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68 Ga-NODAGA-exendin-4 is a promising tracer for β-cell imaging using PET/CT. Possible applications include preoperative visualization of insulinomas and discrimination between focal and diffuse forms of congenital hyperinsulinism. There is also a significant role for this tracer in extending our knowledge on the role of β-cell mass in the pathophysiology of type 1 and type 2 diabetes by enabling noninvasive quantification of tracer uptake as a measure for β-cell mass. Calculating radiation doses from this tracer is important to assess its safety for use in patients (including young children) with benign diseases and healthy individuals. Methods: Six patients with hyperinsulinemic hypoglycemia were included. After intravenous injection of 100 MBq of the tracer, 4 successive PET/CT scans were obtained at 30, 60, 120, and 240 min after injection. Tracer activity in the pancreas, kidneys, duodenum, and remainder of the body were determined, and time-integrated activity coefficients for the measured organs were calculated. OLINDA/EXM software, version 1.1, was applied to calculate radiation doses using the reference adult male and female models and to estimate radiation doses to children. Results: The mean total effective dose for adults was very low (0.71 ± 0.07 mSv for a standard injected dose of 100 MBq). The organ with the highest absorbed dose was the kidney (47.3 ± 10.2 mGy/100 MBq). The estimated effective dose was 2.32 ± 0.32 mSv for an injected dose of 20 MBq in newborns. This dose decreased to 0.77 ± 0.11 mSv/20 MBq for 1-y-old children and 0.59 ± 0.05 mSv for an injected dose of 30 MBq in 5-y-old children. Conclusion: Our human PET/CT-based dosimetric calculations show that the effective radiation doses from the novel tracer 68 Ga-NODAGA-exendin-4 are very low for adults and children. The doses are lower than reported for other polypeptide tracers such as somatostatin analogs (2.1-2.6 mSv/100 MBq) and are beneficial for application as a research tool, especially when repeated examinations are needed., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Absolute quantification of radiotracer distribution using SPECT/CT imaging is of great importance for dosimetry aimed at personalized radionuclide precision treatment. However, its accuracy depends on many factors. Using phantom measurements, this multi-vendor and multi-center study evaluates the quantitative accuracy and inter-system variability of various SPECT/CT systems as well as the effect of patient size, processing software and reconstruction algorithms on recovery coefficients (RC)., Methods: Five SPECT/CT systems were included: Discovery™ NM/CT 670 Pro (GE Healthcare), Precedence™ 6 (Philips Healthcare), Symbia Intevo™, and Symbia™ T16 (twice) (Siemens Healthineers). Three phantoms were used based on the NEMA IEC body phantom without lung insert simulating body mass indexes (BMI) of 25, 28, and 47 kg/m 2 . Six spheres (0.5-26.5 mL) and background were filled with 0.1 and 0.01 MBq/mL 99m Tc-pertechnetate, respectively. Volumes of interest (VOI) of spheres were obtained by a region growing technique using a 50% threshold of the maximum voxel value corrected for background activity. RC, defined as imaged activity concentration divided by actual activity concentration, were determined for maximum (RC max ) and mean voxel value (RC mean ) in the VOI for each sphere diameter. Inter-system variability was expressed as median absolute deviation (MAD) of RC. Acquisition settings were standardized. Images were reconstructed using vendor-specific 3D iterative reconstruction algorithms with institute-specific settings used in clinical practice and processed using a standardized, in-house developed processing tool based on the SimpleITK framework. Additionally, all data were reconstructed with a vendor-neutral reconstruction algorithm (Hybrid Recon™; Hermes Medical Solutions)., Results: RC decreased with decreasing sphere diameter for each system. Inter-system variability (MAD) was 16 and 17% for RC mean and RC max , respectively. Standardized reconstruction decreased this variability to 4 and 5%. High BMI hampers quantification of small lesions (< 10 ml)., Conclusion: Absolute SPECT quantification in a multi-center and multi-vendor setting is feasible, especially when reconstruction protocols are standardized, paving the way for a standard for absolute quantitative SPECT.

Appropriate attenuation correction is important for accurate quantification of SUVs in PET. Patient respiratory motion can introduce a spatial mismatch between respiration-gated PET and CT, reducing quantitative accuracy. In this study, the effect of a patient-specific breathing-instructed CT protocol on the spatial alignment between CT and amplitude-based optimal respiration-gated PET images was investigated. Methods: 18 F-FDG PET/CT imaging was performed on 20 patients. In addition to the standard low-dose free-breathing CT, breath-hold CT was performed. The amplitude limits of the respiration-gated PET were used to instruct patients to hold their breath during CT acquisition at a similar amplitude level. Spatial mismatch was quantified using the position differences between the lung-liver transition in PET and CT images, the distance between PET and CT lesions' centroids, and the amount of overlap as indicated by the Jaccard similarity coefficient. Furthermore, the effect on attenuation correction was quantified by measuring SUVs, metabolic tumor volume, and total lesion glycolysis (TLG) of lung lesions. Results: All patients found the breathing instructions feasible; however, 4 patients had trouble complying with the instructions. In total, 18 patients were included. The average distance between the lung-liver transition between PET and CT was significantly reduced for breath-hold CT (1.7 ± 2.1 mm), compared with standard CT (5.6 ± 7.3 mm) ( P = 0.049). Furthermore, the mean distance between the lesions' centroids on PET and CT was significantly smaller for breath-hold CT (3.6 ± 2.0 mm) than for standard CT (5.5 ± 6.5 mm) ( P = 0.040). Quantification of lung lesion SUV was significantly affected, with a higher SUV mean when breath-hold CT (6.3 ± 3.9 g/cm 3 ) was used for image reconstruction than for standard CT (6.1 ± 3.8 g/cm 3 ) ( P = 0.044). Though metabolic tumor volume was not significantly different, TLG reached statistical significance. Conclusion: Optimal respiration-gated PET in combination with patient-specific breathing-instructed CT results in an improved alignment between PET and CT images and shows an increased SUV mean and TLG. Even though the effects are small, a more accurate SUV and TLG determination is of importance for a more stable PET quantification, which is relevant for radiotherapy planning and therapy response monitoring., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

Static single-time-frame 18 F-FDG PET/CT is useful for the localization and functional characterization of pheochromocytomas and paragangliomas (PPGLs). 18 F-FDG uptake varies between PPGLs with different genotypes, and the highest SUVs are observed in cases of succinate dehydrogenase ( SDH ) mutations, possibly related to enhanced aerobic glycolysis in tumor cells. The exact determinants of 18 F-FDG accumulation in PPGLs are unknown. We performed dynamic PET/CT scanning to assess whether in vivo 18 F-FDG pharmacokinetics has added value over static PET to distinguish different genotypes. Methods: Dynamic 18 F-FDG PET/CT was performed on 13 sporadic PPGLs and 13 PPGLs from 11 patients with mutations in SDH complex subunits B and D, von Hippel-Lindau ( VHL ), RET, and neurofibromin 1 ( NF1 ). Pharmacokinetic analysis was performed using a 2-tissue-compartment tracer kinetic model. The derived transfer rate-constants for transmembranous glucose flux ( K 1 [in], k 2 [out]) and intracellular phosphorylation ( k 3 ), along with the vascular blood fraction (V b ), were analyzed using nonlinear regression analysis. Glucose metabolic rate (MR glc ) was calculated using Patlak linear regression analysis. The SUV max of the lesions was determined on additional static PET/CT images. Results: Both MR glc and SUV max were significantly higher for hereditary cluster 1 ( SDHx, VHL ) tumors than for hereditary cluster 2 ( RET, NF1 ) and sporadic tumors ( P < 0.01 and P < 0.05, respectively). Median k 3 was significantly higher for cluster 1 than for sporadic tumors ( P < 0.01). Median V b was significantly higher for cluster 1 than for cluster 2 tumors ( P < 0.01). No statistically significant differences in K 1 and k 2 were found between the groups. Cutoffs for k 3 to distinguish between cluster 1 and other tumors were established at 0.015 min -1 (100% sensitivity, 15.8% specificity) and 0.636 min -1 (100% specificity, 85.7% sensitivity). MR glc significantly correlated with SUV max ( P = 0.001) and k 3 ( P = 0.002). Conclusion: In vivo metabolic tumor profiling in patients with PPGL can be achieved by assessing 18 F-FDG pharmacokinetics using dynamic PET/CT scanning. Cluster 1 PPGLs can be reliably identified by a high 18 F-FDG phosphorylation rate., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

