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  • 1.
    Aarnio, Mikko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Visualization of Peripheral Pain Generating Processes and Inflammation in Musculoskeletal Tissue using [11C]-D-deprenyl PET2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    An objective visualization and quantification of pain-generating processes in the periphery would alter pain diagnosis and represent an important paradigm shift in pain research. Positron emission tomography (PET) radioligand [11C]-D-deprenyl has shown an elevated uptake in painful inflammatory arthritis and whiplash-associated disorder. However, D-Deprenyl’s molecular binding target and uptake mechanism in inflammation and musculoskeletal injuries are still unknown. The present thesis aimed to gain insight into the mechanisms of D-deprenyl binding and uptake and to verify whether pain-associated sites and inflammation in acute musculoskeletal injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET-computed tomography (PET/CT).

    To identify the D-deprenyl binding target, a high-throughput analysis and competitive radioligand binding studies were performed. D-deprenyl inhibited monoamine oxidase A (MAO-A) activity by 55%, MAO-B activity by 99% and angiotensin-converting enzyme (ACE) by 70%, which identified these enzymes as higher-affinity targets. Furthermore, radioligand receptor binding assays pointed favorably towards the concept of MAO-B as the primary target. To investigate the biochemical characteristics of the binding site, we used radioligand binding assays to assess differences in the binding profile in inflamed human synovial membranes exhibiting varying levels of inflammation. D-deprenyl bound to a single, saturable population of membrane-bound protein in synovial membrane homogenates and the level of inflammation correlated with an increase in D-deprenyl binding affinity.

    To verify whether D-deprenyl can visualize pain-generating processes, patients with musculoskeletal injuries were investigated and followed-up with [11C]-D-deprenyl PET/CT. In the study of eight patients with ankle sprain, the molecular aspects of inflammation and tissue injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. The pain coexisted with increased [11C]-D-deprenyl uptake. In the study of 16 whiplash patients, an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self-rated disability.

    To further evaluate D-Deprenyl’s usefulness as a marker of inflammation, three PET tracers were compared in an animal PET/CT study. Preliminary findings showed that [11C]-D-deprenyl had an almost identical uptake pattern when compared with [11C]-L-deprenyl. The two deprenyl enantiomers showed no signs of specific binding or trapping and therefore may not be useful to study further in models of inflammatory pain, surgical pain, or both.

    This thesis demonstrates that D-deprenyl visualizes painful inflammation in musculoskeletal injuries and that the probable underlying mechanism of [11C]-D-deprenyl uptake is binding to MAO.

    List of papers
    1. High-throughput screening and radioligand binding studies reveal monoamine oxidase-B as the primary binding target for D-deprenyl
    Open this publication in new window or tab >>High-throughput screening and radioligand binding studies reveal monoamine oxidase-B as the primary binding target for D-deprenyl
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    2016 (English)In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 152, p. 231-237Article in journal (Refereed) Published
    Abstract [en]

    Aims: D-deprenyl is a useful positron emission tomography tracer for visualization of inflammatory processes. Studies with [C-11]-D-deprenyl showed robust uptake in peripheral painful sites of patients with rheumatoid arthritis or chronic whiplash injury. The mechanism of preferential D-deprenyl uptake is not yet known, but the existence of a specific binding site was proposed. Thus, in the present study, we sought to identify the binding site for D-deprenyl and verify the hypothesis about the possibility of monoamine oxidase enzymes as major targets for this molecule. Main methods: A high-throughput analysis of D-deprenyl activity towards 165 G-protein coupled receptors and 84 enzyme targets was performed. Additionally, binding studies were used to verify the competition of [H-3]D-deprenyl with ligands specific for targets identified in the high-throughput screen. Key findings: Our high-throughput investigation identified monoamine oxidase-B, monoamine oxidase-A and angiotensin converting enzyme as potential targets for D-deprenyl. Further competitive [3H] D-deprenyl binding studies with specific inhibitors identified monoamine oxidase-B as the major binding site. No evident high-affinity hits were identified among G-protein coupled receptors. Significance: Our study was the first to utilize a high-throughput screening approach to identify putative D-deprenyl targets. It verified 249 candidate proteins and confirmed the role of monoamine oxidase - B in D-deprenyl binding. Our results add knowledge about the possible mechanism of D-deprenyl binding, which might aid in explaining the increased uptake of this compound in peripheral inflammation. Monoamine oxidase-B will be further investigated in future studies utilizing human inflamed synovium.

    Keywords
    D-deprenyl High-throughput screening Binding site
    National Category
    Pharmaceutical Sciences Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-291492 (URN)10.1016/j.lfs.2016.03.058 (DOI)000375728500028 ()27058977 (PubMedID)
    Funder
    Berzelii Centre EXSELENT, 2013-01495
    Available from: 2016-05-03 Created: 2016-05-03 Last updated: 2022-01-29Bibliographically approved
    2. Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.
    Open this publication in new window or tab >>Characterization of the binding site for d-deprenyl in human inflamed synovial membrane.
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    2018 (English)In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 194, p. 26-33Article in journal (Refereed) Published
    Abstract [en]

    Aims: D-Deprenyl when used as a positron emission tomography tracer visualizes peripheral inflammation. The major aim of the current study was to identify and investigate the properties of the binding target for D-deprenyl in synovial membrane explants from arthritic patients.

    Main methods: Thirty patients diagnosed with arthritis or osteoarthritis were enrolled into the study. Homologous and competitive radioligand binding assays utilizing [H-3]D-deprenyl were performed to investigate the biochemical characteristics of the binding site and assess differences in the binding profile in synovial membranes exhibiting varying levels of inflammation.

    Key findings: The [H-3]D-deprenyl binding assay confirmed the existence of a single, saturable population of membrane-bound protein binding sites in synovial membrane homogenates. The macroscopically determined level of inflammation correlated with an increase in [H-3]D-deprenyl binding affinity, without significant alterations in binding site density. Selective monoamine oxidase B inhibitor, selegiline competed for the same site as [H-3]D-deprenyl, but failed to differentiate the samples with regard to their inflammation grade. A monoamine oxidase A inhibitor, pirlindole mesylate showed only weak displacement of [H-3]D-deprenyl binding. No significant alterations in monoamine oxidase B expression was detected, thus it was not confirmed whether it could serve as a marker for ongoing inflammation.

    Significance: Our study was the first to show the biochemical characteristics of the [H-3]D-deprenyl binding site in inflamed human synovium. We confirmed that d-deprenyl could differentiate between patients with varying severity of synovitis in the knee joint by binding to a protein target distinct from monoamine oxidase B.

    Keywords
    Arthritis, Binding target, Monoamine oxidase B, Synovium, d-Deprenyl
    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmaceutical Biochemistry; Medical Biochemistry
    Identifiers
    urn:nbn:se:uu:diva-347601 (URN)10.1016/j.lfs.2017.12.003 (DOI)000425052000004 ()29221756 (PubMedID)
    Funder
    Swedish Research Council, 9459
    Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2022-01-29Bibliographically approved
    3. Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.
    Open this publication in new window or tab >>Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.
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    2017 (English)In: Scandinavian Journal of Pain, ISSN 1877-8860, E-ISSN 1877-8879, Vol. 17, no 1, p. 418-424Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND AND AIMS: Positron emission tomography (PET) with the radioligand [(11)C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [(11)C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [(11)C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown. Further imaging studies of musculoskeletal pain at the molecular level would benefit from establishing a clinical model in a common and well-defined injury in otherwise healthy and drug-naïve subjects. The aim of this study was to investigate if [(11)C]-D-deprenyl uptake would be acutely elevated in unilateral ankle sprain and if tracer uptake would be reduced as a function of healing, and correlated with pain localizations and pain experience.

    METHODS: Eight otherwise healthy patients with unilateral ankle sprain were recruited at the emergency department. All underwent [(11)C]-D-deprenyl PET/CT in the acute phase, at one month and 6-14 months after injury.

    RESULTS: Acute [(11)C]-D-deprenyl uptake at the injury site was a factor of 10.7 (range 2.9-37.3) higher than the intact ankle. During healing, [(11)C]-D-deprenyl uptake decreased, but did not normalize until after 11 months. Patients experiencing persistent pain had prolonged [(11)C]-D-deprenyl uptake in painful locations.

    CONCLUSIONS AND IMPLICATIONS: The data provide further support that [(11)C]-D-deprenyl PET can visualize, quantify and follow processes in peripheral tissue that may relate to soft tissue injuries, inflammation and associated nociceptive signaling. Such an objective correlate would represent a progress in pain research, as well as in clinical pain diagnostics and management.

    Place, publisher, year, edition, pages
    Walter de Gruyter, 2017
    Keywords
    Ankle injuries, Carbon-11, Deprenyl, Inflammation, PET, Pain
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-333782 (URN)10.1016/j.sjpain.2017.10.008 (DOI)000419851500070 ()29126847 (PubMedID)
    Available from: 2017-11-16 Created: 2017-11-16 Last updated: 2019-09-25Bibliographically approved
    4. Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl PET/CT
    Open this publication in new window or tab >>Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl PET/CT
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The understanding of etiological mechanisms of whiplash associated disorder is still inadequate. Objective visualization and quantification of peripheral musculoskeletal injury and possible painful inflammation in whiplash associated disorder would facilitate diagnosis, strengthen patients’ subjective pain reports and aid clinical decisions eventually leading to better treatments. In the current study, we further evaluated the potential to use [11C]D-deprenyl PET/CT to visualize inflammation after whiplash injury. Sixteen patients with whiplash injury grade II were recruited at the emergency department and underwent [11C]D-deprenyl PET/CT in the acute phase and at 6 months after injury. Subjective pain levels, self rated neck disability and active cervical range of motion were recorded at each imaging session. Results showed that the molecular aspects of inflammation and possible tissue injuries after acute whiplash injury could be visualized, objectively quantified and followed over time with [11C]-D-deprenyl PET/CT. An altered [11C]D-deprenyl uptake in the cervical bone structures and facet joints was associated with subjective pain levels and self rated disability during both imaging occasions. These findings may contribute to a better understanding of affected peripheral structures in whiplash injury and strengthens the idea that PET/CT detectable organic lesions in peripheral tissue may be relevant for the development of persistent pain and disability in whiplash injury.

    Perspective: This article presents a novel way of objectively visualizing possible structural damage and inflammation that cause pain and disability in whiplash injury. This PET method can bring an advance in pain research and eventually would facilitate the clinical management of patients in pain.

    Keywords
    Whiplash; deprenyl; inflammation; pain; PET; carbon-11
    National Category
    Medical and Health Sciences
    Research subject
    Molecular Medicine; Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-347602 (URN)
    Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-12
    5. Evaluation of  PET tracers [11C]D-deprenyl, [11C]L-dideuteriumdeprenyl and [18F]FDG for Visualization of Acute Inflammation in a Rat Model of Pain - Preliminary Findings.
    Open this publication in new window or tab >>Evaluation of  PET tracers [11C]D-deprenyl, [11C]L-dideuteriumdeprenyl and [18F]FDG for Visualization of Acute Inflammation in a Rat Model of Pain - Preliminary Findings.
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Purpose: Positron emission tomography with the radioligand [11C]D-deprenyl has shown an increased signal at the location of pain in patients with ankle sprains, rheumatoid arthritis and chronic whiplash injury, but the mechanism of this tracer uptake and its exact binding site in inflammation or tissue injury is still unclear. The aim of this study was to further evaluate [11C]D-deprenyl´s usefulness as a marker of acute inflammation.

    Methods: An animal PET/CT study was performed three days after the induction of a rat model of inflammatory or surgical pain. Fourteen adult male Sprague-Dawley rats and three tracers [11C]D-deprenyl, [11C]L-dideuterumdeprenyl and [18F]fluorodeoxyglucose were used.

    Results: No [11C]D-deprenyl accumulation was seen in a rat model of musculoskeletal pain. In the rat model of inflammatory pain all three ligands were shown to visualize the inflamed ankle joint with much lower uptake in the control ankle joint. The uptake was largest with [11C]D-deprenyl and [11C]L- dideuteriumdeprenyl, where approximately 1 % of the injected dose could be found in the affected ankle joint during the first minutes, whereas the uptake of [18F]FDG was approximately 0.5 % of the injected dose. However, the ratio of uptake of the injected ankle joint versus the control ankle joint was much higher for [18F]FDG (around 10 fold increase) than for the two deprenyl enantiomers (2 – 3 fold increase). The uptake pattern of [11C]D-deprenyl and [11C]L-dideuteriumdeprenyl did not show signs of specific binding or irreversible trapping.

    Conclusions: Contrary to our expectations, of the three tracers only [18F]FDG may be used as markers of peripheral inflammation in a rat model of inflammatory pain. However, as a high site-specificity is required, [11C]D-deprenyl and [11C]L-dideyteriumdeprenyl deserve further exploration regarding sensitivity, specificity and uptake mechanisms in human pain syndromes.

    Keywords
    deprenyl; inflammation; pain; PET; carbon-11
    National Category
    Medical and Health Sciences
    Research subject
    Anaesthesiology and Intensive Care
    Identifiers
    urn:nbn:se:uu:diva-347604 (URN)
    Available from: 2018-04-04 Created: 2018-04-04 Last updated: 2018-04-12
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  • 2.
    Abbasinejad Enger, Shirin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Dosimetry Studies of Different Radiotherapy Applications using Monte Carlo Radiation Transport Calculations2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Developing radiation delivery systems for optimisation of absorbed dose to the target without normal tissue toxicity requires advanced calculations for transport of radiation. In this thesis absorbed dose and fluence in different radiotherapy applications were calculated by using Monte Carlo (MC) simulations.

    In paper I-III external neutron activation of gadolinium (Gd) for intravascular brachytherapy (GdNCB) and tumour therapy (GdNCT) was investigated. MC codes MCNP and GEANT4 were compared. MCNP was chosen for neutron capture reaction calculations. Gd neutron capture reaction includes both very short range (Auger electrons) and long range (IC electrons and gamma) products. In GdNCB the high-energetic gamma gives an almost flat absorbed dose delivery pattern, up to 4 mm around the stent. Dose distribution at the edges and inside the stent may prevent stent edge and in-stent restenosis. For GdNCT the absorbed dose from prompt gamma will dominate over the dose from IC and Auger electrons in an in vivo situation. The absorbed dose from IC electrons will enhance the total absorbed dose in the tumours and contribute to the cell killing.

    In paper IV a model for calculation of inter-cluster cross-fire radiation dose from β-emitting radionuclides in a breast cancer model was developed. GEANT4 was used for obtaining absorbed dose. The dose internally in cells binding the isotope (self-dose) increased with decreasing β-energy except for the radionuclides with substantial amounts of conversion electrons and Auger electrons. An effective therapy approach may be a combination of radionuclides where the high self-dose from nuclides with low β-energy should be combined with the inter-cell cluster cross-fire dose from high energy β-particles.

    In paper V MC simulations using correlated sampling together with importance sampling were used to calculate spectra perturbations in detector volumes caused by the detector silicon chip and its encapsulation. Penelope and EGSnrc were used and yielded similar results. The low energy part of the electron spectrum increased but to a less extent if the silicon detector was encapsulated in low z-materials.

