronald Boellaard, Bart N M van Berckel, Mirthe M Ponsen, Mark Lubberink, Albert D Windhorst, Henk W Berendse, Adriaan A Lammertsma (2007)  Quantification of dopamine transporter binding using [18F]FP-beta-CIT and positron emission tomography.   J Cereb Blood Flow Metab 27: 7. 1397-1406 Jul  
Abstract: The purpose of this study was to compare different kinetic and semi-quantitative methods for analysing human [18F]FP-beta-CIT studies: plasma input models, simplified (SRTM) and full (FRTM) reference tissue models, standard uptake values (SUV) and SUV ratios (SUVr). Both simulations and clinical evaluations were performed to determine the effects of noise, scan duration and blood volume on Akaike model selection, and on precision and accuracy of estimated parameters. For typical noise levels (COV approximately 2.5%) and scan durations (<90 mins), simulations provided poor fits (Akaike criterion) in case of reversible plasma input models showing a relatively high number of outliers compared with the two-tissue irreversible model. Reference tissue models provided more reliable fits, which were nearly independent of noise and scan duration. For clinical data, two tissue irreversible and reversible plasma input models fitted striatum curves equally well (Akaike criterion). BP with plasma input models were less precise and contained more outliers than BP obtained with SRTM or FRTM. Among all methods tested, SRTM showed the highest contrast between patients and controls. When differentiating between patients and controls, SUVr performed almost equally well as SRTM, although contrast between striatum and background was lower. In conclusion, SRTM provided BP estimates with the highest precision and accuracy. Moreover, SRTM provided good contrast between patients and controls, and between striatum and background. SRTM is therefore the method of choice for quantitative [18F]FP-beta-CIT studies. SUVr might be an alternative for larger clinical trials.
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Marinke Westerterp, Jan Pruim, Wim Oyen, Otto Hoekstra, Anne Paans, Eric Visser, Jan van Lanschot, Gerrit Sloof, Ronald Boellaard (2007)  Quantification of FDG PET studies using standardised uptake values in multi-centre trials: effects of image reconstruction, resolution and ROI definition parameters.   Eur J Nucl Med Mol Imaging 34: 3. 392-404 Mar  
Abstract: PURPOSE: Standardised uptake values (SUVs) depend on acquisition, reconstruction and region of interest (ROI) parameters. SUV quantification in multi-centre trials therefore requires standardisation of acquisition and analysis protocols. However, standardisation is difficult owing to the use of different scanners, image reconstruction and data analysis software. In this study we evaluated whether SUVs, obtained at three different institutes, may be directly compared after calibration and correction for inter-institute differences. METHODS: First, an anthropomorphic thorax phantom containing variously sized spheres and activities, simulating tumours, was scanned and processed in each institute to evaluate differences in scanner calibration. Secondly, effects of image reconstruction and ROI method on recovery coefficients were studied. Next, SUVs were derived for tumours in 23 subjects. Of these 23 patients, four and ten were scanned in two institutes on an HR+ PET scanner and nine were scanned in one institute on an ECAT EXACT PET scanner. All phantom and clinical data were reconstructed using iterative reconstruction with various iterations, with both measured (MAC) and segmented attenuation correction (SAC) and at various image resolutions. Activity concentrations (AC) or SUVs were derived using various ROI isocontours. RESULTS: Phantom data revealed differences in SUV quantification of up to 30%. After application-specific calibration, recovery coefficients obtained in each institute were equal to within 15%. Varying the ROI isocontour value resulted in a predictable change in SUV (or AC) for both phantom and clinical data. Variation of image resolution resulted in a predictable change in SUV quantification for large spheres/tumours (>5 cc) only. For smaller tumours (<2 cc), differences of up to 40% were found between high (7 mm) and low (10 mm) resolution images. Similar differences occurred when data were reconstructed with a small number of iterations. Finally, no significant differences between MAC and SAC reconstructed data were observed, except for tumours near the diaphragm. CONCLUSION: Standardisation of acquisition, reconstruction and ROI methods is preferred for SUV quantification in multi-centre trials. Small unavoidable differences in methodology can be accommodated by performing a phantom study to assess inter-institute correction factors.
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Alie Schuitemaker, Bart N M van Berckel, Marc A Kropholler, Reina W Kloet, Cees Jonker, Philip Scheltens, Adriaan A Lammertsma, Ronald Boellaard (2007)  Evaluation of methods for generating parametric (R-[11C]PK11195 binding images.   J Cereb Blood Flow Metab 27: 9. 1603-1615 Sep  
Abstract: Activated microglia can be visualised using (R)-[(11)C]PK11195 (1-[2-chlorophenyl]-N-methyl-N-[1-methyl-propyl]-3-isoquinoline carboxamide) and positron emission tomography (PET). In previous studies, various methods have been used to quantify (R)-[(11)C]PK11195 binding. The purpose of this study was to determine which parametric method would be best suited for quantifying (R)-[(11)C]PK11195 binding at the voxel level. Dynamic (R)-[(11)C]PK11195 scans with arterial blood sampling were performed in 20 healthy and 9 Alzheimer's disease subjects. Parametric images of both volume of distribution (V(d)) and binding potential (BP) were obtained using Logan graphical analysis with plasma input. In addition, BP images were generated using two versions of the basis function implementation of the simplified reference tissue model, two versions of Ichise linearisations, and Logan graphical analysis with reference tissue input. Results of the parametric methods were compared with results of full compartmental analysis using nonlinear regression. Simulations were performed to assess accuracy and precision of each method. It was concluded that Logan graphical analysis with arterial input function is an accurate method for generating parametric images of V(d). Basis function methods, one of the Ichise linearisations and Logan graphical analysis with reference tissue input provided reasonably accurate and precise estimates of BP. In pathological conditions with reduced flow rates or large variations in blood volume, the basis function method is preferred because it produces less bias and is more precise.
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Mark Lubberink, Gert Luurtsema, Bart N M van Berckel, Ronald Boellaard, Rolf Toornvliet, Albert D Windhorst, Eric J F Franssen, Adriaan A Lammertsma (2007)  Evaluation of tracer kinetic models for quantification of P-glycoprotein function using (R)-[11C]verapamil and PET.   J Cereb Blood Flow Metab 27: 2. 424-433 Feb  
Abstract: Diminished P-glycoprotein (P-gp)-mediated transport across the blood-brain barrier may play an important role in several neurodegenerative disorders. In previous studies, a racemic mixture of (R)-[(11)C]verapamil and (S)-[(11)C]verapamil has been used as tracer for assessing P-gp function using positron emission tomography (PET). Quantification, however, is compromised by potential differences in kinetics between these two isomers. The aim of the present study was to evaluate the kinetics of pure (R)-[(11)C]verapamil in humans and to develop a tracer kinetic model for the analysis of P-gp-mediated transport of (R)-[(11)C]verapamil, including the putative contribution of its radioactive metabolites. Dynamic (R)-[(11)C]verapamil PET scans of 10 male volunteers were analysed with various single- or two-tissue compartment models, with separate compartments for N-dealkylated and N-demethylated metabolites, assuming that either (R)-[(11)C]verapamil alone or (R)-[(11)C]verapamil and any combination of metabolites cross the BBB. In addition, six of the subjects underwent two (R)-[(11)C]verapamil scans to evaluate test-retest reliability. One hour after injection, 50% of total plasma radioactivity consisted of labelled metabolites. Most models fitted the data well and the analysis did not point to a definite 'best' model, with differences in optimal model between subjects. The lowest mean test-retest variability (2.9%) was found for a single-tissue model without any metabolite correction. Models with separate metabolite compartments lead to high test-retest variability. Assuming that differences in kinetics of (R)-[(11)C]verapamil and N-dealkylated metabolites are small, a one input, one-tissue model with correction for N-demethylated metabolites only leads to a good compromise between fit quality and test-retest variability.
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Marc A Kropholler, Ronald Boellaard, Bart N M van Berckel, Alie Schuitemaker, Reina W Kloet, Mark J Lubberink, Cees Jonker, Philip Scheltens, Adriaan A Lammertsma (2007)  Evaluation of reference regions for (R)-[(11)C]PK11195 studies in Alzheimer's disease and mild cognitive impairment.   J Cereb Blood Flow Metab 27: 12. 1965-1974 Dec  
Abstract: Inflammation in Alzheimer's disease (AD) may be assessed using (R)-[(11)C]PK11195 and positron emission tomography. Data can be analyzed using the simplified reference tissue model, provided a suitable reference region is available. This study evaluates various reference regions for analyzing (R)-[(11)C]PK11195 scans in patients with mild cognitive impairment (MCI) and probable AD. Healthy subjects (n=10, 30+/-10 years and n=10, 70+/-6 years) and patients with MCI (n=10, 74+/-6 years) and probable AD (n=9, 71+/-6 years) were included. Subjects underwent a dynamic three-dimensional (R)-[(11)C]PK11195 scan including arterial sampling. Gray matter, white matter, total cerebellum and cerebrum, and cluster analysis were evaluated as reference regions. Both plasma input binding potentials of these reference regions (BP(PLASMA)) and corresponding reference region input binding potentials of a target region (BP(SRTM)) were evaluated. Simulations were performed to assess cluster analysis performance at 5% to 15% coefficient of variation noise levels. Reasonable correlations for BP(PLASMA) (R(2)=0.52 to 0.94) and BP(SRTM) (R(2)=0.59 to 0.76) were observed between results using anatomic regions and cluster analysis. For cerebellum white matter, cerebrum white matter, and total cerebrum a considerable number of unrealistic BP(SRTM) values were observed. Cluster analysis did not extract a valid reference region in 10% of the scans. Simulations showed that potentially cluster analysis suffers from negative bias in BP(PLASMA). Most anatomic regions outperformed cluster analysis in terms of absence of both scan rejection and bias. Total cerebellum is the optimal reference region in this patient category.
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Koen M Marques, Paul Knaapen, Ronald Boellaard, Adriaan A Lammertsma, Nico Westerhof, Frans C Visser (2007)  Microvascular function in viable myocardium after chronic infarction does not influence fractional flow reserve measurements.   J Nucl Med 48: 12. 1987-1992 Dec  
Abstract: Fractional flow reserve (FFR) is an index of coronary stenosis severity. FFR is the ratio of hyperemic myocardial flow in the stenotic area to maximal flow in that same territory without stenosis and can be measured with a pressure wire. In patients with prior infarction, measuring FFR in infarct-related arteries may be different for 2 reasons: a smaller mass of viable myocardium depending on the stenotic infarct-related artery and greater microvascular resistance in the infarcted area than in the reference area. When microvascular resistance does not differ between the infarcted and the reference areas, FFR should equal relative flow reserve (RFR). RFR is the ratio of myocardial blood flow in the stenotic area to blood flow in a normally perfused reference area, at maximal hyperemia. H(2)(15)O PET measures myocardial flow within only the viable areas of an infarct and can be used to measure RFR. The present study assessed in patients with chronic myocardial infarction whether microvascular resistance in the infarct is different from that in the reference area. Therefore, the correlation between FFR and RFR using H(2)(15)O PET was studied. METHODS: In the catheterization laboratory, FFR was measured in the infarct-related artery and a reference coronary artery. The H(2)(15)O PET study and FFR measurements were performed on the same day in 22 patients. RESULTS: In 27 patients, the mean interval between the PET study and infarction was 3.3 y. Most patients had an anterior infarction, and the mean ejection fraction was 44%. The mean FFR and RFR values were 0.75 +/- 0.16 and 0.74 +/- 0.18, respectively. A significant correlation (r = 0.81; P < 0.0001) was found between FFR and RFR. The linear regression line was close to the line of identity. CONCLUSION: In patients with chronic myocardial infarction and a reduced ejection fraction, a good correlation was found between FFR measurements in the infarct-related artery and RFR. Because the linear regression line between FFR and RFR was close to the line of identity, one can conclude that microvascular resistance in the viable myocardium does not differ from that in the reference area.
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Arno P van der Weerdt, Ronald Boellaard, Frans C Visser, Adriaan A Lammertsma (2007)  Accuracy of 3D acquisition mode for myocardial FDG PET studies using a BGO-based scanner.   Eur J Nucl Med Mol Imaging 34: 9. 1439-1446 Sep  
Abstract: PURPOSE: The aim of the present study was to evaluate the quantitative and qualitative accuracy of 3D PET acquisitions for myocardial FDG studies. METHODS: Phantom studies were performed with both a homogeneous and an inhomogeneous phantom. Activity profiles were generated along the phantoms using 2D and several 3D reconstructions, varying the 3D scaling value to adjust the scatter correction algorithm. Furthermore, ten patients underwent a dynamic myocardial FDG PET scan, using an interleaved protocol consisting of frames with alternating 2D and 3D acquisition. For each myocardial study, 13 volumes of interest were defined, representing 13 myocardial segments. First, the optimal scaling value for the scatter correction algorithm was determined using data from the phantom and four patient studies. This scaling value was then applied to all ten patients. 2D and 3D acquisitions were compared for both static (i.e. activity concentrations in the last 2D and 3D frames) and dynamic imaging (calculation of the metabolic rate of glucose). RESULTS: For both phantom and patient studies, suboptimal results were obtained when the default scaling value for the scatter correction algorithm was used. After adjusting the scaling value, for all ten myocardial FDG studies, a very good correlation (r2=0.99) was obtained between 2D and 3D data. With the present protocol no significant differences were observed in qualitative interpretation. CONCLUSION: The 3D FDG acquisition mode is accurate and has clear advantages over the 2D mode for myocardial FDG studies. A prerequisite is, however, optimisation of the 3D scatter correction algorithm.
