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Purpose: Targeted radionuclide therapy (TRT) is a cancer treatment with relative therapeutic efficacy across various cancer types. We studied the therapeutic potential of TRT using fibroblast activation protein-α (FAP) targeting sdAbs (4AH29) labelled with 225Ac or 131I in immunocompetent mice in a human FAP (hFAP) expressing lung cancer mouse model. We further explored the combination of TRT with programmed cell death ligand 1 (PD-L1) immune checkpoint blockade (ICB). Methods: We studied the biodistribution and tumour uptake of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 by ex vivo γ-counting. Therapeutic efficacy of [131I]I-GMIB-4AH29 and [225Ac]Ac-DOTA-4AH29 was evaluated in an immunocompetent mouse model. Flow cytometry analysis of tumours from [225Ac]Ac-DOTA-4AH29 treated mice was performed. Treatment with [225Ac]Ac-DOTA-4AH29 was repeated in combination with PD-L1 ICB. Results: The biodistribution showed high tumour uptake of [131I]I-GMIB-4AH29 with 3.5 ± 0.5% IA/g 1 h post-injection (p.i.) decreasing to 0.9 ± 0.1% IA/g after 24 h. Tumour uptake of [225Ac]Ac-DOTA-4AH29 was also relevant with 2.1 ± 0.5% IA/g 1 h p.i. with a less steep decrease to 1.7 ± 0.2% IA/g after 24 h. Survival was significantly improved after treatment with low and high doses [131I]I-GMIB-4AH29 or [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Moreover, we observed significantly higher PD-L1 expression in tumours of mice treated with [225Ac]Ac-DOTA-4AH29 compared to vehicle solution. Therefore, we combined high dose [225Ac]Ac-DOTA-4AH29 with PD-L1 ICB showing therapeutic synergy. Conclusion: [225Ac]Ac-DOTA-4AH29 and [131I]I-GMIB-4AH29 exhibit high and persistent tumour targeting, translating into prolonged survival in mice bearing aggressive tumours. Moreover, we demonstrate that the combination of PD-L1 ICB with [225Ac]Ac-DOTA-4AH29 TRT enhances its therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to evaluate the potential of anatomy-based reconstruction, using microCT information, to improve quantitative accuracy in multiple-pinhole SPECT. Methods: Multiple-pinhole SPECT and microCT images were acquired with the Micro Deluxe Phantom using both hot and cold rod inserts. The phantoms were filled with 3.7 MBq/ml of Tc. To improve microCT contrast, the phantoms were also filled with contrast agent. Emission images were reconstructed using a one-step-late (OSL) modification of the ordered subsets expectation maximization (OSEM) algorithm for incorporation of microCT information, to encourage smoothing within but not across boundaries. To allow quantification, the OSL OSEM algorithm takes into account imperfect camera motion, collimator response, angular variation of the sensitivity, intrinsic camera resolution, attenuation and scatter. For comparison, the emission images were also reconstructed by OSEM using post-reconstruction filtering and by OSL OSEM using a quadratic prior and an edge-preserving prior. In each rod of the phantoms the recovery coefficient (RC), defined as measured divided by the true activity concentration, was expressed as a function of the noise. Different noise levels were obtained by varying the amount of spatial filtering during or after reconstruction and by the use of binominal deviates. Results: Compared to conventional OSEM using post-reconstruction filtering and compared to OSL OSEM using a quadratic prior, our study demonstrated that the use of anatomical information during reconstruction significantly improved the quantitative accuracy in both cold and hot rods with a diameter larger than or equal to 2.4 mm. When compared to the edge-preserving prior, the anatomical prior performs significantly better for hot rods with a diameter ≥2.4 mm. For the 4.0-mm hot rods for example, the RC averaged over the different noise levels was 0.67 ± 0.02 when multiple-pinhole SPECT images were reconstructed using anatomical information, compared to 0.54 ± 0.08, 0.60 ± 0.04 and 0.64 ± 0.02 when OSEM in combination with a post-reconstruction filter, OSL OSEM using a quadratic prior and OSL OSEM using a median root prior was used, respectively. For the 4.0-mm cold rods, the RC averaged over the different noise levels was 0.61 ± 0.03 when the multiple-pinhole SPECT images were reconstructed using anatomical information, compared to 0.54 ± 0.07, 0.53 ± 0.08 and 0.60 ± 0.03 when OSEM in combination with a post-reconstruction filter, OSL OSEM using a quadratic prior and OSL OSEM using a median root prior was used, respectively. Conclusion: Anatomy-based reconstruction using microCT information has the potential to improve quantitative accuracy in multiple-pinhole SPECT. [ABSTRACT FROM AUTHOR]