    List of papers
    1. Monte Carlo calculations of thermal neutron capture in gadolinium: a comparison of GEANT4 and MCNP with measurements.
    Open this publication in new window or tab >>Monte Carlo calculations of thermal neutron capture in gadolinium: a comparison of GEANT4 and MCNP with measurements.
    2006 In: Medical Physics, ISSN 0094-2405, Vol. 33, no 2, p. 337-341Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97526 (URN)
    Available from: 2008-09-19 Created: 2008-09-19Bibliographically approved
    2. Gadolinium neutron capture brachytherapy (GdNCB), a new treatment method for intravascular brachytherapy.
    Open this publication in new window or tab >>Gadolinium neutron capture brachytherapy (GdNCB), a new treatment method for intravascular brachytherapy.
    2006 In: Medical Physics, ISSN 0094-2405, Vol. 33, no 1, p. 46-51Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97527 (URN)
    Available from: 2008-09-19 Created: 2008-09-19Bibliographically approved
    3. Dosimetry for gadolinium neutron capture therapy (GdNCT)
    Open this publication in new window or tab >>Dosimetry for gadolinium neutron capture therapy (GdNCT)
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-97528 (URN)
    Available from: 2008-09-19 Created: 2008-09-19 Last updated: 2010-01-13Bibliographically approved
    4. Cross-fire doses from β-emitting radionuclides in targeted radiotherapy: A theoretical study based on experimentally measured tumor characteristics
    Open this publication in new window or tab >>Cross-fire doses from β-emitting radionuclides in targeted radiotherapy: A theoretical study based on experimentally measured tumor characteristics
    2008 (English)In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 53, no 7, p. 1909-1920Article in journal (Refereed) Published
    Abstract [en]

    A mathematical model based upon histological findings of cell cluster distributions in primary breast cancers and lymph node metastases was developed. The model is unique because it accounts for tumor cell cluster formations within both primary tumors and metastases. The importance of inter-cell cluster cross-fire radiation dose for beta-emitting radionuclides of different energies was studied. The cell clusters were simulated as spheres with 15, 25 and 50 microm radii having a homogeneous radioactivity distribution. The self-dose as well as the dose distribution around the spheres was calculated for seven radionuclides, (90)Y, (188)Re, (32)P, (186)Re, (159)Gd, (131)I and (177)Lu using the GEANT4 Monte Carlo code. Generally, the self-dose was decreasing with increasing energy of the emitted beta particles. An exception was (188)Re which, compared to (32)P, had higher beta energy as well as higher self-dose. This was due to the higher emission of conversion and Auger electrons in the (188)Re-decay. When the cell clusters had a mean distance that was shorter than the maximum range of beta-particles, then the inter-cluster cross-fire radiation contributed significantly to the absorbed dose. Thus, high-energy beta-particles may, in spite of a low self-dose to single clusters, still be favorable to use due to the contribution of inter-cluster cross-fire radiation.

    Keywords
    Cancer, tumor, radiation, therapy
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97529 (URN)10.1088/0031-9155/53/7/007 (DOI)000254175900007 ()18364546 (PubMedID)
    Available from: 2008-09-19 Created: 2008-09-19 Last updated: 2022-01-28Bibliographically approved
    5. Determination of self perturbations of spectra in detectors in photon fields
    Open this publication in new window or tab >>Determination of self perturbations of spectra in detectors in photon fields
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-97530 (URN)
    Available from: 2008-09-19 Created: 2008-09-19 Last updated: 2010-01-13Bibliographically approved
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  • 3.
    Abdsaleh, Shahin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Core Biopsy of Breast and Axillary Lesions: Technical and Clinical Aspects2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aims of this work were to image and analyze the needle behavior at automated core biopsy, to investigate the clinical utility of an alternative core biopsy technique using a semiautomated gun in breast and axillary lesions, and also to compare core biopsy with surgical specimens in malignant breast lesions regarding histologic features and hormone receptor expression.

    In two experimental studies, using butter and silicon phantoms, respectively, the needle pass was imaged and its dynamic behavior studied. It was shown that the needle took a curved course in phantoms. It deviated to the same side as where the tip lay, and the degree of the curvature increased with increasing hardness of the phantoms. Our experimental methods can be applied for imaging of needle behavior and thereby improvement of needle configuration.

    In two clinical studies, a semiautomated gun was used for large needle core biopsy of breast and axillary lesions in two series of 145 and 21 patients, respectively. The sensitivity of the method for diagnosis of malignancy was 87% (108/124), and in 37% (31/83) of cases the full length of the needle notch was filled with specimen. No injury to the neurovascular structures of the axillary area was observed. It was concluded that the semiautomated gun can be used as an alternative to the automated gun when the size and location of the lesion render use of the automatic device uncertain or dangerous, e.g., in small breast lesions or lesions located in the axilla.

    In a series of 129 cases of breast cancer, comparison of core biopsy and surgical specimens showed that core biopsy provided enough information on the histologic type and grade of the lesions. Also, there was moderate to high concordance between the two methods for assessment of progesterone receptors and estrogen receptors (Spearman`s kappa 0.67 and 0.89, respectively).

    List of papers
    1. Behaviour of the 2.1-mm (14 G) Automated Biopsy Needle in Phantoms.
    Open this publication in new window or tab >>Behaviour of the 2.1-mm (14 G) Automated Biopsy Needle in Phantoms.
    2002 In: Acta Radiologica, Vol. 43, no 2, p. 225-229Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94101 (URN)
    Available from: 2006-03-03 Created: 2006-03-03Bibliographically approved
    2. Semiautomatic Core Biopsy.: A Modified Biopsy Technique in Breast Diseases.
    Open this publication in new window or tab >>Semiautomatic Core Biopsy.: A Modified Biopsy Technique in Breast Diseases.
    2003 In: Acta Radiologica, Vol. 44, no 1, p. 47-51Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94102 (URN)
    Available from: 2006-03-03 Created: 2006-03-03Bibliographically approved
    3. Ultrasound-guided Large Needle Core Biopsy of the Axilla.
    Open this publication in new window or tab >>Ultrasound-guided Large Needle Core Biopsy of the Axilla.
    2004 In: Acta Radiologica, Vol. 45, no 2, p. 193-196Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94103 (URN)
    Available from: 2006-03-03 Created: 2006-03-03Bibliographically approved
    4. Dynamic Behaviour of Core Biosy Needle:: High-speed Video Imaging of the Needle Course in Silicon Phantoms.
    Open this publication in new window or tab >>Dynamic Behaviour of Core Biosy Needle:: High-speed Video Imaging of the Needle Course in Silicon Phantoms.
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    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-94104 (URN)
    Available from: 2006-03-03 Created: 2006-03-03 Last updated: 2010-01-13Bibliographically approved
    5. Comparison of Core Needle Biopsy and Surgical Specimens in Malignant Breast Lesions Regarding Histologic Features and Hormone Receptor Expression.
    Open this publication in new window or tab >>Comparison of Core Needle Biopsy and Surgical Specimens in Malignant Breast Lesions Regarding Histologic Features and Hormone Receptor Expression.
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    (English)Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-94105 (URN)
    Available from: 2006-03-03 Created: 2006-03-03 Last updated: 2010-02-03Bibliographically approved
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    FULLTEXT01
  • 4.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Borin, Jesper
    KTH Royal Inst Technol, Dept Prot Sci, S-11417 Stockholm, Sweden..
    Lundmark, Fanny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Rybina, Anastasiya
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Dept Nucl Med, Tomsk 634009, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Hober, Sophia
    KTH Royal Inst Technol, Dept Prot Sci, S-11417 Stockholm, Sweden..
    Zelchan, Roman
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Dept Nucl Med, Tomsk 634009, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Chernov, Vladimir
    Russian Acad Sci, Canc Res Inst, Tomsk Natl Res Med Ctr, Dept Nucl Med, Tomsk 634009, Russia..
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The GRPR Antagonist [99mTc]Tc-maSSS-PEG2-RM26 towards Phase I Clinical Trial: Kit Preparation, Characterization and Toxicity2023In: Diagnostics, ISSN 2075-4418, Vol. 13, no 9, article id 1611Article in journal (Refereed)
    Abstract [en]

    Gastrin-releasing peptide receptors (GRPRs) are overexpressed in the majority of primary prostate tumors and in prostatic lymph node and bone metastases. Several GRPR antagonists were developed for SPECT and PET imaging of prostate cancer. We previously reported a preclinical evaluation of the GRPR antagonist [99mTc]Tc-maSSS-PEG2-RM26 (based on [D-Phe6, Sta13, Leu14-NH2]BBN(6-14)) which bound to GRPR with high affinity and had a favorable biodistribution profile in tumor-bearing animal models. In this study, we aimed to prepare and test kits for prospective use in an early-phase clinical study. The kits were prepared to allow for a one-pot single-step radiolabeling with technetium-99m pertechnetate. The kit vials were tested for sterility and labeling efficacy. The radiolabeled by using the kit GRPR antagonist was evaluated in vitro for binding specificity to GRPR on PC-3 cells (GRPR-positive). In vivo, the toxicity of the kit constituents was evaluated in rats. The labeling efficacy of the kits stored at 4 °C was monitored for 18 months. The biological properties of [99mTc]Tc-maSSS-PEG2-RM26, which were obtained after this period, were examined both in vitro and in vivo. The one-pot (gluconic acid, ethylenediaminetetraacetic acid, stannous chloride, and maSSS-PEG2-RM26) single-step radiolabeling with technetium-99m was successful with high radiochemical yields (>97%) and high molar activities (16–24 MBq/nmol). The radiolabeled peptide maintained its binding properties to GRPR. The kit constituents were sterile and non-toxic when tested in living subjects. In conclusion, the prepared kit is considered safe in animal models and can be further evaluated for use in clinics.

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  • 5.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Sabahnoo, Hamideh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Chernov, Vladimir
    Russian Acad Sci, Canc Res Inst, Dept Nucl Med, Tomsk Natl Res Med Ctr, Tomsk 634009, Russia; Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634009, Russia.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634009, Russia.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab. Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634009, Russia.
    Preclinical Evaluation of 99mTc-Labeled GRPR Antagonists maSSS/SES-PEG2-RM26 for Imaging of Prostate Cancer2021In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 13, no 2, article id 182Article in journal (Refereed)
    Abstract [en]

    Background: Gastrin-releasing peptide receptor (GRPR) is an important target for imaging of prostate cancer. The wide availability of single-photon emission computed tomography/computed tomography (SPECT/CT) and the generator-produced 99mTc can be utilized to facilitate the use of GRPR-targeting radiotracers for diagnostics of prostate cancers.

    Methods: Synthetically produced mercaptoacetyl-Ser-Ser-Ser (maSSS)-PEG2-RM26 and mercaptoacetyl-Ser-Glu-Ser (maSES)-PEG2-RM26 (RM26 = d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) were radiolabeled with 99mTc and characterized in vitro using PC-3 cells and in vivo, using NMRI or PC-3 tumor bearing mice. SPECT/CT imaging and dosimetry calculations were performed for [99mTc]Tc-maSSS-PEG2-RM26.

    Results: Peptides were radiolabeled with high yields (>98%), demonstrating GRPR specific binding and slow internalization in PC-3 cells. [99mTc]Tc-maSSS-PEG2-RM26 outperformed [99mTc]Tc-maSES-PEG2-RM26 in terms of GRPR affinity, with a lower dissociation constant (61 pM vs 849 pM) and demonstrating higher tumor uptake. [99mTc]Tc-maSSS-PEG2-RM26 had tumor-to-blood, tumor-to-muscle, and tumor-to-bone ratios of 97 ± 56, 188 ± 32, and 177 ± 79, respectively. SPECT/CT images of [99mTc]Tc-maSSS-PEG2-RM26 clearly visualized the GRPR-overexpressing tumors. The dosimetry estimated for [99mTc]Tc-maSSS-PEG2-RM26 showed the highest absorbed dose in the small intestine (1.65 × 10−3 mGy/MBq), and the effective dose is 3.49 × 10−3 mSv/MBq.

    Conclusion: The GRPR antagonist maSSS-PEG2-RM26 is a promising GRPR-targeting agent that can be radiolabeled through a single-step with the generator-produced 99mTc and used for imaging of GRPR-expressing prostate cancer.

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  • 6.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Seitova, Kamila
    Siberian State Med Univ, Sci & Res Lab Chem & Pharmaceut Res, Tomsk, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk, Russia..
    Lundmark, Fanny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Bodenko, Vitalina
    Siberian State Med Univ, Sci & Res Lab Chem & Pharmaceut Res, Tomsk, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk, Russia..
    Oroujeni, Maryam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Affibody AB, Solna, Sweden..
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk, Russia..
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry2023In: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 13, article id 1221103Article in journal (Refereed)
    Abstract [en]

    <bold>Introduction:</bold> Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression in vivo using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that Lu-177-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy.<bold>Methods:</bold> BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [Lu-177]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution in vivo, target specificity and dosimetry. [Lu-177]Lu-PSMA-617 was simultaneously evaluated for comparison.<bold>Results:</bold> BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific in vitro and in vivo when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [Lu-177]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities K-D1 = 3.8 nM and K-D2 = 25 nM. The half-maximal inhibitory concentration for Lu-nat-BQ7876 was 59 nM that is equal to 61 nM for Lu-nat-PSMA-617. Cellular processing of [Lu-177]Lu-BQ7876 was accompanied by slow internalization. [Lu-177]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 +/- 3%ID/g) did not differ significantly from tumor uptake (9 +/- 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen.<bold>Discussion:</bold> Biodistribution studies in mice demonstrated that targeting properties of [Lu-177]Lu-BQ7876 are not inferior to properties of [Lu-177]Lu-PSMA-617, but do not offer any decisive advantages.

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  • 7.
    Abouzayed, Ayman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Zedan, Wahed
    Lund Univ, Dept Oncol, Lund, Sweden..
    Altai, Mohamed
    Lund Univ, Dept Oncol, Lund, Sweden..
    Strand, Joanna
    Lund Univ, Dept Oncol, Lund, Sweden..
    Orbom, Anders
    Lund Univ, Dept Oncol, Lund, Sweden..
    Co-injection of anti-HER2 antibody Trastuzumab does not increase efficacy of [Lu-177]Lu-PSMA-617 therapy in an animal model of prostate cancer2023In: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 13, no 3, p. 107-+Article in journal (Refereed)
    Abstract [en]

    One novel option for treating metastatic castration resistant prostate cancer is radionuclide therapy targeting prostate-specific membrane antigen (PSMA), e.g. [Lu-177]Lu-PSMA-617. Overexpression of HER2 has been found in 80% of metastatic cases of prostate cancer. Previous research showed that HER2 is elevated post irradiation in PC-3 prostate cancer cells. Co-treating with anti-HER2 antibody Trastuzumab gave less proliferation of irradiated tumor cells in vitro, and when using radionuclide therapy, also in vivo. The aim of this study is to determine whether the same holds true in PSMA-expressing PC-3 PIP cells using [Lu-177]Lu-PSMA-617 radionuclide therapy. PC-3 PIP and 22Rv1 prostate cancer cells were tested in vitro, treated with 6 Gy of x-rays with or without Trastuzumab incubation. We measured uptake of HER2-targeting affibody [Ga-68]Ga-ABY-025 and cell survival, e.g. using the WST-1 assay. Three groups (n=10 each) of male nude Balb/c mice were inoculated with PC-3 PIP xenograft tumors and treated with just [Lu-177]Lu-PSMA-617 (20 MBq), [Lu-177]Lu-PSMA-617 (20 MBq) and Trastuzumab (4 x 5 mg/kg), or left untreated. Tumor sizes and animal survival was observed. In vitro, x-ray irradiation did reduce survival in 22Rv1 but not PC-3 PIP cells, and there was no significant effect of Trastuzumab treatment. Cells expressed HER2 but not significantly elevated post irradiation. In vivo, mice co-treated with Trastuzumab had significantly longer survival than untreated mice, but not than only [Lu-177]Lu-PSMA-617. Staining of tumor sections showed similar HER2 and PSMA expression across groups. In conclusion, these results give no support for any benefit from co-treatment with anti-HER2 antibody for PSMA-targeted radioligand therapy.

  • 8.
    Abramenkovs, Andris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Nilsson, Sten
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    The α-emitter Ra-223 induces clustered DNA damage and significantly reduces cell survivalManuscript (preprint) (Other academic)
    Abstract [en]

    The bone-seeking radiopharmaceutical Xofigo (Radium-223 dichloride) has demonstrated both extended survival and palliative effects in treatment of bone metastases in patients with prostate cancer. The alpha-particle emitter Ra-223, administered as Ra-223 dichloride, targets regions undergoing active bone remodeling and strongly binds hydroxyapatite found in bone. However, the mechanisms mediating toxicity and properties of Ra-223 binding to hydroxyapatite are not fully understood. In the current study, we show that the alpha-particles originating from the Ra-223 decay chain produce a track-like distribution of the DNA damage response proteins 53BP1 and ɣH2AX and induce high amounts of clustered DNA double-strand breaks in prostate cancer cell nuclei. The Ra-223 treatment inhibited growth of prostate cancer cells, grown in 2D- and 3D- models in vitro, independent of prostate cancer cell type and androgen receptor variant 7 (ARv7) expression. The rapid binding with a high affinity of Ra-223 to bone structures was verified in an in silico assay (KD= 19.2 ± 6.5 e-18) and almost no dissociation was detected within 24 hours. Importantly, there was no significant uptake of Ra-223 in cells. Further, we demonstrate the importance of the local dose-distribution of this treatment; there was more than 100-fold increase in cell killing when Ra-223 was attached to the bone-like hydroxyapatite structure, compared to when the radioactivity was distributed in the cell growth media. However, independent of the exposure condition, the high cell killing efficacy of the Ra-223 was attributed to the clustered DNA damaged sites induced by the released α-particles.

