Accuracy of patient-specific CT organ doses from Monte Carlo simulations: influence of CT-based voxel models.

Monte Carlo simulations using patient CT images as input are the gold standard to perform patient-specific dosimetry. However, in standard clinical practice patient's CT images are limited to the reconstructed CT scan range. In this study, organ dose calculations were performed with ImpactMC for chest and cardiac CT using whole-body and anatomy-specific voxel models to estimate the accuracy of CT organ doses based on the latter model. When the 3D patient model is limited to the CT scan range, CT organ doses from Monte Carlo simulations are the most accurate for organs entirely in the field of view. For these organs only the radiation dose related to scatter from the rest of the body is not incorporated. For organs lying partially outside the field of view organ doses are overestimated by not accounting for the non-irradiated tissue mass. This overestimation depends strongly on the amount of the organ volume located outside the field of view. To get a more accurate estimation of the radiation dose to these organs, the ICRP reference organ masses and densities could form a solution. Except for the breast, good agreement in dose was found for most organs. Voxel models generated from clinical CT examinations do not include the overscan in the z-direction. The availability of whole-body voxel models allowed to study this influence as well. As expected, overscan induces slightly higher organ doses.

Comparison of a 3D CZT and conventional SPECT/CT system for quantitative Lu-177 SPECT imaging.

PURPOSE: Next-generation SPECT/CT systems with CdZnTe (CZT) digital detectors in a ring-like setup are emerging to perform quantitative Lu-177 SPECT imaging in clinical routine. It is essential to assess how the shorter acquisition time might affect the image quality and uncertainty on the mean absorbed dose of the tumors and organs at risk compared to a conventional system. METHODS: A NEMA Image Quality phantom was scanned with a 3D CZT SPECT/CT system (Veriton, by Spectrum Dynamics) using 6 min per bed position and with a conventional SPECT/CT system (Symbia T16, by Siemens) using 16 min per bed position. The sphere-to-background ratio was 12:1 and the background activity concentration ranged from 0.52 to 0.06 MBq/mL. A clinical reconstruction protocol for dosimetry purposes was determined for both systems by maximizing the sphere-to-background ratio while keeping the coefficient of variation of the background as low as possible. The corresponding image resolution was determined by the matching filter method and used for a dose uncertainty assessment of both systems following an established uncertainty model.. RESULTS: The optimized iterative reconstruction protocol included scatter and attenuation correction for both systems and detector response modeling for the Siemens system. For the 3D CZT system, 6 iterations and 8 subsets were combined with a Gaussian post-filter of 3 mm Full Width Half Maximum (FWHM) for post-smoothing. For the conventional system, 16 iterations and 16 subsets were applied with a Gaussian post-smoothing filter of 1 mm FWHM. For these protocols, the sphere-to-background ratio was 18.5% closer to the true ratio for the conventional system compared to the 3D CZT system when considering the four largest spheres. Meanwhile, the background coefficient of variation was very similar for both systems. These protocols resulted in SPECT image resolution of 14.8 mm and 13.6 mm for the 3D CZT and conventional system respectively. Based on these resolution estimates, a 50% dose uncertainty corresponded to a lesion volume of 28 mL for the conventional system and a lesion volume of 33 mL for the 3D CZT system. CONCLUSIONS: An optimized reconstruction protocol for a Veriton system with 6 min of acquisition time per bed position resulted in slightly higher dose uncertainties than a conventional Symbia system using 16 min of acquisition time per bed position. Therefore, a 3D CZT SPECT/CT allows to significantly reduce the acquisition times with only a very limited impact on dose uncertainties such that quantitative Lu-177 SPECT/CT imaging becomes much more accessible for treatment concurrent dosimetry. Nevertheless, the uncertainty of SPECT-based dose estimates remains high.

A systematic review and meta-analysis on the radiation dose of computed tomography in hybrid nuclear medicine imaging.

BACKGROUND: While diagnostic reference levels (DRLs) are well-established for the radiopharmaceutical part, published DRLs for the CT component of positron emission tomography/computed tomography (PET/CT) and single photon emission computed tomography/computed tomography (SPECT/CT) are limited. This systematic review and meta-analysis provides an overview of the different objectives of CT in hybrid imaging and summarizes reported CT dose values for the most common PET/CT and SPECT/CT examinations. Also, an overview of already proposed national DRLs is given. METHODS: A systematic literature search was performed to identify original articles reporting CT dose index volume (CTDIvol), dose-length product (DLP) and/or national DRLs for the most frequently performed PET/CT and/or SPECT/CT examinations. Data were grouped according to the clinical objective: diagnostic (D-CT), anatomical localisation (AL-CT) or attenuation correction (AC-CT) CT. Random-effects meta-analyses were conducted. RESULTS: Twenty-seven articles were identified of which twelve reported national DRLs. For brain and tumour PET/CT imaging, CTDIvol and DLP values were higher for a D-CT (brain: 26.7 mGy, 483 mGy cm; tumour: 8.8 mGy, 697 mGy cm) than for an AC/AL-CT (brain: 11.3 mGy, 216 mGy cm; tumour: 4.3 mGy, 419 mGy cm). Similar conclusions were found for bone and parathyroid SPECT/CT studies: D-CT (bone: 6.5 mGy, 339 mGy cm; parathyroid: 15.1 mGy, 347 mGy cm) results in higher doses than AL-CT (bone: 3.8 mGy, 156 mGy cm; parathyroid: 4.9 mGy, 166 mGy cm). For cardiac (AC-CT), mIBG/octreotide, thyroid and post-thyroid ablation (AC/AL-CT) SPECT/CT pooled mean CTDIvol (DLP) values were 1.8 mGy (33 mGy cm), 4.6 mGy (208 mGy cm), 3.1 mGy (105 mGy cm) and 4.6 mGy (145 mGy cm), respectively. For all examinations, high variability in nuclear medicine practice was observed. CONCLUSION: The large variation in CT dose values and national DRLs highlights the need for optimisation in hybrid imaging and justifies the clinical implementation for nuclear medicine specific DRLs.

