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1.  89Zr-cetuximab PET imaging in patients with advanced colorectal cancer 
Oncotarget  2015;6(30):30384-30393.
Monoclonal antibodies (mAbs) against the epidermal growth factor receptor (EGFR) are used in the treatment of advanced colorectal cancer (mCRC). Approximately 50% of patients benefit despite patient selection for RAS wild type (wt) tumors. Based on the hypothesis that tumor targeting is required for clinical benefit of anti-EGFR treatment, biodistribution and tumor uptake of 89Zr-cetuximab by Positron Emission Tomography (PET), combining the sensitivity of PET with the specificity of cetuximab for EGFR was evaluated. Ten patients with wt K-RAS mCRC received 37 ± 1 MBq 89Zr-cetuximab directly (<2 h) after the first therapeutic dose of cetuximab. PET-scans were performed from 1 hour to 10 days post injection (p.i.). Biodistribution was determined for blood and organs. Uptake in tumor lesions was quantified by Standardized Uptake Value (SUV) and related to response. In 6 of 10 patients 89Zr-cetuximab uptake in tumor lesions was detected. Four of 6 patients with 89Zr-cetuximab uptake had clinical benefit, while progressive disease was observed in 3 of 4 patients without 89Zr-cetuximab uptake. Taken together, tumor uptake of 89Zr-cetuximab can be visualized by PET imaging. The strong relation between uptake and response warrants further clinical validation as an innovative selection method for cetuximab treatment in patients with wt RAS mCRC.
PMCID: PMC4745807  PMID: 26309164
immunoPET; cetuximab; colorectal cancer; 89zirconium; treatment selection
2.  Subclinical synovitis detected by macrophage PET, but not MRI, is related to short-term flare of clinical disease activity in early RA patients: an exploratory study 
Residual subclinical synovitis can still be present in joints of rheumatoid arthritis (RA) patients despite clinical remission and has been linked to ongoing radiological damage. The aim of the present study was to assess subclinical synovitis by positron emission tomography (PET; macrophage tracer 11C-(R)-PK11195) in early RA patients with minimal disease activity without clinically apparent synovitis (MDA); and its relationship with clinical outcome and magnetic resonance imaging (MRI), respectively.
Baseline PET and MRI of hands/wrists were performed in 25 early MDA RA patients (DAS 44 < 1.6; no tender/swollen joints) on combined DMARD therapy. PET tracer uptake (semi-quantitative score: 0–3) and MRI synovitis and bone marrow edema (OMERACT RAMRIS) were assessed in MCP, PIP and wrist joints (22 joints/patient; cumulative score).
Eleven of 25 patients (44 %) showed enhanced tracer uptake in ≥ 1 joint. Fourteen of these 25 (56 %) patients developed a flare within 1 year: 8/11 (73 %) with a positive, and 6/14 (43 %) with a negative PET. In the latter, in 5/6 patients flare was located outside the scan region. Median cumulative PET scores of patients with a subsequent flare in the hands or wrists were significantly higher than those of patients without a flare (1.5 [IQR 0.8–5.3] vs 0.0 [IQR 0.0–1.0], p = 0.04); significance was lost when all flares were considered (1.0 [IQR 0.0–4.0] vs 0.0 [IQR 0.0–1.0], p = 0.10). No difference in cumulative MRI scores was observed between both groups.
Positive PET scans were found in almost half of early RA patients with MDA. Patients with a subsequent flare in hand or wrist had higher cumulative PET scores but not MRI scores, suggesting that subclinical arthritis on PET may predict clinical flare in follow-up.
PMCID: PMC4582930  PMID: 26403667
3.  Stability of FDG-PET Radiomics features: An integrated analysis of test-retest and inter-observer variability 
Acta oncologica (Stockholm, Sweden)  2013;52(7):1391-1397.
Besides basic measurements as maximum standardized uptake value (SUV)max or SUVmean derived from 18F-FDG positron emission tomography (PET) scans, more advanced quantitative imaging features (i.e. “Radiomics” features) are increasingly investigated for treatment monitoring, outcome prediction, or as potential biomarkers. With these prospected applications of Radiomics features, it is a requisite that they provide robust and reliable measurements. The aim of our study was therefore to perform an integrated stability analysis of a large number of PET-derived features in non-small cell lung carcinoma (NSCLC), based on both a test-retest and an inter-observer setup.
Eleven NSCLC patients were included in the test-retest cohort. Patients underwent repeated PET imaging within a one day interval, before any treatment was delivered. Lesions were delineated by applying a threshold of 50% of the maximum uptake value within the tumor. Twenty-three NSCLC patients were included in the inter-observer cohort. Patients underwent a diagnostic whole body PET-computed tomography (CT). Lesions were manually delineated based on fused PET-CT, using a standardized clinical delineation protocol. Delineation was performed independently by five observers, blinded to each other. Fifteen first order statistics, 39 descriptors of intensity volume histograms, eight geometric features and 44 textural features were extracted. For every feature, test-retest and inter-observer stability was assessed with the intra-class correlation coefficient (ICC) and the coefficient of variability, normalized to mean and range. Similarity between test-retest and inter-observer stability rankings of features was assessed with Spearman’s rank correlation coefficient.
Results showed that the majority of assessed features had both a high test-retest (71%) and inter-observer (91%) stability in terms of their ICC. Overall, features more stable in repeated PET imaging were also found to be more robust against inter-observer variability.
Results suggest that further research of quantitative imaging features is warranted with respect to more advanced applications of PET imaging as being used for treatment monitoring, outcome prediction or imaging biomarkers.
PMCID: PMC4533992  PMID: 24047337
4.  Metabolically active tumour volume segmentation from dynamic [18F]FLT PET studies in non-small cell lung cancer 
EJNMMI Research  2015;5:26.
Positron emission tomography (PET) with 18F-3′-deoxy-3′-fluorothymidine ([18F]FLT) can be used to assess tumour proliferation. A kinetic-filtering (KF) classification algorithm has been suggested for segmentation of tumours in dynamic [18F]FLT PET data. The aim of the present study was to evaluate KF segmentation and its test-retest performance in [18F]FLT PET in non-small cell lung cancer (NSCLC) patients.