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Koen M Marques, Paul Knaapen, Ronald Boellaard, Nico Westerhof, Adriaan A Lammertsma, Cees A Visser, Frans C Visser (2007)  Hyperaemic microvascular resistance is not increased in viable myocardium after chronic myocardial infarction.   Eur Heart J 28: 19. 2320-2325 Oct  
Abstract: AIMS: The present study compared microvascular resistance (MR) of viable myocardium in infarct areas with those in reference areas in patients with chronic myocardial infarction (MI). METHODS AND RESULTS: In 27 patients, MR (ratio distal coronary pressure and flow) of reference and viable infarct areas was calculated at baseline and during hyperaemia. H2 15O positron emission tomography (PET) was used to provide myocardial blood flow measurements. In infarct regions, H2 15O PET solely measures flow in viable myocardium, excluding flow in scar tissue. Distal coronary pressure was measured with a pressure wire in the infarct-related and reference artery. The average time between PET study and infarction was 3.3+/-4.4 years. Mean hyperaemic distal coronary pressure was significantly lower in the infarct-related artery. MR varied considerably between patients and was significantly higher in infarct areas at baseline (135+/-38 vs. 118+/-29 mmHg mL min/mL; P<0.05), but not during hyperaemia (39+/-18 vs. 35+/-11 mmHg mL min/mL). The correlation between MR in infarct and reference areas was significant. CONCLUSION: To determine MR, distal coronary pressure measurements should be used. Hyperaemic MR in viable myocardium within the infarcted area is not higher when compared with the reference area. This supports the application of the established fractional flow reserve cut-off value in the setting of chronic MI.
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Alie Schuitemaker, Bart N M van Berckel, Marc A Kropholler, Dick J Veltman, Philip Scheltens, Cees Jonker, Adriaan A Lammertsma, Ronald Boellaard (2007)  SPM analysis of parametric (R)-[11C]PK11195 binding images: plasma input versus reference tissue parametric methods.   Neuroimage 35: 4. 1473-1479 May  
Abstract: (R)-[11C]PK11195 has been used for quantifying cerebral microglial activation in vivo. In previous studies, both plasma input and reference tissue methods have been used, usually in combination with a region of interest (ROI) approach. Definition of ROIs, however, can be labourious and prone to interobserver variation. In addition, results are only obtained for predefined areas and (unexpected) signals in undefined areas may be missed. On the other hand, standard pharmacokinetic models are too sensitive to noise to calculate (R)-[11C]PK11195 binding on a voxel-by-voxel basis. Linearised versions of both plasma input and reference tissue models have been described, and these are more suitable for parametric imaging. The purpose of this study was to compare the performance of these plasma input and reference tissue parametric methods on the outcome of statistical parametric mapping (SPM) analysis of (R)-[11C]PK11195 binding. Dynamic (R)-[11C]PK11195 PET scans with arterial blood sampling were performed in 7 younger and 11 elderly healthy subjects. Parametric images of volume of distribution (Vd) and binding potential (BP) were generated using linearised versions of plasma input (Logan) and reference tissue (Reference Parametric Mapping) models. Images were compared at the group level using SPM with a two-sample t-test per voxel, both with and without proportional scaling. Parametric BP images without scaling provided the most sensitive framework for determining differences in (R)-[11C]PK11195 binding between younger and elderly subjects. Vd images could only demonstrate differences in (R)-[11C]PK11195 binding when analysed with proportional scaling due to intersubject variation in K1/k2 (blood-brain barrier transport and non-specific binding).
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2006
 
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Pontus K E Börjesson, Yvonne W S Jauw, Ronald Boellaard, Remco de Bree, Emile F I Comans, Jan C Roos, Jonas A Castelijns, Maria J W D Vosjan, J Alain Kummer, C René Leemans, Adriaan A Lammertsma, Guus A M S van Dongen (2006)  Performance of immuno-positron emission tomography with zirconium-89-labeled chimeric monoclonal antibody U36 in the detection of lymph node metastases in head and neck cancer patients.   Clin Cancer Res 12: 7 Pt 1. 2133-2140 Apr  
Abstract: PURPOSE: Immuno-positron emission tomography (PET), the combination of PET with monoclonal antibodies (mAb), is an attractive option to improve tumor detection and to guide mAb-based therapy. The long-lived positron emitter zirconium-89 ((89)Zr) has ideal physical characteristics for immuno-PET with intact mAbs but has never been used in a clinical setting. In the present feasibility study, we aimed to evaluate the diagnostic imaging performance of immuno-PET with (89)Zr-labeled-chimeric mAb (cmAb) U36 in patients with squamous cell carcinoma of the head and neck (HNSCC), who were at high risk of having neck lymph node metastases. EXPERIMENTAL DESIGN: Twenty HNSCC patients, scheduled to undergo neck dissection with or without resection of the primary tumor, received 75 MBq (89)Zr coupled to the anti-CD44v6 cmAb U36 (10 mg). All patients were examined by computed tomography (CT) and/or magnetic resonance imaging (MRI) and immuno-PET before surgery. Six patients also underwent PET with (18)F-fluoro-2-deoxy-d-glucose. Immuno-PET scans were acquired up to 144 hours after injection. Diagnostic findings were recorded per neck side (left or right) as well as per lymph node level (six levels per side), and compared with histopathologic outcome. For this purpose, the CT/MRI scores were combined and the best of both scores was used for analysis. RESULTS: Immuno-PET detected all primary tumors (n = 17) as well as lymph node metastases in 18 of 25 positive levels (sensitivity 72%) and in 11 of 15 positive sides (sensitivity 73%). Interpretation of immuno-PET was correct in 112 of 121 operated levels (accuracy 93%) and in 19 of 25 operated sides (accuracy 76%). For CT/MRI, sensitivities of 60% and 73% and accuracies of 90% and 80% were found per level and side, respectively. In the six patients with seven tumor-involved neck levels and sides, immuno-PET and (18)F-fluoro-2-deoxy-d-glucose PET gave comparable diagnostic results. CONCLUSION: In this study, immuno-PET with (89)Zr-cmAb U36 performed at least as good as CT/MRI for detection of HNSCC lymph node metastases.
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Knaapen, Bondarenko, Beek, Götte, Boellaard, van der Weerdt, Visser, van Rossum, Lammertsma (2006)  Impact of Scar on Water-Perfusable Tissue Index in Chronic Ischemic Heart Disease : Evaluation with PET and Contrast-Enhanced MRI.   Mol Imaging Biol Apr  
Abstract: BACKGROUND: The water-perfusable tissue index (PTI) is assumed to differentiate viable myocardium from scar tissue, but histological comparisons in humans are lacking. The present study compares PTI with delayed contrast-enhanced magnetic resonance imaging (DCE-MRI), a validated marker of fibrotic tissue, in patients with ischemic left ventricular (LV) dysfunction. In addition, the optimal PTI threshold for detection of myocardial viability was defined when DCE-MRI was taken as a reference. MATERIALS: Twenty patients with ischemic LV dysfunction were studied with positron emission tomography, using oxygen-15-labeled water and carbon monoxide as tracers, and DCE-MRI. RESULTS: Of the 200 analyzed segments, 112 demonstrated DCE and were subsequently divided in three subgroups according to the severity of enhancement. PTI was 1.04 +/- 0.21 in control segments and gradually decreased with increasing extent of DCE to 0.77 +/- 0.31 for segments with transmural enhancement (p < 0.001). However, PTI progressively underestimated infarct size with increasing quantities of scar tissue (r = 0.61, p < 0.01). A PTI cutoff value of 0.89 yielded the best diagnostic accuracy for detection of myocardial viability with sensitivity and specificity values of 75 and 77%, respectively. CONCLUSIONS: PTI is inversely related to the extent of scar tissue estimated by DCE-MRI in patients with chronic ischemic heart disease and LV dysfunction. However, with increasing quantities of scar tissue, PTI overestimates the extent of residual viable tissue. A PTI threshold of 0.89 yields the best diagnostic accuracy for viability detection.
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Ornella Rimoldi, Klaus P Schäfers, Ronald Boellaard, Federico Turkheimer, Lars Stegger, Marilyn P Law, Adriaan A Lammerstma, Paolo G Camici (2006)  Quantification of subendocardial and subepicardial blood flow using 15O-labeled water and PET: experimental validation.   J Nucl Med 47: 1. 163-172 Jan  
Abstract: The purpose of this study was to assess the feasibility and accuracy of quantifying subendocardial and subepicardial myocardial blood flow (MBF) and the relative coronary flow reserves (CFR) using (15)O-labeled water (H(2)(15)O) and 3-dimensional-only PET. METHODS: Eight pigs were scanned with H(2)(15)O and (15)O-labeled carbon monoxide (C(15)O) after partially occluding the circumflex (n = 3) or the left anterior descending (n = 5) coronary artery, both at rest and during hyperemia induced by intravenous dipyridamole. Radioactive microspheres were injected during each of the H(2)(15)O scans. RESULTS: In a total of 256 paired measurements of MBF, ranging from 0.30 to 4.46 mL.g(-1).min(-1), microsphere and PET MBF were fairly well correlated. The mean difference between the 2 methods was -0.01 +/- 0.52 mL.g(-1).min(-1) with 95% of the differences lying between the limits of agreement of -1.02 and 1.01 mL.g(-1).min(-1). CFR was significantly reduced (P < 0.05) in the ischemic subendocardium (PET = 1.12 +/- 0.45; microspheres = 1.09 +/- 0.50; P = 0.86) and subepicardium (PET = 1.2 +/- 0.35; microspheres = 1.32 +/- 0.5; P = 0.39) in comparison with remote subendocardium (PET = 1.7 +/- 0.62; microspheres = 1.64 +/- 0.61; P = 0.68) and subepicardium (PET = 1.79 +/- 0.73; microspheres = 2.19 +/- 0.86; P = 0.06). CONCLUSION: Dynamic measurements using H(2)(15)O and a 3-dimensional-only PET tomograph allow regional estimates of the transmural distribution of MBF over a wide flow range, although transmural flow differences were underestimated because of the partial-volume effect. PET subendocardial and subepicardial CFR were in good agreement with the microsphere values.
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Marc A Kropholler, Ronald Boellaard, Alie Schuitemaker, Hedy Folkersma, Bart N M van Berckel, Adriaan A Lammertsma (2006)  Evaluation of reference tissue models for the analysis of [11C](R)-PK11195 studies.   J Cereb Blood Flow Metab 26: 11. 1431-1441 Nov  
Abstract: [(11)C](R)-PK11195 is a marker of activated microglia, which can be used to measure inflammation in neurologic disorders. The purpose of the present study was to define the optimal reference tissue model based on a comparison with a validated plasma input model and using clinical studies and Monte Carlo simulations. Accuracy and reproducibility of reference tissue models were evaluated using Monte Carlo simulations. The effects of noise and variation in specific binding, nonspecific binding and blood volume were evaluated. Dynamic positron emission tomography scans were performed on 13 subjects, and radioactivity in arterial blood was monitored online. In addition, blood samples were taken to generate a metabolite corrected plasma input function. Both a (validated) two-tissue reversible compartment model with K(1)/k(2) fixed to whole cortex and various reference tissue models were fitted to the data. Finally, a simplified reference tissue model (SRTM) corrected for nonspecific binding using plasma input data (SRTM(pl_corr)) was investigated. Correlations between reference tissue models (including SRTM(pl_corr)) and the plasma input model were calculated. Monte Carlo simulations indicated that low-specific binding results in decreased accuracy and reproducibility. In this respect, the SRTM and SRTM(pl_corr) performed relatively well. Varying blood volume had no effect on performance. In the clinical evaluation, SRTM(pl_corr) and SRTM had the highest correlations with the plasma input model (R(2)=0.82 and 0.78, respectively). SRTM(pl_corr) is optimal when an arterial plasma input curve is available. Simplified reference tissue model is the best alternative when no plasma input is available.
