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| 2. |
- Aarnio, Mikko, et al.
(author)
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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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Other publication (other academic/artistic)abstract
- 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.
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| 3. |
- Aarnio, Mikko, et al.
(author)
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Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [(11)C]-D-deprenyl PET/CT.
- 2017
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In: Scandinavian Journal of Pain. - : Walter de Gruyter. - 1877-8860 .- 1877-8879. ; 17:1, s. 418-424
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Journal article (peer-reviewed)abstract
- 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.
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| 4. |
- Aarnio, Mikko
(author)
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Visualization of Peripheral Pain Generating Processes and Inflammation in Musculoskeletal Tissue using [11C]-D-deprenyl PET
- 2018
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 5. |
- Aarnio, Mikko, et al.
(author)
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Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl PET/CT
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Other publication (other academic/artistic)abstract
- 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.
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| 6. |
- Aarnio, Mikko, et al.
(author)
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Whiplash injuries associated with experienced pain and disability can be visualized with [11C]-D-deprenyl positron emission tomography and computed tomography
- 2022
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In: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 163:3, s. 489-495
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Journal article (peer-reviewed)abstract
- Knowledge of etiological mechanisms underlying whiplash-associated disorders is incomplete. Localisation and quantification of peripheral musculoskeletal injury and inflammation in whiplash-associated disorders would facilitate diagnosis, strengthen patients' subjective pain reports, and aid clinical decisions, all of which could lead to improved treatment. In this longitudinal observational study, we evaluated combined [11C]-D-deprenyl positron emission tomography and computed tomography after acute whiplash injury and at 6-month follow-up. Sixteen adult patients (mean age 33 years) with whiplash injury grade II were recruited at the emergency department. [11C]-D-deprenyl positron emission tomography and computed tomography, subjective pain levels, self-rated neck disability, and active cervical range of motion were recorded within 7 days after injury and again at 6-month follow-up. Imaging results showed possible tissue injuries after acute whiplash with an altered [11C]-D-deprenyl uptake in the cervical bone structures and facet joints, associated with subjective pain locale and levels, as well as self-rated disability. At follow-up, some patients had recovered and some showed persistent symptoms and reductions in [11C]-D-deprenyl uptake correlated to reductions in pain levels. These findings help identify affected peripheral structures in whiplash injury and strengthen the idea that positron emission tomography and computed tomography detectable organic lesions in peripheral tissue are relevant for the development of persistent pain and disability in whiplash injury.
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| 7. |
- Abouzayed, Ayman, et al.
(author)
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Preclinical Evaluation of 99mTc-Labeled GRPR Antagonists maSSS/SES-PEG2-RM26 for Imaging of Prostate Cancer
- 2021
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In: Pharmaceutics. - : MDPI. - 1999-4923. ; 13:2
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Journal article (peer-reviewed)abstract
- 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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| 8. |
- Adde, Magdalena, 1960-, et al.
(author)
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Little usefullness of mid-treatment FDG-PET and biopsy for treatment intensification in patients with aggressive lymphoma
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Other publication (other academic/artistic)abstract
- Purpose: To evaluate the experiences of introducing mid-treatment FDG-PET in patients with aggressive lymphoma, in a population based program with decentralized examinations, with emphasis on finding patients who would benefit from dose-escalation. Patients and Methods: Twenty-five patients with aggressive lymphoma were included. Twenty-four (95%) of these having an aggressive B-cell lymphoma (84% diffuse large B-cell lymphoma) were treated with CHOP-like treatment given at two week intervals + rituximab. One patient having an anaplastic T-cell lymphoma was treated with CHOEP-14. Mid-treatment FDG-PET was performed and assessed as positive, uncertain or negative for remaining lymphoma. The intention was to perform a biopsy in those with a positive FDG-PET, and, to change to a platina-containing therapy and consolidate with high-dose therapy if viable lymphoma was found. Retrospective review of the PET investigations was done. Living patients were followed for a median of 22 months. Results: At primary analysis five patients (20%) had positive uptake on FDG-PET. Two of them had biopsy-proven viable tumor but did not complete the planned salvage treatment, one due to chemotherapy toxicity and one due to progressive disease during salvage therapy. Two patients had a negative biopsy and one patient had no biopsy due to technical difficulties at diagnosis. These three patients remain in remission after standard treatment. Out of seven patients (28%) having “uncertain” uptake two relapsed. Thirteen patients (52%) were negative,two of whom relapsed giving a negative predictive value of 85%. Conclusion: Mid-treatment FDG PET-CT in order to find patients with biopsy-proven aggressive lymphoma, who can be salvaged with dose escalation, was not feasible in clinical routine.
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| 10. |
- Alhuseinalkhudhur, Ali
(author)
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HER2-receptor quantification in breast cancer patients by imaging with ABY-025 Affibody and PET
- 2024
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Doctoral thesis (other academic/artistic)abstract
- 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.
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