Nine NSCLC patients underwent two 60-min dynamic [18F]FLT PET scans within 7 days prior to treatment. Dynamic scans were reconstructed with filtered back projection (FBP) as well as with ordered subsets expectation maximisation (OSEM). Twenty-eight lesions were identified by an experienced physician. Segmentation was performed using KF applied to the dynamic data set and a source-to-background corrected 50% threshold (A50%) was applied to the sum image of the last three frames (45- to 60-min p.i.). Furthermore, several adaptations of KF were tested. Both for KF and A50% test-retest (TRT) variability of metabolically active tumour volume and standard uptake value (SUV) were evaluated.
KF performed better on OSEM- than on FBP-reconstructed PET images. The original KF implementation segmented 15 out of 28 lesions, whereas A50% segmented each lesion. Adapted KF versions, however, were able to segment 26 out of 28 lesions. In the best performing adapted versions, metabolically active tumour volume and SUV TRT variability was similar to those of A50%. KF misclassified certain tumour areas as vertebrae or liver tissue, which was shown to be related to heterogeneous [18F]FLT uptake areas within the tumour.
For [18F]FLT PET studies in NSCLC patients, KF and A50% show comparable tumour volume segmentation performance. The KF method needs, however, a site-specific optimisation. The A50% is therefore a good alternative for tumour segmentation in NSCLC [18F]FLT PET studies in multicentre studies. Yet, it was observed that KF has the potential to subsegment lesions in high and low proliferative areas.
PMCID: PMC4409618  PMID: 25932353
18F-FLT; Dynamic; PET; NSCLC; Kinetic filtering; Segmentation
5.  A Clinical and Experimental Comparison of Time of Flight PET/MRI and PET/CT Systems 
Molecular Imaging and Biology  2015;17:714-725.
The purpose of the study was to compare image quality and quantitative accuracy of positron emission tomography/magnetic resonance imaging (PET/MRI) and PET/computed tomography (PET/CT) systems with time of flight PET gantries, using phantom and clinical studies.
Identical phantom experiments were performed on both systems. Calibration, uniformity, and standardized uptake value (SUV) recovery were measured. A clinical PET/CT versus PET/MRI comparison was performed using [18F]fluoromethylcholine ([18F]FCH).
Calibration accuracy and image uniformity were comparable between systems. SUV recovery met EANM/EARL requirements on both scanners. Thirty-four lesions with comparable PET image quality were identified. Lesional SUVmax differences of 4 ± 26 % between PET/MRI and PET/CT data were observed (R2 = 0.79, slope = 1.02). In healthy tissues, PET/MRI-derived SUVs were 16 ± 11 % lower than on PET/CT (R2 = 0.98, slope = 0.86).
PET/MRI and PET/CT showed comparable performance with respect to calibration accuracy, image uniformity, and SUV recovery. [18F]FCH uptake values for both healthy tissues and lesions corresponded reasonably well between MR- and CT-based systems, but only in regions free of MR-based attenuation artifacts.
Electronic supplementary material
The online version of this article (doi:10.1007/s11307-015-0826-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4768240  PMID: 25690949
PET/MRI; PET/CT; Multimodality imaging; Prostate cancer; [18F]fluoromethylcholine
6.  FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0 
The purpose of these guidelines is to assist physicians in recommending, performing, interpreting and reporting the results of FDG PET/CT for oncological imaging of adult patients. PET is a quantitative imaging technique and therefore requires a common quality control (QC)/quality assurance (QA) procedure to maintain the accuracy and precision of quantitation. Repeatability and reproducibility are two essential requirements for any quantitative measurement and/or imaging biomarker. Repeatability relates to the uncertainty in obtaining the same result in the same patient when he or she is examined more than once on the same system. However, imaging biomarkers should also have adequate reproducibility, i.e. the ability to yield the same result in the same patient when that patient is examined on different systems and at different imaging sites. Adequate repeatability and reproducibility are essential for the clinical management of patients and the use of FDG PET/CT within multicentre trials. A common standardised imaging procedure will help promote the appropriate use of FDG PET/CT imaging and increase the value of publications and, therefore, their contribution to evidence-based medicine. Moreover, consistency in numerical values between platforms and institutes that acquire the data will potentially enhance the role of semiquantitative and quantitative image interpretation. Precision and accuracy are additionally important as FDG PET/CT is used to evaluate tumour response as well as for diagnosis, prognosis and staging. Therefore both the previous and these new guidelines specifically aim to achieve standardised uptake value harmonisation in multicentre settings.
PMCID: PMC4315529  PMID: 25452219
FDG; PET/CT; Imaging procedure; Tumour; Oncology; Quantification
7.  The use of PET-MRI in the follow-up after radiofrequency- and microwave ablation of colorectal liver metastases 
BMC Medical Imaging  2014;14:27.
Thermal ablation of colorectal liver metastases (CRLM) may result in local progression, which generally appear within a year of treatment. As the timely diagnosis of this progression allows potentially curative local treatment, an optimal follow-up imaging strategy is essential. PET-MRI is a one potential imaging modality, combining the advantages of PET and MRI. The aim of this study is evaluate fluorine-18 deoxyglucose positron emission tomography (FDG) PET-MRI as a modality for detection of local tumor progression during the first year following thermal ablation, as compared to the current standard, FDG PET-CT. The ability of FDG PET-MRI to detect new intrahepatic lesions, and the extent to which FDG PET-MRI alters clinical management, inter-observer variability and patient preference will also be included as secondary outcomes.
Twenty patients undergoing treatment with radiofrequency or microwave ablation for (recurrent) CRLM will be included in this prospective trial. During the first year of follow-up, patients will be scanned at the VU University Medical Center at 3-monthly intervals using a 4-phase liver CT, FDG PET-CT and FDG PET-MRI. Patients treated with chemotherapy <6 weeks prior to scanning or with a contra-indication for MRI will be excluded. MRI will be performed using both whole body imaging (mDixon) and dedicated liver sequences, including diffusion-weighted imaging, T1 in-phase and opposed-phase, T2 and dynamic contrast-enhanced imaging. The results of all modalities will be scored by 4 individual reviewers and inter-observer agreement will be determined. The reference standard will be histology or clinical follow-up. A questionnaire regarding patients’ experience with both modalities will also be completed at the end of the follow-up year.
