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Carlsson, Jörgen
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Publications (10 of 54) Show all publications
Al-Ramadan, A., Mortensen, A., Carlsson, J. & Nestor, M. V. (2018). Analysis of radiation effects in two irradiated tumor spheroid models. Oncology Letters, 15(3), 3008-3016
Open this publication in new window or tab >>Analysis of radiation effects in two irradiated tumor spheroid models
2018 (English)In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 15, no 3, p. 3008-3016Article in journal (Refereed) Published
Abstract [en]

Multicellular spheroids have proven suitable as three-dimensional in vivo-like models of non-vascularized micrometastases. Unlike monolayer-based models, spheroids mirror the cellular milieu and the pathophysiological gradients inside tumor nodules. However, there is limited knowledge of the radiation effects at the molecular level in spheroids of human origin. The present study is a presentation of selected cell biological processes that may easily be analyzed with methods available at routine pathology laboratories. Using gamma irradiated pancreatic neuroendocrine BON1 and colonic adenocarcinoma HCT116 spheroids as model systems, the present study assessed the radiobiological response in these models. Spheroid growth after irradiation was followed over time and molecular responses were subsequently assessed with immunohistochemistry (IHC) staining for descriptive analyses and semi-automatic grading of apoptosis, G(2)-phase and senescence in thin sections of the spheroids. Growth studies demonstrated the BON1 spheroids were slower growing and less sensitive to radiation compared with the HCT116 spheroids. IHC staining for G2-phase was primarily observed in the outer viable P-cell layers of the spheroids, with the 6 Gy irradiated HCT116 spheroids demonstrating a very clear increase in staining intensity compared with unirradiated spheroids. Apoptosis staining results indicated increased apoptosis with increasing radiation doses. No clear association between senescence and radiation exposure in the spheroids were observed. The present results demonstrate the feasibility of the use of multicellular spheroids of human origin in combination with IHC analyses to unravel radiobiological responses at a molecular level. The present findings inspire further investigations, including other relevant IHC-detectable molecular processes in time-and radiation dose-dependent settings.

Keywords
three-dimensional cell culture, spheroids, irradiation, IHC, pancreatic neuroendocrine cancer, colonic adenocarcinoma
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-354258 (URN)10.3892/ol.2017.7716 (DOI)000430818300039 ()29435031 (PubMedID)
Available from: 2018-06-28 Created: 2018-06-28 Last updated: 2018-06-28Bibliographically approved
Sandberg, D. T., Tolmachev, V., Velikyan, I., Olofsson, H., Wennborg, A., Feldwisch, J., . . . Sörensen, J. (2017). Intra-image referencing for simplified assessment of HER2-expression in breast cancer metastases using the Affibody molecule ABY-025 with PET and SPECT.. European Journal of Nuclear Medicine and Molecular Imaging, 44(8), 1337-1346
Open this publication in new window or tab >>Intra-image referencing for simplified assessment of HER2-expression in breast cancer metastases using the Affibody molecule ABY-025 with PET and SPECT.
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2017 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, no 8, p. 1337-1346Article in journal (Refereed) Published
Abstract [en]

PURPOSE: In phase I/II-studies radiolabelled ABY-025 Affibody molecules identified human epidermal growth factor receptor 2 (HER2) expression in breast cancer metastases using PET and SPECT imaging. Here, we wanted to investigate the utility of a simple intra-image normalization using tumour-to-reference tissue-ratio (T/R) as a HER2 status discrimination strategy to overcome potential issues related to cross-calibration of scanning devices.

METHODS: Twenty-three women with pre-diagnosed HER2-positive/negative metastasized breast cancer were scanned with [(111)In]-ABY-025 SPECT/CT (n = 7) or [(68)Ga]-ABY-025 PET/CT (n = 16). Uptake was measured in all metastases and in normal spleen, lung, liver, muscle, and blood pool. Normal tissue uptake variation and T/R-ratios were established for various time points and for two different doses of injected peptide from a total of 94 whole-body image acquisitions. Immunohistochemistry (IHC) was used to verify HER2 expression in 28 biopsied metastases. T/R-ratios were compared to IHC findings to establish the best reference tissue for each modality and each imaging time-point. The impact of shed HER2 in serum was investigated.

