| 1. |
- Tolmachev, Vladimir, et al.
(författare)
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Affibody molecules for epidermal growth factor receptor targeting in vivo : aspects of dimerization and labeling chemistry
- 2009
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 50:2, s. 274-283
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Tidskriftsartikel (refereegranskat)abstract
- Noninvasive detection of epidermal growth factor receptor (EGFR) expression in malignant tumors by radionuclide molecular imaging may provide diagnostic information influencing patient management. The aim of this study was to evaluate a novel EGFR-targeting protein, the ZEGFR:1907 Affibody molecule, for radionuclide imaging of EGFR expression, to determine a suitable tracer format (dimer or monomer) and optimal label. METHODS: An EGFR-specific Affibody molecule, ZEGFR:1907, and its dimeric form, (ZEGFR:1907)2, were labeled with 111In using benzyl-diethylenetriaminepentaacetic acid and with 125I using p-iodobenzoate. Affinity and cellular retention of conjugates were evaluated in vitro. Biodistribution of radiolabeled Affibody molecules was compared in mice bearing EGFR-expressing A431 xenografts. Specificity of EGFR targeting was confirmed by comparison with biodistribution of non-EGFR-specific counterparts. RESULTS: Head-to-tail dimerization of the Affibody molecule improved the dissociation rate. In vitro, dimeric forms demonstrated superior cellular retention of radioactivity. For both molecular set-ups, retention was better for the 111In-labeled tracer than for the radioiodinated counterpart. In vivo, all conjugates accumulated specifically in xenografts and in EGFR-expressing tissues. The retention of radioactivity in tumors was better in vivo for dimeric forms; however, the absolute uptake values were higher for monomeric tracers. The best tracer, 111In-labeled ZEGFR:1907, provided a tumor-to-blood ratio of 100 (24 h after injection). CONCLUSION: The radiometal-labeled monomeric Affibody molecule ZEGFR:1907 has a potential for radionuclide molecular imaging of EGFR expression in malignant tumors.
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| 2. |
- Lindström, Elin, et al.
(författare)
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Evaluation of penalized likelihood estimation reconstruction on a digital time-of-flight PET/CT scanner for 18F-FDG whole-body examinations
- 2018
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 59:7, s. 1152-1158
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Tidskriftsartikel (refereegranskat)abstract
- The resolution and quantitative accuracy of PET are highly influenced by the reconstruction method. Penalized-likelihood estimation algorithms allow for fully convergent iterative reconstruction, generating a higher image contrast than ordered-subsets expectation maximization (OSEM) while limiting noise. In this study, a type of penalized reconstruction known as block-sequential regularized expectation maximization (BSREM) was compared with time-of-flight OSEM (TOF OSEM). Various strengths of noise penalization factor β were tested along with various acquisition durations and transaxial fields of view (FOVs) with the aim of evaluating the performance and clinical use of BSREM for 18F-FDG PET/CT, both quantitatively and in a qualitative visual evaluation. Methods: Eleven clinical whole-body 18F-FDG PET/CT examinations acquired on a digital TOF PET/CT scanner were included. The data were reconstructed using BSREM with point-spread function recovery and β-factors of 133, 267, 400, and 533—and using TOF OSEM with point-spread function—for various acquisition times per bed position and various FOVs. Noise level, signal-to-noise ratio (SNR), signal-to-background ratio (SBR), and SUV were analyzed. A masked evaluation of visual image quality, rating several aspects, was performed by 2 nuclear medicine physicians to complement the analysis. Results: The lowest levels of noise were reached with the highest β-factor, resulting in the highest SNR, which in turn resulted in the lowest SBR. A β-factor of 400 gave noise equivalent to TOF OSEM but produced a significant increase in SUVmax (11%), SNR (22%), and SBR (12%). BSREM with a β-factor of 533 at a decreased acquisition duration (2 min/bed position) was comparable to TOF OSEM at a full acquisition duration (3 min/bed position). Reconstructed FOV had an impact on BSREM outcome measures; SNR increased and SBR decreased when FOV was shifted from 70 to 50 cm. The evaluation of visual image quality resulted in similar scores for reconstructions, although a β-factor of 400 obtained the highest mean whereas a β-factor of 267 was ranked best in overall image quality, contrast, sharpness, and tumor detectability. Conclusion: In comparison with TOF OSEM, penalized BSREM reconstruction resulted in an increased tumor SUVmax and an improved SNR and SBR at a matched level of noise. BSREM allowed for a shorter acquisition than TOF OSEM, with equal image quality.
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| 3. |
- Oroujeni, Maryam, PhD, 1982-, et al.