Direct co-registration of [18F]FDG uptake and histopathology in surgically excised malignancies of the head and neck: a feasibility study.

PURPOSE: Recent technical advancements in PET imaging have improved sensitivity and spatial resolution. Consequently, clinical nuclear medicine will be confronted with PET images on a previously unfamiliar resolution. To better understand [18F]FDG distribution at submillimetric scale, a direct correlation of radionuclide-imaging and histopathology is required. METHODS: A total of five patients diagnosed with a malignancy of the head and neck were injected with a clinical activity of [18F]FDG before undergoing surgical resection. The resected specimen was imaged using a preclinical high-resolution PET/CT, followed by slicing of the specimen. Multiple slices were rescanned using a micro-PET/CT device, and one of the slices was snap-frozen for frozen sections. Frozen sections were placed on an autoradiographic film, followed by haematoxylin and eosin staining to prepare them for histopathological assessment. The results from both autoradiography and histopathology were co-registered using an iterative co-registration algorithm, and regions of interest were identified to study radiotracer uptake. RESULTS: The co-registration between the autoradiographs and their corresponding histopathology was successful in all specimens. The use of this novel methodology allowed direct comparison of autoradiography and histopathology and enabled the visualisation of uncharted heterogeneity in [18F]FDG uptake in both benign and malignant tissue. CONCLUSION: We here describe a novel methodology enabling the direct co-registration of [18F]FDG autoradiography with the gold standard of histopathology in human malignant tissue. The future use of the current methodology could further increase our understanding of the distribution of radionuclides in surgically excised malignancies and hence, improve the integration of pathology and molecular imaging in a multiscale perspective. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05068687.

The Impact of Accelerated HF-rTMS on Canine Brain Metabolism: An [18F]-FDG PET Study in Healthy Beagles.

Background: Repetitive transcranial magnetic stimulation (rTMS) has been proven to be a useful tool for the treatment of several severe neuropsychiatric disorders. Accelerated (a)rTMS protocols may have the potential to result in faster clinical improvements, but the effects of such accelerated paradigms on brain function remain to be elucidated. Objectives: This sham-controlled arTMS study aimed to evaluate the immediate and delayed effects of accelerated high frequency rTMS (aHF-rTMS) on glucose metabolism in healthy beagle dogs when applied over the left frontal cortex. Methods: Twenty-four dogs were randomly divided into four unequal groups: five active (n = 8)/ sham (n = 4) stimulation sessions (five sessions in 1 day), 20 active (n = 8)/ sham (n = 4) stimulation sessions (five sessions/ day for 4 days), respectively. [18F] FDG PET scans were obtained at baseline, 24 h poststimulation, after 1 and 3 months post the last stimulation session. We explicitly focused on four predefined regions of interest (left/right prefrontal cortex and left/right hippocampus). Results: One day of active aHF-rTMS- and not sham- significantly increased glucose metabolism 24 h post-active stimulation in the left frontal cortex only. Four days of active aHF-rTMS only resulted in a nearly significant metabolic decrease in the left hippocampus after 1 month. Conclusions: Like in human psychiatric disorders, active aHF-rTMS in healthy beagles modifies glucose metabolism, although differently immediately or after 1 month post stimulation. aHF-rTMS may be also a valid option to treat mentally disordered dogs.

High-Resolution 18F-FDG PET/CT for Assessing Three-Dimensional Intraoperative Margins Status in Malignancies of the Head and Neck, a Proof-of-Concept.