RESULTS: Spleen was the best reference tissue across modalities, followed by blood pool and lung. Spleen-T/R was highly correlated to PET SUV in metastases after 2 h (r = 0.96, P < 0.001) and reached an accuracy of 100% for discriminating IHC HER2-positive and negative metastases at 4 h (PET) and 24 h (SPECT) after injection. In a single case, shed HER2 resulted in intense tracer retention in blood. In the remaining patients shed HER2 was elevated, but without significant impact on ABY-025 biodistribution.

CONCLUSION: T/R-ratios using spleen as reference tissue accurately quantify HER2 expression with radiolabelled ABY-025 imaging in breast cancer metastases with SPECT and PET. Tracer binding to shed HER2 in serum might affect quantification in the extreme case.

Keywords
Affibody, HER2-receptor, PET, SPECT, Shedding, T/R
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-317746 (URN)10.1007/s00259-017-3650-3 (DOI)000403468900012 ()28261749 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-02-28Bibliographically approved
Sandström, M., Lindskog, K., Velikyan, I., Wennborg, A., Feldwisch, J., Sandberg, D., . . . Lubberink, M. (2016). Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule Ga-68-ABY-025 in Breast Cancer Patients. Journal of Nuclear Medicine, 57(6), 867-871
Open this publication in new window or tab >>Biodistribution and Radiation Dosimetry of the Anti-HER2 Affibody Molecule Ga-68-ABY-025 in Breast Cancer Patients
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2016 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, no 6, p. 867-871Article in journal (Refereed) Published
Abstract [en]

Ga-68-ABY-025 is a radiolabeled Affibody molecule for in vivo diagnosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer tumors with PET. The aim of the present work was to measure the biodistribution and estimate the radiation dosimetry of Ga-68-ABY-025 for 2 different peptide mass doses in a single group of patients using dynamic and serial whole-body PET/CT. Methods: Eight patients with metastatic breast cancer were included. Each patient underwent an abdominal 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 4 h after injection of a low peptide dose (LD) and a high peptide dose (HD), with approximately the same amount of radioactivity, in separate investigations 1 wk apart. As input to the absorbed dose calculations, volumes of interest were drawn on all clearly identifiable source organs: liver, kidneys, spleen, descending aorta, and upper large intestine. Absorbed doses were calculated using OLINDA/EXM, version 1.1. Results: Of the major organs, the highest radionuclide uptake at 1, 2, and 4 h after injection was observed in the kidneys and liver. The highest absorbed organ doses were seen in the kidneys, followed by the liver for both LD and HD Ga-68-ABY-025. Absorbed doses to liver and kidneys were slightly but significantly higher for LD. Total effective dose was 0.030 +/- 0.003 mSv/MBq for LD and 0.028 +/- 0.002 mSv/MBq for HD. Conclusion: The effective dose for a typical 200-MBq administration of Ga-68-ABY-025 is 6.0 mSv for LD and 5.6 mSv for HD. Therefore, from a radiation dosimetry point of view, HD is preferred for PET/CT evaluation of HER2-expressing breast cancer tumors. These effective doses are somewhat higher than earlier published values for other Ga-68-labeled tracers, such as 0.021 +/- 0.003 mSv/MBq for Ga-68-DOTATATE and Ga-68-DOTATOC, mainly because of higher uptake in liver and kidney.