In recent years, different metal artifact reduction methods have been developed for CT. These methods have only recently been introduced for PET/CT even though they could be beneficial for interpretation, segmentation, and quantification of the PET/CT images. In this study, phantom and patient scans were analyzed visually and quantitatively to measure the effect on PET images of iterative metal artifact reduction (iMAR) of CT data. Methods: The phantom consisted of 2 types of hip prostheses in a solution of 18 F-FDG and water. 18 F-FDG PET/CT scans of 14 patients with metal implants (either dental implants, hip prostheses, shoulder prostheses, or pedicle screws) and 68 Ga-labeled prostate-specific membrane antigen ( 68 Ga-PSMA) PET/CT scans of 7 patients with hip prostheses were scored by 2 experienced nuclear medicine physicians to analyze clinical relevance. For all patients, a lesion was located in the field of view of the metal implant. Phantom and patients were scanned in a PET/CT scanner. The standard low-dose CT scans were processed with the iMAR algorithm. The PET data were reconstructed using attenuation correction provided by both standard CT and iMAR-processed CT. Results: For the phantom scans, cold artifacts were visible on the PET image. There was a 30% deficit in 18 F-FDG concentration, which was restored by iMAR processing, indicating that metal artifacts on CT images induce quantification errors in PET data. The iMAR algorithm was useful for most patients. When iMAR was used, the confidence in interpretation increased or stayed the same, with an average improvement of 28% ± 20% (scored on a scale of 0%-100% confidence). The SUV increase or decrease depended on the type of metal artifact. The mean difference in absolute values of SUV mean of the lesions was 3.5% ± 3.3%. Conclusion: The iMAR algorithm increases the confidence of the interpretation of the PET/CT scan and influences the SUV. The added value of iMAR depends on the indication for the PET/CT scan, location and size/type of the prosthesis, and location and extent of the disease., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

In recent years, there have been multiple advances in positron emission tomography/computed tomography (PET/CT) that improve cancer imaging. The present generation of PET/CT scanners introduces new hardware, software, and acquisition methods. This review describes these new developments, which include time-of-flight (TOF), point-spread-function (PSF), maximum-a-posteriori (MAP) based reconstruction, smaller voxels, respiratory gating, metal artefact reduction, and administration of quadratic weight-dependent 18 F-fluorodeoxyglucose (FDG) activity. Also, hardware developments such as continuous bed motion (CBM), (digital) solid-state photodetectors and combined PET and magnetic resonance (MR) systems are explained. These novel techniques have a significant impact on cancer imaging, as they result in better image quality, improved small lesion detectability, and more accurate quantification of radiopharmaceutical uptake. This influences cancer diagnosis and staging, as well as therapy response monitoring and radiotherapy planning. Finally, the possible impact of these developments on the European Association of Nuclear Medicine (EANM) guidelines and EANM Research Ltd. (EARL) accreditation for FDG-PET/CT tumor imaging is discussed.

Purpose To assess whether dynamic fluorine 18 ( 18 F) fluorodeoxyglucose (FDG) positron emission tomography (PET) has added value over static 18 F-FDG PET for tumor delineation in non-small cell lung cancer (NSCLC) radiation therapy planning by using pathology volumes as the reference standard and to compare pharmacokinetic rate constants of 18 F-FDG metabolism, including regional variation, between NSCLC histologic subtypes. Materials and Methods The study was approved by the institutional review board. Patients gave written informed consent. In this prospective observational study, 1-hour dynamic 18 F-FDG PET/computed tomographic examinations were performed in 35 patients (36 resectable NSCLCs) between 2009 and 2014. Static and parametric images of glucose metabolic rate were obtained to determine lesion volumes by using three delineation strategies. Pathology volume was calculated from three orthogonal dimensions (n = 32). Whole tumor and regional rate constants and blood volume fraction (V B ) were computed by using compartment modeling. Results Pathology volumes were larger than PET volumes (median difference, 8.7-25.2 cm 3 ; Wilcoxon signed rank test, P < .001). Static fuzzy locally adaptive Bayesian (FLAB) volumes corresponded best with pathology volumes (intraclass correlation coefficient, 0.72; P < .001). Bland-Altman analyses showed the highest precision and accuracy for static FLAB volumes. Glucose metabolic rate and 18 F-FDG phosphorylation rate were higher in squamous cell carcinoma (SCC) than in adenocarcinoma (AC), whereas V B was lower (Mann-Whitney U test or t test, P = .003, P = .036, and P = .019, respectively). Glucose metabolic rate, 18 F-FDG phosphorylation rate, and V B were less heterogeneous in AC than in SCC (Friedman analysis of variance). Conclusion Parametric images are not superior to static images for NSCLC delineation. FLAB-based segmentation on static 18 F-FDG PET images is in best agreement with pathology volume and could be useful for NSCLC autocontouring. Differences in glycolytic rate and V B between SCC and AC are relevant for research in targeting agents and radiation therapy dose escalation. © RSNA, 2016 Online supplemental material is available for this article.

Radiolabeled exendin is used for non-invasive quantification of beta cells in the islets of Langerhans in vivo. High accumulation of radiolabeled exendin in the islets raised concerns about possible radiation-induced damage to these islets in man. In this work, islet absorbed doses resulting from exendin-imaging were calculated by combining whole organ dosimetry with small scale dosimetry for the islets. Our model contains the tissues with high accumulation of radiolabeled exendin: kidneys, pancreas and islets. As input for the model, data from a clinical study (radiolabeled exendin distribution in the human body) and from a preclinical study with Biobreeding Diabetes Prone (BBDP) rats (islet-to-exocrine uptake ratio, beta cell mass) were used. We simulated 111 In-exendin and 68 Ga-exendin absorbed doses in patients with differences in gender, islet size, beta cell mass and radiopharmaceutical uptake in the kidneys. In all simulated cases the islet absorbed dose was small, maximum 1.38 mGy for 68 Ga and 66.0 mGy for 111 In. The two sources mainly contributing to the islet absorbed dose are the kidneys (33-61%) and the islet self-dose (7.5-57%). In conclusion, all islet absorbed doses are low (<70 mGy), so even repeated imaging will hardly increase the risk on diabetes.

Purpose: Low count single photon emission computed tomography (SPECT) is becoming more important in view of whole body SPECT and reduction of radiation dose. In this study, we investigated the performance of several 3D ordered subset expectation maximization (3DOSEM) and maximum a posteriori (MAP) algorithms for reconstructing low count SPECT images., Materials and Methods: Phantom experiments were conducted using the National Electrical Manufacturers Association (NEMA) NU2 image quality (IQ) phantom. The background compartment of the phantom was filled with varying concentrations of pertechnetate and indiumchloride, simulating various clinical imaging conditions. Images were acquired using a hybrid SPECT/CT scanner and reconstructed with 3DOSEM and MAP reconstruction algorithms implemented in Siemens Syngo MI.SPECT (Flash3D) and Hermes Hybrid Recon Oncology (Hyrid Recon 3DOSEM and MAP). Image analysis was performed by calculating the contrast recovery coefficient (CRC),percentage background variability (N%), and contrast-to-noise ratio (CNR), defined as the ratio between CRC and N%. Furthermore, image distortion is characterized by calculating the aspect ratio (AR) of ellipses fitted to the hot spheres. Additionally, the performance of these algorithms to reconstruct clinical images was investigated., Results: Images reconstructed with 3DOSEM algorithms demonstrated superior image quality in terms of contrast and resolution recovery when compared to images reconstructed with filtered-back-projection (FBP), OSEM and 2DOSEM. However, occurrence of correlated noise patterns and image distortions significantly deteriorated the quality of 3DOSEM reconstructed images. The mean AR for the 37, 28, 22, and 17mm spheres was 1.3, 1.3, 1.6, and 1.7 respectively. The mean N% increase in high and low count Flash3D and Hybrid Recon 3DOSEM from 5.9% and 4.0% to 11.1% and 9.0%, respectively. Similarly, the mean CNR decreased in high and low count Flash3D and Hybrid Recon 3DOSEM from 8.7 and 8.8 to 3.6 and 4.2, respectively. Regularization with smoothing priors could suppress these noise patterns at the cost of reduced image contrast. The mean N% was 6.4% and 6.8% for low count QSP and MRP MAP reconstructed images. Alternatively, regularization with an anatomical Bowhser prior resulted in sharp images with high contrast, limited image distortion, and low N% of 8.3% in low count images, although some image artifacts did occur. Analysis of clinical images suggested that the same effects occur in clinical imaging., Conclusion: Image quality of low count SPECT acquisitions reconstructed with modern 3DOSEM algorithms is deteriorated by the occurrence of correlated noise patterns and image distortions. The artifacts observed in the phantom experiments can also occur in clinical imaging., (Copyright © 2015. Published by Elsevier GmbH.)

