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Velikyan, I., Schweighoefer, P., Feldwisch, J., Seemann, J., Frejd, F. Y., Lindman, H. & Sörensen, J. (2019). Diagnostic HER2-binding radiopharmaceutical, [Ga-68]Ga-ABY-025, for routine clinical use in breast cancer patients. American Journal of Nuclear Medicine and Molecular Imaging, 9(1), 12-23
Open this publication in new window or tab >>Diagnostic HER2-binding radiopharmaceutical, [Ga-68]Ga-ABY-025, for routine clinical use in breast cancer patients
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2019 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 9, no 1, p. 12-23Article in journal (Refereed) Published
Abstract [en]

[Ga-68]Ga-ABY-025/PET-CT targeting human epidermal growth factor receptor type 2 (HER2) has demonstrated its potential clinical value for the detection and quantification of HER2 in a phase I clinical study with breast cancer patients. Previously, the radiopharmaceutical was prepared manually, however larger scale of multicenter clinical trials and routine healthcare requires automation of the production process to limit the operator radiation dose, improve tracer manufacturing robustness, and provide on-line documentation for good manufacturing practice (GMP) compliance. The production of [Ga-68]Ga-ABY-025 was implemented on the Modular-Lab PharmTrace synthesis platform (Eckert & Ziegler) and disposable cassettes were developed. Pharmaceutical grade Ge-68/Ga-68 generator (GalliaPharm (R)) was used in the study. The active pharmaceutical ingredient starting material ABY-025 (GMP grade) was provided by Affibody AB. The patient examinations were conducted using a Discovery MI PET/CT scanner (20 cm FOV, GE Healthcare). Reproducible and GMP compliant fully automated production of [Ga-68]Ga-ABY-025 was developed. The radiochemical purity of the product was 98.7 +/- 0.6% with total peptide content of 315 +/- 15 mu g (n = 3). Radionuclidic purity, sterility, endotoxin content, residual solvent content, and sterile filter integrity were controlled and met acceptance criteria. The product was stable at ambient temperature for at least 2 h. The primary tumor and metastasis were detected with SUVmax values of 8.3 and 16.0, respectively. Automated production of [Ga-68]Ga-ABY-025 was established and the process was validated enabling standardized multicenter phase II and III clinical trials and routine clinical use. Patient examinations conformed to the radiopharmaceutical biodistribution observed in the previous phase I study.

Place, publisher, year, edition, pages
E-CENTURY PUBLISHING CORP, 2019
Keywords
Affibody, breast cancer, clinical study, HER2, GMP, gallium-68
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-379777 (URN)000460442600002 ()
Funder
Swedish Cancer SocietyThe Breast Cancer Foundation
Available from: 2019-03-21 Created: 2019-03-21 Last updated: 2019-03-21Bibliographically approved
Lilja, J., Leuzy, A., Chiotis, K., Savitcheva, I., Sörensen, J. & Nordberg, A. (2019). Spatial normalization of 18F-Flutemetamol PET images using an adaptive principal-component template. Journal of Nuclear Medicine, 60(2), 285-291
Open this publication in new window or tab >>Spatial normalization of 18F-Flutemetamol PET images using an adaptive principal-component template
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2019 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 60, no 2, p. 285-291Article in journal (Refereed) Published
Abstract [en]

Though currently approved for visual assessment only, there is evidence to suggest that quantification of amyloid-β (Aβ) PET images may reduce interreader variability and aid in the monitoring of treatment effects in clinical trials. Quantification typically involves a regional atlas in standard space, requiring PET images to be spatially normalized. Different uptake patterns in Aβ-positive and Aβ-negative subjects, however, make spatial normalization challenging. In this study, we proposed a method to spatially normalize 18F-flutemetamol images using a synthetic template based on principal-component images to overcome these challenges.

Methods: 18F-flutemetamol PET and corresponding MR images from a phase II trial (n = 70), including subjects ranging from Aβ-negative to Aβ-positive, were spatially normalized to standard space using an MR-driven registration method (SPM12). 18F-flutemetamol images were then intensity-normalized using the pons as a reference region. Principal-component images were calculated from the intensity-normalized images. A linear combination of the first 2 principal-component images was then used to model a synthetic template spanning the whole range from Aβ-negative to Aβ-positive. The synthetic template was then incorporated into our registration method, by which the optimal template was calculated as part of the registration process, providing a PET-only–driven registration method. Evaluation of the method was done in 2 steps. First, coregistered gray matter masks generated using SPM12 were spatially normalized using the PET- and MR-driven methods, respectively. The spatially normalized gray matter masks were then visually inspected and quantified. Second, to quantitatively compare the 2 registration methods, additional data from an ongoing study were spatially normalized using both methods, with correlation analysis done on the resulting cortical SUV ratios.