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Paul Knaapen, Marco J W Götte, Walter J Paulus, Jaco J M Zwanenburg, Pieter A Dijkmans, Ronald Boellaard, J Tim Marcus, Jos W R Twisk, Cees A Visser, Albert C van Rossum, Adriaan A Lammertsma, Frans C Visser (2006)  Does myocardial fibrosis hinder contractile function and perfusion in idiopathic dilated cardiomyopathy? PET and MR imaging study.   Radiology 240: 2. 380-388 Aug  
Abstract: PURPOSE: To prospectively evaluate, by using positron emission tomography (PET) and magnetic resonance (MR) imaging, the interrelationships between regional myocardial fibrosis, perfusion, and contractile function in patients with idiopathic dilated cardiomyopathy (DCM). MATERIALS AND METHODS: The study protocol was approved by the hospital ethics committee, and all subjects gave written informed consent. Sixteen patients with idiopathic DCM (mean age, 54 years +/- 11 [standard deviation]; nine men) and six healthy control subjects (mean age, 28 years +/- 2; five men) were examined with PET and MR tissue tagging. Oxygen 15-labeled water and carbon monoxide were used as tracers at PET to assess myocardial blood flow (MBF) and the perfusable tissue index (PTI), which is inversely related to fibrosis. MBF was determined at rest and during pharmacologically induced hyperemia. Maximum circumferential shortening (E(cc)) was determined with MR tissue tagging. Student t tests were performed for comparison of data sets, and linear regression was used to investigate the association between parameters. RESULTS: Mean global hyperemic MBF (2.23 mL/min/mL +/- 0.73), E(cc) (-10.5% +/- 2.9), and PTI (0.95 +/- 0.10) were lower in the patients with DCM than in the control subjects (4.33 mL/min/mL +/- 0.85, -17.4% +/- 0.6, and 1.09 +/- 0.12, respectively; P < .05 for all). In the patients with DCM, regional PTI was related to E(cc) (r = -0.21, P = .009) but not to resting or hyperemic MBF. Furthermore, regional E(cc) was correlated to both resting (r = -0.28, P = .004) and hyperemic MBF (r = -0.29, P < .001). In addition, the ratio of left ventricular end-diastolic volume to mass, as a reflection of wall stress, was related to global hyperemic MBF (r = -0.52, P = .047) and to global E(cc) (r = 0.69, P = .003). CONCLUSION: In idiopathic DCM, the extent of myocardial fibrosis is related to the impairment in contractile function, whereas fibrosis and perfusion do not seem to be interrelated. The degree of impairment of hyperemic myocardial perfusion is related to contractility and end-diastolic wall stress.
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Marinke Westerterp, Jikke M T Omloo, Gerrit W Sloof, Maarten C C M Hulshof, Otto S Hoekstra, Hans Crezee, Ronald Boellaard, Walter L Vervenne, Fiebo J W ten Kate, Jan J B van Lanschot (2006)  Monitoring of response to pre-operative chemoradiation in combination with hyperthermia in oesophageal cancer by FDG-PET.   Int J Hyperthermia 22: 2. 149-160 Mar  
Abstract: PURPOSE: To evaluate the use of positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) to assess early response to pre-operative chemoradiation therapy in combination with external locoregional hyperthermia in patients with oesophageal cancer by correlating the reduction of metabolic activity with histopathologic response. MATERIAL AND METHODS: Twenty-six patients with histopathologically proven intra-thoracic oesophageal cancer (with < or =2 cm gastric involvement), scheduled to undergo a 5-week course of pre-operative chemoradiation therapy and hyperthermia, were included. FDG-PET was performed before (n = 26) and 2 weeks after initiation of therapy (n = 17). FDG uptake was quantitatively assessed by standardized uptake values. RESULTS: After neoadjuvant therapy, 24 of the 26 patients underwent surgery. In 16 patients changes in FDG uptake were correlated to histopathologic response. In these patients, histopathologic evaluation revealed less than 10% viable tumour cells in eight patients (responders) and more than 10% viable tumour cells in eight patients (non-responders). In responders, FDG uptake decreased by a median -44% (-75 to 2); in non-responders, it decreased by a median of -15% (-46 to 40). At a threshold of 31% decrease of FDG uptake compared with baseline, sensitivity to detect response was 75%, with a corresponding specificity of 75%. The positive and negative predictive values were both 75%. CONCLUSION: FDG-PET is a promising tool for early response monitoring in patients undergoing chemoradiation therapy in combination with hyperthermia.
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Maqsood Yaqub, Ronald Boellaard, Marc A Kropholler, Adriaan A Lammertsma (2006)  Optimization algorithms and weighting factors for analysis of dynamic PET studies.   Phys Med Biol 51: 17. 4217-4232 Sep  
Abstract: Positron emission tomography (PET) pharmacokinetic analysis involves fitting of measured PET data to a PET pharmacokinetic model. The fitted parameters may, however, suffer from bias or be unrealistic, especially in the case of noisy data. There are many optimization algorithms, each having different characteristics. The purpose of the present study was to evaluate (1) the performance of different optimization algorithms and (2) the effects of using incorrect weighting factors during optimization in terms of both accuracy and reproducibility of fitted PET pharmacokinetic parameters. In this study, the performance of commonly used optimization algorithms (i.e. interior-reflective Newton methods) and a simulated annealing (SA) method was evaluated. This SA algorithm, known as basin hopping, was modified for the present application. In addition, optimization was performed using various weighting factors. Algorithms and effects of using incorrect weighting factors were studied using both simulated and clinical time-activity curves (TACs). Input data, taken from [(15)O]H(2)O, [(11)C]flumazenil and [(11)C](R)-PK11195 studies, were used to simulate time-activity curves at various variance levels (0-15% COV). Clinical evaluation was based on studies with the same three tracers. SA was able to produce accurate results without the need for selecting appropriate starting values for (kinetic) parameters, in contrast to the interior-reflective Newton method. The latter gave biased results unless it was modified to allow for a range of starting values for the different parameters. For patient studies, where large variability is expected, both SA and the extended Newton method provided accurate results. Simulations and clinical assessment showed similar results for the evaluation of different weighting models in that small to intermediate mismatches between data variance and weighting factors did not significantly affect the outcome of the fits. Large errors were observed only when the mismatch between weighting model and data variance was large. It is concluded that selection of specific optimization algorithms and weighting factors can have a large effect on the accuracy and precision of PET pharmacokinetic analysis. Apart from carefully selecting appropriate algorithms and variance models, further improvement in accuracy might be obtained by using noise reducing strategies, such as wavelet filtering, provided that these methods do not introduce significant bias.
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Paul Knaapen, Olga Bondarenko, Aernout M Beek, Marco J W Götte, Ronald Boellaard, Arno P van der Weerdt, Cees A Visser, Albert C van Rossum, Adriaan A Lammertsma, Frans C Visser (2006)  Impact of scar on water-perfusable tissue index in chronic ischemic heart disease: Evaluation with PET and contrast-enhanced MRI.   Mol Imaging Biol 8: 4. 245-251 Jul/Aug  
Abstract: BACKGROUND: The water-perfusable tissue index (PTI) is assumed to differentiate viable myocardium from scar tissue, but histological comparisons in humans are lacking. The present study compares PTI with delayed contrast-enhanced magnetic resonance imaging (DCE-MRI), a validated marker of fibrotic tissue, in patients with ischemic left ventricular (LV) dysfunction. In addition, the optimal PTI threshold for detection of myocardial viability was defined when DCE-MRI was taken as a reference. MATERIALS: Twenty patients with ischemic LV dysfunction were studied with positron emission tomography, using oxygen-15-labeled water and carbon monoxide as tracers, and DCE-MRI. RESULTS: Of the 200 analyzed segments, 112 demonstrated DCE and were subsequently divided in three subgroups according to the severity of enhancement. PTI was 1.04 +/- 0.21 in control segments and gradually decreased with increasing extent of DCE to 0.77 +/- 0.31 for segments with transmural enhancement (p < 0.001). However, PTI progressively underestimated infarct size with increasing quantities of scar tissue (r = 0.61, p < 0.01). A PTI cutoff value of 0.89 yielded the best diagnostic accuracy for detection of myocardial viability with sensitivity and specificity values of 75 and 77%, respectively. CONCLUSIONS: PTI is inversely related to the extent of scar tissue estimated by DCE-MRI in patients with chronic ischemic heart disease and LV dysfunction. However, with increasing quantities of scar tissue, PTI overestimates the extent of residual viable tissue. A PTI threshold of 0.89 yields the best diagnostic accuracy for viability detection.
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2005
 
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Nanda C Krak, R Boellaard, Otto S Hoekstra, Jos W R Twisk, Corneline J Hoekstra, Adriaan A Lammertsma (2005)  Effects of ROI definition and reconstruction method on quantitative outcome and applicability in a response monitoring trial.   Eur J Nucl Med Mol Imaging 32: 3. 294-301 Mar  
Abstract: PURPOSE: Quantitative measurement of tracer uptake in a tumour can be influenced by a number of factors, including the method of defining regions of interest (ROIs) and the reconstruction parameters used. The main purpose of this study was to determine the effects of different ROI methods on quantitative outcome, using two reconstruction methods and the standard uptake value (SUV) as a simple quantitative measure of FDG uptake. METHODS: Four commonly used methods of ROI definition (manual placement, fixed dimensions, threshold based and maximum pixel value) were used to calculate SUV (SUV([MAN]), SUV15 mm, SUV50, SUV75 and SUVmax, respectively) and to generate "metabolic" tumour volumes. Test-retest reproducibility of SUVs and of "metabolic" tumour volumes and the applicability of ROI methods during chemotherapy were assessed. In addition, SUVs calculated on ordered subsets expectation maximisation (OSEM) and filtered back-projection (FBP) images were compared. RESULTS: ROI definition had a direct effect on quantitative outcome. On average, SUV[MAN), SUV15 mm, SUV50 and SUV75, were respectively 48%, 27%, 34% and 15% lower than SUVmax when calculated on OSEM images. No statistically significant differences were found between SUVs calculated on OSEM and FBP reconstructed images. Highest reproducibility was found for SUV15 mm and SUV[MAN] (ICC 0.95 and 0.94, respectively) and for "metabolic" volumes measured with the manual and 50% threshold ROIs (ICC 0.99 for both). Manual, 75% threshold and maximum pixel ROIs could be used throughout therapy, regardless of changes in tumour uptake or geometry. SUVs showed the same trend in relative change in FDG uptake after chemotherapy, irrespective of the ROI method used. CONCLUSION: The method of ROI definition has a direct influence on quantitative outcome. In terms of simplicity, user-independence, reproducibility and general applicability the threshold-based and fixed dimension methods are the best ROI methods. Threshold methods are in addition relatively independent of changes in size and geometry, however, and may therefore be more suitable for response monitoring purposes.
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Marc A Kropholler, Ronald Boellaard, Alie Schuitemaker, Bart N M van Berckel, Gert Luurtsema, Albert D Windhorst, Adriaan A Lammertsma (2005)  Development of a tracer kinetic plasma input model for (R)-[11C]PK11195 brain studies.   J Cereb Blood Flow Metab 25: 7. 842-851 Jul  
Abstract: (R)-[(11)C]PK11195 ([1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl]-3-isoquinoline carboxamide) is a ligand for the peripheral benzodiazepine receptor, which, in the brain, is mainly expressed on activated microglia. Using both clinical studies and Monte Carlo simulations, the aim of this study was to determine which tracer kinetic plasma input model best describes (R)-[(11)C]PK11195 kinetics. Dynamic positron emission tomography (PET) scans were performed on 13 subjects while radioactivity in arterial blood was monitored online. Discrete blood samples were taken to generate a metabolite corrected plasma input function. One-tissue, two-tissue irreversible, and two-tissue reversible compartment models, with and without fixing K(1)/k(2) ratio, k(4) or blood volume to whole cortex values, were fitted to the data. The effects of fixing parameters to incorrect values were investigated by varying them over a physiologic range and determining accuracy and reproducibility of binding potential and volume of distribution using Monte Carlo simulations. Clinical data showed that a two-tissue reversible compartment model was optimal for analyzing (R)-[(11)C]PK11195 PET brain studies. Simulations showed that fixing the K(1)/k(2) ratio of this model provided the optimal trade-off between accuracy and reproducibility. It was concluded that a two-tissue reversible compartment model with K(1)/k(2) fixed to whole cortex value is optimal for analyzing (R)-[(11)C]PK11195 PET brain studies.
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Paul Knaapen, Willem G van Dockum, Olga Bondarenko, Wouter E M Kok, Marco J W Götte, Ronald Boellaard, Aernout M Beek, Cees A Visser, Albert C van Rossum, Adriaan A Lammertsma, Frans C Visser (2005)  Delayed contrast enhancement and perfusable tissue index in hypertrophic cardiomyopathy: comparison between cardiac MRI and PET.   J Nucl Med 46: 6. 923-929 Jun  
Abstract: Delayed contrast enhancement (DCE) visualized by cardiac MRI (CMR) is a common feature in patients with hypertrophic cardiomyopathy (HCM), presumed to be related to myocardial fibrosis. The pathophysiologic basis of hyperenhancement in this patient group, however, remains unclear as limited histologic comparisons are available. The present study compares the perfusable tissue index (PTI), an alternative marker of myocardial fibrosis obtained by PET, with DCE-CMR in HCM. METHODS: Twenty-one patients with asymmetric septal HCM, 12 chronic myocardial infarction (MI) patients, and 6 age-matched healthy control subjects were studied with DCE-CMR and PET. PET was performed using (15)O-labeled water and carbon monoxide to obtain the PTI. RESULTS: No hyperenhancement was observed in control subjects and the PTI was within normal limits (1.10 +/- 0.07 [mean +/- SD]). In MI patients, the extent of hyperenhancement (25% +/- 16% [mean +/- SD]) was inversely related to the decrease in the PTI (0.94 +/- 0.12; r = -0.65, P < 0.05). Average hyperenhancement in HCM was 14% +/- 12%, predominantly located in the interventricular septum. The PTI in the hypertrophied interventricular septum, however, was not reduced (1.12 +/- 0.13). Furthermore, in contrast to MI patients, there was a modest positive correlation between the extent of DCE and the PTI in HCM (r = 0.45, P < 0.05). CONCLUSION: DCE in the hypertrophied septum of HCM patients is not accompanied by a decline in the PTI, and there is a positive correlation between the extent of DCE and the PTI. These results suggest that hyperenhancement may not be caused solely by fibrotic replacement scarring in this patient group. Other pathologic changes associated with HCM may also cause gadolinium-diethylenetriaminepentaacetic acid hyperenhancement.