Background: Quantitative single photon emission computed tomography (SPECT) is challenging, especially for pancreatic beta cell imaging with 111 In-exendin due to high uptake in the kidneys versus much lower uptake in the nearby pancreas. Therefore, we designed a three-dimensionally (3D) printed phantom representing the pancreas and kidneys to mimic the human situation in beta cell imaging. The phantom was used to assess the effect of different reconstruction settings on the quantification of the pancreas uptake for two different, commercially available software packages., Methods: 3D-printed, hollow pancreas and kidney compartments were inserted into the National Electrical Manufacturers Association (NEMA) NU2 image quality phantom casing. These organs and the background compartment were filled with activities simulating relatively high and low pancreatic 111 In-exendin uptake for, respectively, healthy humans and type 1 diabetes patients. Images were reconstructed using Siemens Flash 3D and Hermes Hybrid Recon, with varying numbers of iterations and subsets and corrections. Images were visually assessed on homogeneity and artefacts, and quantitatively by the pancreas-to-kidney activity concentration ratio., Results: Phantom images were similar to clinical images and showed comparable artefacts. All corrections were required to clearly visualize the pancreas. Increased numbers of subsets and iterations improved the quantitative performance but decreased homogeneity both in the pancreas and the background. Based on the phantom analyses, the Hybrid Recon reconstruction with 6 iterations and 16 subsets was found to be most suitable for clinical use., Conclusions: This work strongly contributed to quantification of pancreatic 111 In-exendin uptake. It showed how clinical images of 111 In-exendin can be interpreted and enabled selection of the most appropriate protocol for clinical use.

Accurate measurement of intratumor heterogeneity using parameters of texture on PET images is essential for precise characterization of cancer lesions. In this study, we investigated the influence of respiratory motion and varying noise levels on quantification of textural parameters in patients with lung cancer., Methods: We used an optimal-respiratory-gating algorithm on the list-mode data of 60 lung cancer patients who underwent 18 F-FDG PET. The images were reconstructed using a duty cycle of 35% (percentage of the total acquired PET data). In addition, nongated images of varying statistical quality (using 35% and 100% of the PET data) were reconstructed to investigate the effects of image noise. Several global image-derived indices and textural parameters (entropy, high-intensity emphasis, zone percentage, and dissimilarity) that have been associated with patient outcome were calculated. The clinical impact of optimal respiratory gating and image noise on assessment of intratumor heterogeneity was evaluated using Cox regression models, with overall survival as the outcome measure. The threshold for statistical significance was adjusted for multiple comparisons using Bonferroni correction., Results: In the lower lung lobes, respiratory motion significantly affected quantification of intratumor heterogeneity for all textural parameters (P < 0.007) except entropy (P > 0.007). The mean increase in entropy, dissimilarity, zone percentage, and high-intensity emphasis was 1.3% ± 1.5% (P = 0.02), 11.6% ± 11.8% (P = 0.006), 2.3% ± 2.2% (P = 0.002), and 16.8% ± 17.2% (P = 0.006), respectively. No significant differences were observed for lesions in the upper lung lobes (P > 0.007). Differences in the statistical quality of the PET images affected the textural parameters less than respiratory motion, with no significant difference observed. The median follow-up time was 35 mo (range, 7-39 mo). In multivariate analysis for overall survival, total lesion glycolysis and high-intensity emphasis were the two most relevant image-derived indices and were considered to be independent significant covariates for the model regardless of the image type considered., Conclusion: The tested textural parameters are robust in the presence of respiratory motion artifacts and varying levels of image noise., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Unlabelled: (18)F-FDG PET is well established in the field of oncology for diagnosis and staging purposes and is increasingly being used to assess therapeutic response and prognosis. Many quantitative indices can be used to characterize tumors on (18)F-FDG PET images, such as SUVmax, metabolically active tumor volume (MATV), total lesion glycolysis, and, more recently, the proposed intratumor uptake heterogeneity features. Although most PET data considered within this context concern the analysis of activity distribution using images obtained from a single static acquisition, parametric images generated from dynamic acquisitions and reflecting radiotracer kinetics may provide additional information. The purpose of this study was to quantify differences between volumetry, uptake, and heterogeneity features extracted from static and parametric PET images of non-small cell lung carcinoma (NSCLC) in order to provide insight on the potential added value of parametric images., Methods: Dynamic (18)F-FDG PET/CT was performed on 20 therapy-naive NSCLC patients for whom primary surgical resection was planned. Both static and parametric PET images were analyzed, with quantitative parameters (MATV, SUVmax, SUVmean, heterogeneity) being extracted from the segmented tumors. Differences were investigated using Spearman rank correlation and Bland-Altman analysis., Results: MATV was slightly smaller on static images (-2% ± 7%), but the difference was not significant (P = 0.14). All derived parameters, including those characterizing tumor functional heterogeneity, correlated strongly between static and parametric images (r = 0.70-0.98, P ≤ 0.0006), exhibiting differences of less than ±25%., Conclusion: In NSCLC primary tumors, parametric and static baseline (18)F-FDG PET images provided strongly correlated quantitative features for both standard (MATV, SUVmax, SUVmean) and heterogeneity quantification. Consequently, heterogeneity quantification on parametric images does not seem to provide significant complementary information compared with static SUV images., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background and Purpose: This study evaluated the use of total lesion glycolysis (TLG) determined by different automatic segmentation algorithms, for early response monitoring in non-small cell lung cancer (NSCLC) patients during concomitant chemoradiotherapy., Materials and Methods: Twenty-seven patients with locally advanced NSCLC treated with concomitant chemoradiotherapy underwent (18)F-fluorodeoxyglucose (FDG) PET/CT imaging before and in the second week of treatment. Segmentation of the primary tumours and lymph nodes was performed using fixed threshold segmentation at (i) 40% SUVmax (T40), (ii) 50% SUVmax (T50), (iii) relative-threshold-level (RTL), (iv) signal-to-background ratio (SBR), and (v) fuzzy locally adaptive Bayesian (FLAB) segmentation. Association of primary tumour TLG (TLGT), lymph node TLG (TLGLN), summed TLG (TLGS=TLGT+TLGLN), and relative TLG decrease (ΔTLG) with overall-survival (OS) and progression-free survival (PFS) was determined using univariate Cox regression models., Results: Pretreatment TLGT was predictive for PFS and OS, irrespective of the segmentation method used. Inclusion of TLGLN improved disease and early response assessment, with pretreatment TLGS more strongly associated with PFS and OS than TLGT for all segmentation algorithms. This was also the case for ΔTLGS, which was significantly associated with PFS and OS, with the exception of RTL and T40., Conclusions: ΔTLGS was significantly associated with PFS and OS, except for RTL and T40. Inclusion of TLGLN improves early treatment response monitoring during concomitant chemoradiotherapy with FDG-PET., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: This radiotherapy planning study evaluated tumour delineation using both optimally respiratory gated and nongated fluorine-18 fluorodeoxyglucose-PET (F-FDG-PET)., Methods: For 22 non-small-cell lung tumours, both scans were used to create the nongated and gated (g) gross tumour volumes (GTVg) together with the accompanying clinical target volumes (CTV) and planning target volumes (PTV). The size of the target volumes (TV) was evaluated and the accompanying radiotherapy plans were created to study the radiation doses to the organs at risk (OAR)., Results: The median volumes of GTVg, CTVg and PTVg were statistically significantly smaller compared with the corresponding nongated volumes, resulting in a median TV reduction of 0.5 cm (interquartile range 0.1-1.2), 1.5 cm (-0.2 to 7.0) and 2.3 cm (-0.5 to 11.3) for the GTVg, CTVg and PTVg, respectively. For the OAR, only the percentage of lung (GTV included) receiving at least 35 Gy was significantly smaller after gating, with a median difference in lung volume receiving at least 35 Gy of 5.7 cm (interquartile range -0.8 to 30.50)., Conclusion: Compared with nongated F-FDG-PET, the TVs obtained with optimally respiratory gated F-FDG-PET were significantly smaller, however, without a clinically relevant difference in radiation dose to the OAR.