(författare)
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Affibody-Mediated PNA-Based Pretargeted Cotreatment Improves Survival of Trastuzumab-Treated Mice Bearing HER2-Expressing Xenografts
- 2022
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 63:7, s. 1046-1051
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of patients with human epidermal growth factor receptor 2 (HER2)-expressing tumors using the monoclonal antibody trastuzumab increases survival. The Affibody-based peptide nucleic acid (PNA)-mediated pretargeted radionuclide therapy has demonstrated efficacy against HER2-expressing xenografts in mice. Structural studies suggest that Affibody molecules and trastuzumab bind to different epitopes on HER2. The aim of this study was to test the hypothesis that a combination of PNA-mediated pretargeted radionuclide therapy and trastuzumab treatment of HER2-expressing xenografts can extend survival compared with monotherapies. Methods: Mutual interference of the primary pretargeting probe Z(HER2:342)-SR-HP1 and trastuzumab in binding to HER2-expressing cell lines was investigated in vitro. Experimental therapy evaluated the survival of mice bearing HER2-expressing SKOV-3 xenografts after treatment with vehicle, trastuzumab only, pretargeting using Affibody-PNA chimera Z(HER2:342)-SR-HP1 and complementary probe Lu-177-HP2, and combination of trastuzumab and pretargeting. The ethical permit limited the study to 90 d. The animals'weightsweremonitored during the study. After study termination, samples of liver and kidneys were evaluated by a veterinary pathologist for toxicity signs. Results: The presence of a large molar excess of trastuzumab had no influence on the affinity of Z(HER2:342)-SR-HP1 binding to HER2-expressing cells in vitro. The affinity of trastuzumab was not affected by a large excess of Z(HER2:342)-SR-HP1. Themedian survival of mice treated with trastuzumab (75.5 d) was significantly longer than the survival of mice treated with a vehicle (59.5 d). Median survival of mice treated with pretargeting was not reached by day 90. Six mice of 10 in this group survived, and 2 had complete remission. All mice in the combination treatment group survived, and tumors in 7 mice had disappeared at study termination. There was no significant difference between animal weights in the different treatment groups. No significant pathologic alterations were detected in livers and kidneys of treated animals. Conclusion: Treatment of mice bearing HER2-expressing xenografts with the combination of trastuzumab and Affibody-mediated PNA-based radionuclide pretargeting significantly increased survival compared with monotherapies. Cotreatment was not toxic for normal tissues.
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| 4. |
- Langen, Britta, et al.
(författare)
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Microarray Studies on 211At Administration in BALB/c Nude Mice Indicate Systemic Effects on Transcriptional Regulation in Non-Thyroid Tissues
- 2017
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:2, s. 346-353
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Targeted α-therapy is a promising treatment option for various types of malignant tumors. Radiolabeled cancer-seeking agents, however, undergo degradation resulting in a certain percentage of free radionuclide in the body. The radiohalogen 211At accumulates in various tissues with specifically high uptake in the thyroid. When normal thyroid function is disturbed due to ionizing radiation (IR) exposure, deleterious effects can occur in tissues that depend on thyroid hormone (TH) regulation for normal physiological function. However, knowledge of systemic effects is still rudimentary. We previously reported similarities in transcriptomic regulation between the thyroid and other tissues despite large differences in absorbed dose from 211At (Langen et al. JNM, 2013). Here, we present supportive evidence on systemic effects after 211At administration. Methods: Expression microarray data from kidney cortex and medulla, liver, lungs, and spleen were used from previous studies where mice were i.v. injected with 0.064–42 kBq 211At and killed after 24 h, or injected with 1.7 kBq 211At and killed after 1, 6, or 168 h. Controls were mock-treated and killed after 24 h. Literature-based gene signatures were used to evaluate the relative impact from IR- or TH-induced regulation. Thyroid- and TH-associated upstream regulators as well as thyroid-related diseases and functions were generated using functional analysis software. Results: Responses in IR- or TH-associated gene signatures were tissue-specific, varied over time, and the relative impact of each gene signature differed between the investigated tissues. The liver showed a clear dominance of TH-responding genes. In the kidney cortex, kidney medulla, and lungs, the TH-associated signature was detected to at least similar extent as the IR-associated signature. The spleen was the single tissue showing regulation of only IR-associated signature genes. Various thyroid-associated diseases and functions were inferred from the data: L-triiodothyronine, TH, TH receptor, and triiodothyronine (reverse) were inferred as upstream-regulators with differences in incidence and strength of regulation depending on tissue type. Conclusion: These findings indicate that transcriptional regulation in various non-thyroid tissues was–in part–induced by thyroid (hormone)-dependent signaling. Consideration of the systemic context between tissues could contribute to normal tissue risk assessment and planning of remedial measures.
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| 5. |
- Rydén, Tobias, et al.