The surgical treatment of head and neck malignancies relies on the complete removal of tumoral tissue, while inadequate margins necessitate the use of adjuvant therapy. However, most positive margins are identified postoperatively as deep margins, and intraoperative identification of the deep positive margins could help achieve adequate surgical margins and decrease adjuvant therapies. To improve deep-margin identification, we investigated whether the use of high-resolution preclinical PET and CT could increase certainty about the surgical margins in three dimensions. Patients with a malignancy of the head and neck planned for surgical resection were administered a clinical activity of 4MBq/kg 18F-FDG approximately one hour prior to surgical initiation. Subsequently, the resected specimen was scanned with a micro-PET-CT imaging device, followed by histopathological assessment. Eight patients were included in the study and intraoperative PET/CT-imaging of 11 tumoral specimens and lymph nodes of three patients was performed. As a result of the increased resolution, differentiation between inflamed and dysplastic tissue versus malignant tissue was complicated in malignancies with increased peritumoral inflammation. The current technique allowed the three-dimensional delineation of 18F-FDG using submillimetric PET/CT imaging. While further optimization and patient stratification is required, clinical implementation could enable deep margin assessment in head and neck resection specimens.

Comparison of an in-house acquired brain F-18 FDG PET normal database with commercially available normal data.

INTRODUCTION: Current guidelines recommend the use of semiautomated assessment of F-18 FDG PET brain studies. Accuracy is influenced by the normal data, which requires knowledge of the included subjects and how they were acquired. Due to confidentiality, such information is often not completely disclosed. Our aim was to determine the variation in FDG uptake between several commercially available and our in-house normal database. METHODS: Our database contains 83 healthy subjects. Outlier detection using SPM further ensured normality, resulting in exclusion of three subjects. The remaining 80 subjects were analyzed using three commercially available software packages. Z-score data per patient and per lobe were extracted and pooled in predefined age groups (18-40, 41-60 and 61-80 years old) with a calculation of mean Z-scores and SD. Correlation between Z-score output of different software was investigated. RESULTS: In the 18-40 years age group, frontotemporal hypermetabolism was found with all software. Decreased cerebellar uptake was found with two software packages. Mean Z-scores are closer to zero in the 41-60 years age group compared to the younger group, and mostly within the normal range in the 61-80 years age group with all software. A moderate to high linear correlation between Z-score output was found, but individual Z-scores varied widely. CONCLUSIONS: The three software packages yielded varying Z-score output, partially explained by an age mismatch between our subjects and subjects in their normal databases. A definitive explanation for the remaining differences is lacking. This emphasizes the importance of age-matched normal data and knowledge of the included databases to allow adequate preprocessing.

Monte Carlo Simulations of the GE Signa PET/MR for Different Radioisotopes.

NEMA characterization of PET systems is generally based on 18F because it is the most relevant radioisotope for the clinical use of PET. 18F has a half-life of 109.7 min and decays into stable 18O via ß+ emission with a probability of over 96% and a maximum positron energy of 0.633 MeV. Other commercially available PET radioisotopes, such as 82Rb and 68Ga have more complex decay schemes with a variety of prompt gammas, which can directly fall into the energy window and induce false coincidence detections by the PET scanner. METHODS: Aim of this work was three-fold: (A) Develop a GATE model of the GE Signa PET/MR to perform realistic and relevant Monte Carlo simulations (B) Validate this model with published sensitivity and Noise Equivalent Count Rate (NECR) data for 18F and 68Ga (C) Use the validated GATE-model to predict the system performance for other PET isotopes including 11C, 15O, 13N, 82Rb, and 68Ga and to evaluate the effect of a 3T magnetic field on the positron range. RESULTS: Simulated sensitivity and NECR tests performed with the GATE-model for different radioisotopes were in line with literature values. Simulated sensitivities for 18F and 68Ga were 21.2 and 19.0/kBq, respectively, for the center position and 21.1 and 19.0 cps/kBq, respectively, for the 10 cm off-center position compared to the corresponding measured values of 21.8 and 20.0 cps/kBq for the center position and 21.1 and 19.6 cps/kBq for the 10 cm off-center position. In terms of NECR, the simulated peak NECR was 216.8 kcps at 17.40 kBq/ml for 18F and 207.1 kcps at 20.10 kBq/ml for 68Ga compared to the measured peak NECR of 216.8 kcps at 18.60 kBq/ml and 205.6 kcps at 20.40 kBq/ml for18F and 68Ga, respectively. For 11C, 13N, and 15O, results confirmed a peak NECR similar to 18F with the effective activity concentration scaled by the inverse of the positron fraction. For 82Rb, and 68Ga, the peak NECR was lower than for 18F while the corresponding activity concentrations were higher. For the higher energy positron emitters, the positron range was confirmed to be tissue-dependent with a reduction of the positron range by a factor of 3 to 4 in the plane perpendicular to the magnetic field and an increased positron range along the direction of the magnetic field. CONCLUSION: Monte-Carlo simulations were used to predict sensitivity and NECR performance of GE Signa PET/MR for 18F, 15O, 13N, 11C, 82Rb, and 68Ga radioisotopes and were in line with literature data. Simulations confirmed that sensitivity and NECR were influenced by the particular decay scheme of each isotope. As expected, the positron range decreased in the direction perpendicular to the 3T magnetic field. However, this will be only partially improving the resolution properties of a clinical PET/MR system due to the limiting spatial resolution of the PET detector.