Background: Red bone marrow (RBM) toxicity is dose-limiting in (pretargeted) radioimmunotherapy (RIT). Previous blood-based and two-dimensional (2D) image-based methods have failed to show a clear dose-response relationship. We developed a three-dimensional (3D) image-based RBM dosimetry approach using the Monte Carlo-based 3D radiobiological dosimetry (3D-RD) software and determined its additional value for predicting RBM toxicity., Methods: RBM doses were calculated for 13 colorectal cancer patients after pretargeted RIT with the two-step administration of an anti-CEA × anti-HSG bispecific monoclonal antibody and a (177)Lu-labeled di-HSG-peptide. 3D-RD RBM dosimetry was based on the lumbar vertebrae, delineated on single photon emission computed tomography (SPECT) scans acquired directly, 3, 24, and 72 h after (177)Lu administration. RBM doses were correlated to hematologic effects, according to NCI-CTC v3 and compared with conventional 2D cranium-based and blood-based dosimetry results. Tumor doses were calculated with 3D-RD, which has not been possible with 2D dosimetry. Tumor-to-RBM dose ratios were calculated and compared for (177)Lu-based pretargeted RIT and simulated pretargeted RIT with (90)Y., Results: 3D-RD RBM doses of all seven patients who developed thrombocytopenia were higher (range 0.43 to 0.97 Gy) than that of the six patients without thrombocytopenia (range 0.12 to 0.39 Gy), except in one patient (0.47 Gy) without thrombocytopenia but with grade 2 leucopenia. Blood and 2D image-based RBM doses for patients with grade 1 to 2 thrombocytopenia were in the same range as in patients without thrombocytopenia (0.14 to 0.29 and 0.11 to 0.26 Gy, respectively). Blood-based RBM doses for two grade 3 to 4 patients were higher (0.66 and 0.51 Gy, respectively) than the others, and the cranium-based dose of only the grade 4 patient was higher (0.34 Gy). Tumor-to-RBM dose ratios would increase by 25% on average when treating with (90)Y instead of (177)Lu., Conclusions: 3D dosimetry identifies patients at risk of developing any grade of RBM toxicity more accurately than blood- or 2D image-based methods. It has the added value to enable calculation of tumor-to-RBM dose ratios.

Unlabelled: Respiratory motion during PET can cause inaccuracies in the quantification of radiotracer uptake, which negatively affects PET-guided radiotherapy planning. Quantitative accuracy can be improved by respiratory gating. However, additional miscalculation of standardized uptake value (SUV) in PET images can be caused by inappropriate attenuation correction due to a spatial mismatch between gated PET and CT. In this study, the effect of respiration-triggered CT on the spatial match between CT and amplitude-based respiration-gated PET images is investigated., Methods: (18)F-FDG PET/CT was performed in 38 patients. Images were acquired on 2 PET/CT scanners, one without and one with continuous bed motion during PET acquisition. The amplitude limits of the amplitude-based respiration-gated PET were used for the respiration-triggered sequential low-dose CT. Both standard (spiral) and triggered CT scans were used to reconstruct the PET data. Spatial mismatch was quantified using the position difference between the lung-liver boundary in PET and CT images, the distance between PET and CT lung lesions' centroids, and the amount of overlap of lesions indicated by the Jaccard similarity coefficient. Furthermore, the effect of attenuation correction was quantified by measuring SUVs in lung lesions., Results: For triggered CT, the average distance between the lung-liver boundary in PET and CT was significantly reduced (4.5 ± 6.7 mm) when compared with standard CT (9.2 ± 8.1 mm) (P < 0.001). The mean distance between the lesions' centroids in PET and CT images was 6.3 ± 4.0 and 5.6 ± 4.2 mm (P = 0.424), for the standard and triggered CT, respectively. Similarly, the Jaccard similarity coefficient was 0.30 ± 0.21 and 0.32 ± 0.20 (P = 0.609) for standard and triggered CT, respectively. For 6 lesions, there was no overlap of PET and CT when the standard CT was used; compared with the triggered CT, these lesions showed (partial) overlap. The maximum and mean SUV increase of the PET/CT compared with the PET/triggered CT was 5.7% ± 11.2% (P < 0.001) and 6.1% ± 10.2% (P = 0.001), respectively., Conclusion: Amplitude-based respiration-gated PET in combination with respiration-triggered CT resulted in a significantly improved match in the area of the liver dome and a significantly higher SUV for lung lesions. However, lesions in the lungs did not show a consistent improvement in spatial match., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Objectives: Respiratory motion artefacts during positron emission tomography (PET) deteriorate image quality, potentially introducing diagnostic uncertainties. The objective of this study was to determine the impact of optimal respiratory gating on clinical staging and management of patients with primary lung cancer., Materials and Methods: From our fast-track outpatient diagnostic program, 55 patients with primary lung cancer, who underwent whole body [(18)F]-fluorodeoxyglucose (FDG) PET, were included. Respiratory gating was performed on bed positions covering the thorax and abdomen. Independent reading was conducted by two nuclear medicine physicians. The observers scored the number and anatomical location of the lesions, lymph node basins and the presence of distant metastasis in non-gated and gated images. A tumor (T), lymph node (N), and metastasis (M) stage was assigned to each patient according to the 7th revision of the TNM classification. Staging accuracy was determined using histopathological data and follow-up CT imaging. In addition, a management plan was created for each patient based on non-gated and gated images by an experienced pulmonologist., Results: For nuclear medicine physician 1 and 2, respiratory gating resulted in detection of more lesions in five and eight patients (9% and 15%) respectively. However, this did not result in any migration in T or M-stage. Migration in N-stage was observed in four and seven patients (7% and 13%) for nuclear medicine physician 1 and 2 respectively. Staging accuracy was slightly improved when respiratory gating was performed. Furthermore, there was substantial agreement in patient management between non-gated and gated images., Conclusions: Respiratory gating improved staging accuracy, mainly in assessment of lymph node involvement. However, the effect on patient management was limited due to the presence of already advanced disease stage in many patients. These findings suggest that the expected impact of respiratory gating will be solely on management of patients with early disease., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: This study aimed to determine the contribution of each muscle of the lower limb to walking using positron emission tomography (PET) with [F]-fluorodeoxyglucose (FDG). Furthermore, we compared our results obtained using volumetric analysis of entire muscles with those obtained using a more traditional approach considering the uptake in only one slice in each segment., Methods: Ten healthy subjects walked on a treadmill at self-selected comfortable walking speed for 90 min, 60 min before and 30 min after intravenous injection of 50-MBq FDG. A PET/computerized tomography scan of the lower limb was made subsequently. The three-dimensional contours of 39 muscles in the left lower limb were semiautomatically determined from magnetic resonance imaging scans. After nonrigidly registering the magnetic resonance imaging to the computerized tomography scans, we superimposed the muscle contours on the PET scans., Results: The muscles with the highest median FDG uptake among all subjects were the soleus, gluteus maximus, vastus lateralis, gastrocnemius medialis, and adductor magnus. We found a wide range of FDG uptake values among subjects, including in some of the most important muscles involved in walking (e.g., soleus, gluteus medius, gastrocnemius medialis). Compared with the volumetric analysis, the single slice analysis did not yield an accurate estimate of the FDG uptake in many of the most active muscles, including the gluteus medius and minimus (overestimated) as well as all the thigh muscles (underestimated)., Conclusions: The distribution of FDG among the muscles varied between subjects, suggesting that each subject had a unique activation pattern. The FDG uptake as estimated from single slices did not correspond well to the uptake obtained from volumetric analysis, which illustrates the added value of our novel three-dimensional image analysis techniques.

Despite considerable improvements in the treatment options for advanced-stage non-small-cell lung cancer (NSCLC), disease-specific survival remains poor. With the aim of improving patient outcome, the treatment paradigm of locally advanced NSCLC has shifted from solely radiotherapy towards combined and intensified treatment approaches. Also, treatment for patients with stage IV (oligo)metastatic NSCLC has evolved rapidly, with therapeutic options that include a number of targeted agents, surgery, and stereotactic ablative radiotherapy. However, personalizing treatment to the individual patient remains difficult and requires monitoring of biological parameters responsible for treatment resistance to facilitate treatment selection, guidance, and adaptation. PET is a well-established molecular imaging platform that enables non-invasive quantification of many biological parameters that are relevant to both local and systemic therapy. With increasing clinical evidence, PET has gradually evolved from a purely diagnostic tool to a multifunctional imaging modality that can be utilized for treatment selection, adaptation, early response monitoring, and follow up in patients with NSCLC. Herein, we provide a comprehensive overview of the available clinical data on the use of this modality in this setting, and discuss future perspectives of PET imaging for the clinical management of patients with locally advanced and metastatic NSCLC.

Objectives: Respiratory motion during PET imaging introduces quantitative and diagnostic inaccuracies, which may result in non-optimal patient management. This study investigated the effects of respiratory gating on image quantification using an amplitude-based optimal respiratory gating (ORG) algorithm., Methods: Whole body FDG-PET/CT was performed in 66 lung cancer patients. The respiratory signal was obtained using a pressure sensor integrated in an elastic belt placed around the patient's thorax. ORG images were reconstructed with 50%, 35%, and 20% of acquired PET data (duty cycle). Lesions were grouped into anatomical locations. Differences in lesion volume between ORG and non-gated images, and mean FDG-uptake (SUVmean) were calculated., Results: Lesions in the middle and lower lobes demonstrated a significant SUVmean increase for all duty cycles and volume decrease for duty cycles of 35% and 20%. Significant increase in SUVmean and decrease in volume for lesions in the upper lobes were observed for a 20% duty cycle. The SUVmean increase for central lesions was significant for all duty cycles, whereas a significant volume decrease was observed for a duty cycle of 20%., Conclusions: This study implies that ORG could influence clinical PET imaging with respect to response monitoring and radiotherapy planning., Key Points: Quantifying lesion volume and uptake in PET is important for patient management. Respiratory motion artefacts introduce inaccuracies in quantification of PET images. Amplitude-based optimal respiratory gating maintains image quality through selection of duty cycle. The effect of respiratory gating on lesion quantification depends on anatomical location.