Improved treatment options for local site recurrences following CRLM ablation mean that accurate post-ablation staging is becoming increasingly important. The combination of the sensitivity of MRI as a detection method for small intrahepatic lesions with the ability of FDG PET to visualize enhanced metabolism at the ablation site suggests that FDG PET-MRI could potentially improve the accuracy of (early) detection of progressive disease, and thus allow swifter and more effective decision-making regarding appropriate treatment.
Trial registration
Trial registration number: NCT01895673
PMCID: PMC4141664  PMID: 25103913
Radiofrequency ablation; Liver neoplasms/secondary; Neoplasm recurrence; Local; Liver neoplasms/surgery; FDG-PET; PET-MRI; Magnetic resonance imaging/methods; Microwave ablation
8.  Diffusion-weighted EPI- and HASTE-MRI and 18F-FDG-PET-CT early during chemoradiotherapy in advanced head and neck cancer 
Main problem
Diffusion-weighted MRI (DW-MRI) has potential to predict chemoradiotherapy (CRT) response in head and neck squamous cell carcinoma (HNSCC) and is generally performed using echo-planar imaging (EPI). However, EPI-DWI is susceptible to geometric distortions. Half-fourier acquisition single-shot turbo spin-echo (HASTE)-DWI may be an alternative. This prospective pilot study evaluates the potential predictive value of EPI- and HASTE-DWI and 18F-fluorodeoxyglucose PET-CT (18F-FDG-PET-CT) early during CRT for locoregional outcome in HNSCC.
Eight patients with advanced HNSCC (7 primary tumors and 25 nodal metastases) scheduled for CRT, underwent DW-MRI (using both EPI- and HASTE-DWI) and 18F-FDG-PET(-CT) pretreatment, early during treatment and three months after treatment. Median follow-up time was 38 months.
No local recurrences were detected during follow-up. Median Apparent Diffusion Coefficient (ADC)EPI-values in primary tumors increased from 77×10–5 mm2/s pretreatment, to 113×10–5 mm2/s during treatment (P=0.02), whereas ADCHASTE did not increase (74 and 74 mm2/s, respectively). Two regional recurrences were diagnosed. During treatment, ADCEPI tended to be higher for patients with regional control [(117.3±12.1)×10–5 mm2/s] than for patients with a recurrence [(98.0±4.2)×10–5 mm2/s]. This difference was not seen with ADCHASTE. No correlations between ΔADCEPI and ΔSUV (Standardized Uptake Value) were found in the primary tumor or nodal metastases.
HASTE-DWI seems to be inadequate in early CRT response prediction, compared to EPI-DWI which has potential to predict locoregional outcome. EPI-DWI and 18F-FDG-PET-CT potentially provide independent information in the early response to treatment, since no correlations were found between ΔADCEPI and ΔSUV.
PMCID: PMC4137183  PMID: 25202659
Chemoradiotherapy (CRT); diffusion-weighted magnetic resonance imaging (DW-MRI); head and neck squamous cell carcinoma (HNSCC); positron emission tomography (PET); treatment response
9.  Recurrent differentiated thyroid cancer: towards personalized treatment based on evaluation of tumor characteristics with PET (THYROPET Study): study protocol of a multicenter observational cohort study 
BMC Cancer  2014;14:405.
After initial treatment of differentiated thyroid carcinoma (DTC) patients are followed with thyroglobulin (Tg) measurements to detect recurrences. In case of elevated levels of Tg and negative neck ultrasonography, patients are treated 'blindly' with Iodine-131 (131I). However, in up to 50% of patients, the post-therapy scan reveals no 131I-targeting of tumor lesions. Such patients derive no benefit from the blind therapy but are exposed to its toxicity. Alternatively, iodine-124 (124I) Positron Emission Tomography/Computed Tomography (PET/CT) has become available to visualize DTC lesions and without toxicity. In addition to this, 18F-fluorodeoxyglucose (18F-FDG) PET/CT detects the recurrent DTC phenotype, which lost the capacity to accumulate iodine. Taken together, the combination of 124I and 18F-FDG PET/CT has potential to stratify patients for treatment with 131I.
In a multicenter prospective observational cohort study the hypothesis that the combination of 124I and 18F-FDG PET/CT can avoid futile 131I treatments in patients planned for ‘blind’ therapy with 131I, is tested.
One hundred patients planned for 131I undergo both 124I and 18F-FDG PET/CT after rhTSH stimulation. Independent of the outcome of the scans, all patients will subsequently receive, after thyroid hormone withdrawal, the 131I therapy. The post 131I therapeutic scintigraphy is compared with the outcome of the 124I and 18F-FDG PET/CT in order to evaluate the diagnostic value of the combined PET modalities.
This study primary aims to reduce the number of futile 131I therapies. Secondary aims are the nationwide introduction of 124I PET/CT by a quality assurance and quality control (QA/QC) program, to correlate imaging outcome with histopathological features, to compare 124I PET/CT after rhTSH and after withdrawal of thyroid hormone, and to compare 124I and 131I dosimetry.
This study aims to evaluate the potential value of the combination of 124I and 18F-FDG PET/CT in the prevention of futile 131I therapies in patients with biochemically suspected recurrence of DTC. To our best knowledge no studies addressed this in a prospective cohort of patients. This is of great clinical importance as a futile 131I is a costly treatment associated with morbidity and therefore should be restricted to those likely to benefit from this treatment.
Trial registration identifier: NCT01641679
PMCID: PMC4058699  PMID: 24906384
Thyroid cancer; Recurrence; 124I; 18F-FDG; PET/CT; Cross-calibration; Thyropet
10.  Relationship between pretreatment FDG-PET and diffusion-weighted MRI biomarkers in diffuse large B-cell lymphoma 
The purpose of this study was to determine the correlation between the 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) standardized uptake value (SUV) and the diffusion-weighted magnetic resonance imaging (MRI) apparent diffusion coefficient (ADC) in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Pretreatment FDG-PET and diffusion-weighted MRI of 21 patients with histologically proven DLBCL were prospectively analyzed. In each patient, maximum, mean and peak standardized uptake value (SUV) was measured in the lesion with visually highest FDG uptake and in the largest lesion. Mean ADC (ADCmean, calculated with b-values of 0 and 1000 s/mm2) was measured in the same lesions. Correlations between FDG-PET metrics (SUVmax, SUVmean, SUVpeak) and ADCmean were assessed using Pearson’s correlation coefficients. In the lesions with visually highest FDG uptake, no significant correlations were found between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.498, P=0.609 and P=0.595, respectively). In the largest lesions, there were no significant correlations either between the SUVmax, SUVmean, SUVpeak and the ADCmean (P=0.992, P=0.843 and P=0.894, respectively). The results of this study indicate that the glycolytic rate as measured by FDG-PET and changes in water compartmentalization and water diffusion as measured by the ADC are independent biological phenomena in newly diagnosed DLBCL. Further studies are warranted to assess the complementary roles of these different imaging biomarkers in the evaluation and follow-up of DLBCL.