  • 9.
    Abramenkovs, Andris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Ra223 induced clustered DNA damage reduces cell survival independently of androgen receptor variant 7 expression2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S634-S635Article in journal (Other academic)
  • 10.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannsjö, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rehabilitation Medicine.
    Howells, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    MRI analysis of diffuse axonal injury - Hemorrhagic lesions in the mesencephalon idicate poor long-term outcome2016In: MRI analysis of diffuse axonal injury - Hemorrhagic lesions in the mesencephalon idicate poor long-term outcome, Springer, 2016, Vol. 7, Suppl. 1, article id B-0814Conference paper (Refereed)
    Abstract [en]

    Purpose: Clinical outcome after traumatic diffuse axonal injury (DAI) is difficult to predict. Three MRI techniques were compared in demonstrating acute brain lesions.  Relationship of the anatomical distribution of the lesions in combination with clinical prognostic factors to outcome after 6 months was evaluated.  

    Methods and Materials: Thirty patients, aged 16-60 years (mean 31.2 years) with severe DAI (Glasgow Motor Score = GMS < 6) were examined with MRI at 1.5T within one week after the injury. A diffusion-weighted (DW) sequence (SE-EPI, b value 1000 s/mm2), a T2*-weighted gradient echo (T2*GRE) sequence and a susceptibility-weighted (SWI) sequence were evaluated by two independent reviewers with short and long neuroradiological experiences. Clinical outcome was assessed with Extended Glasgow Outcome Score (GOSE) after ≥ 6 months.

    Results: Interreviewer agreement for DAI classification was very good (ҡ 0.82 – 0.91) with all three sequences. SWI visualized more lesions than the T2*GRE or DW sequence.  In univariate analysis, number of DW lesions in the deep gray matter area including the internal capsules, number of SWI lesions in the mesencephalon, age, and GMS at admission and discharge correlated significantly with poor outcome.  Multivariate analysis only revealed an independent relation with poor outcome for age (p = 0.011) and lesions in the mesencephalic region including crura cerebri, substantia nigra and tegmentum on SWI (p = 0.032).

    Conclusion: SWI is the most sensitive technique to visualize lesions in DAI. Age over 30 years and hemorrhagic mesencephalic lesions anterior to the tectum are indicators of poor long-term outcome in DAI.

  • 11.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Howells, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Intracranial pressure elevations in diffuse axonal injury: association with nonhemorrhagic MR lesions in central mesencephalic structures2019In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 131, no 2, p. 604-611Article in journal (Refereed)
    Abstract [en]

    Objective: Increased intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI) with diffuse axonal injury (DAI) is not well defined. This study investigated the occurrence of increased ICP and whether clinical factors and lesion localization on MRI were associated with increased ICP in patients with DAI.

    Methods: Fifty-two patients with severe TBI (median age 24 years, range 9–61 years), who had undergone ICP monitoring and had DAI on MRI, as determined using T2*-weighted gradient echo, susceptibility-weighted imaging, and diffusion-weighted imaging (DWI) sequences, were enrolled. The proportion of good monitoring time (GMT) with ICP > 20 mm Hg during the first 120 hours postinjury was calculated and associations with clinical and MRI-related factors were evaluated using linear regression.

    Results: All patients had episodes of ICP > 20 mm Hg. The mean proportion of GMT with ICP > 20 mm Hg was 5%, and 27% of the patients (14/52) spent more than 5% of GMT with ICP > 20 mm Hg. The Glasgow Coma Scale motor score at admission (p = 0.04) and lesions on DWI sequences in the substantia nigra and mesencephalic tegmentum (SN-T, p = 0.001) were associated with the proportion of GMT with ICP > 20 mm Hg. In multivariable linear regression, lesions on DWI sequences in SN-T (8% of GMT with ICP > 20 mm Hg, 95% CI 3%–13%, p = 0.004) and young age (−0.2% of GMT with ICP > 20 mm Hg, 95% CI −0.07% to −0.3%, p = 0.002) were associated with increased ICP.

    Conclusions: Increased ICP occurs in approximately one-third of patients with severe TBI who have DAI. Age and lesions on DWI sequences in the central mesencephalon (i.e., SN-T) are associated with elevated ICP. These findings suggest that MR lesion localization may aid prediction of increased ICP in patients with DAI.

    Abbreviations: ADC = apparent diffusion coefficient; CPP = cerebral perfusion pressure; DAI = diffuse axonal injury; DWI = diffusion-weighted imaging; EVD = external ventricular drain; GCS = Glasgow Coma Scale; GMT = good monitoring time; GOSE = Glasgow Outcome Scale–Extended; ICC = intraclass correlation coefficient; ICP = intracranial pressure; MAP = mean arterial blood pressure; NICU = neurointensive care unit; SN-T = substantia nigra and mesencephalic tegmentum; SWI = susceptibility-weighted imaging; TBI = traumatic brain injury; T2*GRE = T2*-weighted gradient echo.

  • 12.
    Acosta Ruiz, Vanessa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    CT Guided Ablation of T1 Renal Tumors2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The widespread use of medical imaging contributes to the increased detection of incidentally detected small renal tumors, a majority which are often indolent masses found in elderly patients with preexisting chronic kidney disease. In Sweden, partial nephrectomy with minimal invasive surgical approach is the current standard for removing these tumors, although another option is percutaneous image-guided tumor ablation that allows treatment of elderly patients with comorbidities for who surgery is a risk. Due to the lack of long-term follow-up studies and prospective randomized trials, ablation is still considered an alternative option to surgery in Sweden. The aim of this thesis was to evaluate treatment of T1 renal tumors with CT guided radiofrequency (RFA) and microwave ablation (MWA).

    Factors affecting the efficacy rate of complete tumor ablation with RFA after a single session were evaluated (Paper I). Optimal electrode placement and a long tumor distance to the collecting system were associated with an increased primary efficacy. Renal tumor RFA was compared with laparoscopic partial nephrectomy (LPN: Papers II-III): both methods had comparable secondary efficacy rates, but RFA involved several treatment sessions. Total session times and hospitalization times were shorter and complications less frequent for RFA than for LPN (Paper II). After treatment, renal function impact was assessed by evaluation of both renal function quantity and quality through determination of the split renal function (SRF: Paper III). Standard renal function measurements were assessed and both RFA and LPN were nephron sparing when treating small renal tumors and did not affect creatinine or GFR. However, LPN involved greater SRF reduction in the affected kidney than RFA. Initial experience with microwave ablation was evaluated and this new ablation technique demonstrated high efficacy rates with fewer complications, and was comparable with the mid-term results of now established ablation techniques (Paper IV).

    In conclusion, CT guided RFA and MWA are safe and effective treatments for the removal of T1 renal tumors. This thesis provides further insights into the field of thermal ablation of small renal masses, which can aid future treatment selection and patient management.

    List of papers
    1. Predictive factors for complete renal tumor ablation using RFA
    Open this publication in new window or tab >>Predictive factors for complete renal tumor ablation using RFA
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    2016 (English)In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 57, no 7, p. 886-893Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Radiofrequency ablation (RFA) can be used to treat renal masses in patients where surgery is preferably avoided. As tumor size and location can affect ablation results, procedural planning needs to identify these factors to limit treatment to a single session and increase ablation success.

    PURPOSE: To identify factors that may affect the primary efficacy of complete renal tumor ablation with radiofrequency after a single session.

    MATERIAL AND METHODS: Percutaneous RFA (using an impedance based system) was performed using computed tomography (CT) guidance. Fifty-two renal tumors (in 44 patients) were retrospectively studied (median follow-up, 7 months). Data collection included patient demographics, tumor data (modified Renal Nephrometry Score, histopathological diagnosis), RFA treatment data (electrode placement), and follow-up results (tumor relapse). Data were analyzed through generalized estimating equations.

    RESULTS: Primary efficacy rate was 83%. Predictors for complete ablation were optimal electrode placement (P = 0.002, OR = 16.67) and increasing distance to the collecting system (P = 0.02, OR = 1.18). Tumor size was not a predictor for complete ablation (median size, 24 mm; P = 0.069, OR = 0.47), but all tumors ≤2 cm were completely ablated. All papillary tumors and oncocytomas were completely ablated in a single session; the most common incompletely ablated tumor type was clear cell carcinoma (6 of 9).

    CONCLUSION: Optimal electrode placement and a long distance from the collecting system are associated with an increased primary efficacy of renal tumor RFA. These variables need to be considered to increase primary ablation success. Further studies are needed to evaluate the effect of RFA on histopathologically different renal tumors.

    Keywords
    Radiofrequency ablation (RFA); renal tumor; predict; ablation; radiofrequency; ablation success; complete ablation
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-264586 (URN)10.1177/0284185115605681 (DOI)000378051200020 ()26452975 (PubMedID)
    Available from: 2015-10-15 Created: 2015-10-15 Last updated: 2023-06-20Bibliographically approved
    2. Periprocedural outcome after laparoscopic partial nephrectomy versus radiofrequency ablation for T1 renal tumors: A modified R.E.N.A.L nephrometry score adjusted comparison
    Open this publication in new window or tab >>Periprocedural outcome after laparoscopic partial nephrectomy versus radiofrequency ablation for T1 renal tumors: A modified R.E.N.A.L nephrometry score adjusted comparison
    Show others...
    2019 (English)In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 60, no 2, p. 260-268Article in journal (Refereed) Published
    Abstract [en]

    Background: Comparable oncological outcomes have been seen after surgical nephrectomy and thermal ablation of renal tumors recently. However, periprocedural outcome needs to be assessed for aiding treatment decision.

    Purpose: To compare efficacy rates and periprocedural outcome (technical success, session time, hospitalization time, and complications) after renal tumor treatment with laparoscopic partial nephrectomy (LPN) or radiofrequency ablation (RFA).

    Material and Methods: The initial experience with 49 (treated with LPN) and 84 (treated with RFA) consecutive patients for a single renal tumor (diameter ≤ 5 cm, limited to the kidney) during 2007-2014 was evaluated. Patient and tumor characteristics, efficacy rates, and periprocedural outcome were collected retrospectively. The stratified Mantel Haenzel and Van Elteren tests, adjusted for tumor complexity (with the modified R.E.N.A.L nephrometry score [m-RNS]), were used to assess differences in treatment outcomes.

    Results: Primary efficacy rate was 98% for LPN and 85.7% for RFA; secondary efficacy rate was 93.9% for LPN and 95.2% for RFA; and technical success rate was 87.8% for LPN and 100% for RFA. Median session (m-RNS adjusted P < 0.001; LPN 215 min, RFA 137 min) and median hospitalization time were longer after LPN (m-RNS adjusted P < 0.001; LPN 5 days, RFA 2 days). Side effects were uncommon (LPN 2%, RFA 4.8%). Complications were more frequent after LPN (m-RNS adjusted P < 0.001; LPN 42.9%, RFA 10.7%).

    Conclusion: Both methods achieved equivalent secondary efficacy rates. RFA included several treatment sessions, but session and hospitalization times were shorter, and complications were less frequent than for LPN. The differences remained after adjustment for renal tumor complexity.

    Place, publisher, year, edition, pages
    Sage Publications, 2019
    Keywords
    Ablation procedures, interventional, kidney, percutaneous, primary neoplasms
    National Category
    Urology and Nephrology Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-354169 (URN)10.1177/0284185118780891 (DOI)000459621200017 ()29911400 (PubMedID)
    Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2023-10-04Bibliographically approved
    3. Split Renal Function after Treatment of Small Renal Masses: Comparison between Radiofrequency Ablation and Laparoscopic Partial Nephrectomy
    Open this publication in new window or tab >>Split Renal Function after Treatment of Small Renal Masses: Comparison between Radiofrequency Ablation and Laparoscopic Partial Nephrectomy
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-392376 (URN)
    Available from: 2019-09-03 Created: 2019-09-03 Last updated: 2019-09-04
    4. Percutaneous CT Guided Microwave Ablation of 105 T1a-T1b Renal Tumors: Technique Efficacy with a Mean 2-Year Follow-up
    Open this publication in new window or tab >>Percutaneous CT Guided Microwave Ablation of 105 T1a-T1b Renal Tumors: Technique Efficacy with a Mean 2-Year Follow-up
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-392380 (URN)
    Available from: 2019-09-03 Created: 2019-09-03 Last updated: 2019-09-04
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  • 13.
    Acosta Ruiz, Vanessa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Båtelsson, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Onkamo, Elina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Lönnemark, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Dahlman, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Split Renal Function after Treatment of Small Renal Masses: Comparison between Radiofrequency Ablation and Laparoscopic Partial NephrectomyManuscript (preprint) (Other academic)
  • 14.
    Acosta Ruiz, Vanessa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Dahlman, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Brekkan, Einar
    Lönnemark, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Percutaneous CT Guided Microwave Ablation of 105 T1a-T1b Renal Tumors: Technique Efficacy with a Mean 2-Year Follow-upManuscript (preprint) (Other academic)
  • 15.
    Acosta Ruiz, Vanessa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ladjevardi, Sam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Brekkan, Einar
    Uppsala University Hospital, Urology, Uppsala, Sweden.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Lönnemark, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Periprocedural outcome after laparoscopic partial nephrectomy versus radiofrequency ablation for T1 renal tumors: A modified R.E.N.A.L nephrometry score adjusted comparison2019In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 60, no 2, p. 260-268Article in journal (Refereed)
    Abstract [en]

    Background: Comparable oncological outcomes have been seen after surgical nephrectomy and thermal ablation of renal tumors recently. However, periprocedural outcome needs to be assessed for aiding treatment decision.

    Purpose: To compare efficacy rates and periprocedural outcome (technical success, session time, hospitalization time, and complications) after renal tumor treatment with laparoscopic partial nephrectomy (LPN) or radiofrequency ablation (RFA).

    Material and Methods: The initial experience with 49 (treated with LPN) and 84 (treated with RFA) consecutive patients for a single renal tumor (diameter ≤ 5 cm, limited to the kidney) during 2007-2014 was evaluated. Patient and tumor characteristics, efficacy rates, and periprocedural outcome were collected retrospectively. The stratified Mantel Haenzel and Van Elteren tests, adjusted for tumor complexity (with the modified R.E.N.A.L nephrometry score [m-RNS]), were used to assess differences in treatment outcomes.

    Results: Primary efficacy rate was 98% for LPN and 85.7% for RFA; secondary efficacy rate was 93.9% for LPN and 95.2% for RFA; and technical success rate was 87.8% for LPN and 100% for RFA. Median session (m-RNS adjusted P < 0.001; LPN 215 min, RFA 137 min) and median hospitalization time were longer after LPN (m-RNS adjusted P < 0.001; LPN 5 days, RFA 2 days). Side effects were uncommon (LPN 2%, RFA 4.8%). Complications were more frequent after LPN (m-RNS adjusted P < 0.001; LPN 42.9%, RFA 10.7%).

    Conclusion: Both methods achieved equivalent secondary efficacy rates. RFA included several treatment sessions, but session and hospitalization times were shorter, and complications were less frequent than for LPN. The differences remained after adjustment for renal tumor complexity.

  • 16.
    Acosta Ruiz, Vanessa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lönnemark, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Brekkan, Einar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Dahlman, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Predictive factors for complete renal tumor ablation using RFA2016In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 57, no 7, p. 886-893Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Radiofrequency ablation (RFA) can be used to treat renal masses in patients where surgery is preferably avoided. As tumor size and location can affect ablation results, procedural planning needs to identify these factors to limit treatment to a single session and increase ablation success.

    PURPOSE: To identify factors that may affect the primary efficacy of complete renal tumor ablation with radiofrequency after a single session.

    MATERIAL AND METHODS: Percutaneous RFA (using an impedance based system) was performed using computed tomography (CT) guidance. Fifty-two renal tumors (in 44 patients) were retrospectively studied (median follow-up, 7 months). Data collection included patient demographics, tumor data (modified Renal Nephrometry Score, histopathological diagnosis), RFA treatment data (electrode placement), and follow-up results (tumor relapse). Data were analyzed through generalized estimating equations.

    RESULTS: Primary efficacy rate was 83%. Predictors for complete ablation were optimal electrode placement (P = 0.002, OR = 16.67) and increasing distance to the collecting system (P = 0.02, OR = 1.18). Tumor size was not a predictor for complete ablation (median size, 24 mm; P = 0.069, OR = 0.47), but all tumors ≤2 cm were completely ablated. All papillary tumors and oncocytomas were completely ablated in a single session; the most common incompletely ablated tumor type was clear cell carcinoma (6 of 9).

