Computational patient models for simulation of dynamic gamma-camera imaging : Application to renography and peptide receptor radionuclide therapy

Many nuclear medicine investigations rely on gamma-camera imaging to study and quantify the distribution of radiopharmaceuticals or radionuclides in the patient as a function of time. This is typically used for diagnostic studies of physiological functions or for calculation of absorbed doses following radionuclide therapy. In this work, computational patient models (phantoms) have been developed and used for evaluation of quantitative methods and techniques relying on dynamic gamma-camera imaging.Papers I and II concern 99mTc-MAG3 dynamic renography, a well-established diagnostic modality for evaluation of renal function. In paper I, a patient model featuring the pharmacokinetics of 99mTc-MAG3 was presented. The developed framework readily allows modelling of various cases of clinical interest in a systematic manner. Dynamic image acquisition was simulated using the Monte Carlo method, and the resulting image data were encapsulated in the DICOM format to allow processing with software used in clinical practice. In paper II, this data were used to investigate the accuracy and inter-departmental variability in dynamic renography analysis, with participation from 21 nuclear medicine departments in Sweden. We found that the variability in estimates of renal TAC parameters is low and acceptable when renal function is normal, but considerably high when renal function is impaired. The accuracy of relative uptake measurements was negatively affected by the lack of attenuation correction for quantitation. Papers III-IV concern image-based, patient-specific dosimetry in peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. Paper III describes the development of computational patient models for research on image-based dosimetry, based on the same approach as used in paper I. A preliminary evaluation of a realistic dosimetry protocol, based on a single SPECT and four planar scans, was performed and it was shown that absorbed doses to organs and tumours were accurate within ±25 %. In paper IV, the patient models were used in a thorough analysis of uncertainty in renal dosimetry based entirely on SPECT/CT, and a total uncertainty of approximately 6 % (1 standard deviation) was estimated in the absorbed dose to the kidneys. In paper V, the dosimetric impact of the long-lived meta-stable isomer 177mLu was studied. Furthermore, it was investigated if current dosimetry protocols, relying on measurements limited to the first week after treatment, are sufficient to predict the long-term activity retention. The results showed a negligible contribution from 177mLu to the whole-body absorbed dose, and that measurements performed more than one week after treatment are warranted for tumour and whole-body dosimetry. In conclusion, this thesis provides a contribution to the knowledge of measurement accuracy and uncertainty in dynamic renography and 177Lu PRRT

Monte Carlo-based SPECT reconstruction within the SIMIND framework

This paper presents the development and validation of a Monte Carlo-based singe photon emission computed tomography reconstruction program for parallel-hole collimation contained within the SIMIND Monte Carlo framework. The Monte Carlo code is used as an accurate forward-projector and is combined with a simplified back-projector to perform iterative tomographic reconstruction using the Maximum Likelihood Expectation Maximization and Ordered Subsets Expectation Maximization algorithms, together forming a program called SIMREC. The Monte Carlo simulation transforms the estimated source distribution directly from activity to counts in its projections. Hence, the reconstructed image is expressed in activity without reference to an external calibration. The program is tested using phantom measurements of spheres filled with 99mTc, 177Lu and 131I placed in air and centrally and peripherally in a water-filled elliptical phantom. The feasibility of applying the reconstruction to patients is also demonstrated for a range of radiopharmaceuticals. The deviation in total activity in the spheres ranged between -4.1% and 6.2% compared with the activity determined when preparing the phantom. The SIMREC program was found to be accurate with respect to activity estimation and to reconstruct visually acceptable images within a few hours when applied to patient examples

Dynamic (99m)Tc-MAG3 renography: images for quality control obtained by combining pharmacokinetic modelling, an anthropomorphic computer phantom and Monte Carlo simulated scintillation camera imaging.

In dynamic renal scintigraphy, the main interest is the radiopharmaceutical redistribution as a function of time. Quality control (QC) of renal procedures often relies on phantom experiments to compare image-based results with the measurement setup. A phantom with a realistic anatomy and time-varying activity distribution is therefore desirable. This work describes a pharmacokinetic (PK) compartment model for (99m)Tc-MAG3, used for defining a dynamic whole-body activity distribution within a digital phantom (XCAT) for accurate Monte Carlo (MC)-based images for QC. Each phantom structure is assigned a time-activity curve provided by the PK model, employing parameter values consistent with MAG3 pharmacokinetics. This approach ensures that the total amount of tracer in the phantom is preserved between time points, and it allows for modifications of the pharmacokinetics in a controlled fashion. By adjusting parameter values in the PK model, different clinically realistic scenarios can be mimicked, regarding, e.g., the relative renal uptake and renal transit time. Using the MC code SIMIND, a complete set of renography images including effects of photon attenuation, scattering, limited spatial resolution and noise, are simulated. The obtained image data can be used to evaluate quantitative techniques and computer software in clinical renography