PMCID: PMC3999403  PMID: 24795837
FDG-PET; diffusion-weighted MRI; standardized uptake value; apparent diffusion coefficient; diffuse large B-cell lymphoma
11.  Effects of Reusing Baseline Volumes of Interest by Applying (Non-)Rigid Image Registration on Positron Emission Tomography Response Assessments 
PLoS ONE  2014;9(1):e87167.
Reusing baseline volumes of interest (VOI) by applying non-rigid and to some extent (local) rigid image registration showed good test-retest variability similar to delineating VOI on both scans individually. The aim of the present study was to compare response assessments and classifications based on various types of image registration with those based on (semi)-automatic tumour delineation.
Baseline (n = 13), early (n = 12) and late (n = 9) response (after one and three cycles of treatment, respectively) whole body [18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (PET/CT) scans were acquired in subjects with advanced gastrointestinal malignancies. Lesions were identified for early and late response scans. VOI were drawn independently on all scans using an adaptive 50% threshold method (A50). In addition, various types of (non-)rigid image registration were applied to PET and/or CT images, after which baseline VOI were projected onto response scans. Response was classified using PET Response Criteria in Solid Tumors for maximum standardized uptake value (SUVmax), average SUV (SUVmean), peak SUV (SUVpeak), metabolically active tumour volume (MATV), total lesion glycolysis (TLG) and the area under a cumulative SUV-volume histogram curve (AUC).
Non-rigid PET-based registration and non-rigid CT-based registration followed by non-rigid PET-based registration (CTPET) did not show differences in response classifications compared to A50 for SUVmax and SUVpeak,, however, differences were observed for MATV, SUVmean, TLG and AUC. For the latter, these registrations demonstrated a poorer performance for small lung lesions (<2.8 ml), whereas A50 showed a poorer performance when another area with high uptake was close to the target lesion. All methods were affected by lesions with very heterogeneous tracer uptake.
Non-rigid PET- and CTPET-based image registrations may be used to classify response based on SUVmax and SUVpeak. For other quantitative measures future studies should assess which method is valid for response evaluations by correlating with survival data.
PMCID: PMC3904976  PMID: 24489860
12.  18 F-FDG PET standard uptake values of the normal pons in children: establishing a reference value for diffuse intrinsic pontine glioma 
EJNMMI Research  2014;4:8.
Positron emission tomography (PET) scanning with [18 F]fluorodeoxyglucose (18 F-FDG) is a useful diagnostic and prediction tool in brain tumors, but its value in childhood diffuse intrinsic pontine glioma (DIPG) is still unclear. For interpretation of 18 F-FDG PET results in DIPG, uptake values of the normal pons of children of increasing ages are mandatory. The aim of this study was to determine 18 F-FDG standard uptake value ratios (SUVr) of the normal pons and to compare these to those of DIPG.
We studied 36 subjects with a normal, non-affected pons (aged 5 to 23 years) and 6 patients with DIPG (aged 4 to 17 years) who underwent 18 F-FDG PET scanning. Magnetic resonance imaging (MRI) was co-registered to define the regions of interest. SUVr and SUVrmax for the pons/cerebellum (SUVrp/c) and the pons/occipital lobe (SUVrp/o) were calculated. Independent-samples t tests and Mann–Whitney U tests were used to compare the mean SUVr and Pearson’s test for correlations.
For the normal pons, mean SUVrp/c and SUVrp/o were 0.65 (±0.054) and 0.51 (±0.056), respectively. No significant correlations were found between the SUVr of the normal pons and sex, age, nor pontine volume. A modest but statistically significant correlation was found between SUVr and post-injection time acquisition timing. For DIPG, mean SUVrp/c and SUVrp/o were 0.74 (±0.20) and 0.65 (±0.30), respectively, while mean SUVrp(max)/c and SUVrp(max)/o were 1.95 (±0.48) and 1.81 (±0.20), respectively.
The SUVr of the unaffected pons are strikingly constant between children, irrespective of sex and age, and can therefore be well used as a reference value for 18 F-FDG PET studies in DIPG.
PMCID: PMC3910228  PMID: 24472395
Positron emission tomography; [18 F]fluorodeoxyglucose; Pontine glioma; Brain neoplasms; Reference values; Pons
13.  18 F-fluorothymidine uptake in follicular lymphoma and error-prone DNA repair 
EJNMMI Research  2014;4:3.
We observed a disproportional 18 F-fluorothymidine (F-FLT) uptake in follicular lymphoma (FL) relative to its low cell proliferation. We tested the hypothesis that the ‘excess’ uptake of 18 F-FLT in FL is related to error-prone DNA repair and investigated whether this also contributes to 18 F-FLT uptake in diffuse large B cell lymphoma (DLBCL).
We performed immunohistochemical stainings to assess the pure DNA replication marker MIB-1 as well as markers of both DNA replication and repair like PCNA, TK-1 and RPA1 on lymph node biopsies of 27 FLs and 35 DLBCLs. In 7 FL and 15 DLBCL patients, 18 F-FLT-PET had been performed.
18 F-FLT uptake was lower in FL than in DLBCL (median SUVmax 5.7 vs. 8.9, p = 0,004), but the ratio of 18 F-FLT-SUVmax to percentage of MIB-1 positive cells was significantly higher in FL compared with DLBCL (p = 0.001). The median percentage of MIB-1 positive cells was 10% (range, 10% to 20%) in FL and 70% (40% to 80%) in DLBCL. In contrast, the median percentages of PCNA, TK-1 and RPA1 positive cells were 90% (range, 80 to 100), 90% (80 to 100) and 100% (80 to 100) in FL versus 90% (60 to 100), 90% (60 to 100) and 100% (80 to 100) in DLBCL, respectively.