Hepatobiliary scintigraphy and kinetic growth rate predict liver failure after ALPPS: a multi-institutional study.

BACKGROUND: Post hepatectomy liver failure (PHLF) after ALPPS has been related to the discrepancy between liver volume and function. Pre-operative hepatobiliary scintigraphy (HBS) can predict post-operative liver function and guide when it is safe to proceed with major hepatectomy. Aim of this study was to evaluate the role of HBS in predicting PHLF after ALPPS, defining a safe cut-off. METHODS: A multicenter retrospective study was approved by the ALPPS Registry. All patients selected for ALPPS between 2012 and 2018, were evaluated. Every patient underwent HBS during ALPPS evaluation. PHLF was reported according to ISGLS definition, considering grade B or C as clinically significant. RESULTS: 98 patients were included. Thirteen patients experienced PHLF grade B or C (14%) following ALPPS-2. The HBS and the daily gain in volume (KGRFLR) of the future liver remnant (FLR) were significantly lower in PHLF B and C (p = .004 and .041 respectively). ROC curves indicated safe cut-offs of 4.1%/day (AUC = 0.68) for KGRFLR, and of 2.7 %/min/m2 (AUC = 0.75) for HBSFLR. Multivariate analysis confirmed these cut-offs as variables predicting PHLF after ALPPS-2. CONCLUSION: Patients presenting a KGRFLR ≤4.1%/day and a HBSFLR ≤2.7%/min/m2 are at high risk of PHLF and their second stage should be re-discussed.

Noise reduction using a Bayesian penalized-likelihood reconstruction algorithm on a time-of-flight PET-CT scanner.

PURPOSE: Q.Clear is a block sequential regularized expectation maximization (BSREM) penalized-likelihood reconstruction algorithm for PET. It tries to improve image quality by controlling noise amplification during image reconstruction. In this study, the noise properties of this BSREM were compared to the ordered-subset expectation maximization (OSEM) algorithm for both phantom and patient data acquired on a state-of-the-art PET/CT. METHODS: The NEMA IQ phantom and a whole-body patient study were acquired on a GE DMI 3-rings system in list mode and different datasets with varying noise levels were generated. Phantom data was evaluated using four different contrast ratios. These were reconstructed using BSREM with different ß-factors of 300-3000 and with a clinical setting used for OSEM including point spread function (PSF) and time-of-flight (TOF) information. Contrast recovery (CR), background noise levels (coefficient of variation, COV), and contrast-to-noise ratio (CNR) were used to determine the performance in the phantom data. Findings based on the phantom data were compared with clinical data. For the patient study, the SUV ratio, metabolic active tumor volumes (MATVs), and the signal-to-noise ratio (SNR) were evaluated using the liver as the background region. RESULTS: Based on the phantom data for the same count statistics, BSREM resulted in higher CR and CNR and lower COV than OSEM. The CR of OSEM matches to the CR of BSREM with ß = 750 at high count statistics for 8:1. A similar trend was observed for the ratios 6:1 and 4:1. A dependence on sphere size, counting statistics, and contrast ratio was confirmed by the CNR of the ratio 2:1. BSREM with ß = 750 for 2.5 and 1.0 min acquisition has comparable COV to the 10 and 5.0 min acquisitions using OSEM. This resulted in a noise reduction by a factor of 2-4 when using BSREM instead of OSEM. For the patient data, a similar trend was observed, and SNR was reduced by at least a factor of 2 while preserving contrast. CONCLUSION: The BSREM reconstruction algorithm allowed a noise reduction without a loss of contrast by a factor of 2-4 compared to OSEM reconstructions for all data evaluated. This reduction can be used to lower the injected dose or shorten the acquisition time.

NEMA NU 2-2007 performance characteristics of GE Signa integrated PET/MR for different PET isotopes.

BACKGROUND: Fully integrated PET/MR systems are being used frequently in clinical research and routine. National Electrical Manufacturers Association (NEMA) characterization of these systems is generally done with 18F which is clinically the most relevant PET isotope. However, other PET isotopes, such as 68Ga and 90Y, are gaining clinical importance as they are of specific interest for oncological applications and for follow-up of 90Y-based radionuclide therapy. These isotopes have a complex decay scheme with a variety of prompt gammas in coincidence. 68Ga and 90Y have higher positron energy and, because of the larger positron range, there may be interference with the magnetic field of the MR compared to 18F. Therefore, it is relevant to determine the performance of PET/MR for these clinically relevant and commercially available isotopes. METHODS: NEMA NU 2-2007 performance measurements were performed for characterizing the spatial resolution, sensitivity, image quality, and the accuracy of attenuation and scatter corrections for 18F, 68Ga, and 90Y. Scatter fraction and noise equivalent count rate (NECR) tests were performed using 18F and 68Ga. All phantom data were acquired on the GE Signa integrated PET/MR system, installed in UZ Leuven, Belgium. RESULTS: 18F, 68Ga, and 90Y NEMA performance tests resulted in substantially different system characteristics. In comparison with 18F, the spatial resolution is about 1 mm larger in the axial direction for 68Ga and no significative effect was found for 90Y. The impact of this lower resolution is also visible in the recovery coefficients of the smallest spheres of 68Ga in image quality measurements, where clearly lower values are obtained. For 90Y, the low number of counts leads to a large variability in the image quality measurements. The primary factor for the sensitivity change is the scale factor related to the positron emission fraction. There is also an impact on the peak NECR, which is lower for 68Ga than for 18F and appears at higher activities. CONCLUSIONS: The system performance of GE Signa integrated PET/MR was substantially different, in terms of NEMA spatial resolution, image quality, and NECR for 68Ga and 90Y compared to 18F. But these differences are compensated by the PET/MR scanner technologies and reconstructions methods.