    CONCLUSION: Optimal electrode placement and a long distance from the collecting system are associated with an increased primary efficacy of renal tumor RFA. These variables need to be considered to increase primary ablation success. Further studies are needed to evaluate the effect of RFA on histopathologically different renal tumors.

  • 17.
    Adamczuk, Katarzyna
    et al.
    Katholieke Univ Leuven, Lab Cognit Neurol, B-3000 Leuven, Belgium.;Katholieke Univ Leuven, Leuven Inst Neurosci & Dis, Alzheimer Res Ctr, B-3000 Leuven, Belgium..
    Schaeverbeke, Jolien
    Katholieke Univ Leuven, Lab Cognit Neurol, B-3000 Leuven, Belgium.;Katholieke Univ Leuven, Leuven Inst Neurosci & Dis, Alzheimer Res Ctr, B-3000 Leuven, Belgium..
    Nelissen, Natalie
    Katholieke Univ Leuven, Lab Cognit Neurol, B-3000 Leuven, Belgium.;Univ Oxford, Dept Psychiat, Oxford OX3 7JX, England..
    Neyens, Veerle
    Katholieke Univ Leuven, Lab Cognit Neurol, B-3000 Leuven, Belgium.;Katholieke Univ Leuven, Leuven Inst Neurosci & Dis, Alzheimer Res Ctr, B-3000 Leuven, Belgium..
    Vandenbulcke, Mathieu
    Univ Hosp Leuven, Dept Old Age Psychiat, B-3000 Leuven, Belgium..
    Goffin, Karolien
    Katholieke Univ Leuven, Nucl Med & Mol Imaging Dept, B-3000 Leuven, Belgium.;Univ Hosp Leuven, B-3000 Leuven, Belgium..
    Lilja, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. GE Healthcare, S-75323 Uppsala, Sweden..
    Hilven, Kelly
    Katholieke Univ Leuven, Lab Neuroimmunol, B-3000 Leuven, Belgium..
    Dupont, Patrick
    Katholieke Univ Leuven, Lab Cognit Neurol, B-3000 Leuven, Belgium.;Katholieke Univ Leuven, Leuven Inst Neurosci & Dis, Alzheimer Res Ctr, B-3000 Leuven, Belgium..
    Van Laere, Koen
    Katholieke Univ Leuven, Leuven Inst Neurosci & Dis, Alzheimer Res Ctr, B-3000 Leuven, Belgium.;Katholieke Univ Leuven, Nucl Med & Mol Imaging Dept, B-3000 Leuven, Belgium.;Univ Hosp Leuven, B-3000 Leuven, Belgium..
    Vandenberghe, Rik
    Katholieke Univ Leuven, Lab Cognit Neurol, B-3000 Leuven, Belgium.;Katholieke Univ Leuven, Leuven Inst Neurosci & Dis, Alzheimer Res Ctr, B-3000 Leuven, Belgium.;Univ Hosp Leuven, Dept Neurol, B-3000 Leuven, Belgium..
    Amyloid imaging in cognitively normal older adults: comparison between F-18-flutemetamol and C-11-Pittsburgh compound B2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, no 1, p. 142-151Article in journal (Refereed)
    Abstract [en]

    Purpose Preclinical, or asymptomatic, Alzheimer's disease (AD) refers to the presence of positive AD biomarkers in the absence of cognitive deficits. This research concept is being applied to define target populations for clinical drug development. In a prospective community-recruited cohort of cognitively intact older adults, we compared two amyloid imaging markers within subjects: F-18-flutemetamol and C-11-Pittsburgh compound B (PIB). Methods In 32 community-recruited cognitively intact older adults aged between 65 and 80 years, we determined the concordance between binary classification based on F-18-flutemetamol versus C-11-PIB according to semiquantitative assessment (standardized uptake value ratio in composite cortical volume, SUVRcomp) and, alternatively, according to visual reads. We also determined the correlation between F-18-flutemetamol and C-11-PIB SUVR and evaluated how this was affected by the reference region chosen (cerebellar grey matter versus pons) and the use of partial volume correction (PVC) in this population. Results Binary classification based on semiquantitative assessment was concordant between F-18-flutemetamol and C-11-PIB in 94 % of cases. Concordance of blinded binary visual reads between tracers was 84 %. The Spearman correlation between F-18-flutemetamol and C-11-PIB SUVRcomp with cerebellar grey matter as reference region was 0.84, with a slope of 0.98. Correlations in neocortical regions were significantly lower with the pons as reference region. PVC improved the correlation in striatum and medial temporal cortex. Conclusion For the definition of preclinical AD based on F-18-flutemetamol, concordance with C-11-PIB was highest using semiquantitative assessment with cerebellar grey matter as reference region.

  • 18.
    Adams, Christopher
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences.
    Kjeldsen, Frank
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Ion Physics.
    Patriksson, Alexandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    van Der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Gräslund, Astrid
    Papadopolous, Evangelos
    Zubarev, Roman
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Probing Solution-Phase and Gas-Phase Structures of Trp-cage Cations by Chiral Substitution and Spectroscopic Techniques2006In: International Journal of Mass Spectrometry, ISSN 1387-3806, E-ISSN 1873-2798, Vol. 253, no 3, p. 263-273Article in journal (Refereed)
    Abstract [en]

    The relevance of gas-phase protein structure to its solution structure is of the utmost importance in studying biomolecules by mass spectrometry. D-Amino acid substitutions within a minimal protein. Trp-cage. were used to correlate solution-phase properties as measured by circular dichroism with solution/gas-phase conformational features of protein cations probed via charge state distribution (CSD) in electrospray ionization. and gas-phase features revealed by tandem mass spectrometry (MS/MS). The gas-phase features were additionally supported by force-field molecular dynamics simulations. CD data showed that almost any single-residue D-substitution destroys the most prominent CD feature of the "native" all-L isomer, alpha-helicity. CSD was able to qualitatively assess the degree of compactness of solution-phase molecular structures. CSD results were consistent with the all-L form being the most compact in solution among all studied stereoisomers except for the D-Asn(1) isomer. D-substitutions of the aromatic Y(3), W(6) and Q(5) residues generated the largest deviations in CSD data among single amino acid substitutions. consistent with the critical role of these residues in Trp-cage stability. Electron capture dissociation of the stereoisomer dications gave an indication that some gas-phase structural features of Trp-cage are similar to those in solution. This result is supported by MDS data oil five of the studied stereoisomer dications in the gas-phase. The MDS-derived minimum-energy structures possessed more extensive hydrogen bonding than the solution-phase structure of the native form, deviating from the latter by 3-4 angstrom and were not 'inside-out' compared to native structures. MDS data could be correlated with CD data and even with ECD results. which aided in providing a long-range structural constraint for MDS. The overall conclusion is the general resemblance, despite the difference on the detailed level, of the preferred structures in both phases for the mini protein Trp-cage.

  • 19.
    Adeen, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Andersson, Clara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Möjliga orsaker till patienters oro vid magnetkameraundersökningar; en jämförelse mellan två sjukhus: En deskriptiv enkätstudie2021Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background: Magnetic Resonance Imaging (MRI) is a medical imaging technique of which the usage has increased a lot during the last decades. The technique requires the patient to lay completely still in the narrow space during a long time, which causes anxiety for some patients. This results in canceled and postponed examinations and causes stress for the radiographers together with economic consequences for the society.

    Purpose: The purpose of this study is to evaluate the most common reasons for anxiety when undergoing an MRI-scan and to compare differences between two hospitals. The study will also evaluate the patients experiences of the communication and information given by the radiographers before and during an MRI-scan. 

    Method: An empirical quantitative method was chosen. The authors designed a questionnaire that was distributed to the patients after their MRI-scan at Uppsala University Hospital or Enköping Hospital.

    Results: The main reason for anxiety was the fear of what the scan might reveal. Other reasons were the narrow space in the MRI and the requirement to be completely still during the scan. Most of the patients felt calmer by the given communication and information, or declared it had no influence on their anxiety levels. The comparison between the two hospitals resulted in no significant difference (p>0,05). 

    Conclusion: The results from each hospital were very similar to each other and no significant difference was discovered. Overall, the patients became calmer by the communication and information given before and during the examination.

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  • 20.
    Adjeiwaah, Mary
    et al.
    Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden..
    Bylund, Mikael
    Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden..
    Lundman, Josef A.
    Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden..
    Karlsson, Camilla Thellenberg
    Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden..
    Jonsson, Joakim H.
    Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden..
    Nyholm, Tufve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Umea Univ, Dept Radiat Sci, SE-90187 Umea, Sweden.
    Quantifying the Effect of 3T Magnetic Resonance Imaging Residual System Distortions and Patient-Induced Susceptibility Distortions on Radiation Therapy Treatment Planning for Prostate Cancer2018In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 100, no 2, p. 317-324Article in journal (Refereed)
    Abstract [en]

    Purpose: To investigate the effect of magnetic resonance system-and patient-induced susceptibility distortions from a 3T scanner on dose distributions for prostate cancers.

    Methods and Materials: Combined displacement fields from the residual system and patient-induced susceptibility distortions were used to distort 17 prostate patient CT images. VMAT dose plans were initially optimized on distorted CT images and the plan parameters transferred to the original patient CT images to calculate a new dose distribution.

    Results: Maximum residual mean distortions of 3.19 mm at a radial distance of 25 cm and maximum mean patient-induced susceptibility shifts of 5.8 mm were found using the lowest bandwidth of 122 Hz per pixel. There was a dose difference of <0.5% between distorted and undistorted treatment plans. The 90% confidence intervals of the mean difference between the dCT and CT treatment plans were all within an equivalence interval of (-0.5, 0.5) for all investigated plan quality measures.

    Conclusions: Patient-induced susceptibility distortions at high field strengths in closed bore magnetic resonance scanners are larger than residual system distortions after using vendor-supplied 3-dimensional correction for the delineated regions studied. However, errors in dose due to disturbed patient outline and shifts caused by patient-induced susceptibility effects are below 0.5%.

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    fulltext
  • 21.
    Agarwala, Sunita
    et al.
    Natl Inst Technol Durgapur, Comp Sci & Engn, Durgapur, India..
    Kumar, Abhishek
    Univ Hyderabad, Sch Comp & Informat Sci, Hyderabad, India..
    Nandi, Debashis
    Natl Inst Technol Durgapur, Comp Sci & Engn, Durgapur, India..
    Dhara, Ashis Kumar
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Visual Information and Interaction. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Sadhu, Anup
    Med Coll Kolkata, Kolkata, India..
    Thakur, Sumitra Basu
    Med Coll Kolkata, Kolkata, India..
    Bhadra, Ashok Kumar
    Med Coll Kolkata, Kolkata, India..
    Convolutional Neural Networks for Efficient Localization of Interstitial Lung Disease Patterns in HRCT Images2018In: Medical Image Understanding and Analysis: 22nd Conference, MIUA 2018, Southampton, UK, July 9-11, 2018, Proceedings / [ed] Mark Nixon, Sasan Mahmoodi & Reyer Zwiggelaar, Springer Nature , 2018, p. 12-22Conference paper (Refereed)
    Abstract [en]

    Lung field segmentation is the first step towards the development of any computer aided diagnosis (CAD) system for interstitial lung diseases (ILD) observed in chest high resolution computed tomography (HRCT) images. If the segmentation is not done efficiently it will compromise the accuracy of CAD system. In this paper, a deep learning-based method is proposed to localize several interstitial lung disease patterns (ILD) in HRCT images without performing lung field segmentation. In this paper, localization of several ILD patterns is performed in image slice. The pretrained models of ZF and VGG networks were fine-tuned in order to localize ILD patterns using Faster R-CNN framework. The three most difficult ILD patterns consolidation, emphysema, and fibrosis have been used for this study and the accuracy of the method has been evaluated in terms of mean average precision (mAP) and free receiver operating characteristic (FROC) curve. The model achieved mAP value of 75% and 83% on ZF and VGG networks, respectively. The result obtained shows the effectiveness of the method in the localization of different ILD patterns.

  • 22. Aguilar, Carlos
    et al.
    Edholm, Kaijsa
    Simmons, Andrew
    Cavallin, Lena
    Muller, Susanne
    Skoog, Ingmar
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Axelsson, Rimma
    Wahlund, Lars-Olof
    Westman, Eric
    Automated CT-based segmentation and quantification of total intracranial volume2015In: European Radiology, ISSN 0938-7994, E-ISSN 1432-1084, Vol. 25, no 11, p. 3151-3160Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To develop an algorithm to segment and obtain an estimate of total intracranial volume (tICV) from computed tomography (CT) images.

    MATERIALS AND METHODS: Thirty-six CT examinations from 18 patients were included. Ten patients were examined twice the same day and eight patients twice six months apart (these patients also underwent MRI). The algorithm combines morphological operations, intensity thresholding and mixture modelling. The method was validated against manual delineation and its robustness assessed from repeated imaging examinations. Using automated MRI software, the comparability with MRI was investigated. Volumes were compared based on average relative volume differences and their magnitudes; agreement was shown by a Bland-Altman analysis graph.

    RESULTS: We observed good agreement between our algorithm and manual delineation of a trained radiologist: the Pearson's correlation coefficient was r = 0.94, tICVml[manual] = 1.05 × tICVml[automated] - 33.78 (R(2) = 0.88). Bland-Altman analysis showed a bias of 31 mL and a standard deviation of 30 mL over a range of 1265 to 1526 mL.

    CONCLUSIONS: tICV measurements derived from CT using our proposed algorithm have shown to be reliable and consistent compared to manual delineation. However, it appears difficult to directly compare tICV measures between CT and MRI.

    KEY POINTS: • Automated estimation of tICV is in good agreement with manual tracing. • Consistent tICV estimations from repeated measurements demonstrate the robustness of the algorithm. • Automatically segmented volumes seem less variable than those from manual tracing. • Unbiased and automated tlCV estimation is possible from CT.

  • 23.
    Ahlgren, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Molecular Radionuclide Imaging Using Site-specifically Labelled Recombinant Affibody Molecules: Preparation and Preclinical Evaluation2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Radionuclide molecular imaging is an emerging multidisciplinary technique that is used in modern medicine to visualise diseases at cellular and molecular levels. This thesis is based on five papers (I-V) and focuses on the development of site-specific radiolabelled recombinant anti-HER2 Affibody molecules and preclinical evaluations in vitro and in vivo of the labelled conjugates. This work is part of a preclinical development of an Affibody molecule-based tracer for molecular imaging of HER2 expressing tumours.

    Papers I and II report the evaluation of the Affibody molecule ZHER2:2395-C, site-specifically labelled with the radiometals 111In (for SPECT) and 57Co (as a surrogate for 55Co, suitable for PET applications) using a thiol reactive DOTA derivative as a chelator. Both conjugates demonstrated very suitable biodistribution properties, enabling high contrast imaging just a few hours after injection.

    Papers III and IV report the development and optimization of a technique for site-specific labelling of ZHER2:2395-C with 99mTc using an N3S chelating peptide sequence. 99mTc-ZHER2:2395-C demonstrated high and specific tumour uptake and rapid clearance of non-bound tracer from the blood, resulting in high tumour-to-non-tumour ratios shortly after injection, enabling high contrast imaging. In addition, in the study described in paper IV, freeze-dried kits previously developed for 99mTc-labelling were optimised, resulting in the development of a kit in which all the reagents and protein needed for labelling of ZHER2:2395-C with 99mTc were contained in a single vial.

    Paper V reports the evaluation of an anti-HER2 Affibody molecule, ABY-025, with a fundamentally re-engineered scaffold. Despite the profound re-engineering, the biodistribution pattern of 111In-ABY-025 was very similar to that of two variants of the parental molecule.

    It seems reasonable to believe that these results will also be applicable to Affibody molecules towards other targets. Hopefully, this work will also be helpful in the development of other small proteinaceous tracers.