This is the first demonstration of a striking discordance between 18 F-FLT uptake in FL and tumour cell proliferation. High expression of DNA replication and repair markers compared with the pure proliferation marker MIB-1 in FL suggests that this discordance might be due to error-prone DNA repair. While DNA repair-related 18 F-FLT uptake considerably contributes to 18 F-FLT uptake in FL, its contribution to 18 F-FLT uptake in highly proliferative DLBCL is small. This apparently high contribution of DNA repair to the 18 F-FLT signal in FL may hamper studies where 18 F-FLT is used to assess response to cytostatic therapy or to distinguish between FL and transformed lymphoma.
PMCID: PMC3895783  PMID: 24397937
18 F-fluorothymidine uptake; Positron emission tomography; Follicular lymphoma; Non-Hodgkin’s lymphoma; DNA repair
14.  Pemetrexed Induced Thymidylate Synthase Inhibition in Non-Small Cell Lung Cancer Patients: A Pilot Study with 3′-Deoxy-3′-[18F]fluorothymidine Positron Emission Tomography 
PLoS ONE  2013;8(5):e63705.
Pemetrexed is a thymidylate synthase (TS) inhibitor and is effective in non-small cell lung cancer (NSCLC). 3′-deoxy-3′-[18F]fluorothymidine (18F-FLT), a proliferation marker, could potentially identify tumor specific TS-inhibition. The aim of this study was to investigate the effect of pemetrexed-induced TS-inhibition on 18F-FLT uptake 4 hours after pemetrexed administration in metastatic NSCLC patients.
Fourteen NSCLC patients underwent dynamic 18F-FLT positron emission tomography (PET) scans at baseline and 4 hours after the first dose of pemetrexed. Volumes of interest were defined with a 41%, 50% and 70% threshold of the maximum pixel. Kinetic analysis and simplified measures were performed. At one, two, four and six hours after pemetrexed, plasma deoxyuridine was measured as systemic indicator of TS-inhibition. Tumor response measured with response evaluation criteria in solid tumors (RECIST), time to progression (TTP) and overall survival (OS) were determined.
Eleven patients had evaluable 18F-FLT PET scans at baseline and 4 hours after pemetrexed. Two patients had increased 18F-FLT uptake of 35% and 31% after pemetrexed, whereas two other patients had decreased uptake of 31%. In the remaining seven patients 18F-FLT uptake did not change beyond test-retest borders. In all patients deoxyuridine levels raised after administration of pemetrexed, implicating pemetrexed-induced TS-inhibition. 18F-FLT uptake in bone marrow was significantly increased 4 hours after pemetrexed administration. Six weeks after the start of treatment 5 patients had partial response, 4 stable disease and 2 progressive disease. Median TTP was 4.2 months (range 3.0–7.4 months); median OS was 13.0 months (range 5.1–30.8 months). Changes in 18F-FLT uptake were not predictive for tumor response, TTP or OS.
Measuring TS-inhibition in a clinical setting 4 hours after pemetrexed revealed a non-systematic change in 18F-FLT uptake within the tumor. No significant association with tumor response, TTP or OS was observed.
PMCID: PMC3663749  PMID: 23717468
15.  Dual-Phase PET-CT to Differentiate [18F]Fluoromethylcholine Uptake in Reactive and Malignant Lymph Nodes in Patients with Prostate Cancer 
PLoS ONE  2012;7(10):e48430.
To investigate whether time-trends of enhanced [18F]Fluoromethylcholine ([18F]FCH) in lymph nodes (LN) of prostate cancer (PCa) patients can help to discriminate reactive from malignant ones, and whether single time point standardized uptake value (SUV) measurements also suffice.
25 PCa patients with inguinal (presumed benign) and enlarged pelvic LN (presumed malignant) showing enhanced [18F]FCH uptake at dual-phase PET-CT were analyzed. Associations between LN status (benign versus malignant) and SUVmax and SUVmeanA50, determined at 2 min (early) and 30 min (late) post injection, were assessed. We considered two time-trends of [18F]FCH uptake: type A (SUV early > SUV late) and type B (SUV late ≥ SUV early). Histopathology and/or follow-up were used to confirm the assumption that LN with type A pattern are benign, and LN with type B pattern malignant.
Analysis of 54 nodes showed that LN status, time-trends, and ‘late’ (30 min p.i.) SUVmax and SUVmeanA50 parameters were strongly associated (P<0.0001). SUVmax relative difference was the best LN status predictor. All but one inguinal LN showed a decreasing [18F]FCH uptake over time (pattern A), while 95% of the pelvic nodes presented a stable or increasing uptake (pattern B) type.
Time-trends of enhanced [18F]FCH uptake can help to characterize lymph nodes in prostate cancer patients. Single time-point SUV measurements, 30 min p.i., may be a reasonable alternative for predicting benign versus malignant status of lymph nodes, but this remains to be validated in non-enlarged pelvic lymph nodes.
PMCID: PMC3485217  PMID: 23119014
16.  Assessment of tumour size in PET/CT lung cancer studies: PET- and CT-based methods compared to pathology 
EJNMMI Research  2012;2:56.
Positron emission tomography (PET) may be useful for defining the gross tumour volume for radiation treatment planning and for response monitoring of non-small cell lung cancer (NSCLC) patients. The purpose of this study was to compare tumour sizes obtained from CT- and various more commonly available PET-based tumour delineation methods to pathology findings.
Retrospective non-respiratory gated whole body [18F]-fluoro-2-deoxy-D-glucose PET/CT studies from 19 NSCLC patients were used. Several (semi-)automatic PET-based tumour delineation methods and manual CT-based delineation were used to assess the maximum tumour diameter.