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Gerben R Borst, José S A Belderbos, Ronald Boellaard, Emile F I Comans, Katrien De Jaeger, Adriaan A Lammertsma, Joos V Lebesque (2005)  Standardised FDG uptake: a prognostic factor for inoperable non-small cell lung cancer.   Eur J Cancer 41: 11. 1533-1541 Jul  
Abstract: The aim of this study was to investigate the relationship between standardised uptake value (SUV) obtained from [(18)F]fluorodeoxyglucose positron emission tomography (FDG PET) and treatment response/survival of inoperable non-small cell lung cancer (NSCLC) patients treated with high dose radiotherapy. Fifty-one patients were included recording stage, performance, weight loss, tumour volume, histology, lymph node involvement, SUV, and delivered radiation dose. The maximum SUV (SUV(max)) within the primary tumour was a sensitive and specific factor for predicting treatment response. Apart from SUV(max), stage and performance were also independent predictive factors for treatment response. In a multivariate disease-specific survival (DSS) analysis, SUV(max) (P = 0.01), performance status (P = 0.008) and stage (P = 0.04) were prognostic factors. For overall survival (OS), SUV(max) (P = 0.001) and performance (P = 0.06) were important prognostic factors. SUV(max) was an important prognostic factor for survival of inoperable NSCLC patients and a predictive factor for treatment response. Although the number of patients was small, the treatment was not homogeneous and the use of FDG SUV may have had constraints, we still conclude that the FDG SUV is potentially a good indicator for selecting patients for different treatment strategies.
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Lia C Liefaard, Bart A Ploeger, Carla F M Molthoff, Ronald Boellaard, Adriaan A Lammertsma, Meindert Danhof, Rob A Voskuyl (2005)  Population pharmacokinetic analysis for simultaneous determination of B (max) and K (D) in vivo by positron emission tomography.   Mol Imaging Biol 7: 6. 411-421 Nov/Dec  
Abstract: PURPOSE: Changes in GABA(A)-receptor density and affinity play an important role in many forms of epilepsy. A novel approach, using positron emission tomography (PET) and [C-11]flumazenil ([C-11]FMZ), was developed for simultaneous estimation of GABA(A)-receptor properties, characterized by B (max) and K (D). PROCEDURES: Following an injection of [C-11]FMZ (dose range: 1-2,000 mug) to 21 rats, concentration time curves of FMZ in brain (using PET) and blood (using HPLC-UV) were analyzed simultaneously using a population pharmacokinetic (PK) model, containing expressions to describe the time course of the plasma concentration (including distribution to the body), the brain distribution, and the specific binding within the brain. RESULTS: Application of this method in control rats resulted in estimates of B (max) and K (D) (14.5 +/- 3.7 ng/ml and 4.68 +/- 1.5 ng/ml, respectively). CONCLUSIONS: The proposed population PK model allowed for simultaneous estimation of B (max) and K (D) for a group of animals using single injection PET experiments per animal.
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Hadassa A Hofman, Paul Knaapen, Ronald Boellaard, Olga Bondarenko, Marco J W Götte, Willem G van Dockum, Cees A Visser, Albert C van Rossum, Adriaan A Lammertsma, Frans C Visser (2005)  Measurement of left ventricular volumes and function with O-15-labeled carbon monoxide gated positron emission tomography: comparison with magnetic resonance imaging.   J Nucl Cardiol 12: 6. 639-644 Nov/Dec  
Abstract: BACKGROUND: Positron emission tomography (PET) with inhaled oxygen 15-labeled carbon monoxide (CO) is used as a marker of myocardial blood pool. Only a limited number of studies with small numbers of patients have reported on the assessment of left ventricular (LV) volumes by use of O-15-labeled CO. The aim of this study was to compare LV volumes and function as measured by routinely acquired blood pool images by use of gated O-15-labeled CO PET with the reference technique, cardiovascular magnetic resonance imaging (MRI). METHODS AND RESULTS: Thirty-four subjects with a varying degree of LV function were studied. LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were determined by both MRI and gated PET by use of O-15-labeled CO. Volumes were comparable with respect to LVEDV (196 +/- 83 and 192 +/- 91 mL, respectively; P = not significant). LVESV, however, was slightly overestimated by PET (119 +/- 85 and 136 +/- 94 mL, respectively; P < .05), resulting in a significant underestimation of LVEF (44% +/- 19% and 35% +/- 18%, respectively; P < .05). Observed correlations for LVEDV, LVESV, and LVEF were 0.90, 0.96, and 0.86, respectively (all P < .01). CONCLUSIONS: Gated O-15-labeled CO PET measurements of LVEDV, LVESV, and LVEF show good correlation with MRI over a wide range of LV volumes during routinely acquired blood pool images. LVEF, however, may be underestimated compared with MRI.
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Ronald Boellaard, Paul Knaapen, Abraham Rijbroek, Gert J J Luurtsema, Adriaan A Lammertsma (2005)  Evaluation of basis function and linear least squares methods for generating parametric blood flow images using 15O-water and Positron Emission Tomography.   Mol Imaging Biol 7: 4. 273-285 Jul/Aug  
Abstract: PURPOSE: Parametric analysis of (15)O-water positron emission tomography (PET) studies allows determination of blood flow (BF), perfusable tissue fraction (PTF), and volume of distribution (V (d)) with high spatial resolution. In this paper the performance of basis function and linear least squares methods for generating parametric flow data were evaluated. PROCEDURES: Monte Carlo simulations were performed using typical perfusion values for brain, tumor, and heart. Clinical evaluation was performed using seven cerebral and 10 myocardial (15)O-water PET studies. Basis function (BFM), linear least squares (LLS), and generalized linear least squares (GLLS) methods were used to calculate BF, PTF, or V(d). RESULTS: Monte Carlo simulations and human studies showed that, for low BF values (<1 ml/min(-1)ml(-1), BF, PTF, and V(d) were calculated with accuracies better than 5% for all methods tested. For high BF (>2 ml/min(-1)ml(-1)), use of BFM provided more accurate V(d) compared with (G)LLS. CONCLUSIONS: In general, BFM provided the most accurate estimates of BF, PTF, and V(d).
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2004
 
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Henri N J M Greuter, Patricia L B van Ophemert, Gert Luurtsema, Eric J F Franssen, Ronald Boellaard, Adriaan A Lammertsma (2004)  Validation of a multiwell gamma-counter for measuring high-pressure liquid chromatography metabolite profiles.   J Nucl Med Technol 32: 1. 28-32 Mar  
Abstract: OBJECTIVES: The purpose of this study was to verify the accuracy and reproducibility of a multiwell counter to assess its suitability for use within human PET studies in which metabolizing (11)C tracers are used. Such tracers often require metabolite analysis for deriving plasma metabolite-corrected input curves. High-pressure liquid chromatography (HPLC) with on-line activity measurement is often unreliable for later plasma samples due to the poor sensitivity of the on-line activity detector. Fraction collector obtained HPLC samples that are counted in a separate high-sensitivity well counter can be an alternative to overcome poor counting statistics. METHODS: Several experiments to evaluate background counting, reproducibility, and linearity were performed to validate the accuracy, precision, and detection limits of the well counter. In addition, measurements on a series of samples resembling activity profiles as seen within human (11)C-flumazenil studies were performed to evaluate the performance of the well counter for clinically relevant data. RESULTS: The tests proved that the well counter detection limit, linearity, and reproducibility were more than sufficient in circumstances as seen during patient studies for samples with both high and low activity. CONCLUSION: The use of a multiwell counter is a good alternative for the on-line activity detector of the HPLC, allowing derivation of plasma metabolite fractions with high accuracy and reproducibility.
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Arno P van der Weerdt, Ronald Boellaard, Paul Knaapen, Cees A Visser, Adriaan A Lammertsma, Frans C Visser (2004)  Postinjection transmission scanning in myocardial 18F-FDG PET studies using both filtered backprojection and iterative reconstruction.   J Nucl Med 45: 2. 169-175 Feb  
Abstract: The aim of the present study was to evaluate the effect of postinjection transmission scanning (Post-Tx) on both the qualitative interpretation and the quantitative analysis of cardiac (18)F-FDG PET images. Furthermore, the accuracy of 2 different methods to correct for emission contamination was studied. An additional aim of this study was to compare images reconstructed with both standard filtered backprojection (FBP) and an iterative reconstruction algorithm (ordered-subset maximization expectation [OSEM]). METHODS: Sixteen patients underwent dynamic (18)F-FDG imaging. Both before injection of (18)F-FDG and after completing the emission scan, a 10-min transmission scan was performed (Pre-Tx and Post-Tx, respectively). Images were reconstructed using both FBP and OSEM. The emission study reconstructed with Pre-Tx was considered to be the gold standard. Emission studies were also reconstructed with Post-Tx, with and without correction for emission contamination. Correction for emission contamination was performed with either transmission image segmentation (TIS) or by estimating the emission bias from the last emission frame (dwell profile [DP] method). All images were then compared by calculating ratios of (18)F-FDG activity between corresponding myocardial segments in each patient. Furthermore, qualitative grading of (18)F-FDG uptake was compared between the studies. RESULTS: The mean ratio of (18)F-FDG activity between segments from FBP-Post and FBP-Pre was 0.78 +/- 0.08. When TIS and DP were used, the mean ratios were 0.80 +/- 0.07 and 0.94 +/- 0.06, respectively. The use of OSEM resulted in, on average, 2% lower values for (18)F-FDG activity as compared with FBP. The mean normalized (18)F-FDG uptake was higher in FBP-Post, especially in segments with decreased (18)F-FDG activity. Only in the case of DP were no significant differences observed as compared with FBP-Pre. In general, qualitative analysis of the images showed that the agreement between the reconstruction methods was comparable with the reproducibility of FBP-Pre. CONCLUSION: Post-Tx for attenuation correction in cardiac (18)F-FDG PET scans resulted in substantial underestimation of (18)F-FDG activity. More accurate results were obtained with correction for emission contamination using DP. Differences in visual assessment of (18)F-FDG images were small. Finally, iterative reconstruction could be used as an alternative to FBP in static (18)F-FDG imaging of the heart.
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Urvi Joshi, Otto S Hoekstra, Ronald Boellaard, Emile F I Comans, Pieter G H M Raijmakers, Rik J Pijpers, Steven D Miller, Gerrit J J Teule, Arthur van Lingen (2004)  Initial experience with a prototype dual-crystal (LSO/NaI) dual-head coincidence camera in oncology.   Eur J Nucl Med Mol Imaging 31: 4. 596-598 Apr  
Abstract: The aim of this study was to evaluate the in vivo performance of a prototype dual-crystal [lutetium oxyorthosilicate (LSO)/sodium iodide (NaI)] dual-head coincidence camera (DHC) for PET and SPET (LSO-PS), in comparison to BGO-PET with fluorine-18 fluorodeoxyglucose (FDG) in oncology. This follows earlier reports that LSO-PS has noise-equivalent counting (NEC) rates comparable to partial ring BGO-PET, i.e. clearly higher than standard NaI DHCs. Twenty-four randomly selected oncological patients referred for whole-body FDG-PET underwent BGO-PET followed by LSO-PS. Four nuclear medicine physicians were randomised to read a single scan modality, in terms of lesion intensity, location and likelihood of malignancy. BGO-PET was considered the gold standard. Forty-eight lesions were classified as positive with BGO-PET, of which LSO-PS identified 73% (95% CI 60-86%). There was good observer agreement for both modalities in terms of intensity, location and interpretation. Lesions were missed by LSO-PS in 13 patients in the chest ( n=6), neck ( n=3) and abdomen ( n=4). The diameter of these lesions was estimated to be 0.5-1 cm. Initial results justify further evaluation of LSO-PS in specific clinical situations, especially if a role as an instrument of triage for PET is foreseen.