    List of papers
    1. Evaluation of maleimide derivative of DOTA for site-specific labeling of recombinant affibody molecules
    Open this publication in new window or tab >>Evaluation of maleimide derivative of DOTA for site-specific labeling of recombinant affibody molecules
    Show others...
    2008 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 19, no 1, p. 235-243Article in journal (Refereed) Published
    Abstract [en]

    Affibody molecules are a new class of small (7 kDa) scaffold affinity proteins, which demonstrate promising properties as agents for in vivo radionuclide targeting. The Affibody scaffold is cysteine-free and therefore independent of disulfide bonds. Thus, a single thiol group can be engineered into the protein by introduction of one cysteine. Coupling of thiol-reactive bifunctional chelators can enable site-specific labeling of recombinantly produced Affibody molecules. In this study, the use of 1,4,7,10-tetraazacyclododecane-1,4,7-tris-acetic acid-10-maleimidoethylacetamide (MMA-DOTA) for 111 In-labeling of anti-HER2 Affibody molecules His 6-Z HER2:342-Cys and Z HER2:2395-Cys has been evaluated. The introduction of a cysteine residue did not affect the affinity of the proteins, which was 29 pM for His 6-Z HER2:342-Cys and 27 pM for Z HER2:2395-Cys, comparable with 22 pM for the parental Z HER2:342. MMA-DOTA was conjugated to DTT-reduced Affibody molecules with a coupling efficiency of 93% using a 1:1 molar ratio of chelator to protein. The conjugates were labeled with 111 In to a specific radioactivity of up to 7 GBq/mmol, with preserved binding for the target HER2. In vivo, the non-His-tagged variant 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys demonstrated appreciably lower liver uptake than its His-tag-containing counterpart. In mice bearing HER2-expressing LS174T xenografts, 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys showed specific and rapid tumor localization, and rapid clearance from blood and nonspecific compartments, leading to a tumor-to-blood-ratio of 18 +/- 8 already 1 h p.i. Four hours p.i., the tumor-to-blood ratio was 138 +/- 8. Xenografts were clearly visualized already 1 h p.i.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-104530 (URN)10.1021/bc700307y (DOI)000252520300030 ()18163536 (PubMedID)
    Available from: 2009-05-29 Created: 2009-05-28 Last updated: 2017-12-13Bibliographically approved
    2. Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys61]-ZHER2:2395-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors
    Open this publication in new window or tab >>Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys61]-ZHER2:2395-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors
    2010 (English)In: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 12, no 1, p. 54-62Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: Imaging using positron emission tomography (PET) in the field of nuclear medicine is becoming increasingly important. The aim of this study was to develop a method for labeling of affibody molecules with radiocobalt for PET applications. PROCEDURES: The human epidermal growth factor receptors type 2 (HER2) binding affibody molecule DOTA-Z(2395)-C was radiolabeled with (57)Co (used as a surrogate of (55)Co). The binding specificity and cellular processing of the labeled compound was studied in vitro followed by in vivo characterization in normal and tumor-bearing mice. Furthermore, a comparative biodistribution study was performed with a (111)In-labeled counterpart. RESULTS: DOTA-Z(2395)-C was successfully labeled with radiocobalt with nearly quantitative yield. The compound displayed good retention on cells over time and high tumor accumulation of radioactivity in animal studies. Imaging studies showed clear visualization of HER2-positive tumors. Furthermore, the radiocobalt label provided better tumor-to-organ ratios than (111)In. CONCLUSIONS: Radiocobalt is a promising label for affibody molecules for future PET applications.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122173 (URN)10.1007/s11307-009-0238-8 (DOI)000273479300008 ()19557480 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2022-01-28Bibliographically approved
    3. Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine
    Open this publication in new window or tab >>Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine
    Show others...
    2009 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 50, no 5, p. 781-789Article in journal (Refereed) Published
    Abstract [en]

    The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Small (7 kDa) high-affinity anti-HER2 Affibody molecules may be suitable tracers for SPECT visualization of HER2-expressing tumors. The use of generator-produced (99m)Tc as a label would facilitate the prompt translation of anti-HER2 Affibody molecules into use in clinics. METHODS: A C-terminal cysteine was introduced into the Affibody molecule Z(HER2:342) to enable site-specific labeling with (99m)Tc. Two recombinant variants, His(6)-Z(HER2:342)-Cys (dissociation constant [K(D)], 29 pM) and Z(HER2:2395)-Cys, lacking a His tag (K(D), 27 pM), were labeled with (99m)Tc in yields exceeding 90%. The binding specificity and the cellular processing of Affibody molecules were studied in vitro. Biodistribution and gamma-camera imaging studies were performed in mice bearing HER2-expressing xenografts. RESULTS: (99m)Tc-His(6)-Z(HER2:342)-Cys was capable of targeting HER2-expressing SKOV-3 xenografts in SCID mice, but the liver radioactivity uptake was high. A series of comparative biodistribution experiments indicated that the presence of the His tag caused elevated accumulation in the liver. (99m)Tc-Z(HER2:2395)-Cys, not containing a His tag, showed low uptake in the liver and high and specific uptake in HER2-expressing xenografts. Four hours after injection, the radioactivity uptake values (percentage of injected activity per gram of tissue [%IA/g]) were 6.9 +/- 2.5 (mean +/- SD) %IA/g in LS174T xenografts (moderate level of HER2 expression) and 15 +/- 3 %IA/g in SKOV-3 xenografts (high level of HER2 expression). The corresponding tumor-to-blood ratios were 88 +/- 24 and 121 +/- 24, respectively. Both LS174T and SKOV-3 xenografts were clearly visualized with a clinical gamma-camera 1 h after injection of (99m)Tc-Z(HER2:2395)-Cys. CONCLUSION: The Affibody molecule (99m)Tc-Z(HER2:2395)-Cys is a promising tracer for SPECT visualization of HER2-expressing tumors.

    Keywords
    Affibody molecule, technetium, imaging, HER2, C-terminal cysteine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122172 (URN)10.2967/jnumed.108.056929 (DOI)000272487900017 ()19372467 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2022-01-28Bibliographically approved
    4. Kit formulation for 99mTc-labeling of recombinant anti-HER2 Affibody molecules with a C-terminally engineered cysteine
    Open this publication in new window or tab >>Kit formulation for 99mTc-labeling of recombinant anti-HER2 Affibody molecules with a C-terminally engineered cysteine
    2010 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 37, no 5, p. 539-546Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Molecular imaging of HER2-expression in malignant tumors provides potentially important information for patient management. Affibody molecules have shown to be suitable tracers for imaging applications using SPECT or PET. Results from an earlier evaluation of the application of site specific 99mTc-labeling on the Affibody molecule, ZHER2:2395-C, were favorable.

    Methods: As a preparation for clinical application of this tracer we have developed and evaluated a robust single-vial freeze-dried kit, allowing labeling of the Affibody molecule, ZHER2:2395-C, with 99mTc.

    Results: The composition of the kit (containing glucoheptonate, EDTA and tin(II)-chloride), as well as the protein amount and the pertechnetate volume were optimized for a high labeling yield (> 90 %) and minimal presence of reduced hydrolyzed technetium colloids (< 1 %). The specificity to HER2 receptors, the binding competence and the stability in PBS and murine serum were verified in vitro. The shelf-life was also evaluated in vitro, showing no reduction in labeling yield or binding capacity to HER2-expressing cells after over 400 days of storage of the single-vial freeze-dried kit.

    Conclusions: ZHER2:2395-C labeled with 99mTc using the lyophilized kit was stable and resulted in a favorable biodistribution in an in vivo evaluation in normal NMRI mice.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122175 (URN)10.1016/j.nucmedbio.2010.02.009 (DOI)000279412400002 ()20610158 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2017-12-12Bibliographically approved
    5. Targeting of HER2-Expressing Tumors Using 111In-ABY-025, a Second-Generation Affibody Molecule with a Fundamentally Reengineered Scaffold
    Open this publication in new window or tab >>Targeting of HER2-Expressing Tumors Using 111In-ABY-025, a Second-Generation Affibody Molecule with a Fundamentally Reengineered Scaffold
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    2010 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 51, no 7, p. 1131-1138Article in journal (Refereed) Published
    Abstract [en]

    Overexpression of HER2 in breast carcinomas predicts response to trastuzumab therapy. Affibody molecules based on a non-immunoglobulin scaffold have demon-strated high potential for in vivo molecular imaging of HER2-expressing tumors. Re-engineering of the molecular scaffold has led to a second generation of optimized Affibody molecules, having a surface distinctly different from the parental protein domain from staphylococcal protein A. The new tracer showed further increased melting point, stability and overall hydrophilicity compared to the parental molecule, and was shown to be more amenable for chemical peptide synthesis. The goal of this study was to assess potential effects of this extensive re-engineering on HER2 targeting, using ABY-025, a DOTA conjugated variant of the novel tracer.

    Methods: 111In-ABY-025 was compared with previously evaluated parent HER2-binding Affibody tracers in vitro and in vivo. The in vivo behavior was further evaluated in mice bearing SKOV-3 xenografts, in rats and in cynomolgus macaques.

    Results: 111In-ABY-025 bound specifically to HER2 in vitro and in vivo. Direct comparison with the previous generation of HER2-binding tracers showed that ABY-025 retained excellent targeting properties. Rapid blood clearance was shown in mice, rats and macaques. A highly specific tumor uptake of 16.7 ± 2.5 %IA/g was seen at 4 h after injection. The tumor-to-blood ratio was 6.3 at 0.5 h, 88 at 4 h, and increased up to 3 days after injection. Gamma camera imaging of tumors was already possible 0.5 h after injection. Furthermore, repeated i.v. administration of ABY-025 did not induce antibody formation in rats.

    Conclusions: The biodistribution of 111In-ABY-025 was in remarkably good agreement with the parent tracers, despite profound re-engineering of the non-binding surface. The molecule displayed rapid blood clearance in all species investigated and excellent targeting capacity in tumor bearing mice, leading to high tumor-to-organ-ratios and high contrast imaging shortly after injection.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122176 (URN)10.2967/jnumed.109.073346 (DOI)000279430900021 ()20554729 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2022-01-28Bibliographically approved
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  • 24.
    Ahlinder, Linnea
    et al.
    Swedish Def Res Agcy, FOI, Cementvagen 20, SE-90182 Umea, Sweden..
    Lindstrom, Susanne Wiklund
    Swedish Def Res Agcy, FOI, Cementvagen 20, SE-90182 Umea, Sweden..
    Lejon, Christian
    Swedish Def Res Agcy, FOI, Cementvagen 20, SE-90182 Umea, Sweden..
    Geladi, Paul
    Swedish Univ Agr Sci, Dept Forest Biomat & Technol, SE-90183 Umea, Sweden..
    Österlund, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Physics.
    Noise Removal with Maintained Spatial Resolution in Raman Images of Cells Exposed to Submicron Polystyrene Particles2016In: Nanomaterials, E-ISSN 2079-4991, Vol. 6, no 5, article id UNSP 83Article in journal (Refereed)
    Abstract [en]

    The biodistribution of 300 nm polystyrene particles in A549 lung epithelial cells has been studied with confocal Raman spectroscopy. This is a label-free method in which particles and cells can be imaged without using dyes or fluorescent labels. The main drawback with Raman imaging is the comparatively low spatial resolution, which is aggravated in heterogeneous systems such as biological samples, which in addition often require long measurement times because of their weak Raman signal. Long measurement times may however induce laser-induced damage. In this study we use a super-resolution algorithm with Tikhonov regularization, intended to improve the image quality without demanding an increased number of collected pixels. Images of cells exposed to polystyrene particles have been acquired with two different step lengths, i.e., the distance between pixels, and compared to each other and to corresponding images treated with the super-resolution algorithm. It is shown that the resolution after application of super-resolution algorithms is not significantly improved compared to the theoretical limit for optical microscopy. However, to reduce noise and artefacts in the hyperspectral Raman images while maintaining the spatial resolution, we show that it is advantageous to use short mapping step lengths and super-resolution algorithms with appropriate regularization. The proposed methodology should be generally applicable for Raman imaging of biological samples and other photo-sensitive samples.

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  • 25.
    Ahlkvist, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lidell, Tilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Gadoliniumretention, dess inverkan på människokroppen samt vilka förebyggande åtgärder röntgensjuksköterskan kan behöva implementera: En litteraturstudie2024Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background Magnetic resonance imaging exams is becoming more common and therefore the use of gadolinium-based contrast media increases. However, gadolinium retention is a relatively newly discovered phenomenon, and its impact on the human body is still unknown.

    Purpose The purpose of this study is to obtain a deeper understanding of what gadolinium retention is and how it affects the human body, and which implementations radiographers may have to do to adapt the care according to new research within the field.

    Method This study is a systematic literary review. The data collection was made from the databases PubMed and CINAHL. Only scientific studies that fulfilled the inclusion criteria, for example that they were peer-reviewed and primary published, were included. The articles that answered the questions were quality reviewed and the articles that achieved medium or high quality were analysed.

    Results The result of this study shows thar accumulated gadoliniumretention can arise after repeated administrations of gadolinium-based contrast media. No adverse effects in the human body have been demonstrated. To reduce the risk of accumulating gadoliniumretention several studies recommend reducing the dosage and to be cautious when administrating.

    Conclusion Gadoliniumretention can be seen as an increased signal intensity, mainly in dentate nucleus and globus palladius in the human brain after multiple administration of gadolinium-based contrast media. Its adverse effects on the human body are still unknown and more research is needed on how radiographer can adapt the care thereafter.

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  • 26. Ahlstedt, J.
    et al.
    Orbom, A.
    Akesson, A.
    Frejd, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Strand, S.
    Tran, T.
    Simultaneous dual-radionuclide SPECT-imaging of HER2 expression using 99mTc-Affibody/111In-trastuzumab2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S274-S274, article id OP522Article in journal (Other academic)
  • 27.
    Ahlström, Håkan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ekström, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sjöholm, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Strand, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, E.
    Antaros Med, Molndal, Sweden..
    Hagmar, P.
    Antaros Med, Molndal, Sweden..
    Malmberg, Filip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Registration-based automated lesion detection and therapy evaluation of tumors in whole body PET-MR images2017In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no S5, article id 78PArticle in journal (Other academic)
  • 28.
    Ahmad, Nouman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Strand, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis and Human-Computer Interaction.
    Sparresäter, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Tarai, Sambit
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lundström, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bergström, Göran
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Automatic segmentation of large-scale CT image datasets for detailed body composition analysis.2023In: BMC Bioinformatics, E-ISSN 1471-2105, Vol. 24, no 1, article id 346Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Body composition (BC) is an important factor in determining the risk of type 2-diabetes and cardiovascular disease. Computed tomography (CT) is a useful imaging technique for studying BC, however manual segmentation of CT images is time-consuming and subjective. The purpose of this study is to develop and evaluate fully automated segmentation techniques applicable to a 3-slice CT imaging protocol, consisting of single slices at the level of the liver, abdomen, and thigh, allowing detailed analysis of numerous tissues and organs.

    METHODS: The study used more than 4000 CT subjects acquired from the large-scale SCAPIS and IGT cohort to train and evaluate four convolutional neural network based architectures: ResUNET, UNET++, Ghost-UNET, and the proposed Ghost-UNET++. The segmentation techniques were developed and evaluated for automated segmentation of the liver, spleen, skeletal muscle, bone marrow, cortical bone, and various adipose tissue depots, including visceral (VAT), intraperitoneal (IPAT), retroperitoneal (RPAT), subcutaneous (SAT), deep (DSAT), and superficial SAT (SSAT), as well as intermuscular adipose tissue (IMAT). The models were trained and validated for each target using tenfold cross-validation and test sets.

    RESULTS: The Dice scores on cross validation in SCAPIS were: ResUNET 0.964 (0.909-0.996), UNET++ 0.981 (0.927-0.996), Ghost-UNET 0.961 (0.904-0.991), and Ghost-UNET++ 0.968 (0.910-0.994). All four models showed relatively strong results, however UNET++ had the best performance overall. Ghost-UNET++ performed competitively compared to UNET++ and showed a more computationally efficient approach.

    CONCLUSION: Fully automated segmentation techniques can be successfully applied to a 3-slice CT imaging protocol to analyze multiple tissues and organs related to BC. The overall best performance was achieved by UNET++, against which Ghost-UNET++ showed competitive results based on a more computationally efficient approach. The use of fully automated segmentation methods can reduce analysis time and provide objective results in large-scale studies of BC.

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  • 29.
    Ahmed, Adan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bemötande av barn på röntgen2016Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Barnen är oftast rädda och oroliga då de kommer till en röntgenundersökning på grund av att det är en främmande miljö utrustad med högteknologisk apparatur som är skrämmande för barnet. För att bemöta dessa barn behöver röntgensjuksköterskan ha kunskap och färdigheter om bemötande av barn. Ett bra samspel mellan röntgensjuksköterskan och barnen som bygger på ömsesidig tillit och respekt ger trygghet hos barnet och det kan samarbeta bättre under röntgenundersökningen. På en kort tid, ofta mindre än 5 minuter, måste en röntgensjuksköterska överföra viktig information om undersökningen till barnet. Därför är det viktigt för röntgensjuksköterskan att ha kunskap om gott bemötande av barn.