Keywords
Affibody, breast cancer metastases, dosimetry, HER2-receptor, Ga-68-gallium
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-298861 (URN)10.2967/jnumed.115.169342 (DOI)000377052400035 ()26912439 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-07-11 Created: 2016-07-11 Last updated: 2017-11-28Bibliographically approved
Velikyan, I., Wennborg, A., Feldwisch, J., Lindman, H., Carlsson, J. & Sörensen, J. (2016). Good manufacturing practice production of [68Ga]Ga-ABY-025 for HER2 specific breast cancer imaging.. American Journal of Nuclear Medicine and Molecular Imaging, 6(2), 135-153
Open this publication in new window or tab >>Good manufacturing practice production of [68Ga]Ga-ABY-025 for HER2 specific breast cancer imaging.
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2016 (English)In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 6, no 2, p. 135-153Article in journal (Refereed) Published
Abstract [en]

Therapies targeting human epidermal growth factor receptor type 2 (HER2) have revolutionized breast cancer treatment, but require invasive biopsies and rigorous histopathology for optimal patient stratification. A non-invasive and quantitative diagnostic method such as positron emission tomography (PET) for the pre-therapeutic determination of the presence and density of the HER2 would significantly improve patient management efficacy and treatment cost. The essential part of the PET methodology is the production of the radiopharmaceutical in compliance with good manufacturing practice (GMP). The use of generator produced positron emitting (68)Ga radionuclide would provide worldwide accessibility of the agent. GMP compliant, reliable and highly reproducible production of [(68)Ga]Ga-ABY-025 with control over the product peptide concentration and amount of radioactivity was accomplished within one hour. Two radiopharmaceuticals were developed differing in the total peptide content and were validated independently. The specific radioactivity could be kept similar throughout the study, and it was 6-fold higher for the low peptide content radiopharmaceutical. Intrapatient comparison of the two peptide doses allowed imaging optimization. The high peptide content decreased the uptake in healthy tissue, in particular liver, improving image contrast. The later imaging time points enhanced the contrast. The combination of high peptide content radiopharmaceutical and whole-body imaging at 2 hours post injection appeared to be optimal for routine clinical use.

Keywords
Affibody, GMP, Gallium-68, HER2, breast cancer, clinical study
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-319478 (URN)000398120000004 ()27186441 (PubMedID)
Available from: 2017-04-05 Created: 2017-04-05 Last updated: 2017-11-29Bibliographically approved
Sörensen, J., Velikyan, I., Sandberg, D., Wennborg, A., Feldwisch, J., Tolmachev, V., . . . Lindman, H. (2016). Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [(68)Ga]ABY-025 Affibody PET/CT. Theranostics, 6(2), 262-271
Open this publication in new window or tab >>Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [(68)Ga]ABY-025 Affibody PET/CT
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2016 (English)In: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 6, no 2, p. 262-271Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Positron Emission Tomography (PET) imaging of HER2 expression could potentially be used to select patients for HER2-targed therapy, predict response based on uptake and be used for monitoring. In this phase I/II study the HER2-binding Affibody molecule ABY-025 was labeled with (68)Ga-gallium ([(68)Ga]ABY-025) for PET to study effect of peptide mass, test-retest variability and correlation of quantified uptake in tumors to histopathology.

EXPERIMENTAL DESIGN: Sixteen women with known metastatic breast cancer and on-going treatment were included and underwent FDG PET/CT to identify viable metastases. After iv injection of 212±46 MBq [(68)Ga]ABY-025 whole-body PET was performed at 1, 2 and 4 h. In the first 10 patients (6 with HER2-positive and 4 with HER2-negative primary tumors), [(68)Ga]ABY-025 PET/CT with two different doses of injected peptide was performed one week apart. In the last six patients (5 HER2-positive and 1 HER2-negative primary tumors), repeated [(68)Ga]ABY-025 PET were performed one week apart as a test-retest of uptake in individual lesions. Biopsies from 16 metastases in 12 patients were collected for verification of HER2 expression by immunohistochemistry and in-situ hybridization.

RESULTS: Imaging 4h after injection with high peptide content discriminated HER2-positive metastases best (p<0.01). PET SUV correlated with biopsy HER2-scores (r=0.91, p<0.001). Uptake was five times higher in HER2-positive than in HER2-negative lesions with no overlap (p=0.005). The test-retest intra-class correlation was r=0.996. [(68)Ga]ABY-025 PET correctly identified conversion and mixed expression of HER2 and targeted treatment was changed in 3 of the 16 patients.

CONCLUSION: [(68)Ga]ABY-025 PET accurately quantifies whole-body HER2-receptor status in metastatic breast cancer.