Radiation Dosimetry and Biodistribution of 18F-PSMA-11 for PET Imaging of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) is highly overexpressed in prostate cancer. Many PSMA analog radiotracers for PET/CT prostate cancer staging have been developed, such as 68Ga-PSMA-11. This radiotracer has achieved good results in multiple clinical trials, but because of the superior imaging characteristics of 18F-fluoride, 18F-PSMA-11 was developed. The aim of this study was to evaluate the administration safety and radiation dosimetry of 18F-PSMA-11. Methods: Six patients (aged 62-68 y; mean, 66 ± 2 y) with suspected prostate cancer recurrence after previous treatment were administered 2 MBq of 18F-PSMA-11 per kilogram of body weight and then underwent low-dose PET/CT imaging at 0, 20, 50, 90, and 300 min after injection. To evaluate the safety of administration, vital parameters were monitored. To assess toxicity, full blood count and biochemical parameters were determined. According to the latest International Commission on Radiological Protection recommendations, radiation dosimetry analysis was performed using IDAC-Dose 2.1. For blood activity measurement, small samples of venous blood were collected at various time points after injection. The unbound 18F-fluoride fraction was determined in plasma at 20, 50, and 90 min after administration to evaluate the defluorination rate of 18F-PSMA-11. Results: After injection, 18F-PSMA-11 cleared rapidly from the blood. At 5 h after injection, 29.0% ± 5.9% of the activity was excreted in urine. The free 18F fraction in plasma increased from 9.7% ± 1.0% 20 min after injection to 22.2% ± 1.5% 90 min after injection. The highest tracer uptake was observed in kidneys, bladder, spleen, and liver. No study drug-related adverse events were observed. The calculated mean effective dose was 12.8 ± 0.6 µSv/MBq. Conclusion:18F-PSMA-11 can be safely administered and results in a mean effective dose of 12.8 ± 0.6 µSv/MBq. Therefore, the total radiation dose is lower than for other PSMA PET agents and in the same range as 18F-DCFPyL.

Hemodynamic changes in ALPPS influence liver regeneration and function: results from a prospective study.

BACKGROUND: Excessive increase of portal flow and pressure following extended hepatectomy have been associated to insufficient growth or function of the future liver remnant (FLR), with the risk of post-hepatectomy liver failure (PHLF). We prospectively assess the influence of liver hemodynamics on FLR regeneration and function in Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS). METHODS: Twenty-three patients underwent ALPPS; liver hemodynamics were assessed throughout the procedures. Volume and function of the FLR were evaluated by angio-CT and 99mTc-Mebrofenin-scintigraphy. RESULTS: The portal vein flow at the end of stage-1 correlated with the increase of the FLR volume (p = 0.002). Patients with portal vein pressure (PVP) < 20 mmHg and hepatic to portal vein gradients (HVPG) < 15 mmHg at the end of ALPPS-1 showed higher FLR regeneration (76.7% vs. 30.6%, p = 0.04) and function (26.7% vs. -0.13%, p = 0.02). FLR regeneration was inversely correlated with baseline FLR/Total Liver Volume (p = 0.002) and FLR/Body Weight (p = 0.02). No correlation was found between volumes and function (p = 0.13). CONCLUSION: Liver hemodynamic stress at the end of ALPPS-1 influences the increase of the FLR volume and function, which is higher with PVP < 20 and HVPG < 15 mmHg. Liver volume overestimates liver function and could be imprecise to set stage-2 timing.

99mTc-labelled S-HYNIC certolizumab pegol in rheumatoid arthritis and spondyloarthritis patients: a biodistribution and dosimetry study.