50%, adaptive 41% threshold-based and contrast-oriented delineation methods showed good agreement with pathology after removing two outliers (R2=0.82). An absolute SUV threshold of 2.5 also showed a good agreement with pathology after the removal of 5 outliers (R2: 0.79), but showed a significant overestimation in the maximum diameter (19.8 mm, p<0.05). Adaptive 50%, relative threshold level and gradient-based methods did not show any outliers, provided only small, non-significant differences in maximum tumour diameter (<4.7 mm, p>0.10), and showed fair correlation (R2>0.62) with pathology. Although adaptive 70% threshold-based methods showed underestimation compared to pathology (36%), it provided the best precision (SD: 14%) together with good correlation (R2=0.81). Good correlation between CT delineation and pathology was observed (R2=0.77). However, CT delineation showed a significant overestimation compared with pathology (3.8 mm, p<0.05).
PET-based tumour delineation methods provided tumour sizes in agreement with pathology and may therefore be useful to define the (metabolically most) active part of the tumour for radiotherapy and response monitoring purposes.
PMCID: PMC3502476  PMID: 23034289
Tumour delineation; Tumour diameter; FDG PET; Non-small cell lung cancer
17.  Bone formation rather than inflammation reflects Ankylosing Spondylitis activity on PET-CT: a pilot study 
Positron Emission Tomography - Computer Tomography (PET-CT) is an interesting imaging technique to visualize Ankylosing Spondylitis (AS) activity using specific PET tracers. Previous studies have shown that the PET tracers [18F]FDG and [11C](R)PK11195 can target inflammation (synovitis) in rheumatoid arthritis (RA) and may therefore be useful in AS. Another interesting tracer for AS is [18F]Fluoride, which targets bone formation. In a pilot setting, the potential of PET-CT in imaging AS activity was tested using different tracers, with Magnetic Resonance Imaging (MRI) and conventional radiographs as reference.
In a stepwise approach different PET tracers were investigated. First, whole body [18F]FDG and [11C](R)PK11195 PET-CT scans were obtained of ten AS patients fulfilling the modified New York criteria. According to the BASDAI five of these patients had low and five had high disease activity. Secondly, an extra PET-CT scan using [18F]Fluoride was made of two additional AS patients with high disease activity. MRI scans of the total spine and sacroiliac joints were performed, and conventional radiographs of the total spine and sacroiliac joints were available for all patients. Scans and radiographs were visually scored by two observers blinded for clinical data.
No increased [18F]FDG and [11C](R)PK11195 uptake was noticed on PET-CT scans of the first 10 patients. In contrast, MRI demonstrated a total of five bone edema lesions in three out of 10 patients. In the two additional AS patients scanned with [18F]Fluoride PET-CT, [18F]Fluoride depicted 17 regions with increased uptake in both vertebral column and sacroiliac joints. In contrast, [18F]FDG depicted only three lesions, with an uptake of five times lower compared to [18F]Fluoride, and again no [11C](R)PK11195 positive lesions were found. In these two patients, MRI detected nine lesions and six out of nine matched with the anatomical position of [18F]Fluoride uptake. Conventional radiographs showed structural bony changes in 11 out of 17 [18F]Fluoride PET positive lesions.
Our PET-CT data suggest that AS activity is reflected by bone activity (formation) rather than inflammation. The results also show the potential value of PET-CT for imaging AS activity using the bone tracer [18F]Fluoride. In contrast to active RA, inflammation tracers [18F]FDG and [11C](R)PK11195 appeared to be less useful for AS imaging.
PMCID: PMC3446444  PMID: 22471910
18.  Validity of Simplified 3′-Deoxy-3′-[18F]Fluorothymidine Uptake Measures for Monitoring Response to Chemotherapy in Locally Advanced Breast Cancer 
Molecular Imaging and Biology  2012;14(6):777-782.
Positron emission tomography using 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT) has been suggested as a means for monitoring response to chemotherapy. The aim of this study was to evaluate the validity of simplified uptake measures for assessing response to chemotherapy using [18F]FLT in locally advanced breast cancer (LABC).
Fifteen LABC patients underwent dynamic [18F]FLT scans both prior to and after the first cycle of chemotherapy with fluorouracil, epirubicin or doxorubicin, and cyclophosphamide. The net uptake rate constant of [18F]FLT, Ki, determined by non-linear regression (NLR) of an irreversible two-tissue compartment model was used as the gold standard. In addition to Patlak graphical analysis, standardised uptake values (SUV) and tumour-to-whole blood ratio (TBR) were used for analysing [18F]FLT data. Correlations and relationships between simplified uptake measures and NLR before and after chemotherapy were assessed using regression analysis.
No significant differences in both pre- and post-chemotherapy relationships between any of the simplified uptake measures and NLR were found. However, changes in SUV between baseline and post-therapy scans showed a significant negative bias and slope less than one, while TBR did not.
In LABC, TBR instead of SUV may be preferred for monitoring response to chemotherapy with [18F]FLT.
PMCID: PMC3492702  PMID: 22392642
PET; FLT; SUV; Modelling; Response monitoring
19.  Biodistribution, radiation dosimetry and scouting of 90Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin’s lymphoma using 89Zr-ibritumomab tiuxetan and PET 
Positron emission tomography (PET) with 89Zr-ibritumomab tiuxetan can be used to monitor biodistribution of 90Y-ibritumomab tiuxetan as shown in mice. The aim of this study was to assess biodistribution and radiation dosimetry of 90Y-ibritumomab tiuxetan in humans on the basis of 89Zr-ibritumomab tiuxetan imaging, to evaluate whether co-injection of a therapeutic amount of 90Y-ibritumomab tiuxetan influences biodistribution of 89Zr-ibritumomab tiuxetan and whether pre-therapy scout scans with 89Zr-ibritumomab tiuxetan can be used to predict biodistribution of 90Y-ibritumomab tiuxetan and the dose-limiting organ during therapy.
Seven patients with relapsed B-cell non-Hodgkin’s lymphoma scheduled for autologous stem cell transplantation underwent PET scans at 1, 72 and 144 h after injection of ~70 MBq 89Zr-ibritumomab tiuxetan and again 2 weeks later after co-injection of 15 MBq/kg or 30 MBq/kg 90Y-ibritumomab tiuxetan. Volumes of interest were drawn over liver, kidneys, lungs, spleen and tumours. Ibritumomab tiuxetan organ absorbed doses were calculated using OLINDA. Red marrow dosimetry was based on blood samples. Absorbed doses to tumours were calculated using exponential fits to the measured data.