Results: All scans were successfully spatially normalized using the proposed method with no manual adjustments performed. Both visual and quantitative comparison between the PET- and MR-driven methods showed high agreement in cortical regions. 18F-flutemetamol quantification showed strong agreement between the SUV ratios for the PET- and MR-driven methods (R2 = 0.996; pons reference region).

Conclusion: The principal-component template registration method allows for robust and accurate registration of 18F-flutemetamol images to a standardized template space, without the need for an MR image.

Keywords
Alzheimer disease, amyloid-beta, PET, F-18-flutemetamol, adaptive template
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-357431 (URN)10.2967/jnumed.118.207811 (DOI)000457479800030 ()29903930 (PubMedID)
Funder
VINNOVA, 2013-05175
Available from: 2018-08-16 Created: 2018-08-16 Last updated: 2019-03-07Bibliographically approved
Harms, H. J., Hansson, N. H., Kero, T., Baron, T., Tolbod, L. P., Kim, W. Y., . . . Sörensen, J. (2018). Automatic calculation of myocardial external efficiency using a single 11C-acetate PET scan.. Journal of Nuclear Cardiology, 25(6), 1937-1944
Open this publication in new window or tab >>Automatic calculation of myocardial external efficiency using a single 11C-acetate PET scan.
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2018 (English)In: Journal of Nuclear Cardiology, ISSN 1071-3581, E-ISSN 1532-6551, Vol. 25, no 6, p. 1937-1944Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Myocardial external efficiency (MEE) is defined as the ratio of kinetic energy associated with cardiac work [forward cardiac output (FCO)*mean systemic pressure] and the chemical energy from oxygen consumed (MVO2) by the left ventricular mass (LVM). We developed a fully automated method for estimating MEE based on a single 11C-acetate PET scan without ECG-gating.

METHODS AND RESULTS: Ten healthy controls, 34 patients with aortic valve stenosis (AVS), and 20 patients with mitral valve regurgitation (MVR) were recruited in a dual-center study. MVO2 was calculated using washout of 11C -acetate activity. FCO and LVM were calculated automatically using dynamic PET and parametric image formation. FCO and LVM were also obtained using cardiac magnetic resonance (CMR) in all subjects. The correlation between MEEPET-CMR and MEEPET was high (r = 0.85, P < 0.001) without significant bias. MEEPET was 23.6 ± 4.2% for controls and was lowered in AVS (17.2 ± 4.3%, P < 0.001) and in MVR (18.0 ± 5.2%, P = 0.004). MEEPET was strongly associated with both NYHA class (P < 0.001) and the magnitude of valvular dysfunction (mean aortic gradient: P < 0.001, regurgitant fraction: P = 0.009).

CONCLUSION: A single 11C-acetate PET yields accurate and automated MEE results on different scanners. MEE might provide an unbiased measurement of the phenotypic response to valvular disease.

Keywords
11C-acetate, Myocardial efficiency, myocardial energetics, positron emission tomography
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-356783 (URN)10.1007/s12350-018-1338-0 (DOI)000452340400009 ()29946824 (PubMedID)
Available from: 2018-08-07 Created: 2018-08-07 Last updated: 2019-01-24Bibliographically approved
Vorobyeva, A., Westerlund, K., Mitran, B., Altai, M., Rinne, S. S., Sörensen, J., . . . Tolmachev, V. (2018). Development of a PET Imaging Approach for Selection of Patients for Affibody-Based PNA-Mediated Pretargeted Radionuclide Therapy. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY.. European Journal of Nuclear Medicine and Molecular Imaging, 45(Supplement 1), S104-S104
Open this publication in new window or tab >>Development of a PET Imaging Approach for Selection of Patients for Affibody-Based PNA-Mediated Pretargeted Radionuclide Therapy
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, no Supplement 1, p. S104-S104Article in journal, Meeting abstract (Other academic) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-373340 (URN)10.1007/s00259-018-4148-3 (DOI)000449266201004 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY.
Note

Meeting Abstract: OP-313

Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Vorobyeva, A., Westerlund, K., Mitran, B., Altai, M., Rinne, S., Sörensen, J., . . . Karlström, A. E. (2018). Development of an optimal imaging strategy for selection of patients for affibody-based PNA-mediated radionuclide therapy. Scientific Reports, 8, Article ID 9643.
Open this publication in new window or tab >>Development of an optimal imaging strategy for selection of patients for affibody-based PNA-mediated radionuclide therapy
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 9643Article in journal (Refereed) Published
Abstract [en]