The purpose of this study was to demonstrate the feasibility of accurate quantification in pinhole SPECT using micro-CT information. Pinhole SPECT scans were performed using a clinical dual-head gamma camera. Each pinhole SPECT scan was followed by a micro-CT acquisition. Functional and anatomical images were coregistered using six point sources visible with both modalities. Pinhole SPECT images were reconstructed iteratively. Attenuation correction was based on micro-CT information. Scatter correction was based on dual and triple-energy window methods. Phantom and animal experiments were performed. A phantom containing nine vials was filled with different concentrations of 99mTc. Three vials were also filled with CT contrast agent to increase attenuation. Activity concentrations measured on the pinhole SPECT images were compared with activity concentrations measured by the dose calibrator. In addition, 11 mice were injected with 99mTc-labelled Nanobodies. After acquiring functional and anatomical images, the animals were killed and the liver activity was measured using a gamma-counter. Activity concentrations measured on the reconstructed images were compared with activity concentrations measured with the gamma counter. The phantom experiments demonstrated an average error of −27.3 ± 15.9% between the activity concentrations measured on the uncorrected pinhole SPECT images and in the dose calibrator. This error decreased significantly to −0.1 ± 7.3% when corrections were applied for nonuniform attenuation and scatter. The animal experiment revealed an average error of −18.4 ± 11.9% between the activity concentrations measured on the uncorrected pinhole SPECT images and measured with the gamma counter. This error decreased to −7.9 ± 10.4% when attenuation and scatter correction was applied. Attenuation correction obtained from micro-CT data in combination with scatter correction allows accurate quantification in pinhole SPECT. [ABSTRACT FROM AUTHOR]

In vivo bioluminescence imaging (BLI) is a promising technique for non-invasive tumour imaging. d-luciferin can be administrated intraperitonealy or intravenously. This will influence its availability and, therefore, the bioluminescent signal. The aim of this study is to compare the repeatability of BLI measurement after IV versus IP administration of d-luciferin and assess the correlation between photon emission and histological cell count both in vitro and in vivo. Fluc-positive R1M cells were subcutaneously inoculated in nu/nu mice. Dynamic BLI was performed after IV or IP administration of d-luciferin. Maximal photon emission (PEmax) was calculated. For repeatability assessment, every acquisition was repeated after 4 h and analysed using Bland–Altman method. A second group of animals was serially imaged, alternating IV and IP administration up to 21 days. When mice were killed, PEmax after IV administration was correlated with histological cell number. The coefficients of repeatability were 80.2% (IV) versus 95.0% (IP). Time-to-peak is shorter, and its variance lower for IV ( p < 0.0001). PEmax was 5.6 times higher for IV. A trend was observed towards lower photon emission per cell in larger tumours. IV administration offers better repeatability and better sensitivity when compared to IP. In larger tumours, multiple factors may contribute to underestimation of tumour burden. It might, therefore, be beneficial to test novel therapeutics on small tumours to enable an accurate evaluation of tumour burden. [ABSTRACT FROM AUTHOR]

The aim of this study was to improve the uniformity of the axial spatial resolution and sensitivity in pinhole single-photon emission computed tomography (SPECT) and to extend the axial field of view, by using a dedicated three-pinhole collimator. A rectangular tungsten plate with three pinhole apertures of 1.5 mm diameter was designed to image a cylindrical field of view of 55 mm diameter and 160 mm axial length using a clinical gamma camera. To evaluate the non-uniformity of spatial resolution and noise, a multiple-disk phantom was built. The phantom was filled with Tc-99m, and data were acquired using a circular orbit and reconstructed with a dedicated iterative reconstruction algorithm. The axial spatial resolution together with the noise was measured in each disk. These measurements were compared to a single-pinhole system using an identical acquisition geometry and reconstruction. At the central slice, a spatial resolution of 2.7 mm was observed for both the three-pinhole and single-pinhole geometries. At 17.5 mm from the central slice, the axial spatial resolution deteriorated to 10.3 mm when using a single pinhole, while the spatial resolution remained 2.7 mm for the three-pinhole system. In the central slice, 19% noise was observed for both geometries. At 31.5 mm from this central slice, the noise remained 19% for the three-pinhole geometry, while it increased to 32% using a single pinhole. The presented three-pinhole collimator improves the uniformity of the axial spatial resolution and sensitivity in pinhole SPECT and consequently extends the axial field of view, a requirement for whole-body small-animal imaging. [ABSTRACT FROM AUTHOR]