BACKGROUND: Biologicals directed against tumour necrosis factor (TNF) have proven their efficacy in the treatment of spondyloarthritis and rheumatoid arthritis. We present a radiolabelling method for certolizumab pegol (CZP), a commercially available humanized Fab'-fragment directed against TNF. A biodistribution and dosimetry study was conducted. Tc-S-HYNIC CZP was synthesized. The in vitro TNF neutralizing activity was tested by exposing L929s-cells to various concentrations 99mTc-S-HYNIC CZP and measuring TNF-induced cytotoxicity. For biodistribution and dosimetry, WB images and blood and urine sampling were performed up to 24 h pi. Cumulative activities were estimated using mono-exponential fitting, and organ doses were estimated using OLINDA/EXM. The effective dose was calculated using the International Commission on Radiological Protection 103 recommendations. The uptake of the tracer in the peripheral joints was assessed visually and semiquantitatively. RESULTS: In vitro tests showed blocking of TNF cytotoxicity by the 99mTc-S-HYNIC CZP formulation comparable to the effect obtained with the unlabelled CZP with or without the HYNIC linker. We analysed eight patients with rheumatoid arthritis or spondyloarthritis. The highest mean absorbed organ doses were recorded for kidneys, spleen, and liver: 56 (SD 7), 34 (SD 6), and 33 (SD 7) µGy/MBq. The effective dose was 6.1 (SD 0.9) mSv for a mean injected activity of 690 (SD 35) MBq. The urinary excretion was 15.1% (SD 8.1) of the IA at 22.5 h. Blood analysis yielded a distribution half-life of 1.2 h (SD 1.5) and an elimination half-life of 26.9 h (SD 2.7). Visual analysis of the scans revealed marked tracer accumulation in the clinically affected peripheral joints. In addition, there was a statistically significant higher uptake of the tracer in the swollen joints (median uptake ratio compared to background of 3.3 in rheumatoid arthritis and 2.4 in peripheral spondyloarthritis) compared to clinically negative joints (respectively 1.3 and 1.6). CONCLUSIONS: We present a radiolabelling technique for CZP, a Fab'-fragment directed against TNF and currently used as a therapeutic agent in rheumatology. An effective dose of 6.1 mSv (SD 0.9) was estimated. We confirmed the uptake of this new radiopharmaceutical in clinically affected peripheral joints.

Validation of 18F-FDG PET at conventional and delayed intervals for the discrimination of high-grade from low-grade gliomas: a stereotactic PET and MRI study.

AIM: The aim of this study was to validate 18F-FDG PET imaging for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs). METHODS: Twenty-one patients with gliomas undergoing a stereotactic biopsy underwent PET scanning at conventional and delayed intervals, diagnostic and stereotactic MR examinations. To calculate the uptake at the biopsy site, a 2-mm voxel was selected. Uptake in this voxel was expressed as a percentage of the average uptake per voxel in the normal brain. The difference in uptake between HGG and LGG at conventional and late intervals and the difference in uptake difference between HGG and LGG at both intervals were analyzed using t tests as well as a mixed-model analysis of variance. RESULTS: At conventional intervals, uptake in LGG was 67% of that in the normal brain. Between early and late intervals, a significant decrease in uptake of 11% (±2.5%) was noted (P = 0.001). Uptake in HGG at conventional intervals was 138% of that in the normal brain. Between early and late intervals, a significant increase in uptake of 43% (±11%) was noted (P = 0.005). The difference in uptake between HGG and LGG was significant both at conventional and delayed intervals (P < 0.001). Moreover, the difference in uptake between both groups was significantly greater (31%) at delayed than at conventional intervals (2%) (P < 0.001). CONCLUSIONS: The results of this correlative study between tumor grade and 18F-FDG uptake both determined at the stereotactic biopsy site indicate that PET, particularly at delayed intervals, is valid for discriminating LGG from HGG.

SIRT of liver metastases: physiological and pathophysiological considerations.

Available literature on the differences in circulation and microcirculation of normal liver and liver metastases as well as in rheology of the different radiolabelled microspheres [(99m)Tc-labelled macroaggregates of albumin (MAA), (90)Y-TheraSpheres and (90)Y-SIR-spheres] used in selective internal radiation therapy (SIRT) are reviewed and implications thereof on the practice of SIRT discussed. As a result of axial accumulation and skimming, large microspheres are preferentially deposited in regions of high flow, whereas smaller microspheres are preferentially diverted to regions of low flow. As flow to normal liver tissue is considerably variable between segments and also within one segment, microspheres will be delivered heterogeneously within the microvasculature of normal liver tissue. This non-uniformity in microsphere distribution in normal liver tissue has a significant "liver-sparing" effect on the dose distribution of (90)Y-labelled microspheres. Arterial flow to liver metastases is most pronounced in the hypervascular rim of metastases, followed by the smaller metastases and finally by the central hypoperfused region of the larger metastases. Because of the wide variability in size of labelled MAAs and because of the skimming effect, existing differences in flow between metastatic lesions of variable size are likely exaggerated on (99m)Tc-MAA scintigraphy when compared to (90)Y-TheraSpheres and (90)Y-SIR-spheres (smaller variability in size and probably also in specific activity). Ideally, labelled MAAs would contain a size range similar to that of (90)Y-SIR-spheres or (90)Y-TheraSpheres. Furthermore, the optimal number of MAA particles to inject for the pretreatment planning scintigraphy warrants further exploration as it was shown that concentrated suspensions of microspheres produce more optimal tumour to normal liver distribution ratios. Finally, available data suggest that the flow-based heterogeneous distribution of microspheres to metastatic lesions of variable size might be optimized, that is rendered more homogeneous, through the combined use of angiotensin II and degradable starch microspheres.