Affibody molecules are engineered scaffold proteins, which demonstrated excellent binding to selected tumor-associated molecular abnormalities in vivo and highly sensitive and specific radionuclide imaging of Her2-expressing tumors in clinics. Recently, we have shown that peptide nucleic acid (PNA)-mediated affibody-based pretargeted radionuclide therapy using beta-emitting radionuclide Lu-177 extended significantly survival of mice bearing human Her2-expressing tumor xenografts. In this study, we evaluated two approaches to use positron emission tomography (PET) for stratification of patients for affibody-based pretargeting therapy. The primary targeting probe Z(HER2:342)SR-HP1 and the secondary probe HP2 (both conjugated with DOTA chelator) were labeled with the positron-emitting radionuclide Ga. Biodistribution of both probes was measured in BALB/C nu/nu mice bearing either SKOV-3 xenografts with high Her2 expression or DU-145 xenografts with low Her2 expression. (68)GaHP2 was evaluated in the pretargeting setting. Tumor uptake of both probes was compared with the uptake of pretargeted Lu-177-HP2. The uptake of both Ga-68-Z(HER2:342)SR-HP1 and Ga-68-HP2 depended on Her2-expression level providing clear discrimination of between tumors with high and low Her2 expression. Tumor uptake of Ga-68-HP2 correlated better with the uptake of Lu-177-HP2 than the uptake of Ga-68 Z(HER2:342) SR-HP1. The use of Ga-68-HP2 as a theranostics counterpart would be preferable approach for clinical translation.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-360010 (URN)10.1038/s41598-018-27886-0 (DOI)000436078500006 ()29942011 (PubMedID)
Funder
Swedish Research Council, 2015-02353Swedish Research Council, 2015-02509Swedish Research Council, 2016-05207VINNOVA, 2015-02509Swedish Cancer Society, CAN 2015/350Swedish Cancer Society, 2014/474Swedish Society for Medical Research (SSMF)
Available from: 2018-09-13 Created: 2018-09-13 Last updated: 2018-09-13Bibliographically approved
Lubberink, M., Widström, C., Jonasson, M., Appel, L., Fällmar, D., Nyholm, D., . . . Danfors, T. (2018). Differential diagnosis of patients with parkinsonian syndrome using multilinear regression to disease-specific C-11-PE2I-PET templates and classification tree learning. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S409-S409
Open this publication in new window or tab >>Differential diagnosis of patients with parkinsonian syndrome using multilinear regression to disease-specific C-11-PE2I-PET templates and classification tree learning
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S409-S409Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372967 (URN)000449266204001 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-01-10Bibliographically approved
Lindström, E., Sundin, A., Trampal, C., Lindsjö, L., Ilan, E., Danfors, T., . . . Lubberink, M. (2018). Evaluation of penalized likelihood estimation reconstruction on a digital time-of-flight PET/CT scanner for 18F-FDG whole-body examinations. Journal of Nuclear Medicine, 59(7), 1152-1158
Open this publication in new window or tab >>Evaluation of penalized likelihood estimation reconstruction on a digital time-of-flight PET/CT scanner for 18F-FDG whole-body examinations
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2018 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, no 7, p. 1152-1158Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
FDG, Image Reconstruction, Molecular Imaging, PET/CT, block-sequential regularized expectation maximization, image reconstruction, penalization factor
National Category
Medical and Health Sciences Medical Image Processing
Identifiers
urn:nbn:se:uu:diva-343272 (URN)10.2967/jnumed.117.200790 (DOI)000437237200037 ()29449445 (PubMedID)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-09-18Bibliographically approved
Alhuseinalkhudhur, A., Lubberink, M., Velikyan, I., Tolmachev, V., Frejd, F., Feldwisch, J., . . . Sörensen, J. (2018). Kinetic Analysis of the HER2-binding ABY-025 Affibody Using Dynamic PET in Patients with Metastatic Breast Cancer. Paper presented at 31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY. European Journal of Nuclear Medicine and Molecular Imaging, 45, S457-S457
Open this publication in new window or tab >>Kinetic Analysis of the HER2-binding ABY-025 Affibody Using Dynamic PET in Patients with Metastatic Breast Cancer
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2018 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S457-S457Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Springer, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-372956 (URN)000449266204116 ()
Conference
31st Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 13-17, 2018, Dusseldorf, GERMANY
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-01-24Bibliographically approved
von Below, C., Wassberg, C., Grzegorek, R., Kullberg, J., Gestblom, C., Sörensen, J., . . . Ahlström, H. (2018). MRI and 11C acetate PET/CT for prediction of regional lymph node metastasis in newly diagnosed prostate cancer. Radiology and Oncology, 52(1), 90-97
Open this publication in new window or tab >>MRI and 11C acetate PET/CT for prediction of regional lymph node metastasis in newly diagnosed prostate cancer
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2018 (English)In: Radiology and Oncology, ISSN 1318-2099, E-ISSN 1581-3207, Vol. 52, no 1, p. 90-97Article in journal (Refereed) Published
Abstract [en]

Background:

C acetate PET/CT parameters in predicting regional lymph node (LN) metastasis of newly diagnosed prostate cancer (PCa).