Unlabelled: Respiratory motion during PET has a significant effect on the quantification of radiotracer uptake in PET images. Even when respiratory motion is considered using PET gating techniques, inaccuracies in standardized uptake values can be caused by inappropriate attenuation correction due to a spatial mismatch between PET and CT. In this study, the effect of breath-hold CT imaging on the spatial match between CT and amplitude-based respiratory-gated PET images is investigated., Methods: Whole-body (18)F-FDG PET/CT imaging was performed in 52 patients with 125 lung lesions. (18)F-FDG PET was performed using optimized, amplitude-based respiratory gating. For CT, 36 patients were randomly assigned to the free-breathing (FB) group and 16 to the rest-expiratory breath-hold (BH) group. Spatial mismatch between the PET and CT images was quantified by measuring the distance between the centroids of PET and CT lesions and calculating the Jaccard similarity coefficient (JSC)., Results: In the upper lobes, the average distance between the centroids of the PET and CT lesions was 4.7 ± 3.1 and 6.0 ± 3.0 mm for the FB and BH groups, respectively (P = 0.11). For the middle and lower lobes, the distances were 5.8 ± 4.3 and 5.1 ± 2.9 mm (P = 0.70), respectively, and for the central region 4.8 ± 4.6 and 5.6 ± 2.0 mm (P = 0.24), respectively. The JSC for the upper lobes was 0.28 ± 0.17 and 0.28 ± 0.19, for the FB and the BH group, respectively (P = 0.83). For the middle and lower lobes, the JSC was 0.22 ± 0.16 and 0.28 ± 0.18 (P = 0.20), respectively, and for the central region 0.39 ± 0.17 and 0.13 ± 0.04 (P = 0.04), respectively., Conclusion: Providing breathing instructions to the patients during the CT acquisition did not improve the spatial alignment between the respiratory-gated PET images and the CT images. The difficulty experienced in using this clinical protocol, such as patient compliance and operator dependence, emphasizes the need for other strategies., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Introduction: Biological features of non-small-cell lung carcinomas (NSCLCs) are important determinants for prognosis. In this study, differences in glucose metabolism between adeno- and squamous cell NSCLCs were quantified using the hypoxia and glycolysis-related markers glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), monocarboxylate transporter 1 (MCT1) and 4 (MCT4) vasculature, and 18-fluoro-2-deoxyglucose (FDG)-uptake. Relevance of these markers for disease-free survival (DFS) was analyzed., Methods: Patients with curatively resected stage I to II and resectable stage IIIA, cN0-1 adeno- or squamous cell NSCLC, of whom fresh-frozen lung resection biopsies and pretreatment FDG-positron emission tomography (PET) scans were available, were included in this study (n = 108). FDG-uptake was quantified by calculating total lesion glycolysis (TLG). Metabolic marker expression was measured by immunofluorescent staining (protein) and quantitative polymerase chain reaction (messenger ribonucleic acid [mRNA]). Patients were retrospectively evaluated for DFS., Results: mRNA and protein expression of metabolic markers, with the exception of MCT4, and TLG were higher in squamous cell carcinomas than in adenocarcinomas, whereas adenocarcinomas were better vascularized. Adenocarcinomas had a worse DFS compared with squamous cell carcinomas (p = 0.016) based on the potential to metastasize. High TLG was associated with a worse DFS only in adenocarcinomas., Conclusion: Our findings suggest that the adenocarcinomas exhibit glycolysis under normoxic conditions, whereas squamous cell carcinomas are exposed to diffusion-limited hypoxia resulting in a very high anaerobic glycolytic rate. Although squamous cell carcinomas have a higher FDG-uptake, in general regarded as a poor prognostic factor, adenocarcinomas have a higher metastatic potential and a worse DFS. These findings show that FDG-PET should be interpreted in relation to histology. This may improve the prognostic potential of FDG-PET and may aid in exploiting FDG-PET in treatment strategies allied to histology.

Purpose: Pretargeted radioimmunotherapy (PRIT) with bispecific antibodies (bsMAb) and a radiolabeled peptide reduces the radiation dose to normal tissues. Here we report the accuracy of an (111)In-labeled pretherapy test dose for personalized dosing of (177)Lu-labeled IMP288 following pretargeting with the anti-CEA × anti-hapten bsMAb, TF2, in patients with metastatic colorectal cancer (CRC)., Methods: In 20 patients bone marrow absorbed doses (BMD) and doses to the kidneys were predicted based on blood samples and scintigrams acquired after (111)In-IMP288 injection for individualized dosing of PRIT with (177)Lu-IMP288. Different dose schedules were studied, varying the interval between the bsMAb and peptide administration (5 days vs. 1 day), increasing the bsMAb dose (75 mg vs. 150 mg), and lowering the peptide dose (100 μg vs. 25 μg)., Results: TF2 and (111)In/(177)Lu-IMP288 clearance was highly variable. A strong correlation was observed between peptide residence times and individual TF2 blood concentrations at the time of peptide injection (Spearman's ρ = 0.94, P < 0.0001). PRIT with 7.4 GBq (177)Lu-IMP288 resulted in low radiation doses to normal tissues (BMD <0.5 Gy, kidney dose <3 Gy). Predicted (177)Lu-IMP288 BMD were in good agreement with the actual measured doses (mean ± SD difference -0.0026 ± 0.028 mGy/MBq). Hematological toxicity was mild in most patients, with only two (10 %) having grade 3-4 thrombocytopenia. A correlation was found between platelet toxicity and BMD (Spearman's ρ = 0.58, P = 0.008). No nonhematological toxicity was observed., Conclusion: These results show that individual high activity doses in PRIT in patients with CEA-expressing CRC could be safely administered by predicting the radiation dose to red marrow and kidneys, based on dosimetric analysis of a test dose of TF2 and (111)In-IMP288.

Purpose: Radiotherapy of head and neck cancer induces changes in tumour cell proliferation during treatment, which can be depicted by the PET tracer (18)F-fluorothymidine (FLT). In this study, three advanced semiautomatic PET segmentation methods for delineation of the proliferative tumour volume (PV) before and during (chemo)radiotherapy were compared and related to clinical outcome., Methods: The study group comprised 46 patients with 48 squamous cell carcinomas of the head and neck, treated with accelerated (chemo)radiotherapy, who underwent FLT PET/CT prior to treatment and in the 2nd and 4th week of therapy. Primary gross tumour volumes were visually delineated on CT images (GTV CT). PVs were visually determined on all PET scans (PV VIS). The following semiautomatic segmentation methods were applied to sequential PET scans: background-subtracted relative-threshold level (PV RTL), a gradient-based method using the watershed transform algorithm and hierarchical clustering analysis (PV W&C), and a fuzzy locally adaptive Bayesian algorithm (PV FLAB)., Results: Pretreatment PV VIS correlated best with PV FLAB and GTV CT. Correlations with PV RTL and PV W&C were weaker although statistically significant. During treatment, the PV VIS, PV W&C and PV FLAB significant decreased over time with the steepest decline over time for PV FLAB. Among these advanced segmentation methods, PV FLAB was the most robust in segmenting volumes in the third scan (67 % of tumours as compared to 40 % for PV W&C and 27 % for PV RTL). A decrease in PV FLAB above the median between the pretreatment scan and the scan obtained in the 4th week was associated with better disease-free survival (4 years 90 % versus 53 %)., Conclusion: In patients with head and neck cancer, FLAB proved to be the best performing method for segmentation of the PV on repeat FLT PET/CT scans during (chemo)radiotherapy. This may potentially facilitate radiation dose adaptation to changing PV.

Aim: The aim of the study was to compare standardized uptake values (SUVs) in liver tissue obtained using whole-body unenhanced low-dose computed tomography (CT) with those obtained using contrast-enhanced high-dose CT for PET attenuation correction in PET/CT scanning., Materials and Methods: Ten patients scheduled for (18)F-FDG PET and contrast-enhanced CT of the abdomen were included in this study. PET data were corrected for attenuation using both unenhanced low-dose CT images and contrast-enhanced high-dose CT images. Differences in SUV(mean) and SUV(max) were compared in three liver regions., Results: The average SUV(mean) and SUV(max) of all regions were 2.43 and 2.91 g/cm in the unenhanced data set and 2.53 and 3.17 g/cm in the enhanced data set, respectively., Conclusion: SUV(mean) and SUV(max) were significantly elevated in liver tissue when using PET images corrected for attenuation with contrast-enhanced high-dose CT compared with PET images corrected with unenhanced low-dose CT. Although the differences may not be relevant in daily clinical practice, unenhanced and contrast-enhanced CT should not be selected randomly for attenuation correction if exact quantitative results are required.