(författare)
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Deep learning generation of synthetic intermediate projections improves 177 Lu SPECT images reconstructed with sparsely acquired projections
- 2021
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 62:4, s. 528-534
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Tidskriftsartikel (refereegranskat)abstract
- The aims were to decrease 177Lu-SPECT (single-photon emission computed tomography) acquisition time by reducing the number of projections and to circumvent image degradation by adding deep learning-generated synthesized projections. Methods: We constructed a deep convolutional U-structured network for generating synthetic intermediate projections (CUSIP). The number of SPECT investigations was 352 for training, 37 for validation, and 15 for testing. The input was every fourth projection of 120 acquired SPECT projections, i.e., 30 projections. The output was 30 synthetic intermediate projections (SIPs) per CUSIP. SPECT images were reconstructed with 120 or 30 projections, or 120 projections where 90 SIPs were generated from the 30 projections (30-120SIP); using 3 CUSIPs. The reconstructions were performed with two ordered subset expectation maximization (OSEM) algorithms: attenuation-corrected (AC)-OSEM, and attenuation, scatter, and collimator response-corrected (ASCC)-OSEM. Image quality of SIPs and SPECT images were quantitatively evaluated with root mean square error, peak signal-to-noise-ratio (PSNR), and structural similarity (SSIM) index metrics. From a Jaszczak SPECT Phantom, the recovery and signal-to-noise ratio (SNR) were determined. In addition, an experienced observer qualitatively assessed the SPECT image quality of the test set. Kidney activity concentrations, as determined from the different SPECT images, were compared. Results: The generated SIPs had a mean SSIM value of 0.926 (0.061). For AC-OSEM, the reconstruction with 30-120SIP had higher SSIM (0.993 vs. 0.989; p<0.001) and PSNR (49.5 vs. 47.2; p<0.001) values than the reconstruction with 30 projections. ASCC-OSEM had higher SSIM and PSNR values than AC-OSEM (p<0.001). There was a minor loss in recovery for the 30-120SIP set, but SNR was clearly improved compared to the 30-projection set. The observer assessed 27/30 of the images reconstructed with 30 projections as having unacceptable noise levels, whereas corresponding values were 2/60 for the 30-120SIP and 120 projection sets. Image quality did not differ significantly between the 30-120SIP and 120 projection reconstructions. The kidney activity concentration was similar between the different projection sets, excepting a minor reduction of 2.5% for the ASCC-OSEM 30-120SIP. Conclusion: Adopting synthetic intermediate projections for sparsely acquired projections considerably recovers image quality and could allow reduced SPECT acquisition time in clinical dosimetry protocols.
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| 6. |
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| 7. |
- Minarik, David, et al.
(författare)
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Denoising of Scintillation Camera Images Using a Deep Convolutional Neural Network: A Monte Carlo Simulation Approach
- 2020
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 61:2, s. 298-303
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Tidskriftsartikel (refereegranskat)abstract
- Scintillation camera images contain a large amount of Poisson noise. We have investigated whether noise can be removed in whole-body bone scans using convolutional neural networks (CNNs) trained with sets of noisy and noiseless images obtained by Monte Carlo simulation. Methods: Three CNNs were generated using 3 different sets of training images: simulated bone scan images, images of a cylindric phantom with hot and cold spots, and a mix of the first two. Each training set consisted of 40,000 noiseless and noisy image pairs. The CNNs were evaluated with simulated images of a cylindric phantom and simulated bone scan images. The mean squared error between filtered and true images was used as difference metric, and the coefficient of variation was used to estimate noise reduction. The CNNs were compared with gaussian and median filters. A clinical evaluation was performed in which the ability to detect metastases for CNN- and gaussian-filtered bone scans with half the number of counts was compared with standard bone scans. Results: The best CNN reduced the coefficient of variation by, on average, 92%, and the best standard filter reduced the coefficient of variation by 88%. The best CNN gave a mean squared error that was on average 68% and 20% better than the best standard filters, for the cylindric and bone scan images, respectively. The best CNNs for the cylindric phantom and bone scans were the dedicated CNNs. No significant differences in the ability to detect metastases were found between standard, CNN-, and gaussian-filtered bone scans. Conclusion: Noise can be removed efficiently regardless of noise level with little or no resolution loss. The CNN filter enables reducing the scanning time by half and still obtaining good accuracy for bone metastasis assessment.
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| 8. |
- Sadik, May, 1970, et al.