  • 30.
    Ahnesjö, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    van Veelen, Bob
    Elekta Brachytherapy, NL-3905 TH Veenendaal, Netherlands..
    Tedgren, Asa Carlsson
    Linkoping Univ, Fac Hlth Sci, Dept Med & Hlth Sci IMH, Radiat Phys, SE-58185 Linkoping, Sweden.;Karolinska Univ Hosp, Dept Med Phys, Sect Radiotherapy Phys & Engn, SE-17176 Stockholm, Sweden..
    Collapsed cone dose calculations for heterogeneous tissues in brachytherapy using primary and scatter separation source data2017In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, E-ISSN 1872-7565, Vol. 139, p. 17-29Article in journal (Refereed)
    Abstract [en]

    Background and Objective: Brachytherapy is a form of radiation therapy using sealed radiation sources inserted within or in the vicinity of the tumor of, e.g., gynecological, prostate or head and neck cancers. Accurate dose calculation is a crucial part of the treatment planning. Several reviews have called for clinical software with model-based algorithms that better take into account the effects of patient individual distribution of tissues, source-channel and shielding attenuation than the commonly employed TG-43 formalism which simply map homogeneous water dose distributions onto the patient. In this paper we give a comprehensive and thorough derivation of such an algorithm based on collapsed cone point-kernel superposition, and describe details of its implementation into a commercial treatment planning system for clinical use. Methods: A brachytherapy version of the collapsed-cone algorithm using analytical raytraces of the primary photon radiation followed by successive scattering dose calculation for once and multiply scattered photons is described in detail, including derivation of the corresponding set of recursive equations for energy transport along cone axes/transport lines and the coupling to clinical source modeling. Specific implementation issues for setting up of the calculation grid, handling of intravoxel gradients and voxels partly containing non patient applicator material are given. Results: Sample runs for two clinical cases are shown, one being a gynecological application with a tungsten-shielded applicator and one a breast implant. These two cases demonstrate the impact of improved dose calculation versus TG-43 formalism. Conclusions: Use of model-based dose calculation algorithms for brachytherapy taking the three-dimensional treatment geometry into account increases the dosimetric accuracy in planning and follow up of treatments. The comprehensive description and derivations provided gives a rigid background for further clinical, educational and research applications.

  • 31.
    Ahnfelt, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Dahlman, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Segelsjö, Monica
    Magnusson, Mats O
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Accuracy of iodine quantification using dual-energy computed tomography with focus on low concentrations.2022In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 63, no 5, p. 623-631, article id 2841851211009462Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Iodine quantification using dual-energy computed tomography (DECT) is helpful in characterizing, and follow-up after treatment of tumors. Some malignant masses, for instance papillary renal cell carcinomas (p-RCC), are hard to differentiate from benign lesions because of very low contrast enhancement. In these cases, iodine concentrations might be very low, and it is therefore important that iodine quantification is reliable even at low concentrations if this technique is used.

    PURPOSE: To examine the accuracy of iodine quantification and to determine whether it is also accurate for low iodine concentrations.

    MATERIAL AND METHODS: Twenty-six syringes with different iodine concentrations (0-30 mg I/mL) were scanned in a phantom model using a DECT scanner with two different kilovoltage and image reconstruction settings. Iodine concentrations were measured and compared to known concentration. Absolute and relative errors were calculated.

    RESULTS: For concentrations of 1 mg I/mL or higher, there was an excellent correlation between true and measured iodine concentrations for all settings (R = 0.999-1.000; P < 0.001). For concentrations <1.0 mg I/mL, the relative error was greater. Absolute and relative errors were smaller using tube voltages of 80/Sn140 kV than 100/Sn140 kV (P < 0.01). Reconstructions using a 3.0-mm slice thickness had less variance between repeated acquisitions versus 0.6 mm (P < 0.001).

    CONCLUSION: Iodine quantification using DECT was in general very accurate, but for concentrations < 1.0 mg I/mL the technique was less reliable. Using a tube voltage with larger spectral separation was more accurate and the result was more reproducible using thicker image reconstructions.

  • 32.
    Ajithkumar, Thankamma
    et al.
    Cambridge Univ Hosp, Dept Oncol, Cambridge, England.
    Horan, Gail
    Cambridge Univ Hosp, Dept Oncol, Cambridge, England.
    Padovani, Laetitia
    Assistance Publ Hop Marseille, Dept Radiat Oncol, Marseille, France.
    Thorp, Nicky
    Clatterbridge Canc Ctr, Dept Oncol, Liverpool, Merseyside, England.
    Timmermann, Beate
    Univ Essen Gesamthsch, West German Proton Ctr, Essen, Germany.
    Alapetite, Claire
    Inst Curie, Dept Radiat Oncol, Paris, France;Inst Curie, Proton Ctr, Paris, France;Inst Curie, Dept Radiat Oncol, Orsay, France;Inst Curie, Proton Ctr, Orsay, France.
    Gandola, Lorenza
    Fdn IRCCS Ist Nazl Tumori, Dept Radiat Oncol, Milan, Italy.
    Ramos, Monica
    Hosp Univ Vall dHebron, Barcelona, Spain.
    Van Beek, Karen
    UZ Leuven, Radiotherapie Oncol, Leuven, Belgium.
    Christiaens, Melissa
    UZ Leuven, Radiotherapie Oncol, Leuven, Belgium.
    Lassen-Ramshad, Yasmin
    Aarhus Univ Hosp, Danish Ctr Particle Therapy, Aarhus, Denmark.
    Magelssen, Henriette
    Norwegian Radium Hosp, Oslo Univ Hosp, Dept Oncol, Oslo, Norway.
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Saran, Frank
    Royal Marsden Hosp, Dept Oncol, Sutton, Surrey, England.
    Rombi, Barbara
    Santa Chiara Hosp, Proton Therapy Ctr, Trento, Italy.
    Kortmann, Rolf
    Univ Leipzig, Dept Radiat Oncol, Leipzig, Germany.
    Janssens, Geert O.
    Univ Med Ctr Utrecht, Dept Radiat Oncol, Utrecht, Netherlands;Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands.
    SIOPE - Brain tumor group consensus guideline on craniospinal target volume delineation for high-precision radiotherapy2018In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 128, no 2, p. 192-197Article in journal (Refereed)
    Abstract [en]

    Objective: To develop a consensus guideline for craniospinal target volume (TV) delineation in children and young adults participating in SIOPE studies in the era of high-precision radiotherapy. Methods and materials: During four consensus meetings (Cambridge, Essen, Liverpool, and Marseille), conventional field-based TV has been translated into image-guided high-precision craniospinal TV by a group of expert paediatric radiation oncologists and enhanced by MRI images of liquor distribution. Results: The CTVcranial should include the whole brain, cribriform plate, most inferior part of the temporal lobes, and the pituitary fossa. If the full length of both optic nerves is not included, the dose received by different volumes of optic nerve should be recorded to correlate with future patterns of relapse (no consensus). The CTVcranial should be modified to include the dural cuffs of cranial nerves as they pass through the skull base foramina. Attempts to spare the cochlea by excluding CSF within the internal auditory canal should be avoided. The CTVspinal should include the entire subarachnoid space, including nerve roots laterally. The lower limit of the spinal CTV is at the lower limit of the thecal sac, best visible on MRI scan. There is no need to include sacral root canals in the spinal CTV. Conclusion: This consensus guideline has the potential to improve consistency of craniospinal TV delineation in an era of high-precision radiotherapy. This proposal will be incorporated in the RTQA guidelines of future SIOPE-BTG trials using CSI.

  • 33.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Larsson, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Thicknesses of individual layers of artery wall indicate increased cardiovascular risk in severe pre-eclampsia2014In: Ultrasound in Obstetrics and Gynecology, ISSN 0960-7692, E-ISSN 1469-0705, Vol. 43, no 6, p. 675-680Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Pre-eclampsia, especially severe pre-eclampsia, is associated with an increased risk of cardiovascular disease later in life. However, ultrasound assessments of the common carotid artery intima-media thickness (CCA-IMT) do not convincingly demonstrate this. The aim of this study was to assess whether the individual thickness of the CCA intima and media layers and calculation of intima/media ratio (I/M) indicate an increased cardiovascular risk in women with previous severe pre-eclampsia.

    METHODS: The thicknesses of the CCA intima and media layers were obtained by non-invasive high-frequency ultrasound (22 MHz) in 42 women with previous severe pre-eclampsia and 44 women with previous normal pregnancies. A thick intima, thin media and high I/M are signs of a less healthy artery wall.

    RESULTS: Women with previous severe pre-eclampsia had a thicker CCA intima and a higher I/M than women with previous normal pregnancies, also after adjustment for mean arterial pressure, body mass index and CCA-IMT (all p < 0.0001). CCA-IMT did not differ significantly between the groups. In receiver operating characteristic curve analysis, intima thickness and I/M clearly discriminated between women with and without previous pre-eclampsia (c value about 0.95), whereas CCA-IMT did not (c = 0.52).

    CONCLUSIONS: Estimation of the individual CCA intima and media layers using high-frequency ultrasound and calculation of the I/M clearly demonstrated the well known increased cardiovascular risk in women with pre-eclampsia, whereas CCA-IMT did not. This method appears preferable to measuring CCA-IMT for imaging arterial effects and the increased cardiovascular risk in women with previous severe pre-eclampsia.

  • 34.
    Alakade, Miriam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Areskog, Rasmus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Röntgensjuksköterskors upplevelse av stress under covid-19-pandemin: En intervjustudie2021Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Background: Since the beginning of 2020, the world has contracted the covid-19 pandemic, which has a negative impact on employee well-being. According to several studies, the pandemic has resulted in negative side effects such as stress, depression and burnout. 

    Aim: The aim of the study was to investigate X-ray nurses' experiences of stress during the covid-19 pandemic and how the pandemic affects their work and health. 

    Method: The study was conducted as a qualitative interview study with semi-structured interview questions, which 11 X-ray nurses took part in. The method for data analysis was a qualitative content analysis with an inductive approach. 

    Results: Most of the participants experienced a high level of work-related stress during their work, which varied among the units. The factors that have most given rise to stress were the workload, the lack of knowledge, the work demands and the fear of becoming infected and passing on the disease. In addition, the stress has affected the participants both mentally and physically in different ways, but some participants were able to handle the stress. There was also more or less influence on the X-ray department regarding workload, care implementation and atmosphere, where the workload had been affected the most. 

    Conclusion: Work-related stress is experienced by most X-ray nurses. The factors that lead to this stress varied greatly between individuals. All participants claimed that stress has increased since the start of the covid-19 pandemic, and that increased workload is a factor in this. 

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  • 35. Alcorn, S. R.
    et al.
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Dieckmann, K.
    McNutt, T. R.
    Chen, M. J.
    Ermoian, R. P.
    Ford, E. C.
    MacDonald, S.
    Nechesnyuk, A.
    Tryggestad, E. J.
    Smith, K.
    Villar, R. C.
    Winey, B.
    Terezakis, S. A.
    Predictors of Setup Accuracy in Image-Guided CNS Radiation Therapy: Prospective Data From a Multinational Pediatrics Consortium2014In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 90, no S1, p. S723-S723Article in journal (Other academic)
  • 36.
    Alcorn, Sara R.
    et al.
    Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA..
    Zhou, Xian Chiong
    Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA..
    Bojechko, Casey
    Univ Washington, Seattle, WA 98195 USA..
    Rubo, Rodrigo A.
    Ctr Infantil Boldrini, Sao Paulo, Brazil.;Ctr Infantil Boldrini, Regiao, Brazil..
    Chen, Michael J.
    Grp Apoio Ao Adolescente & Crianca Com Canc, Sao Paulo, Brazil..
    Dieckmann, Karin
    Univ Klin Strahlentherapie & Strahlenbiol, Vienna, Austria..
    Ermoian, Ralph P.
    Univ Washington, Seattle, WA 98195 USA..
    Ford, Eric C.
    Univ Washington, Seattle, WA 98195 USA..
    Kobyzeva, Daria
    Fed Sci Clin Ctr Childrens Hematol Oncol & Immuno, Moscow, Russia..
    MacDonald, Shannon M.
    Massachusetts Gen Hosp, Boston, MA 02114 USA..
    McNutt, Todd R.
    Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA..
    Nechesnyuk, Alexey
    Fed Sci Clin Ctr Childrens Hematol Oncol & Immuno, Moscow, Russia..
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sjöstrand, Håkan
    Uppsala Univ Hosp, Uppsala, Sweden..
    Smith, Koren S.
    Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA..
    Stock, Markus
    Univ Klin Strahlentherapie & Strahlenbiol, Vienna, Austria..
    Tryggestad, Erik J.
    Mayo Clin, Rochester, MN USA..
    Villar, Rosangela C.
    Ctr Infantil Boldrini, Sao Paulo, Brazil.;Ctr Infantil Boldrini, Regiao, Brazil..
    Winey, Brian A.
    Massachusetts Gen Hosp, Boston, MA 02114 USA..
    Terezakis, Stephanie A.
    Univ Minnesota, Dept Radiat Oncol & Mol Radiat Sci, 420 Delaware St, Minneapolis, MN 55455 USA..
    Low-Dose Image-Guided Pediatric CNS Radiation Therapy: Final Analysis From a Prospective Low-Dose Cone-Beam CT Protocol From a Multinational Pediatrics Consortium2020In: Technology in Cancer Research & Treatment, ISSN 1533-0346, E-ISSN 1533-0338, Vol. 19, article id 1533033820920650Article in journal (Refereed)
    Abstract [en]

    Background: Lower-dose cone-beam computed tomography protocols for image-guided radiotherapy may permit target localization while minimizing radiation exposure. We prospectively evaluated a lower-dose cone-beam protocol for central nervous system image-guided radiotherapy across a multinational pediatrics consortium.

    Methods: Seven institutions prospectively employed a lower-dose cone-beam computed tomography central nervous system protocol (weighted average dose 0.7 mGy) for patients <= 21 years. Treatment table shifts between setup with surface lasers versus cone-beam computed tomography were used to approximate setup accuracy, and vector magnitudes for these shifts were calculated. Setup group mean, interpatient, interinstitution, and random error were estimated, and clinical factors were compared by mixed linear modeling.

    Results: Among 96 patients, with 2179 pretreatment cone-beam computed tomography acquisitions, median age was 9 years (1-20). Setup parameters were 3.13, 3.02, 1.64, and 1.48 mm for vector magnitude group mean, interpatient, interinstitution, and random error, respectively. On multivariable analysis, there were no significant differences in mean vector magnitude by age, gender, performance status, target location, extent of resection, chemotherapy, or steroid or anesthesia use. Providers rated >99% of images as adequate or better for target localization.

    Conclusions: A lower-dose cone-beam computed tomography protocol demonstrated table shift vector magnitude that approximate clinical target volume/planning target volume expansions used in central nervous system radiotherapy. There were no significant clinical predictors of setup accuracy identified, supporting use of this lower-dose cone-beam computed tomography protocol across a diverse pediatric population with brain tumors.