123I-2-iodo-tyrosine (123I-2IT) has been identified as a promising new amino acid tracer in animals. Uptake is mediated by LAT1 transport, which is increased in tumour cells. In this study we present the human biodistribution and first clinical results in glioma patients. For the biodistribution study, six male volunteers received 60–95 MBq 123I-2IT. Whole-body scans and blood and urine samples were obtained up to 24 h after injection; dosimetry was calculated using OLINDA 1.0 software. Initial clinical evaluation of 123I-2IT SPECT was performed in 35 patients with suspected or known glioma, either as primary diagnosis or for detection of recurrence. Tumour-to-background (T/B) ratios were calculated for semi-quantitative analysis. The results were correlated with clinical and MRI follow-up data or histology. 123I-2IT showed both renal and intestinal clearance. Bladder (0.12 mGy/MBq) and small intestine (0.03 mGy/MBq) received the highest absorbed doses. The effective dose equivalent and effective dose were estimated at 0.020 and 0.016 mSv/MBq, respectively. In patients, 123I-2IT SPECT did not differentiate between neoplastic and non-neoplastic lesions after an indeterminate MRI. In follow-up of known glioma, 13/15 patients with disease recurrence had increased T/B values (range 1.39–3.91). Out of seven recurrence-negative patients, two showed an important increase in T/B, in one case due to radionecrosis (T/B 1.59) and in the other probably due to residual but stable disease (T/B 2.07). 123I-2IT has a favourable biodistribution for a tumour imaging agent. It shows increased uptake in central nervous system glioma and is potentially useful in the follow-up of glioma patients. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to investigate the intra-individual reproducibility of left ventricular volume and ejection fraction measurements in living rat using pinhole gated single-photon emission computed tomography (SPECT). Methods: Eight normal male Wistar rats underwent four pinhole gated SPECT acquisitions over a 1-month period. Two pinhole gated myocardial perfusion SPECT studies were acquired at a 1-week interval after injecting the animals with 439±52 MBq of 99mTc-sestamibi. Subsequently, 1 week after the perfusion studies, two pinhole gated blood pool SPECT studies were acquired at a 1-week interval after in vivo labelling of the red blood cells using 520±49 MBq of 99mTc-pertechnetate. Pinhole gated SPECT acquisitions were done on a single-head gamma camera equipped with a pinhole collimator with a 3-mm opening and 165-mm focal length. Parameters of acquisition were as follows: 44 mm radius of rotation, 360° rotation using a circular orbit, 64 projections, 64×64 matrix, gating using 16 time frames and 22-min acquisition time. The projection data were reconstructed with a modified version of OSEM taking into account the pinhole geometry and incorporating a prior assumption about the temporal properties of gated SPECT studies to reduce noise. Left ventricular volumes and ejection fraction were measured using automatic quantification algorithms. Inter-study, inter-observer and intra-observer reproducibility was investigated. Results: Pinhole gated myocardial perfusion and pinhole gated blood pool images were of high quality in all animals. No significant differences were observed between the repeated measurements. The pinhole gated myocardial perfusion SPECT studies indicated that differences between repeated measurements larger than 41 μl for end-diastolic volume, 17 μl for endsystolic volume and 3% for ejection fraction were significant. The pinhole gated blood pool SPECT studies indicated that differences between repeated measurements larger than 42 μl for end-diastolic volume, 38 μl for endsystolic volume and 5% for ejection fraction were significant. In addition to the reproducibility measures, the accuracy of volume measurements in pinhole gated blood pool SPECT was confirmed by a phantom study. Excellent correlations were observed between the measured volumes and the actual phantom volumes. Conclusion: Pinhole gated SPECT is an accurate and reproducible technique for cardiac studies of small animals. Because this technique is non-invasive, the same animal can be imaged repetitively, allowing follow-up studies. [ABSTRACT FROM AUTHOR]

Reducing the acquisition time of whole-body fluorine-18 fluorodeoxyglucose positron emission tomography (18F­FDG PET) (corrected for attenuation) is of major importance in clinical practice. With the introduction of lutetium oxyorthosilicate (LSO), the acquisition time can be dramatically reduced, provided that patients are injected with larger amounts of tracer and/or the system is operated in 3D mode. The aim of this study was to determine the optimal dose of 18F­FDG required in order to achieve good-to-excellent image quality when a ‘3-min emission, 2-min transmission/bed position’ protocol is used for an LSO PET camera. A total of 218 consecutive whole-body 18F­FDG PET studies were evaluated retrospectively. After excluding patients with liver metastases, hyperglycaemia and paravenous injections, the final study population consisted of 186 subjects (112 men, 74 women, age 59±15 years). Patients were injected with an activity of 18F­FDG ranging from 2.23 to 15.21 MBq/kg. Whole-body images corrected for attenuation (3 min emission, 2 min transmission/bed position) were acquired with an LSO PET camera (Ecat Accel,Siemens) 60 min after tracer administration. Patients were positioned with their arms along the body. Image reconstruction was done iteratively and a post-reconstruction filter was applied. Image quality was scored visually by two independent observers using a five-point scoring scale (poor, reasonable, good, very good, excellent). In addition, the coefficient of variability (COV) was measured in a region of interest over the liver in order to quantify noise. Of the images obtained in 118 patients injected with ≥8 MBq/kg 18F­FDG, 92% and 90% were classified as good, very good or excellent by observer 1 and observer 2, respectively. The COV averaged 10.63%±3.19% for doses 8 MBq/kg and 16.46%±5.14% for doses <8 MBq/kg. Administration of an 18F­FDG dose of ≥8 MBq/kg results in images of good to excellent quality in the vast majority of patients when using an LSO PET camera and applying a 3-min emission, 2-min transmission/bed position acquisition protocol. At lower doses, a rapid decline in image quality and increasing noise are observed. Alternative protocols should be adopted in order to compensate for the loss in image quality when doses <8 MBq/kg are used. [ABSTRACT FROM AUTHOR]