(författare)
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3D prostate gland uptake of 18F-choline - association with overall survival in patients with hormone-naïve prostate cancer
- 2017
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Ingår i: Journal of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:supplement 1, s. 544-
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Tidskriftsartikel (refereegranskat)abstract
- Objectives : To develop a completely automated method to quantify prostate gland uptake of 18F-choline in PET/CT images and to study the relationship between this measure, clinical data and overall survival in patients with prostate cancer. Methods : An automated method for segmentation of the prostate gland in CT images was developed using a training group of 100 patients who had undergone PET/CT scanning. The algorithms were trained based on the manual segmentations of the prostate gland in the 100 CT scans performed by a single radiologist. A multi-atlas-based method was used applied for automated segmentation of the prostate gland. Each of a subset of the training images was registered separately to the test image. By applying the resulting transformations to the manual delineations a rough segmentation of the test image was obtained. This segmentation was refined using a random-forest classifier and the final segmentation was obtained with graph cuts. Voxels in the 18F-choline PET scans having a standard uptake value (SUV) >2.65 and localized in the prostate gland in the corresponding CT scan were defined as abnormal. Automated calculation of the following five PET measurements was performed: The maximal SUV within the prostate gland - SUVmax The average SUV within the abnormal part of the prostate gland - SUVmean The volume of abnormal uptake within the prostate gland - VOL The product SUVmean x VOL defined as Total Lesion Uptake - TLU The fraction of the prostate with abnormal uptake related to the whole volume of the prostate gland - FRAC The automated quantification method was retrospectively applied to a separate test group of 46 prostate cancer patients, aged 53-94 years, who had undergone 18F-choline PET/CT. These patients have previously been selected for a study aiming to compare whole-body bone scans, 18F-choline-PET/CT and 18F-NaF PET/CT with magnetic resonance imaging. The study entry criteria were biopsy-proven prostate cancer, a positive whole-body bone scan consistent with bone metastases, and no history of androgen deprivation. The association between the automated PET measurements, age, PSA, Gleason score and overall survival was evaluated using a univariate Cox proportional hazards regression model. Kaplan-Meier estimates were used to estimate the survival difference between patients with values above and below the median value for all variables analyzed. Results : The fraction of the prostate with abnormal uptake related to the whole volume of the prostate gland - FRAC and age were significantly associated with overall survival (Table) while PSA, Gleason score and other PET measurements were not. The patients with a FRAC above the median value (58.2%) had a significantly shorter median survival time than patients with a value below the median value (2.8 years vs. 5.5 years; p=0.04), see Figure. Conclusion : A completely automated method of quantifying 18F-choline PET uptake in the prostate gland yielded a measure of disease extent that was significantly associated with overall survival in patients with hormone-naïve prostate cancer. The method can also be applied to PET/CT scans with other tracers such as FDG or PSMA-targeted agents. It is our hope that these preliminary data will inspire further evaluation of this type of objective quantification of PET/CT scans.
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| 9. |
- Sadik, May, 1970, et al.
(författare)
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Automated 3D segmentation of the prostate gland in CT images - a first step towards objective measurements of prostate uptake in PET and SPECT images
- 2017
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Ingår i: Journal of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:supplement 1
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Tidskriftsartikel (refereegranskat)abstract
- Objectives : Uptake of PSMA-targeted tracers and choline in the prostate gland may serve as guidance for management of patients with prostate cancer. Our aim was to develop objectively measured PET/CT and SPECT/CT imaging biomarkers reflecting such uptake. In this study we took the first step by introducing and validating a completely automated algorithm for 3D-segmentation of the prostate gland in CT images. Methods : A group of 100 patients who had undergone 18F-FDG PET/CT scanning was used as training set. A single radiologist performed manual segmentations of the prostate gland in all 100 CT scans using a custom software tool. A multi-atlas-based method was used applied for automated segmentation of the prostate gland. Each of a subset of the training images was registered separately to the test image. By applying the resulting transformations to the manual delineations a rough segmentation of the test image was obtained. This segmentation was refined using a random-forest classifier and the final segmentation was obtained with graph cuts. A separate validation group comprised 46 patients (aged 53-94 years) with biopsy-proven prostate cancer, who had undergone both 18F-fluoromethylcholine PET/CT and 18F-sodiumfluoride PET/CT within a time frame of 3 weeks as part of a previous research project. A diagnostic contrast-enhanced CT scan (64-slice helical, 120 kV, ’smart mA’ maximum 400 mA) was obtained with a CT slice thickness of 3.75 mm. We speculated that the volume of the prostate gland and in particular the fraction of the gland that had abnormally high tracer accumulation, might be useful biomarkers helping to improve management and prognostication in cancer patients. The reproducibility of automated measurements of the prostate gland volume was therefore studied using the two CT scans from each patient in the validation set. Results : The automatically measured prostate gland volumes in the validation set ranged between 13 ml and 90 ml with a mean of 48 ml. The mean difference between the two volume measurements in each patient was 2.4 ml with an SD of 6.6 ml. The difference was less than 10 ml in 41 of the 46 cases. Conclusion : We have demonstrated a reproducible and automated algorithm for 3D-segmentation of the prostate gland in CT images. This is a first step towards objective measurements of prostate gland tracer uptake in PET and SPECT examinations, because PET and SPECT images alone do not allow for accurate segmentation of the prostate gland, which instead depends on proper segmentation based on the corresponding CT scans.
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