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R Boellaard, A van Lingen, S C M van Balen, A A Lammertsma (2004)  Optimization of attenuation correction for positron emission tomography studies of thorax and pelvis using count-based transmission scans.   Phys Med Biol 49: 4. N31-N38 Feb  
Abstract: The quality of thorax and pelvis transmission scans and therefore of attenuation correction in PET depends on patient thickness and transmission rod source strength. The purpose of the present study was to assess the feasibility of using count-based transmission scans, thereby guaranteeing more consistent image quality and more precise quantification than with fixed transmission scan duration. First, the relation between noise equivalent counts (NEC) of 10 min calibration transmission scans and rod source activity was determined over a period of 1.5 years. Second, the relation between transmission scan counts and uniform phantom diameter was studied numerically, determining the relative contribution of counts from lines of response passing through the phantom as compared with the total number of counts. Finally, the relation between patient weight and transmission scan duration was determined for 35 patients, who were scanned at the level of thorax or pelvis. After installation of new rod sources, the NEC of transmission scans first increased slightly (5%) with decreasing rod source activity and after 3 months decreased with a rate of 2-3% per month. The numerical simulation showed that the number of transmission scan counts from lines of response passing through the phantom increased with phantom diameter up to 7 cm. For phantoms larger than 7 cm, the number of these counts decreased at approximately the same rate as the total number of transmission scan counts. Patient data confirmed that the total number of transmission scan counts decreased with increasing patient weight with about 0.5% kg(-1). It can be concluded that count-based transmission scans compensate for radioactive decay of the rod sources. With count-based transmission scans, rod sources can be used for up to 1.5 years at the cost of a 50% increased transmission scan duration. For phantoms with diameters of more than 7 cm and for patients scanned at the level of thorax or pelvis, use of count-based transmission scans is feasible and results in statistically more consistent transmission scans as compared with fixed transmission scan duration.
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Mark Lubberink, Ronald Boellaard, Arno P van der Weerdt, Frans C Visser, Adriaan A Lammertsma (2004)  Quantitative comparison of analytic and iterative reconstruction methods in 2- and 3-dimensional dynamic cardiac 18F-FDG PET.   J Nucl Med 45: 12. 2008-2015 Dec  
Abstract: The aim of this work was to compare the quantitative accuracy of iteratively reconstructed cardiac (18)F-FDG PET with that of filtered backprojection for both 2-dimensional (2D) and 3-dimensional (3D) acquisitions and to establish an optimal procedure for imaging myocardial viability with (18)F-FDG PET. METHODS: Eight patients underwent dynamic cardiac (18)F-FDG PET using an interleaved 2D/3D scan protocol, enabling comparison of 2D and 3D acquisitions within the same patient and study. A 10-min transmission scan was followed by a 10-min, 25-frame dynamic 3D scan and then by a series of 10 alternating 5-min 3D and 2D scans. Images were reconstructed with filtered backprojection (FBP) or attenuation-weighted ordered-subsets expectation maximization (OSEM), combined with Fourier rebinning (FORE) for 3D acquisitions, applying all usual corrections. Regions of interest (ROIs) were drawn in the myocardium, left ventricle, and ascending aorta, with the last 2 being used to define image-derived input functions (IDIFs). Patlak graphical analysis was used to compare net (18)F-FDG uptake in the myocardium, calculated from either 2D or 3D data, after reconstruction with FBP or OSEM. Either IDIFs or arterial sampling was used as the input function. The same analysis was performed on parametric images. RESULTS: A good correlation (r(2) > 0.99) was found between net (18)F-FDG uptake values for a myocardium ROI determined using each acquisition and reconstruction method and blood-sampling input functions. A similar result was found for parametric images. The ascending aorta was the best choice for IDIF definition. CONCLUSION: Good correlation and no bias of net (18)F-FDG uptake in relation to that based on FBP images, combined with less image noise, make 3D acquisition with FORE plus attenuation-weighted OSEM reconstruction the preferred choice for cardiac (18)F-FDG PET studies.
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Iris Verel, Gerard W M Visser, Maria J W D Vosjan, Ronald Finn, Ronald Boellaard, Guus A M S van Dongen (2004)  High-quality 124I-labelled monoclonal antibodies for use as PET scouting agents prior to 131I-radioimmunotherapy.   Eur J Nucl Med Mol Imaging 31: 12. 1645-1652 Dec  
Abstract: PURPOSE: Monoclonal antibodies (MAbs) labelled with 124I are an attractive option for quantitative imaging with positron emission tomography (PET) in a scouting procedure prior to 131I-radioimmunotherapy (131I-RIT). In this study, three important items in the labelling of MAbs with 124I were introduced to obtain optimal and reproducible product quality: restoration of radiation-induced inorganic deterioration of the starting 124I solution, radiation protection during and after 124I labelling, and synchronisation of the I/MAb molar ratio. METHODS: A new method was applied, using an NaIO3/NaI carrier mix, realising in one step >90% restoration of deteriorated 124I into the iodide form and chemical control over the I/MAb molar ratio. Chimeric MAb (cMAb) U36 and the murine MAbs 425 and E48 were labelled with 124I using the so-called Iodogen-coated MAb method, as this method provides optimal quality conjugates under challenging radiation conditions. As a standardising condition, NaIO3/NaI carrier mix was added at a stoichiometric I/MAb molar ratio of 0.9. For comparison, MAbs were labelled with 131I and with a mixture of 124I, 123I, 126I and 130I. RESULTS: Labelling with 124I in this setting resulted in overall yields of >70%, a radiochemical purity of >95%, and preservation of MAb integrity and immunoreactivity, including at the patient dose level (85 MBq). No significant quality differences were observed when compared with 131I products, while the iodine isotope mixture gave exactly the same labelling efficiency for each of the isotopes, excluding a different chemical reactivity of 124I-iodide. The scouting performance of 124I-cMAb U36 labelled at the patient dose level was evaluated in biodistribution studies upon co-injection with 131I-labelled cMAb U36, and by PET imaging in nude mice bearing the head and neck cancer xenograft line HNX-OE. 124I-cMAb and 131I-cMAb U36 labelled with a synchronised I/MAb molar ratio gave fully concordant tissue uptake values. Selective tumour uptake was confirmed with immuno-PET, revealing visualisation of 15 out of 15 tumours. CONCLUSION: These results pave the way for renewed evaluation of the potential of 124I-immuno-PET for clinical applications.
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Ronald Boellaard, Nanda C Krak, Otto S Hoekstra, Adriaan A Lammertsma (2004)  Effects of noise, image resolution, and ROI definition on the accuracy of standard uptake values: a simulation study.   J Nucl Med 45: 9. 1519-1527 Sep  
Abstract: Semiquantitative standard uptake values (SUVs) are used for tumor diagnosis and response monitoring. However, the accuracy of the SUV and the accuracy of relative change during treatment are not well documented. Therefore, an experimental and simulation study was performed to determine the effects of noise, image resolution, and region-of-interest (ROI) definition on the accuracy of SUVs. METHODS: Experiments and simulations are based on thorax phantoms with tumors of 10-, 15-, 20-, and 30-mm diameter and background ratios (TBRs) of 2, 4, and 8. For the simulation study, sinograms were generated by forward projection of the phantoms. For each phantom, 50 sinograms were generated at 3 noise levels. All sinograms were reconstructed using ordered-subset expectation maximization (OSEM) with 2 iterations and 16 subsets, with or without a 6-mm gaussian filter. For each tumor, the maximum pixel value and the average of a 50%, a 70%, and an adaptive isocontour threshold ROI were derived as well as with an ROI of 15 x 15 mm. The accuracy of SUVs was assessed using the average of 50 ROI values. Treatment response was simulated by varying the tumor size or the TBR. RESULTS: For all situations, a strong correlation was found between maximum and isocontour-based ROI values resulting in similar dependencies on image resolution and noise of all studied SUV measures. A strong variation with tumor size of > or =50% was found for all SUV values. For nonsmoothed data with high noise levels this variation was primarily due to noise, whereas for smoothed data with low noise levels partial-volume effects were most important. In general, SUVs showed under- and overestimations of > or =50% and depended on all parameters studied. However, SUV ratios, used for response monitoring, were only slightly dependent of ROI definition but were still affected by noise and resolution. CONCLUSION: The poor accuracy of the SUV under various conditions may hamper its use for diagnosis, especially in multicenter trials. SUV ratios used to measure response to treatment, however, are less dependent on noise, image resolution, and ROI definition. Therefore, the SUV might be more suitable for response-monitoring purposes.
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Odile A van den Heuvel, Dick J Veltman, Henk J Groenewegen, Raymond J Dolan, Danielle C Cath, Ronald Boellaard, Catalina T Mesina, Anton J L M van Balkom, Patricia van Oppen, Menno P Witter, Adriaan A Lammertsma, Richard van Dyck (2004)  Amygdala activity in obsessive-compulsive disorder with contamination fear: a study with oxygen-15 water positron emission tomography.   Psychiatry Res 132: 3. 225-237 Dec  
Abstract: Previous imaging studies of obsessive-compulsive symptom states have implicated frontal-striatal and limbic regions in the pathophysiology of obsessive-compulsive disorder (OCD). Functional imaging studies, however, have yielded inconsistent results, presumably due to methodological differences (patient inclusion criteria, stimulus paradigm, imaging technique, and absence of control groups). In the present study, randomized presentation of contamination-related and neutral visual stimuli was used to investigate the neurophysiological correlates of contamination fear in a group of medication-free OCD patients with washing behaviors and healthy controls. A total of 21 subjects (11 OCD patients and 10 healthy controls) were scanned using H(2)(15)O positron emission tomography (PET). Subjects were presented with pictures of clean and dirty surroundings and were requested to make indoor/outdoor decisions to control for attention differences. State anxiety and obsessionality were rated after each scan using visual analogue scales. Main effects of stimulus type (contamination vs. neutral) were found in bilateral occipital cortex in both groups. A significant group interaction effect was observed in the left amygdala reflecting enhanced activity in response to contamination stimuli in OCD patients. Sensitization effects were observed in the right amygdala in the OCD group; these paralleled an increase in levels of distress and obsessionality as well as a decrease in dorsolateral prefrontal activity. The findings of the present study are consistent with the hypothesis of decreased frontal-striatal control of limbic structures, specifically the amygdala, resulting in an inadequate fear response in OCD patients with contamination fear.
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PMID 
Paul Knaapen, Ronald Boellaard, Marco J W Götte, Pieter A Dijkmans, Linda M C van Campen, Carel C de Cock, Gert Luurtsema, Cees A Visser, Adriaan A Lammertsma, Frans C Visser (2004)  Perfusable tissue index as a potential marker of fibrosis in patients with idiopathic dilated cardiomyopathy.   J Nucl Med 45: 8. 1299-1304 Aug  
Abstract: A varying degree of interstitial and perivascular fibrosis is a common finding in idiopathic dilated cardiomyopathy (DCM). The perfusable tissue index (PTI), obtained with PET, is a noninvasive tool for assessing myocardial fibrosis on a regional level. Measurements of the PTI in DCM, however, have not been performed yet. This study was undertaken to test the hypothesis that the PTI is reduced in patients with DCM. METHODS: Fifteen patients with an advanced stage of DCM (New York Heart Association class III or IV and left ventricular ejection fraction [LVEF] < 35%) and 11 healthy control subjects were studied. PET was performed using H(2)(15)O and C(15)O to obtain the perfusable tissue fraction (PTF) and the anatomic tissue fraction (ATF), respectively. RESULTS: The PTI (=PTF/ATF) was reduced in DCM compared with control subjects (0.91 +/- 0.12 vs. 1.12 +/- 0.10; P < 0.01). Heterogeneity of the PTI, expressed as the coefficient of variation, was increased in DCM versus that of healthy control subjects (0.18 +/- 0.07 vs. 0.13 +/- 0.06; P < 0.05). There was no correlation between the PTI and echocardiographically derived LVEF in both groups. CONCLUSION: The PTI was reduced in patients with an advanced stage of DCM. Interstitial and perivascular fibrosis may be responsible for this reduction. Furthermore, the degree of the PTI reduction was variable in DCM patients, both on a regional level and between patients. Noninvasive assessment of fibrosis with the PTI offers the opportunity to evaluate the effects of fibrosis on regional myocardial function, correlate fibrosis with prognosis, and monitor pharmaceutical intervention.
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2003
 
PMID 
Odile A van den Heuvel, Ronald Boellaard, Dick J Veltman, Catalina Mesina, Adriaan A Lammertsma (2003)  Attenuation correction of PET activation studies in the presence of task-related motion.   Neuroimage 19: 4. 1501-1509 Aug  
Abstract: Motion-induced misalignment between transmission and emission scans can result in erroneous estimation of regional tissue activity concentrations. If this motion is of a random nature, mismatch between transmission and emission scans is likely to result in diminished signal-to-noise ratios. In the case of task-related motion, however, corresponding systematic reconstruction artefacts may lead to false-positive or false-negative results. The purpose of the present study was to investigate whether implementation of an image registration (IR) method, which allows for motion-corrected attenuation correction, would improve accuracy of H(2)(15)O PET activation studies. To evaluate the performance of this method, phantom studies as well as studies in human subjects were performed. Results were compared with three alternative methods: standard attenuation correction without motion correction, calculated attenuation correction, and no attenuation correction. The phantom measurements showed that, for quantitative assessment of regional activity concentrations, the IR method was superior to the other attenuation correction methods. In a single-subject study with intentional task-related motion during a visual stimulation paradigm, false-positive results, obtained with the standard attenuation correction method, disappeared after attenuation correction using the IR method. Finally, a group analysis of 11 patients indicated that an increase in signal-to-noise ratio was obtained with the IR method. Therefore, in our view, the IR method should be considered as a first choice for attenuation correction in PET activation studies.