The highest 90Y absorbed dose was observed in liver (3.2 ± 1.8 mGy/MBq) and spleen (2.9 ± 0.7 mGy/MBq) followed by kidneys and lungs. The red marrow dose was 0.52 ± 0.04 mGy/MBq, and the effective dose was 0.87 ± 0.14 mSv/MBq. Tumour absorbed doses ranged from 8.6 to 28.6 mGy/MBq. Correlation between predicted pre-therapy and therapy organ absorbed doses as based on 89Zr-ibritumomab tiuxetan images was high (Pearson correlation coefficient r = 0.97). No significant difference between pre-therapy and therapy tumour absorbed doses was found, but correlation was lower (r = 0.75).
Biodistribution of 89Zr-ibritumomab tiuxetan is not influenced by simultaneous therapy with 90Y-ibritumomab tiuxetan, and 89Zr-ibritumomab tiuxetan scout scans can thus be used to predict biodistribution and dose-limiting organ during therapy. Absorbed doses to spleen were lower than those previously estimated using 111In-ibritumomab tiuxetan. The dose-limiting organ in patients undergoing stem cell transplantation is the liver.
PMCID: PMC3276758  PMID: 22218876
Immuno-PET; Molecular imaging; Radioimmunotherapy; Ibritumomab tiuxetan; 89Zr; 90Y; Dosimetry; Lymphoma
20.  Measurement of metabolic tumor volume: static versus dynamic FDG scans 
EJNMMI Research  2011;1:35.
Metabolic tumor volume assessment using positron-emission tomography [PET] may be of interest for both target volume definition in radiotherapy and monitoring response to therapy. It has been reported, however, that metabolic volumes derived from images of metabolic rate of glucose (generated using Patlak analysis) are smaller than those derived from standardized uptake value [SUV] images. The purpose of this study was to systematically compare metabolic tumor volume assessments derived from SUV and Patlak images using a variety of (semi-)automatic tumor delineation methods in order to identify methods that can be used reliably on (whole body) SUV images.
Dynamic [18F]-fluoro-2-deoxy-D-glucose [FDG] PET data from 10 lung and 8 gastrointestinal cancer patients were analyzed retrospectively. Metabolic tumor volumes were derived from both Patlak and SUV images using five different types of tumor delineation methods, based on various thresholds or on a gradient.
In general, most tumor delineation methods provided more outliers when metabolic volumes were derived from SUV images rather than Patlak images. Only gradient-based methods showed more outliers for Patlak-based tumor delineation. Median measured metabolic volumes derived from SUV images were larger than those derived from Patlak images (up to 59% difference) when using a fixed percentage threshold method. Tumor volumes agreed reasonably well (< 26% difference) when applying methods that take local signal-to-background ratio [SBR] into account.
Large differences may exist in metabolic volumes derived from static and dynamic FDG image data. These differences depend strongly on the delineation method used. Delineation methods that correct for local SBR provide the most consistent results between SUV and Patlak images.
PMCID: PMC3285530  PMID: 22214394
tumor delineation; tumor volume; FDG PET; Patlak; SUV
21.  Quantitative relationship between coronary artery calcium score and hyperemic myocardial blood flow as assessed by hybrid 15O-water PET/CT imaging in patients evaluated for coronary artery disease 
Journal of Nuclear Cardiology  2011;19(2):256-264.
The incremental value of CAC over traditional risk factors to predict coronary vasodilator dysfunction and inherent myocardial blood flow (MBF) impairment is only scarcely documented (MBF). The aim of this study was therefore to evaluate the relationship between CAC content, hyperemic MBF, and coronary flow reserve (CFR) in patients undergoing hybrid 15O-water PET/CT imaging.
We evaluated 173 (mean age 56 ± 10, 78 men) patients with a low to intermediate likelihood for coronary artery disease (CAD), without a documented history of CAD, undergoing vasodilator stress 15O-water PET/CT and CAC scoring. Obstructive coronary artery disease was excluded by means of invasive (n = 44) or CT-based coronary angiography (n = 129).
91 of 173 patients (52%) had a CAC score of zero. Of those with CAC, the CAC score was 0.1-99.9, 100-399.9, and ≥400 in 31%, 12%, and 5% of patients, respectively. Global CAC score showed significant inverse correlation with hyperemic MBF (r = −0.32, P < .001). With increasing CAC score, there was a decline in hyperemic MBF on a per-patient basis [3.70, 3.30, 2.68, and 2.53 mL · min−1 · g−1, with total CAC score of 0, 0.1-99.9, 100-399.9, and ≥400, respectively (P < .001)]. CFR showed a stepwise decline with increasing levels of CAC (3.70, 3.32, 2.94, and 2.93, P < .05). Multivariate analysis, including age, BMI, and CAD risk factors, revealed that only age, male gender, BMI, and hypercholesterolemia were associated with reduced stress perfusion. Furthermore, only diabetes and age were independently associated with CFR.
In patients without significant obstructive CAD, a greater CAC burden is associated with a decreased hyperemic MBF and CFR. However, this association disappeared after adjustment for traditional CAD risk factors. These results suggest that CAC does not add incremental value regarding hyperemic MBF and CFR over established CAD risk factors in patients without obstructive CAD.
PMCID: PMC3313028  PMID: 22076826
Coronary artery calcium; hyperemic myocardial blood flow; coronary risk factors
22.  Coronary risk factors and myocardial blood flow in patients evaluated for coronary artery disease: a quantitative [15O]H2O PET/CT study 
There has been increasing interest in quantitative myocardial blood flow (MBF) imaging over the last years and it is expected to become a routinely used technique in clinical practice. Positron emission tomography (PET) using [15O]H2O is the established gold standard for quantification of MBF in vivo. A fundamental issue when performing quantitative MBF imaging is to define the limits of MBF in a clinically suitable population. The aims of the present study were to determine the limits of MBF and to determine the relationship among coronary artery disease (CAD) risk factors, gender and MBF in a predominantly symptomatic patient cohort without significant CAD.
A total of 128 patients (mean age 54 ± 10 years, 50 men) with a low to intermediate pretest likelihood of CAD were referred for noninvasive evaluation of CAD using a hybrid PET/computed tomography (PET/CT) scanner. MBF was quantified with [15O]H2O at rest and during adenosine-induced hyperaemia. Obstructive CAD was excluded in these patients by means of invasive or CT-based coronary angiography.