Head-to-head comparison of a Si-photomultiplier-based and a conventional photomultiplier-based PET-CT system

Background: A novel generation of PET scanners based on silicon (Si)-photomultiplier (PM) technology has recently been introduced. Concurrently, there has been development of new reconstruction methods aimed at increasing the detectability of small lesions without increasing image noise. The combination of new detector technologies and new reconstruction algorithms has been found to increase image quality. However, it is unknown to what extent the demonstrated improvement of image quality is due to scanner hardware development or improved reconstruction algorithms. To isolate the contribution of the hardware, this study aimed to compare the ability to detect small hotspots in phantoms using the latest generation SiPM-based PET/CT scanner (GE Discovery MI) relative to conventional PM-based PET/CT scanner (GE Discovery 690), using identical reconstruction protocols. Materials and methods: Two different phantoms (NEMA body and Jasczcak) with fillable spheres (31 μl to 26.5 ml) and varying sphere-to-background-ratios (SBR) were scanned in one bed position for 15–600 s on both scanners. The data were reconstructed using identical reconstruction parameters on both scanners. The recovery-coefficient (RC), noise level, contrast (spherepeak/backgroundpeak-value), and detectability of each sphere were calculated and compared between the scanners at each acquisition time. Results: The RC-curves for the NEMA phantom were near-identical for both scanners at SBR 10:1. For smaller spheres in the Jaszczak phantom, the contrast was 1.22 higher for the DMI scanner at SBR 15:1. The ratio decreased for lower SBR, with a ratio of 1.03 at SBR 3.85:1. Regarding the detectability of spheres, the sensitivity was 98% and 88% for the DMI and D690, respectively, for SBR 15:1. For SBR 7.5, the sensitivity was 75% and 83% for the DMI and D690, respectively. For SBR 3.85:1, the sensitivity was 43% and 30% for the DMI and D690, respectively. Conclusion: Marginally higher contrast in small spheres was seen for the SiPM-based scanner but there was no significant difference in detectability between the scanners. It was difficult to detect differences between the scanners, suggesting that the SiPM-based detectors are not the primary reason for improved image quality

Pharmacokinetic digital phantoms for accuracy assessment of image-based dosimetry in (177)Lu-DOTATATE peptide receptor radionuclide therapy.

Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with (177)Lu-DOTATATE. Three individual voxel phantoms from the XCAT population were generated and assigned a dynamic activity distribution based on a compartment model for (177)Lu-DOTATATE, designed specifically for this purpose. The compartment model was fitted to time-activity data from 10 patients, primarily acquired using quantitative scintillation camera imaging. S values for all phantom source-target combinations were calculated based on Monte-Carlo simulations. Combining the S values and time-activity curves, reference values of the absorbed dose to the phantom kidneys, liver, spleen, tumours and whole-body were calculated. The phantoms were used in a virtual dosimetry study, using Monte-Carlo simulated gamma-camera images and conventional methods for absorbed-dose calculations. The characteristics of the SPECT and WB planar images were found to well represent those of real patient images, capturing the difficulties present in image-based dosimetry. The phantoms are expected to be useful for further studies and optimisation of clinical dosimetry in (177)Lu PRRT

Dose-reduced [18F]PSMA-1007 PET is feasible for functional imaging of the renal cortex

BackgroundIn Prostate-specific membrane antigen (PSMA) positron emission tomography with computed tomography (PET-CT), there is significant renal uptake. The standard in renal cortical functional imaging is scintigraphy with technetium-99m labeled dimercaptosuccinic acid (DMSA). Using [68Ga]Ga-PSMA-11 PET for renal imaging has been suggested, but using [18F]PSMA-1007 has not been explored. The aims of this study were to establish the optimal time point for renal imaging after [18F]PSMA-1007 injection, to investigate the reproducibility of split renal uptake measurements, and to determine the margin for reduction in administered activity.MethodsTwelve adult male patients with prostate cancer underwent [18F]PSMA-1007 PET-CT at 8 time points up to 5.5 h post-injection (p.i.). List-mode data were binned to durations of 10 to 120 s per bed position (bp). Left renal percentage of total renal uptake (LRU%) was measured, and the difference between highest and lowest measurement per patient (“delta max”) was calculated. Images acquired at 1 h, 2 h, and 5.5 h p.i. with durations of 10 to 120 s/bp were rated regarding image quality.ResultsImaging at 2 h p.i. with 60 s/bp yielded acceptable quality in all cases. Increasing acquisition time to 15 min for a single bp would allow reducing administered activity to 0.27 MBq/kg, resulting in an effective dose of 0.4 mSv for a 1-year old child weighing 10 kg. The median delta max of LRU% measurements was 2.7% (range 1.8–7.3%).ConclusionsRenal [18F]PSMA-1007 PET-CT is feasible, with imaging 2 h p.i., acceptable split renal uptake variability, and effective dose and acquisition time comparable to those of [99mTc]Tc-DMSA scintigraphy