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PMID 
Iris Verel, Gerard W M Visser, Ronald Boellaard, Marijke Stigter-van Walsum, Gordon B Snow, Guus A M S van Dongen (2003)  89Zr immuno-PET: comprehensive procedures for the production of 89Zr-labeled monoclonal antibodies.   J Nucl Med 44: 8. 1271-1281 Aug  
Abstract: The use of immuno-PET, the combination of PET with monoclonal antibodies (mAbs), is an attractive option to improve tumor detection and mAb quantification. The long-lived positron emitter (89)Zr has ideal physical characteristics for immuno-PET, such as a half-life of 3.27 d, which is compatible with the time needed for intact mAbs to achieve optimal tumor-to-nontumor ratios. Thus far, a major limitation in the use of (89)Zr has been the lack of suitable methods for its stable coupling to mAbs. In this article, practical protocols for reproducible isolation of highly pure (89)Zr and the production of optimal-quality mAb-(89)Zr conjugates are provided. METHODS: (89)Zr was produced by a (p,n) reaction on natural yttrium ((89)Y), isolated with a hydroxamate column, and used for labeling of premodified mAbs. mAbs were premodified with a novel bifunctional derivative of the chelate desferrioxamine B (Df) via a new linker chemistry. To this end, Df was initially succinylated (N-sucDf), temporarily filled with Fe(III), esterified by use of tetrafluorophenol, and then directly coupled to mAbs. Chimeric mAb (cmAb) U36, directed against head and neck cancer, was used for in vitro and in vivo evaluation. The in vitro stability of cmAb U36-N-sucDf-(89)Zr was assessed in human serum, and its in vivo behavior was evaluated by biodistribution and PET imaging studies in tumor-bearing nude mice. A cmAb U36-Df-(89)Zr conjugate containing a previously described succinimide ring-thioether unit in the linker was used as a reference. RESULTS: (89)Zr was produced in large batches (6.5-13.5 GBq) and isolated with improved radionuclidic purity (>99.99%) and high yield (>94%). The Df-premodified mAbs gave (89)Zr-labeling efficiencies of 80% within 30 min, resulting in conjugates with preserved integrity and immunoreactivity. With respect to stability, the novel cmAb U36-N-sucDf-(89)Zr conjugate appeared to be superior to the reference conjugate. In vivo, the novel conjugate demonstrated selective tumor targeting, and on PET images obtained at 24, 48, and 72 h after injection of this conjugate, small tumors in the range of 19-154 mg were readily visualized. CONCLUSION: Methods were developed for improved purification of the long-lived positron emitter (89)Zr. Moreover, a novel bifunctional Df chelate was synthesized for the reproducible coupling of (89)Zr to mAbs. The suitability of such conjugates to detect millimeter-sized tumors in xenograft-bearing nude mice was demonstrated.
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PMID 
R Boellaard, F Buijs, H W A M de Jong, M Lenox, T Gremillion, A A Lammertsma (2003)  Characterization of a single LSO crystal layer high resolution research tomograph.   Phys Med Biol 48: 4. 429-448 Feb  
Abstract: The purpose of this study was to determine the performance of a single lutetium oxy-orthosilicate (LSO) crystal layer High Resolution Research Tomograph (HRRT) positron emission tomography (PET) scanner. The HRRT is a high resolution PET scanner designed for human brain and small animal imaging. The scanner consists of eight panel detectors, which have one layer of 2.1 x 2.1 x 7.5 mm thick LSO crystals. Several phantom studies were performed to determine scanner characteristics, such as resolution, scatter fraction, count rate and noise equivalent count rates (NECR). NECR curves were measured according to both NEMA NU2-1994 and NU2-2001 for three different energy windows, i.e. lower level discriminators (lld) of 350, 400 and 450 keV and an upper level discriminator (uld) of 650 keV. Accuracy of scatter and single photon attenuation corrections was evaluated according to NU2-1994. Data were acquired using a ring difference of 67 and a span of 9. Reconstructions were performed using FORE + 2D FBP or OSEM. Transaxial resolution varied from 2.7 to 2.9 mm FWHM between I and 10 cm off centre locations, and axial resolution varied from 3.2 to 4.4 mm FWHM. Scatter fractions (NU2-1994) equalled 0.31, 0.42 and 0.54 for lld of 450, 400 and 350 keV, respectively. NECR data were highest for an lid of 400 keV and showed a maximum of 46 kcps at 38 kBq cm(-3). Lower NECR values were observed according to NU2-2001, but were still optimal for an lld of 400 keV. After scatter and attenuation corrections, pixel values within water, air and teflon inserts of the NU2-1994 phantom were 14, 4 and 35% of the background activity, respectively. The single layer LSO HRRT scanner shows excellent spatial resolution, making it suitable for small animal studies. The low count rate performance, due to the small amount of LSO, prohibits studies of the human brain, but is sufficient for studies in small laboratory animals.
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PMID 
G Luurtsema, C F M Molthoff, A D Windhorst, J W Smit, H Keizer, R Boellaard, A A Lammertsma, E J F Franssen (2003)  (R)- and (S)-[11C]verapamil as PET-tracers for measuring P-glycoprotein function: in vitro and in vivo evaluation.   Nucl Med Biol 30: 7. 747-751 Oct  
Abstract: The mdr1 gene product P-glycoprotein (P-gp) is involved in the bioavailability and pharmacokinetics of various drugs. Racemic [(11)C]verapamil has been used to image P-gp expression in vivo. A racemic tracer, however, is not suitable for quantification. The purpose of the present study was to identify the most appropriate enantiomer of [(11)C]verapamil as a potential PET-tracer for quantifying P-gp function. The two enantiomers, (R)- and (S)-[(11)C]verapamil, were synthesized and studied in vivo. For the in vivo model mdr1a/1b double gene knock-out and wild type mice were used. The in vitro study made use of the LLC-PK1 MDR cell line to examine the P-gp mediated transport of both enantiomers. The biodistribution of (R)- and (S)-[(11)C]verapamil in dKO and WT mice demonstrated no stereoselectivity of verapamil for P-gp in the blood-brain barrier and in the testes. In addition, no significant differences in P-gp transport for both enantiomers were observed in the in vitro experiments. Previous studies have shown that (R)-verapamil is metabolized less in man and that it has lower affinity for calcium channels. Since (R)- and (S)-verapamil have equal transport for P-gp, the (R)-enantiomer seems to be the best and safest candidate as PET-tracer for measuring P-gp function in vivo.
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PMID 
Catalina T Mesina, Ronald Boellaard, Geurt Jongbloed, Aad W van der Vaart, Adriaan A Lammertsma (2003)  Experimental evaluation of iterative reconstruction versus filtered back projection for 3D [15O]water PET activation studies using statistical parametric mapping analysis.   Neuroimage 19: 3. 1170-1179 Jul  
Abstract: Iterative reconstructions are increasingly used for clinical PET studies owing to the better noise properties compared with filtered backprojection (FBP). The purpose of the present study was to compare ordered subsets expectation maximization (OSEM) iterative reconstruction with FBP as input for statistical parametric mapping (SPM) analysis of PET activation studies. Two phantom studies were performed simulating both motor and cognitive tasks and acquiring data with both high and low statistics. In contrast to clinical studies, where no a priori information is known, phantom studies allow for an accurate and detailed comparison between different reconstruction techniques. The significance of "activations" during "tasks" was determined using SPM99 software. Using region of interest analysis of SPM results, it was found that the maximum and average t values within each hot spot of the phantom were higher for OSEM than for FBP. In addition, OSEM4 x 16 (4 iterations, 16 subsets) produced fewer false-positive voxels than FBP, OSEM1 x 16 and OSEM2 x 16. In conclusion, for PET activation studies use of OSEM4 x 16 seems to give the best tradeoff between signal detection and noise reduction.
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PMID 
R Boellaard, H W A M de Jong, C F M Molthoff, F Buijs, M Lenox, R Nutt, A A Lammertsma (2003)  Use of an in-field-of-view shield to improve count rate performance of the single crystal layer high-resolution research tomograph PET scanner for small animal brain scans.   Phys Med Biol 48: 23. N335-N342 Dec  
Abstract: The count rate performance of the single LSO crystal layer high-resolution research tomograph (HRRT-S) PET scanner is limited by the processing speed of its electronics. Therefore, the feasibility of using an in-field-of-view (in-FOV) shield to improve the noise equivalent count rates (NECR) for small animal brain studies was investigated. The in-FOV shield consists of a lead tube of 12 cm length, 6 cm inner diameter and 9 mm wall thickness. It is large enough to shield the activity in the body of a rat or mouse. First, the effect of this shield on NECR was studied. Secondly, a number of experiments were performed to assess the effects of the shield on the accuracy of transmission scan data and, next, on reconstructed activity distribution in the brain. For activities below 150 MBq NECR improved only by 5-10%. For higher activities NECR maxima of 1.2E4 cps at 200 MBq and 2.2E4 cps at 370 MBq were found without and with shield, respectively. Listmode data taken without shield, however, were corrupted for activities above 75 MBq due to data overrun problems (time tag losses) of the electronics. When the shield was used data overrun was avoided up to activities of 150 MBq. For the unshielded part of the phantom, transmission scan data were the same with and without shield. The estimated scatter contribution was approximately 8.5% without and 5.5% with shield. Reconstructed emission data showed a difference up to 5% in the unshielded part of the phantom at 5 mm or more from the edge of the shielding. Of this 5% about 3% results from the difference in the uncorrected scatter contribution. In conclusion, an in-FOV shield can be used successfully in an HRRT PET scanner to improve NECR and accuracy of small animal brain studies. The latter is especially important when high activities are required for tracers with low brain uptake or when multiple animals are scanned simultaneously.
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DOI   
PMID 
Iris Verel, Gerard W M Visser, Otto C Boerman, Julliette E M van Eerd, Ron Finn, Ronald Boellaard, Maria J W D Vosjan, Marijke Stigter-van Walsum, Gordon B Snow, Guus A M S van Dongen (2003)  Long-lived positron emitters zirconium-89 and iodine-124 for scouting of therapeutic radioimmunoconjugates with PET.   Cancer Biother Radiopharm 18: 4. 655-661 Aug  
Abstract: Antibody-PET imaging might be of value for the selection of radioimmunotherapy (RIT) candidates to confirm tumor targeting and to estimate radiation doses to tumor and normal tissues. One of the requirements to be set for such a scouting procedure is that the biodistributions of the diagnostic and therapeutic radioimmunoconjugates should be similar. In the present study we evaluated the potential of the positron emitters zirconium-89 ((89)Zr) and iodine-124 ((124)I) for this approach, as these radionuclides have a relatively long half-life that matches with the kinetics of MAbs in vivo (t(1/2) 3.27 and 4.18 days, respectively). After radiolabeling of the head and neck squamous cell carcinoma (HNSCC)-selective chimeric antibody (cMAb) U36, the biodistribution of two diagnostic (cMAb U36-N-sucDf-(89)Zr and cMAb U36-(124)I) and three therapeutic radioimmunoconjugates (cMAb U36-p-SCN-Bz-DOTA-(88)Y-with (88)Y being substitute for (90)Y, cMAb U36-(131)I, and cMAb U36-MAG3-(186)Re) was assessed in mice with HNSCC-xenografts, at 24, 48, and 72 hours after injection. Two patterns of biodistribution were observed, one pattern matching for (89)Zr- and (88)Y-labeled cMAb U36 and one pattern matching for (124)I-, (131)I-, and (186)Re-cMAb U36. The most remarkable differences between both patterns were observed for uptake in tumor and liver. Tumor uptake levels were 23.2 +/- 0.5 and 24.1 +/- 0.7%ID/g for the (89)Zr- and (88)Y-cMAb U36 and 16.0 +/- 0.8, 15.7 +/- 0.79 and 17.1 +/- 1.6%ID/g for (124)I-, (131)I-, and (186)Re-cMAb U36-conjugates, respectively, at 72 hours after injection. For liver these values were 6.9 +/- 0.8 ((89)Zr), 6.2 +/- 0.8 ((88)Y), 1.7 +/- 0.1 ((124)I), 1.6 +/- 0.1 ((131)I), and 2.3 +/- 0.1 ((186)Re), respectively. These preliminary data justify the further development of antibody-PET with (89)Zr-labeled MAbs for scouting of therapeutic doses of (90)Y-labeled MAbs. In such approach (124)I-labeled MAbs are most suitable for scouting of (131)I- and (186)Re-labeled MAbs.