Standardized added metabolic activity (SAM): a partial volume independent marker of total lesion glycolysis in liver metastases.

PURPOSE: The standardized added metabolic activity (SAM) is a new marker of total lesion glycolysis that avoids partial volume effect (PVE) and thresholding. SAM is calculated by drawing a volume of interest (VOI(1)) around the tumour and a larger VOI (VOI(2)) around VOI(1). Subtracting the background activity in VOI(2)-VOI(1) from VOI(1) yields SAM. If VOI(1) is set at a reasonable distance from the tumour, PVE are avoided. Phantom and initial clinical validation data are presented. METHODS: Spheres of a Jaszczak phantom were filled with a 5.4, 3.64 and 2.0 times higher concentration relative to background activity and positron emission tomography (PET) data were acquired during 10 min. SAM of all spheres was expressed as a percentage of the expected value (the actual activity ratio minus 1). In 15 patients a 10-min list-mode acquisition PET study centred on their primary squamous cell carcinoma (PSCC) was performed and images of 1-10 min reconstructed. SAM1-9min values of PSCC were expressed as a percentage of SAM10min. Nineteen patients suffering from liver metastases treated with chemotherapy underwent PET/CT prior to (scan 1) and after 3-6 cycles of chemotherapy (scan 2). SAM and maximum standardized uptake values (SUV(max)) of the liver lesions on scan 1 (SAM1 and SUV(max)1) and the percentage reduction between both ΔSAM and ΔSUV(max) were related to Response Evaluation Criteria in Solid Tumors (RECIST) response. RESULTS: For the phantom acquisitions, the mean normalized SAM/sphere volume calculated was 94.9 % (SD 5.9 %) of the expected value. In the PSCC patients, the mean difference between SAM1min and SAM10min was only 4 % (SD 5 %). SUV(max)1min and SUV(max)10min proved to be not significantly different, but the variability was slightly larger than that of SAM (SD 6.4 %). SAM1 and ΔSAM values for responders versus non-responders were, respectively, 57 (SD 119) versus 297 (SD 625) for SAM1 (p = 0.2) and 99 % (SD 3 %) versus 32 % (SD 44 %) for ΔSAM (p = 0.001). SUV(max)1 and ΔSUV(max) values in responders versus non-responders were, respectively, 3.9 (SD 2.4) versus 6.3 (SD 3.1) for SUV(max)1 (p = 0.08) and 94 % (SD 17) versus 7 % (SD 40 %) for ΔSUV(max) (p = 0.0001). The AUC of ΔSAM and ΔSUV(max) were not significantly different on receiver-operating characteristic (ROC) analysis (AUC 1.0 and 0.99, respectively, p = 0.6). CONCLUSION: SAM is a promising parameter for tumour response assessment of liver metastases by means of (18)F-fluorodeoxyglucose PET.

Tuberculous lymphadenitis: FDG PET and CT findings in responsive and nonresponsive disease.

PURPOSE: No data is available on the different FDG PET and CT findings in the lymph nodes (LN) of patients with HIV and tuberculosis (TB) who respond compared with those who do not respond to anti-TB treatment by 4 months after initiation of TB treatment. These findings were the focus of our study. METHODS: PET/CT scans performed at 4 months after initiation of TB treatment in 20 consecutive HIV patients were analysed. SUVmax values were obtained for all regions of LN involvement. The diameter of the LNs was measured and the CT enhancement (LNs showing peripheral rim enhancement with central low attenuation, PRECLO, in comparison with homogeneously involved LNs) and the calcification patterns of involved LNs assessed. The relationship between the PET and CT findings and the clinical outcome, response or nonresponse, was evaluated. RESULTS: FDG PET identified 91 sites of LN involvement, 20 of which were not identified by CT. SUVmax values were significantly higher in nonresponders (8 patients, SUVmax 11.2 ± 4.0, mean ± SD) when compared to responders (12 patients, SUVmax 2.6 ± 2.3; p = 0.0001). In ROC analysis (AUC 0.952) a cut-off value of 4.5 for SUVmax yielded a sensitivity and specificity of 95% and 85% for discriminating nonresponding from responding LNs. LNs were significantly larger in nonresponders (1.9 ± 0.4 cm) than in responders (1.4 ± 0.4 cm; p = 0.0001); the AUC in the ROC analysis was 0.76. PRECLO LNs were significantly larger (2.2 ± 0.3 cm) than homogeneous involved LN basins (1.5 ± 0.4 cm) and LN basins with calcification (1.4 ± 0.5 cm; p = 0.001). Using the presence of at least one LN basin with PRECLO as a criterion for nonresponse, responders could be separated from nonresponders with a sensitivity of 88% and a specificity of 66%. CONCLUSION: LNs responding to TB treatment could be differentiated from nonresponding LNs with a sensitivity and specificity of 95% and 85% using a SUVmax cut-off value of 4.5 and a sensitivity and specificity of 88% and 66% using the presence of at least one LN basin with PRECLO.