Optimization of [18F]PSMA-1007 PET-CT using regularized reconstruction in patients with prostate cancer

Background: Prostate-specific membrane antigen (PSMA) radiotracers such as [18F]PSMA-1007 used with positron emission tomography-computed tomography (PET-CT) is promising for initial staging and detection of recurrent disease in prostate cancer patients. The block-sequential regularization expectation maximization algorithm (BSREM) is a new PET reconstruction algorithm, which provides higher image contrast while also reducing noise. The aim of the present study was to evaluate the influence of different acquisition times and different noise-suppressing factors in BSREM (β values) in [18F]PSMA-1007 PET-CT regarding quantitative data as well as a visual image quality assessment. We included 35 patients referred for clinical [18F]PSMA-1007 PET-CT. Four megabecquerels per kilogramme were administered and imaging was performed after 120 min. Eighty-four image series per patient were created with combinations of acquisition times of 1–4 min/bed position and β values of 300–1400. The noise level in normal tissue and the contrast-to-noise ratio (CNR) of pathological uptakes versus the local background were calculated. Image quality was assessed by experienced nuclear medicine physicians. Results: The noise level in the liver, spleen, and muscle was higher for low β values and low acquisition times (written as activity time products (ATs = administered activity × acquisition time)) and was minimized at maximum AT (16 MBq/kg min) and maximum β (1400). There was only a small decrease above AT 10. The median CNR increased slowly with AT from approximately 6 to 12 and was substantially lower at AT 4 and higher at AT 14–16. At AT 4–6, many images were regarded as being of unacceptable quality. For AT 8, β values of 700–900 were considered of acceptable quality. Conclusions: An AT of 8 (for example as in our study, 4 MB/kg with an acquisition time of 2 min) with a β value of 700 performs well regarding noise level, CNR, and visual image quality assessment

Uncertainty propagation for SPECT/CT-based renal dosimetry in (177)Lu peptide receptor radionuclide therapy.

A computer model of a patient-specific clinical (177)Lu-DOTATATE therapy dosimetry system is constructed and used for investigating the variability of renal absorbed dose and biologically effective dose (BED) estimates. As patient models, three anthropomorphic computer phantoms coupled to a pharmacokinetic model of (177)Lu-DOTATATE are used. Aspects included in the dosimetry-process model are the gamma-camera calibration via measurement of the system sensitivity, selection of imaging time points, generation of mass-density maps from CT, SPECT imaging, volume-of-interest delineation, calculation of absorbed-dose rate via a combination of local energy deposition for electrons and Monte Carlo simulations of photons, curve fitting and integration to absorbed dose and BED. By introducing variabilities in these steps the combined uncertainty in the output quantity is determined. The importance of different sources of uncertainty is assessed by observing the decrease in standard deviation when removing a particular source. The obtained absorbed dose and BED standard deviations are approximately 6% and slightly higher if considering the root mean square error. The most important sources of variability are the compensation for partial volume effects via a recovery coefficient and the gamma-camera calibration via the system sensitivity

Long-term retention of 177Lu/177mLu-Dotatate in patients investigated by gamma spectrometry and gamma camera imaging.

Dosimetry in peptide receptor radionuclide therapy using (177)Lu-Dotatate is based on patient imaging during the first week after administration, and determination of the activity retention as a function of time for different tissues. For calculation of the absorbed dose it is generally assumed that the long-term activity retention follows the pattern determined from the first week. This work aims to investigate the validity of this assumption by performing additional patient measurements between 5 and 10 weeks after administration. A further aim is to investigate to what extent absorbed dose values are affected when including these measurements, also taking into account the radionuclide impurity of (177)mLu and build-up of secondary (177)Lu from the (177)mLu decay