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PMID 
Henri N J M Greuter, Ronald Boellaard, Arthur van Lingen, Eric J F Franssen, Adriaan A Lammertsma (2003)  Measurement of 18F-FDG concentrations in blood samples: comparison of direct calibration and standard solution methods.   J Nucl Med Technol 31: 4. 206-209 Dec  
Abstract: OBJECTIVE: The purpose of this study was to compare the accuracy and reliability of 2 well counter methods for measuring the activity concentration of (18)F-FDG in blood samples. METHODS: Three to 5 blood samples from 154 patient studies were weighed and measured in a well counter. The (18)F-FDG activity concentration was derived using, first, a direct calibration factor to convert measured well counter readings into activity concentration and, second, a comparison of measured counts with those of a specified standard solution. RESULTS: The ratio between the activity concentration results of the 2 methods was 0.996 +/- 0.033, indicating that the methods provided equal results. CONCLUSION: Because the standard solution method is more prone to human error, less reproducible, and more labor intensive, preference should be given to the direct calibration method.
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DOI   
PMID 
Catalina T Mesina, Ronald Boellaard, Odile A van den Heuvel, Dick J Veltman, Geurt Jongbloed, Aad W van der Vaart, Adriaan A Lammertsma (2003)  Effects of attenuation correction and reconstruction method on PET activation studies.   Neuroimage 20: 2. 898-908 Oct  
Abstract: The outcome of Statistical Parametric Mapping (SPM) analyses of PET activation studies depends among others, on the quality of reconstructed data. In general, filtered back-projection (FBP) is used for reconstruction in PET activation studies. There is, however, increasing interest in iterative reconstruction algorithms such as ordered subset expectation maximization (OSEM) algorithms. The aim of the present study was to investigate the effects of reconstruction techniques and attenuation correction (AC) on the detection of activation foci following statistical analysis with SPM. First, a replicate study was performed to assess the effects of the reconstruction method on pixel variance. Second, a phantom study was performed to evaluate the influence of both locations of an activated area and applied reconstruction method on SPM outcome. A volumetric method was used to compute the number of false positive voxels for all reconstructions. In addition, average t values within activation foci and for false positive voxels were calculated. For the assessment of the effects of reconstruction on clinical data, a group of 11 patients was studied. For all reconstructions SPM maps were created and compared. Both the clinical and the phantom data showed that use of iterative reconstruction methods reduced false positive results, while showing similar SPM results within activated areas as FBP. Reconstruction of data without attenuation correction reduced noise for FBP only, but did not affect the quality of SPM results for OSEM. It is concluded that OSEM is a good alternative for FBP reconstructions providing SPM results with less noise.
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PMID 
Iris Verel, Gerard W M Visser, Ronald Boellaard, Otto C Boerman, Julliette van Eerd, Gordon B Snow, Adriaan A Lammertsma, Guus A M S van Dongen (2003)  Quantitative 89Zr immuno-PET for in vivo scouting of 90Y-labeled monoclonal antibodies in xenograft-bearing nude mice.   J Nucl Med 44: 10. 1663-1670 Oct  
Abstract: Immuno-PET as a scouting procedure before radioimmunotherapy (RIT) aims at the confirmation of tumor targeting and the accurate estimation of radiation dose delivery to both tumor and normal tissues. Immuno-PET with (89)Zr-labeled monoclonal antibodies (mAbs) and (90)Y-mAb RIT might form such a valuable combination. In this study, the biodistribution of (89)Zr-labeled and (88)Y-labeled mAb ((88)Y as substitute for (90)Y) was compared and the quantitative imaging performance of (89)Zr immuno-PET was evaluated. METHODS: Chimeric mAb (cmAb) U36, directed against an antigen preferentially expressed in head and neck cancer, was labeled with (89)Zr using the bifunctional chelate N-succinyldesferrioxamine B (N-sucDf) and with (88)Y using the bifunctional chelate p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-SCN-Bz-DOTA). The radioimmunoconjugates were coinjected in xenograft-bearing nude mice, and biodistribution was determined at 3, 24, 48, 72, and 144 h after injection. (89)Zr was evaluated and compared with (18)F in phantom studies to determine linearity, resolution, and recovery coefficients, using a high-resolution research tomograph PET scanner. The potential of PET to quantify cmAb U36-N-sucDf-(89)Zr was evaluated by relating image-derived tumor uptake data (noninvasive method) to (89)Zr uptake data derived from excised tumors (invasive method). RESULTS: (89)Zr-N-sucDf-labeled and (88)Y-p-SCN-Bz-DOTA-labeled cmAb U36 showed a highly similar biodistribution, except for sternum and thigh bone at later time points (72 and 144 h after injection). Small differences were found in kidney and liver. Imaging performance of (89)Zr approximates that of (18)F, whereas millimeter-sized (19-154 mg) tumors were visualized in xenograft-bearing mice after injection of cmAb U36-N-sucDf-(89)Zr. After correction for partial-volume effects, an excellent correlation was found between image-derived (89)Zr tumor radioactivity and gamma-counter (89)Zr values of excised tumors (R(2) = 0.79). CONCLUSION: The similar biodistribution and the favorable imaging characteristics make (89)Zr a promising candidate for use as a positron-emitting surrogate for (90)Y.
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2002
 
PMID 
Bianca M Klabbers, Jan C de Munck, Ben J Slotman, Hans A Langendijk, Remco de Bree, Otto S Hoekstra, Ronald Boellaard, Adriaan A Lammertsma (2002)  Matching PET and CT scans of the head and neck area: development of method and validation.   Med Phys 29: 10. 2230-2238 Oct  
Abstract: Positron emission tomography (PET) provides important information on tumor biology, but lacks detailed anatomical information. Our aim in the present study was to develop and validate an automatic registration method for matching PET and CT scans of the head and neck. Three difficulties in achieving this goal are (1) nonrigid motions of the neck can hamper the use of automatic ridged body transformations; (2) emission scans contain too little anatomical information to apply standard image fusion methods; and (3) no objective way exists to quantify the quality of the match results. These problems are solved as follows: accurate and reproducible positioning of the patient was achieved by using a radiotherapy treatment mask. The proposed method makes use of the transmission rather than the emission scan. To obtain sufficient (anatomical) information for matching, two bed positions for the transmission scan were included in the protocol. A mutual information-based algorithm was used as a registration technique. PET and CT data were obtained in seven patients. Each patient had two CT scans and one PET scan. The datasets were used to estimate the consistency by matching PET to CT1, CT1 to CT2, and CT2 to PET using the full circle consistency test. It was found that using our method, consistency could be obtained of 4 mm and 1.3 degrees on average. The PET voxels used for registration were 5.15 mm, so the errors compared quite favorably with the voxel size. Cropping the images (removing the scanner bed from images) did not improve the consistency of the algorithm. The transmission scan, however, could potentially be reduced to a single position using this approach. In conclusion, the represented algorithm and validation technique has several features that are attractive from both theoretical and practical point of view, it is a user-independent, automatic validation technique for matching CT and PET scans of the head and neck, which gives the opportunity to compare different image enhancements.
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2001
 
PMID 
R Boellaard, A van Lingen, S C van Balen, B G Hoving, A A Lammertsma (2001)  Characteristics of a new fully programmable blood sampling device for monitoring blood radioactivity during PET.   Eur J Nucl Med 28: 1. 81-89 Jan  
Abstract: The first performance tests of a new fully programmable blood sampling device for monitoring blood radioactivity during positron emission tomography (PET) are described. Blood is withdrawn through 1-mm internal diameter tubing using an infusion pump which can be operated at rates varying from 0 to 600 ml/h. Activity in blood is measured by a 6-cm-thick bismuth germanate crystal connected to a photomultiplier tube and multichannel analyser (MCA) which are positioned within 6 cm lead shielding. Positioning of the tubing is an exact and simple procedure. The minimal readout time of the MCA is 1 s. Two independent energy windows can be set. Operation of the pump and MCA is fully controlled by a PC, i.e. sampling time, interval time and pump rate can be varied at any time during the PET scan by user-defined scripts. A number of characteristics of the new system were studied, such as sensitivity, dead time, linearity, effect of background radiation and pump rate as a function of input pressure. In addition, dispersion was measured as a function of pump rate. Finally, first clinical results were compared with manual samples. The sensitivity equalled 0.7 and 0.2 cps/Bq for 511- and 1022-keV 30% energy windows, respectively, and the system dead time was 500 ns. The system remained linear within 2% with activity concentrations up to 2.5 MBq/cc. Short-term reproducibility was better than 3% for a 1-h period. Long-term reproducibility was about 5% (ISD), which was mainly caused by variation in the diameter of the tubing. If the device was positioned in such a way that maximum shielding was directed towards the patient, the effects of background radiation from the patient on the measured activity concentration for clinically relevant conditions was minimal (<3%). Pump rate varied with input pressure, but remained constant for a given pressure. Dispersion constants smaller than 0.14 s(-1) were observed for pump rates higher than 300 ml/h, indicating that the system dispersion is small. Clinical data showed an excellent agreement to within 3% (ISD) between the results obtained with the new system and manual samples. With the continuous blood sampler radioactivity in blood can be measured accurately during the entire course of the PET scan. Furthermore, the system is fully programmable allowing adjustment of all parameters during a single PET scan.
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PMID 
R Boellaard, A van Lingen, A A Lammertsma (2001)  Experimental and clinical evaluation of iterative reconstruction (OSEM) in dynamic PET: quantitative characteristics and effects on kinetic modeling.   J Nucl Med 42: 5. 808-817 May  
Abstract: The purpose of this study was to investigate the quantitative properties and effects of ordered-subset expectation maximization (OSEM) on kinetic modeling compared with filtered backprojection (FBP) in dynamic PET studies. Both phantom and patient studies were performed. METHODS: For phantom studies dynamic two-dimensional emission scans with 10-min frames and 20-min scan intervals were acquired over a 14-h period using an HR+ PET scanner. Various phantoms were scanned: 2-, 5-, 10-, and 20-cm-diameter phantoms filled with an 18F solution (300 kBq/mL) and a NEMA phantom filled with an 18F background (40 kBq/mL) and a cold or 11C insert (450 kBq/mL). Transmission (Tx) scans of 5-60 min were acquired. Data were reconstructed using FBP Hanning 0.5 and OSEM with 2-12 iterations and 12 or 24 subsets. Quantitative accuracy and noise characteristics were assessed. For patient studies, five cardiac, three oncologic, and three brain dynamic 18F-FDG scans were used. Five reconstructions were performed: FBP Hanning 0.5, and OSEM 2 x 12 and OSEM 4 x 16 with and without 5-mm full width at half maximum smoothing. Time-activity curves were calculated using volumes of interest. The input function was derived from arterial sampling. Metabolic rate of glucose (MRglu) was calculated with a standard two-tissue compartment model and Patlak analysis. RESULTS: Contribution of Tx noise to the reconstructed image was smaller for OSEM than for FBP. Differences in signal-to-noise ratio between FBP and OSEM depended on number of iterations and phantom size. Bias with OSEM was observed for regions enclosed within a 5- to 10-fold hotter background. For cardiac studies OSEM 2 x 12 and OSEM 4 x 16 resulted in 13% and 21% higher pixel values and 9% and 15% higher MRglu values compared with FBP. Smoothing decreased all these values to 2%. Similar results were found for most tumor studies. For brain studies MRglu of FBP and OSEM 4 x 16 agreed within 2%. Use of OSEM image-derived input functions for cardiac PET studies resulted in a decrease in calculated MRglu of about 15%. CONCLUSION: For most PET studies OSEM has equal quantitative accuracy as FBP. The higher pixel and MRglu values are explained by the better resolution of OSEM. However, OSEM does not provide accurate image-derived input functions for FDG cardiac PET studies because of bias in regions located within a hotter background.
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PMID 
A P van der Weerdt, L J Klein, R Boellaard, C A Visser, F C Visser, A A Lammertsma (2001)  Image-derived input functions for determination of MRGlu in cardiac (18)F-FDG PET scans.   J Nucl Med 42: 11. 1622-1629 Nov  
Abstract: Image-derived input functions (IDIF) are frequently used in cardiac (18)F-FDG PET studies for determination of the myocardial metabolic rate of glucose (MRGlu). The purpose of this study was to assess which vascular structure is most suited for defining the IDIF, using online arterial blood sampling (AS) as the gold standard. METHODS: In 18 patients with ischemic heart disease, 370 MBq FDG were injected during a hyperinsulinemic euglycemic clamp. Studies were performed with a Siemens/CTI HR+ PET scanner using a dynamic scanning protocol. A fully automated blood-sampling device was used for continuous AS. IDIF were obtained using regions of interest (ROIs) of 3 different sizes defined on the left ventricle (LV), left atrium (LA), ascending aorta (AA), and descending aorta (DA). MRGlu was calculated with all input functions. Ratios between MRGlu obtained with IDIF and AS were calculated for each patient. RESULTS: Time-activity curves from smaller ROIs suffered more from statistical noise with only a modest reduction of spillover effects, which led to more variation in calculated MRGlu. Mean ratios of MRGlu obtained with IDIF and AS were close to 1 when AA and DA (0.97 +/- 0.07 and 1.00 +/- 0.11, respectively) were used to define the input function. However, when LA and LV were used, mean ratios were 0.81 +/- 0.06 and 0.79 +/- 0.08, respectively, reflecting a significant underestimation of MRGlu. The use of AA for defining the input function resulted in the best agreement with AS and the smallest interobserver variation. CONCLUSION: The ascending aorta is the structure of choice for defining IDIF and a large ROI (diameter, approximately 15 mm) should be used to minimize the effects of statistical noise.