Unlabelled: This study investigated the feasibility of quantitative accuracy and harmonized image quality in (89)Zr-PET/CT multicenter studies., Methods: Five PET/CT scanners from 3 vendors were included. (89)Zr activity was measured in a central dose calibrator before delivery. Local activity assays were based on volume as well as on the local dose calibrator. Accuracy and image noise were determined from a cross calibration experiment. Image quality was assessed from recovery coefficients derived from different volume-of-interest (VOI) methods (VOI A 50%, based on a 3-dimensional isocontour at 50% of the maximum voxel value with local background correction; VOI Max, based on the voxel with the highest uptake; and VOI 3Dpeak, based on a spheric VOI of 1.2-cm diameter positioned so as to maximize the enclosed average). PET images were analyzed before and after postreconstruction smoothing, applied to match image noise., Results: PET/CT accuracy and image noise ranged from -3% to 10% and from 13% to 22%, respectively. VOI 3Dpeak produced the most reproducible recovery coefficients. After calibration of the local dose calibrator to the central dose calibrator, differences between the local activity assays were within 6%., Conclusion: This study showed that quantitative accuracy and harmonized image quality can be reached in (89)Zr PET/CT multicenter studies.

Purpose: Several studies showed potential for monitoring response to systemic therapy in metastatic colorectal cancer patients with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Before (18)F-FDG PET can be implemented for response evaluation the repeatability should be known. This study was performed to assess the magnitude of the changes in standardized uptake value (SUV), volume and total lesion glycolysis (TLG) in colorectal liver metastases and validate the biological basis of (18)F-FDG PET in colorectal liver metastases., Methods: Twenty patients scheduled for liver metastasectomy underwent two (18)F-FDG PET scans within 1 week. Bland-Altman analysis was performed to assess repeatability of SUV(max), SUV(mean), volume and TLG. Tumours were delineated using an adaptive threshold method (PET(SBR)) and a semiautomatic fuzzy locally adaptive Bayesian (FLAB) delineation method., Results: Coefficient of repeatability of SUV(max) and SUV(mean) were ∼39 and ∼31 %, respectively, independent of the delineation method used and image reconstruction parameters. However, repeatability was worse in recently treated patients. The FLAB delineation method improved the repeatability of the volume and TLG measurements compared to PET(SBR), from coefficients of repeatability of over 85 % to 45 % and 57 % for volume and TLG, respectively. Glucose transporter 1 (GLUT1) expression correlated to the SUV(mean). Vascularity (CD34 expression) and tumour hypoxia (carbonic anhydrase IX expression) did not correlate with (18)F-FDG PET parameters., Conclusion: In conclusion, repeatability of SUV(mean) and SUV(max) was mainly affected by preceding systemic therapy. The repeatability of tumour volume and TLG could be improved using more advanced and robust delineation approaches such as FLAB, which is recommended when (18)F-FDG PET is utilized for volume or TLG measurements. Improvement of repeatability of PET measurements, for instance by dynamic PET scanning protocols, is probably necessary to effectively use PET for early response monitoring.

Over the last decade, small-animal PET imaging has become a vital platform technology in cancer research. With the development of molecularly targeted therapies and drug combinations requiring evaluation of different schedules, the number of animals to be imaged within a PET experiment has increased. This paper describes experimental design requirements to reach statistical significance, based on the expected change in tracer uptake in treated animals as compared to the control group, the number of groups that will be imaged, and the expected intra-animal variability for a given tracer. We also review how high-throughput studies can be performed in dedicated small-animal PET, high-resolution clinical PET systems and planar positron imaging systems by imaging more than one animal simultaneously. Customized beds designed to image more than one animal in large-bore small-animal PET scanners are described. Physics issues related to the presence of several rodents within the field of view (i.e. deterioration of spatial resolution and sensitivity as the radial and the axial offsets increase, respectively, as well as a larger effect of attenuation and the number of scatter events), which can be assessed by using the NEMA NU 4 image quality phantom, are detailed.

Purpose: [(18)F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) images are usually quantitatively analyzed in "whole-tumor" volumes of interest. Also parameters determined with dynamic PET acquisitions, such as the Patlak glucose metabolic rate (MR(glc)) and pharmacokinetic rate constants of two-tissue compartment modeling, are most often derived per lesion. We propose segmentation of tumors to determine tumor heterogeneity, potentially useful for dose-painting in radiotherapy and elucidating mechanisms of FDG uptake., Methods and Materials: In 41 patients with 104 lesions, dynamic FDG-PET was performed. On MR(glc) images, tumors were segmented in quartiles of background subtracted maximum MR(glc) (0%-25%, 25%-50%, 50%-75%, and 75%-100%). Pharmacokinetic analysis was performed using an irreversible two-tissue compartment model in the three segments with highest MR(glc) to determine the rate constants of FDG metabolism., Results: From the highest to the lowest quartile, significant decreases of uptake (K(1)), washout (k(2)), and phosphorylation (k(3)) rate constants were seen with significant increases in tissue blood volume fraction (V(b))., Conclusions: Tumor regions with highest MR(glc) are characterized by high cellular uptake and phosphorylation rate constants with relatively low blood volume fractions. In regions with less metabolic activity, the blood volume fraction increases and cellular uptake, washout, and phosphorylation rate constants decrease. These results support the hypothesis that regional tumor glucose phosphorylation rate is not dependent on the transport of nutrients (i.e., FDG) to the tumor., (Copyright © 2012 Elsevier Inc. All rights reserved.)

During the treatment of colorectal liver metastases, evaluation of treatment efficacy is of the utmost importance for decision making. The aim of the present study was to explore the ability of preclinical imaging modalities to detect experimental liver metastases. Nine male Wag/Rij rats underwent a laparotomy with intraportal injection of CC531 tumor cells. On days 7, 10, and 14 after tumor induction, sequential positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) scans were acquired of each rat. At each time point, three rats were euthanized and the metastases in the liver were documented histologically. Topographically, the liver was divided into eight segments and the image findings were compared on a segment-by-segment basis with the histopathologic findings. Sixty-four liver segments were analyzed, 20 of which contained tumor deposits. The overall sensitivity of PET, CT, and MRI was 30%, 25%, and 20%, respectively. For the detection of tumors with a histologic diameter exceeding 1 mm (n  =  8), the sensitivity of PET, CT, and MRI was 63%, 38%, and 38%, respectively. The overall specificity of PET, CT, and MRI was 98%, 100%, and 93%, respectively. This study showed encouraging detectability and sensitivity for preclinical imaging of small liver tumors and provides valuable information on the imaging techniques for designing future protocols.

Unlabelled: This study aimed to estimate the radiation absorbed doses to normal tissues and tumor lesions during radioimmunotherapy with (177)Lu-cG250. Serial planar scintigrams after injection of (111)In-cG250 or (177)Lu-cG250 in patients with metastasized renal cell carcinoma were analyzed quantitatively. The estimated radiation doses were correlated with observed hematologic toxicity. In addition, the accuracy of the predicted therapeutic absorbed doses, based on diagnostic (111)In-cG250 data, were determined., Methods: Twenty patients received a diagnostic tracer activity of (111)In-cG250 (185 MBq), followed by radioimmunotherapy with (177)Lu-cG250. The administered activity of (177)Lu-cG250 was escalated by entering 3 patients at each activity level starting at 1,110 MBq/m(2), with increments of 370 MBq/m(2). After each diagnostic and therapeutic administration, whole-body scintigraphic images and pharmacokinetic data were acquired. Hematologic toxicity was graded using the Common Toxicity Criteria, version 3.0. Diagnostic (111)In-cG250 data were used to simulate (177)Lu and (90)Y data by correcting for the difference in physical decay. Absorbed doses were calculated for the whole body, red marrow, organs, and tumor metastases for the therapeutic (177)Lu-cG250, simulated (177)Lu-cG250, and simulated (90)Y-cG250 data., Results: Observed hematologic toxicity, especially platelet toxicity, correlated significantly with the administered activity (r = 0.85), whole-body absorbed dose (r = 0.65), and red marrow dose (r = 0.62 and 0.75). An inverse relationship between the mass and absorbed dose of the tumor lesions was observed. Calculated mean absorbed doses were similar for the simulated and measured (177)Lu-cG250 data. Absorbed doses (whole body and red marrow) based on the simulated (177)Lu-cG250 data correlated with the observed platelet toxicity (r = 0.65 and 0.82). The tumor-to-red marrow dose ratio was higher for radioimmunotherapy with (177)Lu-cG250 than for radioimmunotherapy with (90)Y-cG250, indicating that (177)Lu has a wider therapeutic window for radioimmunotherapy with cG250 than (90)Y., Conclusion: In patients with metastasized renal cell carcinoma, hematologic toxicity after treatment with (177)Lu-cG250 can be predicted on the basis of administered activity and whole-body and red marrow-absorbed dose. Diagnostic (111)In-cG250 data can be used to accurately predict absorbed doses and myelotoxicity of radioimmunotherapy with (177)Lu-cG250. These estimations indicate that in these patients, higher radiation doses can be guided to the tumors with (177)Lu-cG250 than with (90)Y-cG250.