Global average baseline MBF values were 0.91 ± 0.34 and 1.09 ± 0.30  ml·min−1·g−1 (range 0.54–2.35  and 0.59–2.75 ml·min−1·g−1) in men and women, respectively (p < 0.01). However, no gender-dependent difference in baseline MBF was seen following correction for rate–pressure product (0.98 ± 0.45 and 1.09 ± 0.30 ml·min−1·g−1 in men and women, respectively; p = 0.08). Global average hyperaemic MBF values were 3.44 ± 1.20 ml·min−1·g−1 in the whole study population, and 2.90 ± 0.85 and 3.78 ± 1.27 ml·min−1·g−1 (range 1.52–5.22 and 1.72–8.15 ml·min−1·g−1) in men and women, respectively (p < 0.001). Multivariate analysis identified male gender, age and body mass index as having an independently negative impact on hyperaemic MBF.
Gender, age and body mass index substantially influence reference values and should be corrected for when interpreting hyperaemic MBF values.
PMCID: PMC3227802  PMID: 22005845
Myocardial blood flow; Positron emission tomography; Non-obstructive CAD; CAD risk factors; Gender
23.  Impact of [18F]FDG PET imaging parameters on automatic tumour delineation: need for improved tumour delineation methodology 
Delineation of tumour boundaries is important for quantification of [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) studies and for definition of biological target volumes in radiotherapy. Several (semi-)automatic tumour delineation methods have been proposed, but these methods differ substantially in estimating tumour volume and their performance may be affected by imaging parameters. The main purpose of this study was to explore the performance dependence of various (semi-)automatic tumour delineation methods on different imaging parameters, i.e. reconstruction parameters, noise levels and tumour characteristics, and thereby the need for standardization or inter-institute calibration.
Six different types of delineation methods were evaluated by assessing accuracy and precision in estimating tumour volume from simulations and phantom experiments. The evaluated conditions were various tumour sizes, iterative reconstruction algorithm settings and image filtering, tumour to background ratios (TBR), noise levels and region growing initializations.
The accuracy of all automatic delineation methods was influenced when imaging parameters were varied. The performance of all tumour delineation methods depends on variation of TBR, image resolution and image noise level, and to a lesser extent on number of iterations during image reconstruction or the initialization method of the region generation. For sphere sizes larger than 20 mm diameter a contrast-oriented method provided the most accurate results, on average, over all simulated conditions. For threshold-based methods the accuracy of tumour delineation improved after image denoising/filtering.
The accuracy and precision of all studied tumour delineation methods was affected by physiological and imaging parameters. The latter illustrates the need for optimizing imaging parameters and/or for careful calibration and optimization of delineation methods.
Electronic supplementary material
The online version of this article (doi:10.1007/s00259-011-1899-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3228515  PMID: 21858528
Tumour delineation; Volume of interest (VOI); [18F]FDG; Positron emission tomography (PET); Tumour volume
24.  Evaluation of a cumulative SUV-volume histogram method for parameterizing heterogeneous intratumoural FDG uptake in non-small cell lung cancer PET studies 
Standardized uptake values (SUV) are commonly used for quantification of whole-body [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) studies. Changes in SUV following therapy, however, only provide a proper measure of response in case of homogeneous FDG uptake in the tumour. The purpose of this study was therefore to implement and characterize a method that enables quantification of heterogeneity in tumour FDG uptake.
Cumulative SUV-volume histograms (CSH), describing % of total tumour volume above % threshold of maximum SUV (SUVmax), were calculated. The area under a CSH curve (AUC) is a quantitative index of tumour uptake heterogeneity, with lower AUC corresponding to higher degrees of heterogeneity. Simulations of homogeneous and heterogeneous responses were performed to assess the value of AUC-CSH for measuring uptake and/or response heterogeneity. In addition, partial volume correction and image denoising was applied prior to calculating AUC-CSH. Finally, the method was applied to a number of human FDG scans.
Partial volume correction and noise reduction improved CSH curves. Both simulations and clinical examples showed that AUC-CSH values corresponded with level of tumour heterogeneity and/or heterogeneity in response. In contrast, this correspondence was not seen with SUVmax alone. The results indicate that the main advantage of AUC-CSH above other measures, such as 1/COV (coefficient of variation), is the possibility to measure or normalize AUC-CSH in different ways.
AUC-CSH might be used as a quantitative index of heterogeneity in tracer uptake. In response monitoring studies it can be used to address heterogeneity in response.
PMCID: PMC3151405  PMID: 21617975
Positron emission tomography (PET); Standardized uptake value (SUV); Intratumoural heterogeneity; Cumulative SUV-volume histogram (CSH); Intensity-volume histograms (IVH)
25.  Measuring response to therapy using FDG PET: semi-quantitative and full kinetic analysis 
Imaging with positron emission tomography (PET) using 18F-2-fluoro-2-deoxy-D-glucose (FDG) plays an increasingly important role for response assessment in oncology. Several methods for quantifying FDG PET results exist. The goal of this study was to analyse and compare various semi-quantitative measures for response assessment with full kinetic analysis, specifically in assessment of novel therapies.
Baseline and response dynamic FDG studies from two different longitudinal studies (study A: seven subjects with lung cancer and study B: six subjects with gastrointestinal cancer) with targeted therapies were reviewed. Quantification of tumour uptake included full kinetic methods, i.e. nonlinear regression (NLR) and Patlak analyses, and simplified measures such as the simplified kinetic method (SKM) and standardized uptake value (SUV). An image-derived input function was used for NLR and Patlak analysis.
There were 18 and 9 lesions defined for two response monitoring studies (A and B). In all cases there was excellent correlation between Patlak- and NLR-derived response (R2 > 0.96). Percentage changes seen with SUV were significantly different from those seen with Patlak for both studies (p < 0.05). After correcting SUV for plasma glucose, SUV and Patlak responses became similar for study A, but large differences remained for study B. Further analysis revealed that differences in responses amongst methods in study B were primarily due to changes in the arterial input functions.
Use of simplified methods for assessment of drug efficacy or treatment response may provide different results than those seen with full kinetic analysis.
PMCID: PMC3070082  PMID: 21210109
FDG PET; SUV; Patlak; NLR; Response monitoring

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