Notes:
1998
 
PMID 
R Boellaard, M Essers, M van Herk, B J Mijnheer (1998)  New method to obtain the midplane dose using portal in vivo dosimetry.   Int J Radiat Oncol Biol Phys 41: 2. 465-474 May  
Abstract: PURPOSE: The aim of this study was to develop a method to derive the midplane dose [i.e., the two-dimensional (2D) dose distribution in the middle of a patient irradiated with high-energy photon beams] from transmission dose data measured with an electronic portal imaging device (EPID). A prerequisite for this method was that it could be used without additional patient information (i.e., independent of a treatment-planning system). Second, we compared the new method with several existing (conventional) methods that derive the midline dose from entrance and exit dose measurements. METHODS AND MATERIALS: The proposed method first calculates the 2D contribution of the primary and scattered dose component at the exit side of the patient or phantom from the measured transmission dose. Then, a correction is applied for the difference in contribution for both dose components between exit side and midplane, yielding the midplane dose. To test the method, we performed EPID transmission dose measurements and entrance, midplane, and exit dose measurements using an ionization chamber in homogeneous and symmetrical inhomogeneous phantoms. The various methods to derive the midplane dose were also tested for asymmetrical inhomogeneous phantoms applying two opposing fields. A number of combinations of inhomogeneities (air, cork, and aluminum), phantom thicknesses, field sizes, and a few irregularly shaped fields were investigated, while each experiment was performed in 4-, 8-, and 18-MV open and wedged beams. RESULTS: Our new method can be used to assess the midplane dose for most clinical situations within 2% relative to ionization chamber measurements. Similar results were found with other methods. In the presence of large asymmetrical inhomogeneities (e.g., lungs), discrepancies of about 8% have been found (for small field sizes) using our transmission dose method, owing to the absence of lateral electron equilibrium. Applying the other methods, differences between predicted and measured midplane doses were even larger, up to 10%. For large field sizes, the agreement between measured and predicted midplane dose was within 3% using our transmission dose method. CONCLUSIONS: Using our new method, midplane doses were estimated with a similar or higher accuracy compared with existing conventional methods for in vivo dosimetry. The advantage of our new method is that the midplane dose can be determined in the entire (2D) field. With our method, portal in vivo dosimetry is an accurate alternative for conventional in vivo dosimetry.
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PMID 
R Boellaard, M van Herk, H Uiterwaal, B Mijnheer (1998)  First clinical tests using a liquid-filled electronic portal imaging device and a convolution model for the verification of the midplane dose.   Radiother Oncol 47: 3. 303-312 Jun  
Abstract: BACKGROUND AND PURPOSE: Recently, algorithms have been developed to derive the patient dose from portal dose measurements using a liquid-filled electronic portal imaging device. These algorithms have already been validated for several phantom geometries irradiated under clinical conditions. It is the aim of the present study to investigate the applicability of a liquid-filled electronic portal imaging device in combination with these algorithms for two-dimensional midplane dose verification in clinical practice. MEASUREMENTS AND METHODS: Portal dose images were obtained during several patient treatments under routine clinical conditions. Measurements were performed to verify the midplane dose during radiotherapy of larynx cancer with 4 MV beams, breast and lung cancer with 8 MV beams and prostate cancer with both 8 and 18 MV beams. Midplane doses, determined from portal dose measurements and analyzed with our algorithms, were compared with midplane doses calculated with our three-dimensional (3D) treatment planning system (TPS). RESULTS: For the larynx treatment the measured 2D midplane dose agreed within 2.0% with TPS calculations in most parts of the field. Larger differences were found in a small region below the skin due to the absence of electron equilibrium, which is not taken into account in our portal dose analysis. For breast irradiations the measured midplane dose showed a homogeneous distribution in the AP direction in the axial plane, while high dose regions were observed in the cranial and caudal part of the breast. Portal dose measurements and TPS calculations agreed within 2.5% for most of the prostate and lung irradiations. For a few of the prostate and lung treatments larger local differences were found due to differences between the actual patient anatomy and the planning CT data, e.g. as a result of variable gas filling in the rectum and anatomical changes in the lung. CONCLUSIONS: Portal dose measurements with a liquid-filled electronic portal imaging device can be used to determine the 2D midplane dose for various treatment sites in clinical practice. Portal in vivo dosimetry has proven to be important in detecting changes in the patient's anatomy and its influence on the dose delivery. It is concluded that portal dosimetry is an excellent tool for accurate and independent verification of the dose in the entire (2D) midplane during patient treatment. However, a limited number of patients were involved in this study and the results are therefore preliminary. More research is needed to fully assess the clinical value of portal dose measurements.
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1997
 
PMID 
R Boellaard, M van Herk, B J Mijnheer (1997)  A convolution model to convert transmission dose images to exit dose distributions.   Med Phys 24: 2. 189-199 Feb  
Abstract: The aim of this study is to develop a model which computes exit dose values from transmission dose data obtained during patient treatment with an electronic portal imaging device (EPID). The proposed model convolves the primary dose distribution, derived from transmission dose distributions at large air gaps, with a scatter kernel to obtain the exit dose. The influence of inhomogeneities on the scatter contribution is taken into account by using a radiological path length model. To determine the parameters of the model, an extensive set of transmission dose measurements was performed behind various phantoms in an 8 MV beam using a liquid-filled EPID. The influence on the transmission dose of field size, phantom thickness, air gap between phantom and detector, and source-phantom distance was investigated. At air gaps larger than 50 cm the distribution of scattered dose is almost flat and its contribution to the total dose is relatively small, thus allowing an accurate separation of the primary and scattered dose by subtraction. Scattered dose distributions for air gaps smaller than 50 cm were obtained by subtracting the primary dose (corrected for divergence) from the measured total transmission dose. The resulting scattered dose distribution behind homogeneous phantoms has a Gaussian shaped profile, which becomes wider with increasing air gap. The relative contribution of scattered dose depends on the phantom thickness and is maximal for a thickness of about 10 cm. Using these results, the parameters of the convolution model (i.e., the shape of the scatter kernel) were determined. With the model the absolute exit dose is predicted with an accuracy of about 2% (1 s.d.) within the entire radiation field for homogeneous phantoms. Inhomogeneities are taken into account by calculating the radiological path length from the measured primary dose, i.e., without using CT data. By using the measured radiological path length the exit dose can be determined for inhomogeneous phantoms with an accuracy of 2.5%. It is concluded that, using our convolution model, EPID measurements at large air gaps can be used to estimate absolute exit doses in an 8 MV beam with an accuracy of 2.5%.
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PMID 
R Boellaard, M van Herk, H Uiterwaal, B Mijnheer (1997)  Two-dimensional exit dosimetry using a liquid-filled electronic portal imaging device and a convolution model.   Radiother Oncol 44: 2. 149-157 Aug  
Abstract: BACKGROUND AND PURPOSE: To determine the accuracy of two-dimensional exit dose measurements with an electronic portal imaging device, EPID, using a convolution model for a variety of clinically relevant situations. MATERIALS AND METHODS: Exit doses were derived from portal dose images, obtained with a liquid-filled EPID at distances of 50 cm or more behind the patient, by using a convolution model. The resulting on- and off-axis exit dose values were first compared with ionization chamber exit dose measurements for homogeneous and inhomogeneous phantoms in open and wedged 4,8 and 18 MV photon beams. The accuracy of the EPID exit dose measurements was then determined for a number of anthropomorphic phantoms (lung and larynx) irradiated under clinical conditions and for a few patients treated in an 8 MV beam. The latter results were compared with in vivo exit dose measurements using diodes. RESULTS: The exit dose can be determined from portal images with an accuracy of 1.2% (1 SD) compared with ionization chamber measurements for open beams and homogeneous phantoms at all tested beam qualities. In the presence of wedges and for inhomogeneous phantoms the average relative accuracy slightly deteriorated to 1.7% (1 SD). For lung phantoms in a 4 MV beam a similar accuracy was obtained after refinement of our convolution model, which requires knowledge of the patient contour. Differences between diode and EPID exit dose measurements for an anthropomorphic lung phantom in an 8 MV beam were 2.5% at most, with an average agreement within 1% (1 SD). For larynx phantoms in a 4 MV beam exit doses obtained with an ionization chamber and EPID agreed within 1.5% (1 SD). Finally, exit doses in a few patients irradiated in an 8 MV beam could be determined with the EPID with an accuracy of 1.1% (1 SD) relative to exit dose measurements using diodes. CONCLUSIONS: Portal images, obtained with our EPID and analyzed with our convolution model, can be used to determine the exit dose distribution with an accuracy of 1.7% (1 SD) for most clinically relevant situations. EPID exit dosimetry is therefore a good alternative for diode dosimetry. The EPID system is a powerful tool in a dosimetric quality control programme during high dose/high precision radiotherapy.
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1996
 
PMID 
M Essers, R Boellaard, M van Herk, H Lanson, B Mijnheer (1996)  Transmission dosimetry with a liquid-filled electronic portal imaging device.   Int J Radiat Oncol Biol Phys 34: 4. 931-941 Mar  
Abstract: PURPOSE: To assess the accuracy of transmission dose rate measurements for various phantom-detector geometries, performed with an electronic portal imaging device (EPID) and to compare these transmission dose rate values with exit dose rate data. METHODS AND MATERIALS: Transmission dose rate values on the central beam axis and beam profiles were measured with an EPID consisting of a matrix of liquid-filled ionization chambers. These data were compared with transmission and exit dose rate values, obtained using air-filled ionization chambers for a number of field sizes, phantom thickness, and phantom-detector distances. Various homogeneous and inhomogeneous phantoms were applied. RESULTS: The increase in dose rate with field size is larger for the EPID than in air, due to the larger amount of side scatter in the EPID. The difference has been taken into account by a deconvolution of the EPID images. An additional build-up layer on top of the commercial device is needed to reach dose maximum at the liquid ionization chambers for photon beam energies higher than about 4 MV. The transmission off-axis ratios (OAR) determined with the EPID and in air agreed within 2% for all tested cases, after deconvolution of the EPID signal. The agreement between the EPID-and exit-OAR decreased with increasing phantom-detector distance and the presence of inhomogeneities. For a phantom-detector distance of about 10 cm, the EPID- and exit-OARs agree within 2.5%. The difference could be up to 8% for an air inhomogeneity and a phantom-detector distance of 30 cm. CONCLUSIONS: The difference between EPID measurements and measurements in air can be explained by side scatter effects in the EPID and lack of adequate buildup, and can easily be taken into account. The loss of scatter compared with the situation at the exit side of the phantom explains the difference between transmission and exit dose values. At short phantom-detector distances, good agreement exists between transmission and exit dose rate. This implies that at this distance, the EPID can be used for simple comparison with exit dose calculations during patient treatments. At larger distances, more sophisticated conversion methods are required.
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PMID 
R Boellaard, M van Herk, B J Mijnheer (1996)  The dose response relationship of a liquid-filled electronic portal imaging device.   Med Phys 23: 9. 1601-1611 Sep  
Abstract: To use a liquid-filled portal imaging device (EPID) for transmission dosimetry, it is necessary to understand its dosimetric properties. Therefore, the relation between the pixel values (i.e., ionization currents) of an electronic portal imaging device and the dose rate measured with an ionization chamber in a mini-phantom was investigated. First, a model was introduced to describe the ionization current of the matrix of liquid-filled ionization chambers for pulsed radiation. With this model the relation between ionization current and dose rate is explained qualitatively. Next, buildup measurements were performed at different photon beam energies to assess the amount of buildup material required to obtain electronic equilibrium in the detector. This additional buildup material significantly decreased the image quality, which can hamper patient setup verification, at only the 25 MV beam. Pixel values were then compared with measurements made with a Farmer-type ionization chamber in a mini-phantom at various dose rates. In addition, the influence of a number of accelerator and EPID settings (photon beam energy, pulse rate frequency, gantry rotation angle, and image acquisition modes) on the pixel value was investigated. Subsequently, the dose response relationships of three commercially obtained EPIDs of the same type were compared. For all types of measurements the relation between ionization current and dose rate is described within 1% (1 SD) by an equation with two terms: one term proportional to the square root of the dose rate and another term linear to the dose rate. For images obtained under a typical clinical situation (applying the "normal" acquisition mode at an 8 MV beam with a pulse rate frequency of 400 Hz at a transmission dose rate of 100 cGy/min) the contribution of the square root and linear term to the EPID signal is 94% and 6%, respectively. The weight factors of both terms depend on the photon beam energy, pulse rate frequency, and image acquisition mode. It is concluded that the EPID is useful for dosimetry purposes with 1% (1 SD) accuracy, but that the dose response relationship has to be determined for each EPID and accelerator setting.
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