Unlabelled: Several commercial small-animal SPECT scanners using multipinhole collimation are presently available. However, generally accepted standards to characterize the performance of these scanners do not exist. Whereas for small-animal PET, the National Electrical Manufacturers Association (NEMA) NU 4 standards have been defined in 2008, such standards are still lacking for small-animal SPECT. In this study, the image quality parameters associated with the NEMA NU 4 image quality phantom were determined for a small-animal multipinhole SPECT scanner., Methods: Multiple whole-body scans of the NEMA NU 4 image quality phantom of 1-h duration were performed in a U-SPECT-II scanner using (99m)Tc with activities ranging between 8.4 and 78.2 MBq. The collimator contained 75 pinholes of 1.0-mm diameter and had a bore diameter of 98 mm. Image quality parameters were determined as a function of average phantom activity, number of iterations, postreconstruction spatial filter, and scatter correction. In addition, a mouse was injected with (99m)Tc-hydroxymethylene diphosphonate and was euthanized 6.5 h after injection. Multiple whole-body scans of this mouse of 1-h duration were acquired for activities ranging between 3.29 and 52.7 MBq., Results: An increase in the number of iterations was accompanied by an increase in the recovery coefficients for the small rods (RC(rod)), an increase in the noise in the uniform phantom region, and a decrease in spillover ratios for the cold-air- and water-filled scatter compartments (SOR(air) and SOR(wat)). Application of spatial filtering reduced image noise but lowered RC(rod). Filtering did not influence SOR(air) and SOR(wat). Scatter correction reduced SOR(air) and SOR(wat). The effect of total phantom activity was primarily seen in a reduction of image noise with increasing activity. RC(rod), SOR(air), and SOR(wat) were more or less constant as a function of phantom activity. The relation between acquisition and reconstruction settings and image quality was confirmed in the (99m)Tc-hydroxymethylene diphosphonate mouse scans., Conclusion: Although developed for small-animal PET, the NEMA NU 4 image quality phantom was found to be useful for small-animal SPECT as well, allowing for objective determination of image quality parameters and showing the trade-offs between several of these parameters on variation of acquisition and reconstruction settings.

Aim: In therapy response monitoring by [¹⁸F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), different tumor delineations are used, resulting in different values for change in glucose metabolic rate (ΔMR(glu)). We propose a technique to compare metabolic rates in a region of interest (ROI) based on fixed volumes rather than on fixed thresholds. This method involves change in lesion size., Methods: In 49 patients with colorectal carcinoma (CRC) and 50 patients with non-small cell lung carcinoma (NSCLC) scheduled for chemotherapy, FDG-PET was performed at baseline and during chemotherapy. A ROI(fixed thresholds) was determined by using a 50% threshold on both baseline and follow-up FDG-PET. A ROI(fixed volumes) was determined by using a 50% threshold, determined on the series with the largest tumor volume. This ROI(fixed volumes) is used on consecutive scans. Predictive effects of both methods were investigated by survival analysis for overall and progression free survival., Results: In CRC, only ROI(fixed volumes) based ΔMR(glu) showed significant predictive ability. In NSCLC, both techniques showed significant predictive ability. During multivariate analysis, ROI(fixed volumes) determined ΔMR(glu) was an independent predictor for both overall and progression free survival in NSCLC whereas ROI(fixed thresholds) determined MRglu was not. After dichotomization at the median ΔMR(glu), median survival ratio was higher in ROI(fixed volumes) than ROI(fixed thresholds) for CRC (overall survival: 1.78 vs 1.25, progression free survival: 1.57 vs 1.21) and NSCLC (overall survival: 2.01 vs 2.01, progression free survival: 2.93 vs 2.13)., Conclusion: ROI(fixed volumes) based ΔMR(glu) shows better correlation with survival than ΔMR(glu) determined from a ROI(fixed thresholds).

AIM: In therapy response monitoring by [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), different tumor delineations are used, resulting in different values for change in glucose metabolic rate (DMRglu). We propose a technique to compare metabolic rates in a region of interest (ROI) based on fixed volumes rather than on fixed thresholds. This method involves change in lesion size. METHODS: In 49 patients with colorectal carcinoma (CRC) and 50 patients with non-small cell lung carcinoma (NSCLC) scheduled for chemotherapy, FDG-PET was performed at baseline and during chemotherapy. A ROIfixed thresholds was determined by using a 50% threshold on both baseline and follow-up FDG-PET. A ROIfixed volumes was determined by using a 50% threshold, determined on the series with the largest tumor volume. This ROIfixed volumes is used on consecutive scans. Predictive effects of both methods were investigated by survival analysis for overall and progression free survival. RESULTS: In CRC, only ROIfixed volumes based DMRglu showed significant predictive ability. In NSCLC, both techniques showed significant predictive ability. During multivariate analysis, ROIfixed volumes determined DMRglu was an independent predictor for both overall and progression free survival in NSCLC whereas ROIfixed thresholds determined MRglu was not. After dichotomization at the median DMRglu, median survival ratio was higher in ROIfixed volumes than ROIfixed thresholds for CRC (overall survival: 1.78 vs 1.25, progression free survival: 1.57 vs 1.21) and NSCLC (overall survival: 2.01 vs 2.01, progression free survival: 2.93 vs 2.13). CONCLUSION: ROIfixed volumes based DMRglu shows better correlation with survival than DMRglu determined from a ROIfixed thresholds.

Purpose: This review aims to provide insight into the factors that influence quantification of glucose metabolism by FDG PET images in oncology as well as their influence on repeated measures studies (i.e. treatment response assessment), offering improved understanding both for clinical practice and research., Methods: Structural PubMed searches have been performed for the many factors affecting quantification of glucose metabolism by FDG PET. Review articles and references lists have been used to supplement the search findings., Results: Biological factors such as fasting blood glucose level, FDG uptake period, FDG distribution and clearance, patient motion (breathing) and patient discomfort (stress) all influence quantification. Acquisition parameters should be adjusted to maximize the signal to noise ratio without exposing the patient to a higher than strictly necessary radiation dose. This is especially challenging in pharmacokinetic analysis, where the temporal resolution is of significant importance. The literature is reviewed on the influence of attenuation correction on parameters for glucose metabolism, the effect of motion, metal artefacts and contrast agents on quantification of CT attenuation-corrected images. Reconstruction settings (analytical versus iterative reconstruction, post-reconstruction filtering and image matrix size) all potentially influence quantification due to artefacts, noise levels and lesion size dependency. Many region of interest definitions are available, but increased complexity does not necessarily result in improved performance. Different methods for the quantification of the tissue of interest can introduce systematic and random inaccuracy., Conclusions: This review provides an up-to-date overview of the many factors that influence quantification of glucose metabolism by FDG PET.

Unlabelled: The positron emitters (18)F, (68)Ga, (124)I, and (89)Zr are all relevant in small-animal PET. Each of these radionuclides has different positron energies and ranges and a different fraction of single photons emitted. Average positron ranges larger than the intrinsic spatial resolution of the scanner (for (124)I and (68)Ga) will deteriorate the effective spatial resolution and activity recovery coefficient (RC) for small lesions or phantom structures. The presence of single photons (for (124)I and (89)Zr) could increase image noise and spillover ratios (SORs)., Methods: Image noise, expressed as percentage SD in a uniform region (%SD), RC, and SOR (in air and water) were determined using the NEMA NU 4 small-animal image-quality phantom filled with 3.7 MBq of total activity of (18)F, (68)Ga, (124)I, or (89)Zr. Filtered backprojection (FBP), ordered-subset expectation maximization in 2 dimensions, and maximum a posteriori (MAP) reconstructions were compared. In addition to the NEMA NU 4 image-quality parameters, spatial resolutions were determined using small glass capillaries filled with these radionuclides in a water environment., Results: The %SD for (18)F, (68)Ga, (124)I, and (89)Zr using FBP was 6.27, 6.40, 6.74, and 5.83, respectively. The respective RCs were 0.21, 0.11, 0.12, and 0.19 for the 1-mm-diameter rod and 0.97, 0.65, 0.64, and 0.88 for the 5-mm-diameter rod. SORs in air were 0.01, 0.03, 0.04, and 0.01, respectively, and in water 0.02, 0.10, 0.13, and 0.02. Other reconstruction algorithms gave similar differences between the radionuclides. MAP produced the highest RCs. For the glass capillaries using FBP, the full widths at half maximum for (18)F, (68)Ga, (124)I, and (89)Zr were 1.81, 2.46, 2.38, and 1.99 mm, respectively. The corresponding full widths at tenth maximum were 3.57, 6.52, 5.87, and 4.01 mm., Conclusion: With the intrinsic spatial resolution (approximately 1.5 mm) of this latest-generation small-animal PET scanner, the finite positron range has become the limiting factor for the overall spatial resolution and activity recovery in small structures imaged with (124)I and (68)Ga. The presence of single photons had only a limited effect on the image noise. MAP, as compared with the other reconstruction algorithms, increased RC and decreased %SD and SOR.