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    FULLTEXT01
  • 37.
    Aleksyniene, Ramune
    et al.
    Aalborg Univ Hosp, Dept Nucl Med, DK-9000 Aalborg, Denmark..
    Iyer, Victor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Aalborg Univ Hosp, Dept Nucl Med, DK-9000 Aalborg, Denmark..
    Bertelsen, Henrik Christian
    Aalborg Univ Hosp, Dept Nucl Med, DK-9000 Aalborg, Denmark..
    Nilsson, Majbritt Frost
    Aalborg Univ Hosp, Dept Nucl Med, DK-9000 Aalborg, Denmark..
    Khalid, Vesal
    Aalborg Univ, Dept Clin Med, DK-9220 Aalborg, Denmark.;Aalborg Univ Hosp, Orthopaed Res Unit, DK-9000 Aalborg, Denmark..
    Schonheyder, Henrik Carl
    Aalborg Univ Hosp, Dept Clin Microbiol, DK-9000 Aalborg, Denmark..
    Larsen, Lone Heimann
    Aalborg Univ Hosp, Dept Clin Microbiol, DK-9000 Aalborg, Denmark..
    Nielsen, Poul Torben
    Aalborg Univ Hosp, Dept Orthopaed Surg, Interdisciplinary Orthopaed, DK-9000 Aalborg, Denmark..
    Kappel, Andreas
    Aalborg Univ Hosp, Dept Orthopaed Surg, Interdisciplinary Orthopaed, DK-9000 Aalborg, Denmark..
    Thomsen, Trine Rolighed
    Aalborg Univ, Ctr Microbial Communities, DK-9220 Aalborg, Denmark.;Danish Technol Inst, Med Biotechnol, DK-8000 Aarhus, Denmark..
    Lorenzen, Jan
    Danish Technol Inst, Med Biotechnol, DK-8000 Aarhus, Denmark..
    Ørsted, Iben
    Aalborg Univ Hosp, Dept Infect Dis, DK-9000 Aalborg, Denmark..
    Simonsen, Ole
    Aalborg Univ Hosp, Dept Orthopaed Surg, Interdisciplinary Orthopaed, DK-9000 Aalborg, Denmark..
    Jordal, Peter Lüttge
    Danish Technol Inst, Med Biotechnol, DK-8000 Aarhus, Denmark..
    Rasmussen, Sten
    Aalborg Univ, Dept Clin Med, DK-9220 Aalborg, Denmark.;Aalborg Univ Hosp, Orthopaed Res Unit, DK-9000 Aalborg, Denmark..
    The Role of Nuclear Medicine Imaging with F-18-FDG PET/CT, Combined In-111-WBC/(99)mTc-Nanocoll, and Tc-99m-HDP SPECT/CT in the Evaluation of Patients with Chronic Problems after TKA or THA in a Prospective Study2022In: Diagnostics, ISSN 2075-4418, Vol. 12, no 3, article id 681Article in journal (Refereed)
    Abstract [en]

    Background: The aim of this prospective study was to assess the diagnostic value of nuclear imaging with F-18-FDG PET/CT (FDG PET/CT), combined In-111-WBC/(99)mTc-Nanocoll, and Tc-99m-HDP SPECT/CT (dual-isotope WBC/bone marrow scan) for patients with chronic problems related to knee or hip prostheses (TKA or THA) scheduled by a structured multidisciplinary algorithm.

    Materials and Methods: Fifty-five patients underwent imaging with Tc-99m-HDP SPECT/CT (bone scan), dual-isotope WBC/bone marrow scan, and FDG PET/CT. The final diagnosis of prosthetic joint infection (PJI) and/or loosening was based on the intraoperative findings and microbiological culture results and the clinical follow-up.

    Results: The diagnostic performance of dual-isotope WBC/bone marrow SPECT/CT for PJI showed a sensitivity of 100% (CI 0.74-1.00), a specificity of 97% (CI 0.82-1.00), and an accuracy of 98% (CI 0.88-1.00); for PET/CT, the sensitivity, specificity, and accuracy were 100% (CI 0.74-1.00), 71% (CI 0.56-0.90), and 79% (CI 0.68-0.93), respectively.

    Conclusions: In a standardized prospectively scheduled patient group, the results showed highly specific performance of combined dual-isotope WBC/bone marrow SPECT/CT in confirming chronic PJI. FDG PET/CT has an appropriate accuracy, but the utility of its use in the clinical diagnostic algorithm of suspected PJI needs further evidence.

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    FULLTEXT01
  • 38.
    Alemany, Montserrat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Stenborg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Terent, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sonninen, Pirkko
    Röntgenavdelningen, Åbo universitetssjukhus, Åbo, Finland.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Coexistence of microhemorrhages and acute spontaneous brain hemorrhage: correlation with signs of microangiopathy and clinical data2006In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 238, no 1, p. 240-7Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To evaluate prospectively with magnetic resonance (MR) imaging the coexistence of microhemorrhages (MHs) in white patients with acute spontaneous intraparenchymal hemorrhage (IPH) and acute ischemic stroke and to study the association with imaging findings of microangiopathy and various clinical data. MATERIALS AND METHODS: Before examinations, informed consents were signed by either the patient or a relative. The study was carried out with the approval of the local ethics committee. MR imaging was performed in 90 patients with acute stroke: 45 with acute spontaneous IPHs (24 men and 21 women; median age, 65 and 68 years, respectively) and 45 age-matched control subjects without intracranial hemorrhages (26 men and 19 women; median age for both, 67 years), as determined at computed tomography. MR imaging included transverse T1- and T2-weighted spin-echo, transverse fluid-attenuated inversion recovery, transverse and coronal T2*-weighted gradient-echo, and, in 50 patients, diffusion-weighted sequences. Presence of MHs and signs of microangiopathy, such as T2 hyperintensities or lacunae, were recorded in the white and deep gray matter. The relationships between MH and IPH and between MH and T2 hyperintensities were analyzed by means of regression analysis. Different clinical features, such as arterial hypertension or diabetes, were registered and correlated with the image findings by means of regression analysis. RESULTS: MHs were found in 64% of patients with IPH (29 of 45) and 18% of control subjects (eight of 45). A statistically significant relationship between MH and IPH was determined (P < .001). Among the 29 patients with IPH and MH, 24 (83%) had T2 hyperintensities and 13 (45%) had lacunae; among the 16 patients without MH, seven (44%) had T2 hyperintensities and three (19%) had lacunae. A relationship between MH and occurrence and extent of T2 hyperintensities was also identified (P < .001). There was no clear relationship with the clinical data studied. CONCLUSION: The results support a correlation between the presence of imaging signs of cerebral microangiopathy, clinically silent MHs, and acute IPHs. RSNA, 2006.

  • 39.
    Alemany Ripoll, Montserrat
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    MRI Diagnosis of Intracranial Hemorrhage: Experimental and Clinical Studies2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The purpose of this work was to improve the diagnosis of intracranial hemorrhage with MRI, using, among others, T2*-w GE sequences. Various sequences were tested in rabbits at two magnetic field strengths. Then, the most effective technique was applied to stroke patients.

    Experimental studies: The MR detectability of small experimental haematomas in the brain and of blood in the cerebrospinal fluid (CSF) spaces of 30 rabbits was evaluated. MRI examinations were performed at determined intervals. The last MR images were compared to formalin fixed brain sections and, in 16 rabbits, also to the histological findings. T2*-weighted GE sequences revealed all the intraparenchymal haematomas at 1.5 T, appearing strongly hypointense. Their signal patterns remained unchanged during the follow-up. Blood in the CSF spaces was best detected at 1.5T with T2*-weighted GE sequences during the first 2 days. FLAIR and SE sequences were rather insensitive.

    Clinical studies: MR examinations were performed at 1.5T, including T1- and T2-w SE, FLAIR and T2*-w GE sequences. In the first clinical study, 66 intraparenchymal hematomas (IPH) of different sizes and ages were examined. T2*-w GE sequence was the most sensitive. On all the sequences, we found a big variety of signal patterns, without a clear relationship to the age of the hematomas.

    In a second clinical study, MR examinations were performed to 83 patients with acute stroke: 43 presented acute IPH and 40 were used as controls. Old microhemorrhages (OMHs) were found in 60% of the patients with IPH, and in 15% of the controls.

    Conclusion: T2*-weighted GE sequences are capable of revealing very small intraparenchymal hemorrhages at any stage, and blood in CSF spaces during at least the first 2 days. The age of IPHs cannot reliably be estimated with MRI. We have found a correlation between the presence of OMHs and acute intraparenchymal hematomas.

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    FULLTEXT01
  • 40.
    Alhuseinalkhudhur, Ali
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    HER2-receptor quantification in breast cancer patients by imaging with ABY-025 Affibody and PET2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Breast cancer is the most common malignancy in women worldwide. Human epidermal growth factor receptor type 2 (HER2) is overexpressed in up to 20% of breast cancer cases and is considered an important prognostic factor and a therapeutic target. With the introduction of HER2-targeted therapy, it was important to recognize patients who will likely benefit from such treatment. Immunohistochemistry staining performed on a tumor biopsy, with in situ hybridization to detect gene amplification if needed, is the current gold standard method for HER2 receptor quantification. However, in cases with multiple metastases, it is both unfeasible and impractical to perform multiple biopsies without risking higher morbidity. Molecular imaging with tracers specifically targeting HER2 receptors provides a non-invasive approach, which allows full body quantification without the serious side effects associated with invasive biopsies. The molecule of focus in this thesis work is Affibody ZHER2:2891 (ABY-025) molecule that has a high affinity and selectivity towards HER2 receptors.

    This thesis is based on four original articles. The first part focused on the aspect of breast cancer imaging using HER2-targeting gallium-labeled tracer 68Ga-ABY-025 in positron emission tomography (PET) and its role in predicting breast cancer outcome. The second part was to investigate the effect of different risk factors on developing brain metastasis, the overall survival and the effect of HER2-targeted treatment on breast cancer brain metastasis based on Uppsala County cancer registry.

    We demonstrated that HER2-binding Affibody PET kinetics can be explained using a two-tissue compartment model and SUV values correlated well with the influx rates calculated using kinetic modeling, supporting its use to measure actual HER2 receptor binding. Phase II study demonstrated the potential of 68Ga-ABY-025 PET to predict the treatment outcome more accurately compared to biopsy HER2-status that uses the traditional immunohistochemistry staining and in situ hybridization techniques. 68Ga-ABY-025 PET provided accurate staging and reduced false positive 18F-FDG PET results in HER2-positive cases. HER2-positive molecular subtypes were associated with an increased risk of developing brain metastasis. Yet, longer survival times were observed in HER2-positive subtypes receiving HER2-targeted therapy.

    List of papers
    1. Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer
    Open this publication in new window or tab >>Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer
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    2020 (English)In: EJNMMI Research, E-ISSN 2191-219X, Vol. 10, no 1, article id 21Article in journal (Refereed) Published
    Abstract [en]

    Background: High expression of human epidermal growth factor receptor type 2 (HER2) represents an aggressive subtype of breast cancer. Anti-HER2 treatment requires a theragnostic approach wherein sufficiently high receptor expression in biopsy material is mandatory. Heterogeneity and discordance of HER2 expression between primary tumour and metastases, as well as within a lesion, present a complication for the treatment and require multiple biopsies. Molecular imaging using the HER2-targeting Affibody peptide ABY-025 radiolabelled with Ga-68-gallium for PET/CT is currently under investigation as a non-invasive tool for whole-body evaluation of metastatic HER2 expression. Initial studies demonstrated a high correlation between Ga-68-ABY-025 standardized uptake values (SUVs) and histopathology. However, detecting small liver lesions might be compromised by high background uptake. This study aimed to explore the applicability of kinetic modelling and parametric image analysis for absolute quantification of Ga-68-ABY-025 uptake and HER2-receptor expression and how that relates to static SUVs.

    Methods: Dynamic Ga-68-ABY-025 PET of the upper abdomen was performed 0-45 min post-injection in 16 patients with metastatic breast cancer. Five patients underwent two examinations to test reproducibility. Parametric images of tracer delivery (K-1) and irreversible binding (K-i) were created with an irreversible two-tissue compartment model and Patlak graphical analysis using an image-derived input function from the descending aorta. A volume of interest (VOI)-based analysis was performed to validate parametric images. SUVs were calculated from 2 h and 4 h post-injection static whole-body images and compared to K-i.

    Results: Characterization of HER2 expression in smaller liver metastases was improved using parametric images. K-i values from parametric images agreed very well with VOI-based gold standard (R-2 > 0.99, p < 0.001). SUVs of metastases at 2 h and 4 h post-injection were highly correlated with K-i values from both the two-tissue compartment model and Patlak method (R-2 = 0.87 and 0.95, both p < 0.001). Ga-68-ABY-025 PET yielded high test-retest reliability (relative repeatability coefficient for Patlak 30% and for the two-tissue compartment model 47%).

    Conclusion: Ga-68-ABY-025 binding in HER2-positive metastases was well characterized by irreversible two-tissue compartment model wherein K-i highly correlated with SUVs at 2 and 4 h. Dynamic scanning with parametric image formation can be used to evaluate metastatic HER2 expression accurately.

    Place, publisher, year, edition, pages
    SPRINGEROPEN, 2020
    Keywords
    HER2 receptor, Metastatic breast cancer, Affibody, Dynamic PET, Kinetic modelling
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-408918 (URN)10.1186/s13550-020-0603-9 (DOI)000522034700001 ()32201920 (PubMedID)
    Funder
    Swedish Cancer SocietyThe Breast Cancer Foundation
    Available from: 2020-04-17 Created: 2020-04-17 Last updated: 2023-12-14Bibliographically approved
    2. Human Epidermal Growth Factor Receptor 2-Targeting [68Ga]Ga-ABY-025 PET/CT Predicts Early Metabolic Response in Metastatic Breast Cancer.
    Open this publication in new window or tab >>Human Epidermal Growth Factor Receptor 2-Targeting [68Ga]Ga-ABY-025 PET/CT Predicts Early Metabolic Response in Metastatic Breast Cancer.
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    2023 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 64, no 9, p. 1364-1370Article in journal (Refereed) Published
    Abstract [en]

    Imaging using the human epidermal growth factor receptor 2 (HER2)-binding tracer 68Ga-labeled ZHER2:2891-Cys-MMA-DOTA ([68Ga]Ga-ABY-025) was shown to reflect HER2 status determined by immunohistochemistry and in situ hybridization in metastatic breast cancer (MBC). This single-center open-label phase II study investigated how [68Ga]Ga-ABY-025 uptake corresponds to biopsy results and early treatment response in both primary breast cancer (PBC) planned for neoadjuvant chemotherapy and MBC. Methods: Forty patients with known positive HER2 status were included: 19 with PBC and 21 with MBC (median, 3 previous treatments). [68Ga]Ga-ABY-025 PET/CT, [18F]F-FDG PET/CT, and core-needle biopsies from targeted lesions were performed at baseline. [18F]F-FDG PET/CT was repeated after 2 cycles of therapy to calculate the directional change in tumor lesion glycolysis (Δ-TLG). The largest lesions (up to 5) were evaluated in all 3 scans per patient. SUVs from [68Ga]Ga-ABY-025 PET/CT were compared with the biopsied HER2 status and Δ-TLG by receiver operating characteristic analyses. Results: Trial biopsies were HER2-positive in 31 patients, HER2-negative in 6 patients, and borderline HER2-positive in 3 patients. The [68Ga]Ga-ABY-025 PET/CT cutoff SUVmax of 6.0 predicted a Δ-TLG lower than -25% with 86% sensitivity and 67% specificity in soft-tissue lesions (area under the curve, 0.74 [95% CI, 0.67-0.82]; P = 0.01). Compared with the HER2 status, this cutoff resulted in clinically relevant discordant findings in 12 of 40 patients. Metabolic response (Δ-TLG) was more pronounced in PBC (-71% [95% CI, -58% to -83%]; P < 0.0001) than in MBC (-27% [95% CI, -16% to -38%]; P < 0.0001), but [68Ga]Ga-ABY-025 SUVmax was similar in both with a mean SUVmax of 9.8 (95% CI, 6.3-13.3) and 13.9 (95% CI, 10.5-17.2), respectively (P = 0.10). In multivariate analysis, global Δ-TLG was positively associated with the number of previous treatments (P = 0.0004) and negatively associated with [68Ga]Ga-ABY-025 PET/CT SUVmax (P = 0.018) but not with HER2 status (P = 0.09). Conclusion: [68Ga]Ga-ABY-025 PET/CT predicted early metabolic response to HER2-targeted therapy in HER2-positive breast cancer. Metabolic response was attenuated in recurrent disease. [68Ga]Ga-ABY-025 PET/CT appears to provide an estimate of the HER2 expression required to induce tumor metabolic remission by targeted therapies and might be useful as an adjunct diagnostic tool.