Keywords
Affibody; breast cancer metastases; clinical study; HER2-receptor; Ga-68-gallium
National Category
Cancer and Oncology
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-277714 (URN)10.7150/thno.13502 (DOI)000371806900010 ()26877784 (PubMedID)
Funder
Swedish Cancer SocietyBreast Cancer Research Foundation, BCRF
Available from: 2016-02-22 Created: 2016-02-22 Last updated: 2018-02-28Bibliographically approved
Carlsson, J., Wester, K., De La Torre, M., Malmström, P.-U. & Gardmark, T. (2015). EGFR-expression in primary urinary bladder cancer and corresponding metastases and the relation to HER2-expression. On the possibility to target these receptors with radionuclides. Radiology and Oncology, 49(1), 50-58
Open this publication in new window or tab >>EGFR-expression in primary urinary bladder cancer and corresponding metastases and the relation to HER2-expression. On the possibility to target these receptors with radionuclides
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2015 (English)In: Radiology and Oncology, ISSN 1318-2099, E-ISSN 1581-3207, Vol. 49, no 1, p. 50-58Article in journal (Refereed) Published
Abstract [en]

Background. There is limited effect of tyrosine kinase inhibitors or "naked" antibodies binding EGFR or HER2 for therapy of metastasized urinary bladder canter and these methods are therefore not routinely used. Targeting radionuclides to the extracellular domain of the receptors is potentially a better possibility. Methods. EGFR- and HER2-expression was analyzed for primary tumors and corresponding metastases from 72 patients using immunohistochemistry and the internationally recommended HercepTest. Intracellular mutations were not analyzed since only the receptors were considered as targets and intracellular abnormalities should have minor effect on radiation dose. Results. EGFR was positive in 71% of the primary tumors and 69% of corresponding metastases. Local and distant metastases were EGFR-positive in 75% and 66% of the cases, respectively. The expression frequency of HER2 in related lesions was slightly higher (data from previous study). The EGFR-positive tumors expressed EGFR in metastases in 86% of the cases. The co-expression of EGFR and HER2 was 57% for tumors and 53% for metastases. Only 3% and 10% of the lesions were negative for both receptors in tumors and metastases, respectively. Thus, targeting these receptors with radionuclides might be applied for most patients. Conclusions. At least one of the EGFR- or HER2-receptors was present in most cases and co-expressed in more than half the cases. It is therefore interesting to deliver radionuclides for whole-body receptor-analysis, dosimetry and therapy. This can hopefully compensate for resistance to other therapies and more patients can hopefully be treated with curative instead of palliative intention.

Keywords
EGFR, HER2, radionuclides, resistance, urinary bladder cancer metastases
National Category
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-251515 (URN)10.2478/raon-2014-0015 (DOI)000350712100008 ()25810701 (PubMedID)
Available from: 2015-04-23 Created: 2015-04-20 Last updated: 2017-12-04Bibliographically approved
Velikyan, I., Wennborg, A., Feldwisch, J., Orlova, A., Tolmachev, V., Lindman, H., . . . Sörensen, J. (2015). Good manufacturing practice compliant production of a Ga-68-labelled Affibody agent for breast cancer imaging: first-in-human. Journal of labelled compounds & radiopharmaceuticals, 58, S358-S358
Open this publication in new window or tab >>Good manufacturing practice compliant production of a Ga-68-labelled Affibody agent for breast cancer imaging: first-in-human
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2015 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, p. S358-S358Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-284899 (URN)000369950200359 ()
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2017-11-30Bibliographically approved
Lindman, H., Wennborg, A., Velikyan, I., Feldwisch, J., Tolmachev, V., Sandberg, D., . . . Sörensen, J. (2015). Non-invasive determination of HER2-expression in metastatic breast cancer by using Ga-68-ABY025 PET/CT.. Paper presented at Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), MAY 29-JUN 02, 2015, Chicago, IL. Journal of Clinical Oncology, 33(15)
Open this publication in new window or tab >>Non-invasive determination of HER2-expression in metastatic breast cancer by using Ga-68-ABY025 PET/CT.
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2015 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 33, no 15Article in journal, Meeting abstract (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-261481 (URN)000358036900326 ()
Conference
Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), MAY 29-JUN 02, 2015, Chicago, IL
Note