The aim of this guideline is to provide a minimum standard for the acquisition and interpretation of PET and PET/CT scans with [18F]-fluorodeoxyglucose (FDG). This guideline will therefore address general information about[18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) and is provided to help the physician and physicist to assist to carrying out,interpret, and document quantitative FDG PET/CT examinations,but will concentrate on the optimisation of diagnostic quality and quantitative information.

Unlabelled: For the quantification of dynamic (18)F-FDG PET studies, the arterial plasma time-activity concentration curve (APTAC) needs to be available. This can be obtained using serial sampling of arterial blood or an image-derived input function (IDIF). Arterial sampling is invasive and often not feasible in practice; IDIFs are biased because of partial-volume effects and cannot be used when no large arterial blood pool is in the field of view. We propose a mathematic function, consisting of an initial linear rising activity concentration followed by a triexponential decay, to describe the APTAC. This function was fitted to 80 oncologic patients and verified for 40 different oncologic patients by area-under-the-curve (AUC) comparison, Patlak glucose metabolic rate (MR(glc)) estimation, and therapy response monitoring (Delta MR(glc)). The proposed function was compared with the gold standard (serial arterial sampling) and the IDIF., Methods: To determine the free parameters of the function, plasma time-activity curves based on arterial samples in 80 patients were fitted after normalization for administered activity (AA) and initial distribution volume (iDV) of (18)F-FDG. The medians of these free parameters were used for the model. In 40 other patients (20 baseline and 20 follow-up dynamic (18)F-FDG PET scans), this model was validated. The population-based curve, individually calibrated by AA and iDV (APTAC(AA/iDV)), by 1 late arterial sample (APTAC(1 sample)), and by the individual IDIF (APTAC(IDIF)), was compared with the gold standard of serial arterial sampling (APTAC(sampled)) using the AUC. Additionally, these 3 methods of APTAC determination were evaluated with Patlak MR(glc) estimation and with Delta MR(glc) for therapy effects using serial sampling as the gold standard., Results: Excellent individual fits to the function were derived with significantly different decay constants (P < 0.001). Correlations between AUC from APTAC(AA/iDV), APTAC(1 sample), and APTAC(IDIF) with the gold standard (APTAC(sampled)) were 0.880, 0.994, and 0.856, respectively. For MR(glc), these correlations were 0.963, 0.994, and 0.966, respectively. In response monitoring, these correlations were 0.947, 0.982, and 0.949, respectively. Additional scaling by 1 late arterial sample showed a significant improvement (P < 0.001)., Conclusion: The fitted input function calibrated for AA and iDV performed similarly to IDIF. Performance improved significantly using 1 late arterial sample. The proposed model can be used when an IDIF is not available or when serial arterial sampling is not feasible.

Unlabelled: In this study, we examined the in vivo relationship between functional tumor vasculature, determined by dynamic contrast-enhanced (DCE-) MRI, and tumor metabolism, determined by dynamic (18)F-FDG PET, during cytotoxic treatment of patients with colorectal liver metastases., Methods: Twenty-three patients underwent DCE-MRI (using gadolinium dimeglumine) and dynamic (18)F-FDG PET at baseline and after 3 treatment cycles, unless treatment was terminated because of toxicity. Parameters for vasculature (rate constant between extravascular extracellular space and blood plasma [k(ep)] and volume transfer constant [K(trans)]), extracellular space (v(e)), tumor size (the maximal axial diameter of each included lesion [MAD]), and metabolism (glucose metabolic rates [MR(glc)]) were derived, and changes during treatment were correlated. Overall survival (OS) and progression-free survival (PFS) served as outcome measures for the predictive abilities of pretreatment parameters and of treatment-related parameter changes., Results: Pretreatment MR(glc) and MAD were individually predictive for OS and PFS. During treatment, K(trans) increased significantly, but this increase could not be confirmed in a lesion-by-lesion analysis. MR(glc) decreased significantly (P < 0.001). No correlations were found for changes in DCE-MRI parameters and DeltaMR(glc). No relationship was found between changes in DCE-MRI parameters and OS or PFS. DeltaMR(glc) was able to predict OS (P = 0.008) after correction for confounders., Conclusion: The efficacy of cytotoxic chemotherapy assessed by reduction in tumor metabolism does not depend on pretreatment properties of the tumor vasculature determined by DCE-MRI. Cytotoxic chemotherapy does not alter DCE-MRI-derived properties of tumor vasculature but decreases glucose consumption of tumor cells.

Objectives: The aim of this prospective study was to assess the influence of different normalization procedures on relative changes in standardized uptake values (SUV) of F-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for the assessment of chemotherapy response in patients with colorectal carcinoma (CRC) and nonsmall cell lung carcinoma (NSCLC)., Methods: In 97 patients with CRC (n = 48) and NSCLC (n = 49), FDG-PET was performed before and during the course of chemotherapy. Relative changes in SUV (DeltaSUV) were determined after correction for injected dose and bodyweight, lean body mass, body surface area or a combination of bodyweight and plasma glucose. The predictive value for overall and progression-free survival with respect to the different normalized DeltaSUVs was assessed., Results: In both CRC and NSCLC, no differences were seen in the degree of change between the four SUV-normalizations during chemotherapy. Cox regression analysis for overall survival showed significant hazard ratios of 1.14-1.16 per 10% SUV change in CRC and 1.10-1.13 in NSCLC and for progression-free survival hazard ratios of 1.15 per 10% DeltaSUV change in CRC and 1.10-1.12 in NSCLC., Conclusion: Relative changes in SUV is a strong predictor for survival in both CRC and NSCLC. None of the four normalization methods showed statistical advantage over the other. Therefore, simplifying the methods for analysis of FDG-PET data can improve the incorporation of FDG-PET in clinical treatment-response monitoring and may facilitate application in multicentre trials.

Unlabelled: The Inveon small-animal PET scanner is characterized by a large, 127-mm axial length and a 161-mm crystal ring diameter. The associated high sensitivity is obtained by using all lines of response (LORs) up to the maximum ring difference (MRD) of 79, for which the most oblique LORs form acceptance angles of 38.3 degrees with transaxial planes. The result is 2 phenomena that are normally not encountered in PET scanners: a parallax or depth-of-interaction effect in the axial direction and the breakdown of Fourier rebinning (FORE). Both effects cause a deterioration of axial spatial resolution. Limiting the MRD to smaller values reduces this axial blurring at the cost of sensitivity. Alternatively, 3-dimensional (3D) reconstruction techniques can be used in which the rebinning step is absent. The aim of this study was to experimentally determine the spatial resolution and sensitivity of the Inveon for its whole field of view (FOV)., Methods: Spatial resolution and sensitivity were measured using filtered backprojection (FBP) with FORE, FBP with LOR angle-weighted adapted FORE (AFORE), and 3D ordered-subset expectation maximization followed by maximum a posteriori reconstruction (OSEM3D/MAP)., Results: Tangential and radial full width at half maximum (FWHM) showed almost no dependence on the MRD using FORE and FBP. Tangential FWHMs were 1.5 mm in the center of the FOV (CFOV) and 1.8 mm at the edge of the FOV (EFOV). Radial FWHMs were 1.5 and 3.0 mm in the CFOV and EFOV, respectively. In contrast, axial FWHMs increased with the MRD and ranged between 1.1 and 2.0 mm in the CFOV and between 1.5 and 2.7 mm in the EFOV for a MRD between 1 and 79. AFORE improved the axial resolution for a large part of the FOV, but image noise increased. OSEM3D/MAP yielded uniform spatial resolution in all directions, with an average FWHM of 1.65+/-0.06 mm. Sensitivity in the CFOV for the default energy and coincidence time window was 0.068; peak sensitivity was 0.111., Conclusion: The Inveon showed high spatial resolution and high sensitivity, both of which can be maintained using OSEM3D/MAP reconstruction instead of rebinning and 2D algorithms.