Patients and methods:

C acetate PET/CT (53 patients) before extended pelvic LN dissection. For each patient the visually most suspicious LN was assessed for mean apparent diffusion coefficient (ADCmean), maximal standardized uptake value (SUVmax), size and shape and the primary tumour for T stage on MRI and ADCmean and SUVmax in the index lesion. The variables were analysed in simple and multiple logistic regression analysis.

Results:

All variables, except ADCmean and SUVmax of the primary tumor, were independent predictors of LN metastasis. In multiple logistic regression analysis the best model was ADCmean in combintion with MRI T-stage where both were independent predictors of LN metastasis, this combination had an AUC of 0.81 which was higher than the AUC of 0.65 for LN ADCmean alone and the AUC of 0.69 for MRI T-stage alone.

Conclusions:

Several quantitative and qualitative imaging parameters are predictive of regional LN metastasis in PCa. The combination of ADCmean in lymph nodes and T-stage on MRI was the best model in multiple logistic regression with increased predictive value compared to lymph node ADCmean and T-stage on MRI alone.

Keywords
diffusion magnetic resonance imaging, lymph node excision, lymph nodes, positronemission tomography, prostatic neoplasm
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-346994 (URN)10.2478/raon-2018-0001 (DOI)000426260900012 ()29520210 (PubMedID)
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-05-16Bibliographically approved
Tolbod, L. P., Nielsen, M. M., Pedersen, B. G., Hoyer, S., Harms, H. J., Borre, M., . . . Sörensen, J. (2018). Non-invasive quantification of tumor blood flow in prostate cancer using O-15-H2O PET/CT. American Journal of Nuclear Medicine and Molecular Imaging, 8(5), 292-302
Open this publication in new window or tab >>Non-invasive quantification of tumor blood flow in prostate cancer using O-15-H2O PET/CT
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2018 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 8, no 5, p. 292-302Article in journal (Refereed) Published
Abstract [en]

Tumor blood flow (TBF) measurements in prostate cancer (PCa) provide an integrative index of tumor growth, which could be important for primary diagnosis and therapy response evaluation. O-15-water PET is the noninvasive gold standard but is technically demanding. The aim of this study was to compare the accuracy of three different non-invasive strategies with an invasively measured arterial input function (BSIF): Using image-derived input functions (IDIF) from either 1) a separate heart scan or 2) the pelvic scan or 3) a populations-based input function (PBIF). Nine patients with biopsy-verified PCa scheduled for prostatectomy were included. All patients were characterized with serum levels of PSA (s-PSA), multiparametric magnetic resonance imaging (mpMRl) and post-surgical histopathology Gleason Grade. Dynamic O-15-water was performed of the heart and the pelvic area 15 minutes apart. TBF estimated from both wash-in (K-1) and wash-out (k(2)) constants was calculated using a one-compartmental model. Results: Mean (range) s PSA was 12 (3-27) ng/mL, Gleason Grade Group was 2.9 (1-5), k(2) was 0.44 (0.007-1.2), and K-1 was 0.24 (0.07-0.55) mL,/mL/min. k(2) (BSIF)correlated with s-PSA (r=0.86, P<0.01) and Gleason Grade Group (rho=0.78, P=0.01). BSIF, heart-IDIF and PBIF provided near-identical k(2) and K-1 (r>0.95, P<0.001) with slopes near unity. The correlations of BSIF and pelvic-IDIF rate constants were good (r>0.95, P<0.001), but individual errors high. In conclusion, non-invasive protocols for O-15-water PET with IDIF or PBIF accurately measures perfusion in prostate cancer and might be useful for evaluation of tumor aggressiveness and treatment response.

Place, publisher, year, edition, pages
E-CENTURY PUBLISHING CORP, 2018
Keywords
Tumor blood flow, O-15-H2O, prostate cancer
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-369434 (URN)000449784600002 ()30510847 (PubMedID)
Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2019-01-22Bibliographically approved
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