Meeting Abstract: 11067

Available from: 2015-09-03 Created: 2015-09-01 Last updated: 2017-12-04Bibliographically approved
Sörensen, J., Sandberg, D., Sandström, M., Wennborg, A., Feldwisch, J., Tolmachev, V., . . . Lindman, H. (2014). First-in-Human Molecular Imaging of HER2 Expression in Breast Cancer Metastases Using the In-111-ABY-025 Affibody Molecule. Journal of Nuclear Medicine, 55(5), 730-735
Open this publication in new window or tab >>First-in-Human Molecular Imaging of HER2 Expression in Breast Cancer Metastases Using the In-111-ABY-025 Affibody Molecule
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2014 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no 5, p. 730-735Article in journal (Refereed) Published
Abstract [en]

The expression status of human epidermal growth factor receptor type 2 (HER2) predicts the response of HER2-targeted therapy in breast cancer. ABY-025 is a small reengineered Affibody molecule targeting a unique epitope of the HER2 receptor, not occupied by current therapeutic agents. This study evaluated the distribution, safety, dosimetry, and efficacy of In-111-ABY-025 for determining the HER2 status in metastatic breast cancer. Methods: Seven patients with metastatic breast cancer and HER2-positive (n = 5) or - negative (n 5 2) primary tumors received an intravenous injection of approximately 100 mu g (similar to 140 MBq) of In-111-ABY-025. Planar gamma-camera imaging was performed after 30 min, followed by SPECT/CT after 4, 24, and 48 h. Blood levels of radioactivity, antibodies, shed serum HER2, and toxicity markers were evaluated. Lesional HER2 status was verified by biopsies. The metastases were located by F-18-FDG PET/CT 5 d before In-111-ABY-025 imaging. Results: Injection of In-111-ABY-025 yielded a mean effective dose of 0.15 mSv/MBq and was safe, well tolerated, and without drug-related adverse events. Fast blood clearance allowed high-contrast HER2 images within 4-24 h. No anti-ABY025 antibodies were observed. When metastatic uptake at 24 h was normalized to uptake at 4 h, the ratio increased in HER2-positive metastases and decreased in negative ones (P, < 0.05), with no overlap and confirmation by biopsies. In 1 patient, with HER2- positive primary tumor, In-111-ABY-025 imaging correctly suggested a HER2negative status of the metastases. The highest normal-tissue uptake was in the kidneys, followed by the liver and spleen. Conclusion: In-111-ABY- 025 appears safe for use in humans and is a promising noninvasive tool for discriminating HER2 status in metastatic breast cancer, regardless of ongoing HER2-targeted antibody treatment.

Keywords
Affibody, breast cancer metastases, clinical study, HER2 receptor, In-111 imaging
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-227273 (URN)10.2967/jnumed.113.131243 (DOI)000335968000017 ()
Funder
Swedish Cancer Society, 110565, 120415
Available from: 2014-06-30 Created: 2014-06-24 Last updated: 2017-12-05Bibliographically approved
Velikyan, I., Wennborg, A., Feldwisch, J., Orlova, A., Tolmachev, V., Lubberink, M., . . . Sörensen, J. (2014). GMP compliant preparation of a (68)Gallium-labeled Affibody analogue for breast cancer patient examination: first-in-man. Paper presented at Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 18-22, 2014, Gothenburg, SWEDEN. European Journal of Nuclear Medicine and Molecular Imaging, 41(S2), S228-S229, Article ID OP308.
Open this publication in new window or tab >>GMP compliant preparation of a (68)Gallium-labeled Affibody analogue for breast cancer patient examination: first-in-man
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2014 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S228-S229, article id OP308Article in journal, Meeting abstract (Other academic) Published
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-247709 (URN)000348841900217 ()
Conference
Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), OCT 18-22, 2014, Gothenburg, SWEDEN
Available from: 2015-03-24 Created: 2015-03-23 Last updated: 2017-12-04Bibliographically approved
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