Nuclear medicine imaging in tuberculosis using commercially available radiopharmaceuticals.

In this paper, data available on nuclear medicine imaging using commercially available radiopharmaceuticals for the differentiation, staging, and prediction or assessment of the response to treatment in tuberculosis (TB) are reviewed. Limited available studies suggest that single photon emission computed tomography (SPECT) using either 201Tl, 99mTc-sestamibi, or 99mTc-tetrofosmin is accurate (≥85%) and has a high negative predictive value (≥90%) for the differentiation of TB from carcinoma in patients presenting with a solitary pulmonary nodule (SPN). The criteria for detection of TB on 201Tl SPECT are nondepiction of the suspicious lesion in the delayed image or a negative retention index [washout on the delayed images (3­4 h postinjection) vs. the early image (5­15 min postinjection)] and a comparable-to-background uptake on 99mTc-sestamibi or 99mTc-tetrofosmin SPECT. Another SPECT tracer of potential interest for the differentiation of TB from malignant SPN that warrants further exploration, is N-isopropyl-p-[123I]iodoamphetamine (123I-IMP). In contrast, 18F-fluorodeoxyglucose (18F-FDG) PET is unable to differentiate malignancy from TB and thus cannot be used as a tool to reduce futile biopsy/thoracotomy in these patients. A limited number of studies have reported on the potential of nuclear medicine imaging in assessment of the extent of disease in patients with extrapulmonary TB using 67Ga-citrate SPECT and 18F-FDG PET, respectively. 67Ga-citrate SPECT was shown to be as sensitive as bone scintigraphy for the detection of bone infection and was found to be complementary to computed tomography (CT) imaging. 18F-FDG PET was found to be significantly more efficient when compared with CT, respectively, in over half of patients for the identification of sites of lymph node involvement that were missed by CT and often the only sites of extrapulmonary TB identified. Unfortunately, 18F-FDG PET findings did not lead to alterations in treatment planning in any of the patients under study. Additional studies confirming these findings are urgently required. Similar to the setting of SPN, 18F-FDG PET cannot differentiate malignant lymph node involvement from lymph node involvement by TB. These results and the recent findings of Demura and colleagues using 18F-FDG PET further suggest that nuclear medicine imaging techniques could be used for the evaluation of therapeutic response. Prospective studies, focusing on specific subgroups of patients in whom such an imaging approach might be clinically relevant, for example in multidrug-resistant TB patients, are warranted. In acquired immunodeficiency syndrome patients, 67Ga scintigraphy proved to be a reliable and sensitive method for the primary detection and follow-up of opportunistic pneumonias, including TB. Combining 201Tl scintigraphy with 67Ga scintigraphy was shown to increase the specificity for both pulmonary and extrapulmonary TB, which is a 67Ga(+) and 201Tl(-) mismatch pattern in acquired immunodeficiency syndrome patients that is specific for mycobacterial infections. Finally, the results obtained using both SPECT and PET indicate that nuclear medicine could be an important noninvasive method for the determination of disease activity, detection of extrapulmonary TB, and determination of response to therapy.

99mTc-labeled tricarbonyl his-CNA35 as an imaging agent for the detection of tumor vasculature.

UNLABELLED: Given the importance of angiogenesis for a tumor's survival and growth, several therapeutic strategies rely on the selective inhibition of angiogenesis and the destruction of existing tumor vasculature. These strategies raise the need for a noninvasive tool to evaluate tumor vasculature. We describe the radiosynthesis and evaluation of an imaging tracer that specifically binds tumor subendothelial collagen and thereby images tumor vasculature. METHODS: (99m)Tc-tricarbonyl was prepared and labeled with His-collagen-binding adhesion protein 35 (CNA35). After in vitro specificity testing, in vivo biodistribution and dosimetric studies were performed in healthy nude mice via planar imaging. (99m)Tc-(CO)(3) His-CNA35 was evaluated for in vivo imaging of tumor vasculature in a HT29 colorectal carcinoma xenograft. RESULTS: The labeling procedure yielded a compound with 95%-99% radiochemical purity and good in vitro stability. An in vitro binding test confirmed specificity and functionality. (99m)Tc-(CO)(3) His-CNA35 rapidly cleared from the blood and predominantly accumulated in the kidneys and liver. The effective dose for a proposed single injection of 500 MBq of (99m)Tc-(CO)(3) His-CNA35 is 3.70 mSv per organ or 2.01 mSv/g of tissue. Tumors were successfully visualized, and uptake correlated with ex vivo immunohistochemical staining of tumor vasculature. CONCLUSION: (99m)Tc-(CO)(3) His-CNA35 may be a useful radioligand for the in vivo detection of tumor vasculature through subendothelial collagen binding. A noninvasive method of imaging tumor vasculature that could provide a reliable assessment of tumor vasculature would allow evaluation of the effectiveness of commonly used antiangiogenic therapies and determination of their optimal dosing and scheduling.