    Place, publisher, year, edition, pages
    Society of Nuclear Medicine, 2023
    Keywords
    HER2 positive, PET/CT, [68Ga]Ga-ABY-025, affibody molecules, breast cancer
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-514020 (URN)10.2967/jnumed.122.265364 (DOI)001120138300009 ()37442602 (PubMedID)
    Available from: 2023-10-13 Created: 2023-10-13 Last updated: 2024-01-08Bibliographically approved
    3. 68Ga-ABY-025 PET in HER2-positive breast cancer: assessment of small axillary lesions
    Open this publication in new window or tab >>68Ga-ABY-025 PET in HER2-positive breast cancer: assessment of small axillary lesions
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-517671 (URN)
    Available from: 2023-12-11 Created: 2023-12-11 Last updated: 2023-12-14
    4. Overall survival amongst patients with breast cancer brain metastasis: A cohort study based on Uppsala county cancer registry
    Open this publication in new window or tab >>Overall survival amongst patients with breast cancer brain metastasis: A cohort study based on Uppsala county cancer registry
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-517673 (URN)
    Available from: 2023-12-11 Created: 2023-12-11 Last updated: 2023-12-14
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  • 41.
    Alhuseinalkhudhur, Ali
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sundin, Tora
    Frejd, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Feldwisch, Joachim
    Iyer, Victor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    68Ga-ABY-025 PET in HER2-positive breast cancer: assessment of small axillary lesionsManuscript (preprint) (Other academic)
  • 42.
    Alhuseinalkhudhur, Ali
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sundin, Tora
    Frejd, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hartman, Johan
    Iyer, Victor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Feldwisch, Joachim
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rönnlund, Caroline
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Translational PET Imaging.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Human Epidermal Growth Factor Receptor 2-Targeting [68Ga]Ga-ABY-025 PET/CT Predicts Early Metabolic Response in Metastatic Breast Cancer.2023In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 64, no 9, p. 1364-1370Article in journal (Refereed)
    Abstract [en]

    Imaging using the human epidermal growth factor receptor 2 (HER2)-binding tracer 68Ga-labeled ZHER2:2891-Cys-MMA-DOTA ([68Ga]Ga-ABY-025) was shown to reflect HER2 status determined by immunohistochemistry and in situ hybridization in metastatic breast cancer (MBC). This single-center open-label phase II study investigated how [68Ga]Ga-ABY-025 uptake corresponds to biopsy results and early treatment response in both primary breast cancer (PBC) planned for neoadjuvant chemotherapy and MBC. Methods: Forty patients with known positive HER2 status were included: 19 with PBC and 21 with MBC (median, 3 previous treatments). [68Ga]Ga-ABY-025 PET/CT, [18F]F-FDG PET/CT, and core-needle biopsies from targeted lesions were performed at baseline. [18F]F-FDG PET/CT was repeated after 2 cycles of therapy to calculate the directional change in tumor lesion glycolysis (Δ-TLG). The largest lesions (up to 5) were evaluated in all 3 scans per patient. SUVs from [68Ga]Ga-ABY-025 PET/CT were compared with the biopsied HER2 status and Δ-TLG by receiver operating characteristic analyses. Results: Trial biopsies were HER2-positive in 31 patients, HER2-negative in 6 patients, and borderline HER2-positive in 3 patients. The [68Ga]Ga-ABY-025 PET/CT cutoff SUVmax of 6.0 predicted a Δ-TLG lower than -25% with 86% sensitivity and 67% specificity in soft-tissue lesions (area under the curve, 0.74 [95% CI, 0.67-0.82]; P = 0.01). Compared with the HER2 status, this cutoff resulted in clinically relevant discordant findings in 12 of 40 patients. Metabolic response (Δ-TLG) was more pronounced in PBC (-71% [95% CI, -58% to -83%]; P < 0.0001) than in MBC (-27% [95% CI, -16% to -38%]; P < 0.0001), but [68Ga]Ga-ABY-025 SUVmax was similar in both with a mean SUVmax of 9.8 (95% CI, 6.3-13.3) and 13.9 (95% CI, 10.5-17.2), respectively (P = 0.10). In multivariate analysis, global Δ-TLG was positively associated with the number of previous treatments (P = 0.0004) and negatively associated with [68Ga]Ga-ABY-025 PET/CT SUVmax (P = 0.018) but not with HER2 status (P = 0.09). Conclusion: [68Ga]Ga-ABY-025 PET/CT predicted early metabolic response to HER2-targeted therapy in HER2-positive breast cancer. Metabolic response was attenuated in recurrent disease. [68Ga]Ga-ABY-025 PET/CT appears to provide an estimate of the HER2 expression required to induce tumor metabolic remission by targeted therapies and might be useful as an adjunct diagnostic tool.

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  • 43.
    Alhuseinalkhudhur, Ali
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Res Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk, Russia.
    Frejd, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Affibody AB, Solna, Sweden.
    Feldwisch, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Affibody AB, Solna, Sweden.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kinetic analysis of HER2-binding ABY-025 Affibody molecule using dynamic PET in patients with metastatic breast cancer2020In: EJNMMI Research, E-ISSN 2191-219X, Vol. 10, no 1, article id 21Article in journal (Refereed)
    Abstract [en]

    Background: High expression of human epidermal growth factor receptor type 2 (HER2) represents an aggressive subtype of breast cancer. Anti-HER2 treatment requires a theragnostic approach wherein sufficiently high receptor expression in biopsy material is mandatory. Heterogeneity and discordance of HER2 expression between primary tumour and metastases, as well as within a lesion, present a complication for the treatment and require multiple biopsies. Molecular imaging using the HER2-targeting Affibody peptide ABY-025 radiolabelled with Ga-68-gallium for PET/CT is currently under investigation as a non-invasive tool for whole-body evaluation of metastatic HER2 expression. Initial studies demonstrated a high correlation between Ga-68-ABY-025 standardized uptake values (SUVs) and histopathology. However, detecting small liver lesions might be compromised by high background uptake. This study aimed to explore the applicability of kinetic modelling and parametric image analysis for absolute quantification of Ga-68-ABY-025 uptake and HER2-receptor expression and how that relates to static SUVs.

    Methods: Dynamic Ga-68-ABY-025 PET of the upper abdomen was performed 0-45 min post-injection in 16 patients with metastatic breast cancer. Five patients underwent two examinations to test reproducibility. Parametric images of tracer delivery (K-1) and irreversible binding (K-i) were created with an irreversible two-tissue compartment model and Patlak graphical analysis using an image-derived input function from the descending aorta. A volume of interest (VOI)-based analysis was performed to validate parametric images. SUVs were calculated from 2 h and 4 h post-injection static whole-body images and compared to K-i.

    Results: Characterization of HER2 expression in smaller liver metastases was improved using parametric images. K-i values from parametric images agreed very well with VOI-based gold standard (R-2 > 0.99, p < 0.001). SUVs of metastases at 2 h and 4 h post-injection were highly correlated with K-i values from both the two-tissue compartment model and Patlak method (R-2 = 0.87 and 0.95, both p < 0.001). Ga-68-ABY-025 PET yielded high test-retest reliability (relative repeatability coefficient for Patlak 30% and for the two-tissue compartment model 47%).

    Conclusion: Ga-68-ABY-025 binding in HER2-positive metastases was well characterized by irreversible two-tissue compartment model wherein K-i highly correlated with SUVs at 2 and 4 h. Dynamic scanning with parametric image formation can be used to evaluate metastatic HER2 expression accurately.

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  • 44.
    Alhuseinalkhudhur, Ali
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Frejd, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Feldwisch, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kinetic Analysis of the HER2-binding ABY-025 Affibody Using Dynamic PET in Patients with Metastatic Breast Cancer2018In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, p. S457-S457Article in journal (Other academic)
  • 45.
    Almhagen, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. The Skandion Clinic, Uppsala, Sweden.
    Boersma, David J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. ACMIT Gmbh, A-2700 Wiener Neustadt, Austria.
    Nyström, H.
    Skandion Clin, Uppsala, Sweden;DCPT, Aarhus, Denmark.
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    A beam model for focused proton pencil beams2018In: Physica medica (Testo stampato), ISSN 1120-1797, E-ISSN 1724-191X, Vol. 52, p. 27-32Article in journal (Refereed)
    Abstract [en]

    Introduction: We present a beam model for Monte Carlo simulations of the IBA pencil beam scanning dedicated nozzle installed at the Skandion Clinic. Within the nozzle, apart from entrance and exit windows and the two ion chambers, the beam traverses vacuum, allowing for a beam that is convergent downstream of the nozzle exit. Materials and methods: We model the angular, spatial and energy distributions of the beam phase space at the nozzle exit with single Gaussians, controlled by seven energy dependent parameters. The parameters were determined from measured profiles and depth dose distributions. Verification of the beam model was done by comparing measured and GATE acquired relative dose distributions, using plan specific log files from the machine to specify beam spot positions and energy. Results: GATE-based simulations with the acquired beam model could accurately reproduce the measured data. The gamma index analysis comparing simulated and measured dose distributions resulted in > 95% global gamma index pass rates (3%/2 mm) for all depths. Conclusion: The developed beam model was found to be sufficiently accurate for use with GATE e.g. for applications in quality assurance (QA) or patient motion studies with the IBA pencil beam scanning dedicated nozzles.

  • 46.
    Almqvist, Hakan
    et al.
    Karolinska Inst, Dept Clin Neurosci, S-17176 Solna, Sweden;Karolinska Univ Hosp, Dept Neuroradiol, S-17176 Solna, Sweden.
    Mazya, Michael
    Karolinska Inst, Dept Clin Neurosci, S-17176 Solna, Sweden;Karolinska Univ Hosp, Dept Neurol, Stockholm, Sweden.
    Falk Delgado, Alberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Delgado, Anna Falk
    Karolinska Inst, Dept Clin Neurosci, S-17176 Solna, Sweden;Karolinska Univ Hosp, Dept Neuroradiol, S-17176 Solna, Sweden.
    Radiological evaluation in patients with clinical suspicion of cerebral venous sinus thrombosis presenting with nontraumatic headache-a retrospective observational study with a validation cohort2020In: BMC Medical Imaging, ISSN 1471-2342, E-ISSN 1471-2342, Vol. 20, no 1, article id 24Article in journal (Refereed)
    Abstract [en]

    Background Clinical suspicion of cerebral venous sinus thrombosis (CVST) is imprecise due to non-specific symptoms such as headache. The aim was to retrospectively assess the diagnostic value of nonenhanced CT (neCT) in patients with nontraumatic headache and clinically suspected CVST. Methods A retrospective consecutive series of patients referred 2013-2015 for radiology were evaluated. Eligible patients had nontraumatic headache and suspicion of CVST stated in the referral, investigated with CT venography (CTV) and nonenhanced CT (neCT). neCT scans were re-evaluated for the presence of CVST or other pathology. All CTVs were checked for the presence of CVST. The validation cohort consisted of 10 patients with nontraumatic CVT (2017-2019). Results Less than 1% (1/104) had a suspected thrombus on neCT, confirmed by subsequent CTV. The remaining 99% had a CTV excluding CVST. Eleven percent had other imaging findings explaining their symptoms. In the patient with CVST, the thrombosed dural sinus was high attenuating (maximum HU 89) leading to the suspicion of CVST confirmed by CTV. The validation cohort (n = 10) confirmed the presence of a high attenuating (HU > 65) venous structure in the presence of a confirmed thrombus in all patients presenting within 10 days (suspicion written in referral, 10%). Conclusions Despite clinical suspicion, imaging findings of CVST in nontraumatic headache are uncommon. Evaluating neCT for high attenuation in dural sinuses, followed by CTV for confirmation in selected cases seems reasonable. CVST should be recognized by all radiologists and requires a high level of awareness when reading neCT for other indications.

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  • 47.
    Almqvist Terán, Nicolas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Loayza, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ericson, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Abu Hamdeh, Sami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Svedung-Wettervik, Teodor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    In Reply to the Letter to the Editor Regarding "Posterior Fossa Volume and Dimensions: Relation to Pathophysiology and Surgical Outcomes in Classical Trigeminal Neuralgia"2023In: World Neurosurgery, ISSN 1878-8750, E-ISSN 1878-8769, Vol. 180, article id 268Article in journal (Other academic)
  • 48.
    Almqvist Téran, Nicolas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Loayza, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ericson, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Abu Hamdeh, Sami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Svedung Wettervik, Teodor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Neurosurgery.
    Posterior Fossa Volume and Dimensions: Relation to Pathophysiology and Surgical Outcomes in Classic Trigeminal Neuralgia2023In: World Neurosurgery, ISSN 1878-8750, E-ISSN 1878-8769, Vol. 179, p. e397-e403Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: A small posterior fossa (PF) has been hypothesized to explain the increased incidence of trigeminal neuralgia (TN) in females and could make microvascular decompression (MVD) more challenging. The aim of this study was to investigate the association between the PF volume and dimensions in relation to biological sex, type of neurovascular conflict (NVC), and outcome after MVD in classic TN.

    METHODS: In this observational study, 84 patients with TN operated on with MVD with a preoperative head computed tomography(CT) scan were included. Eighty-two adults without TN who had undergone head CT for other reasons were included as controls. PF volume and dimensions (x-axis, y-axis, and z-axis) were evaluated on the CT scans. For the patients with TN, Barrow Neurological Institute (BNI) grade was evaluated 6 months after MVD.

    RESULTS: There was no difference in PF volume or dimensions between the patients with TN and controls. Women showed a smaller volume and narrower (x-axis) PF than men, but these differences did not manifest when comparing patients with TN and controls within each sex. Patients with an NVC involving the superior cerebellar artery had a narrower (x-axis) and shorter (y-axis) PF than did patients with an NVC resulting from other arteries. PF volume or dimensions were not associated with BNI grade after MVD.

    CONCLUSIONS: PF anatomy was related to the NVC type but did not differ between patients with TN and controls and was not related to the surgical outcome after MVD.

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  • 49.
    Almqvist, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Sjöström, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Jensen, Holger J.
    Danmark.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    In vitro characterization of 211 At-labeled antibody A33: a potential therapeutic agent against metastatic colorectal carcinoma2005In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 20, no 5, p. 514-523Article in journal (Refereed)
    Abstract [en]

    The humanized antibody A33 binds to the A33 antigen, expressed in 95% of primary and metastatic colorectal carcinomas. The restricted pattern of expression in normal tissue makes this antigen a possible target for radioimmunotherapy of colorectal micrometastases. In this study, the A33 antibody was labeled with the therapeutic nuclide 211At using N-succinimidyl para-(tri-methylstannyl)benzoate (SPMB). The in vitro characteristics of the 211At-benzoate-A33 conjugate (211At-A33) were investigated and found to be similar to those of 125I-benzoate-A33 (125I-A33) in different assays. Both conjugates bound with high affinity to SW1222 cells (Kd = 1.7 ± 0.2 nM, and 1.8 ± 0.1 nM for 211At-A33 and 125I-A33, respectively), and both showed good intracellular retention (70% of the radioactivity was still cell associated after 20 hours). The cytotoxic effect of 211At-A33 was also confirmed. After incubation with 211At-A33, SW1222 cells had a survival of approximately 0.3% when exposed to some 150 decays per cell (DPC). The cytotoxic effect was found to be dose-dependent, as cells exposed to only 56 DPC had a survival of approximately 5%. The 211At-A33 conjugate shows promise as a potential radioimmunotherapy agent for treatment of micrometastases originating from colorectal carcinoma.

  • 50.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Rinne, Sara S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Schulga, Alexey
    Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia.
    Deyev, Sergey
    Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia;Natl Res Tomsk Polytech Univ, Tomsk, Russia;Sechenov Univ, Ctr BioMed Engn, Moscow, Russia.
    Vorobyeva, Anzhelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science. Natl Res Tomsk Polytech Univ, Tomsk, Russia.
    On the prevention of kidney uptake of radiolabeled DARPins2020In: EJNMMI Research, E-ISSN 2191-219X, Vol. 10, article id 7Article in journal (Refereed)
    Abstract [en]

    Background: Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins (14-18 kDa) that demonstrated promising tumor-targeting properties in preclinical studies. However, high renal accumulation of activity for DARPins labeled with residualizing labels is a limitation for targeted radionuclide therapy. A better understanding of the mechanisms behind the kidney uptake of DARPins could aid the development of strategies to reduce it. In this study, we have investigated whether the renal uptake of [Tc-99m]Tc(CO)(3)-G3 DARPin could be reduced by administration of compounds that act on various parts of the reabsorption system in the kidney.

    Results: Co-injection of lysine or Gelofusine was not effective for the reduction of kidney uptake of [Tc-99m]Tc(CO)(3)-G3. Administration of sodium maleate before the injection of [Tc-99m]Tc(CO)(3)-G3 reduced the kidney-associated activity by 60.4 +/- 10.3%, while administration of fructose reduced it by 46.9 +/- 7.6% compared with the control. The decrease in the kidney uptake provided by sodium maleate was also observed for [Tc-99m]Tc(CO)(3)-9_29 DARPin. Preinjection of colchicine, probenecid, mannitol, or furosemide had no effect on the kidney uptake of [Tc-99m]Tc(CO)(3)-G3. Kidney autoradiography showed mainly cortical accumulation of activity for all studied groups.

    Conclusion: Common clinical strategies were not effective for the reduction of kidney uptake of [Tc-99m]Tc(CO)(3)-G3. Both fructose and maleate lower the cellular ATP level in the proximal tubule cells and their reduction of the kidney reuptake indicates the involvement of an ATP-driven uptake mechanism. The decrease provided by maleate for both G3 and 9_29 DARPins indicates that their uptake proceeds through a mechanism independent of DARPin structure and binding site composition.

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