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  • 201.
    Strand, Joanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Nordeman, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Honarvar, Hadis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Larhed, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Site-Specific Radioiodination of HER2-Targeting Affibody Molecules using 4-Iodophenethylmaleimide Decreases Renal Uptake of Radioactivity2015Inngår i: ChemistryOpen, ISSN 2191-1363, Vol. 4, nr 2, s. 174-182Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are small scaffold-based affinity proteins with promising properties as probes for radionuclide-based molecular imaging. However, a high reabsorption of radiolabeled Affibody molecules in kidneys is an issue. We have shown that the use of I-125-3-iodo-((4-hydroxyphenyl)ethyl)maleimide (IHPEM) for site-specific labeling of cysteine-containing Affibody molecules provides high tumor uptake but low radioactivity retention in kidneys. We hypothesized that the use of 4-iodophenethylmaleimide (IPEM) would further reduce renal retention of radioactivity because of higher lipophilicity of radiometabolites. An anti-human epidermal growth factor receptor type2 (HER2) Affibody molecule (Z(HER2:2395)) was labeled using I-125-IPEM with an overall yield of 45 +/- 3%. I-125-IPEM-Z(HER2:2395) bound specifically to HER2-expressing human ovarian carcinoma cells (SKOV-3 cell line). In NMRI mice, the renal uptake of I-125-IPEM-Z(HER2:2395) (24 +/- 2 and 5.7 +/- 0.3%IAg(-1)at 1 and 4 h after injection, respectively) was significantly lower than uptake of I-125-IHPEM-Z(HER2:2395) (50 +/- 8 and 12 +/- 2%IAg(-1)at 1 and 4 h after injection, respectively). In conclusion, the use of a more lipophilic linker for the radioiodination of Affibody molecules reduces renal radioactivity.

  • 202.
    Ståhl, Stefan
    et al.
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Gräslund, Torbjörn
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Karlström, Amelie Eriksson
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Frejd, Fredrik Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Affibody AB, Gunnar Asplunds Alle 24, SE-17169 Solna, Sweden..
    Nygren, Per-Åke
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Löfblom, John
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Affibody Molecules in Biotechnological and Medical Applications2017Inngår i: Trends in Biotechnology, ISSN 0167-7799, E-ISSN 1879-3096, Vol. 35, nr 8, s. 691-712Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are small (6.5-kDa) affinity proteins based on a three-helix bundle domain framework. Since their introduction 20 years ago as an alternative to antibodies for biotechnological applications, the first therapeutic affibody molecules have now entered clinical development and more than 400 studies have been published in which affibody molecules have been developed and used in a variety of contexts. In this review, we focus primarily on efforts over the past 5 years to explore the potential of affibody molecules for medical applications in oncology, neurodegenerative, and inflammation disorders, including molecular imaging, receptor signal blocking, and delivery of toxic payloads. In addition, we describe recent examples of biotechnological applications, in which affibody molecules have been exploited as modular affinity fusion partners.

  • 203.
    Summer, D
    et al.
    Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Oroujeni, Maryam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Andersson, K. G.
    Division of Protein Technology, KTH Royal Institute of Technology, SE-10691 Stockholm, Sweden.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Löfblom, J.n
    Division of Protein Technology, KTH Royal Institute of Technology, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Decristoforo, C
    Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.
    PP15 89Zr-Siderophore-Affibody conjugates for imaging EGFR expression2018Inngår i: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 8, nr S1, artikkel-id 5Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Aim: Zirconium-89 has gained great interest for PET, when imaging at late time points is required. Desferrioxamine B (DFO), is mostly used for this radionuclide as bifunctional chelator (BFC) and we recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study reports on the comparison of FSC and DFO as BFCs for 89Zr labelling of the affibody ZEGFR:2377 targeting Epidermal Growth Factor Receptors (EGFR).

    Methods: FSC-ZEGFR:2377 and DFO-ZEGFR:2377 were evaluated regarding labeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution and microPET-CT imaging.

    Results: Both conjugates showed increased labelling yields at elevated temperature (85°C). Both conjugates revealed remarkable specificity, affinity and slow cell-line dependent internalisation. Labeling at 85°C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake but clear improvement as compared to 89Zr-DFO-ZEGFR:2377, labeled at room temperature, which was confirmed by MicroPET-CT imaging.

    Conclusion: We were able to show that FSC is a suitable alternative to DFO for labeling of biomolecules with zirconium-89. Furthermore our findings indicate that 89Zr- labeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.

  • 204.
    Summer, Dominik
    et al.
    Med Univ Innsbruck, Dept Nucl Med, Anichstr 35, A-6020 Innsbruck, Austria..
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Oroujeni, Maryam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Andersson, Ken G.
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Löfblom, John
    KTH Royal Inst Technol, Div Prot Technol, SE-10691 Stockholm, Sweden..
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Decristoforo, Clemens
    Med Univ Innsbruck, Dept Nucl Med, Anichstr 35, A-6020 Innsbruck, Austria..
    Cyclic versus Noncyclic Chelating Scaffold for Zr-89-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression2018Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, nr 1, s. 175-185Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Zirconium-89 is an emerging radionuclide for positron emission tomography (PET) especially for biomolecules with slow e pharmacokinetics as due to its longer half-life, in comparison to fluorine 18 and gallium-68, imaging at late time points is feasible. Desferrioxamine B (DFO), a linear bifunctional chelator (BFC) is mostly used for this radionuclide so far but shows limitations regarding stability. Our group recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study was designed to compare FSC and DFO head-to head as bifunctional chelators for "Zr-radiolabeled EGFR-targeting ZEGFR:2377 affibody bioconjugates. FSC-ZEGFR:2377 and DFOZEGFR:2377 were evaluated regarding radiolabeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution, and microPET-CT imaging. Both conjugates were efficiently labeled with zirconium-89 at room temperature but radiochemical yields increased substantially at elevated temperature, 85 degrees C. Both 89Zr-FSC-ZEGFR:2377 and Zr-89-DFO-ZEGFR:2377 revealed remarkable specificity, affinity and slow cell-line dependent internalization. Radiolabeling at 85 degrees C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake. In comparison 89ZrDFO-ZEGFR:2377, radiolabeled at room temperature, showed a significant difference regarding tumor-to-organ ratios. MicroPET-CT imaging studies of Zr-89-FSC-ZEGFR:2377 as well as Zr-89-DFO-ZEGFR:2377 confirmed these findings. In summary we were able to show that FSC is a suitable alternative to DFO for radiolabeling of biomolecules with zirconium-89. Furthermore, our findings indicate that Zr-89-radiolabeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.

  • 205.
    Sörensen, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Sandberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Wennborg, Anders
    Feldwisch, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Olofsson, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [(68)Ga]ABY-025 Affibody PET/CT2016Inngår i: Theranostics, ISSN 1838-7640, E-ISSN 1838-7640, Vol. 6, nr 2, s. 262-271Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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

  • 206.
    Sörensen, Jens
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wennborg, Anders
    Feldwisch, Joachim
    Sandberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Olofsson, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Carlsson, Jorgen
    Lindman, Henrik
    Accuracy of [Ga-68]ABY-025 PET/CT for determination of HER2-expression in metastatic breast cancer2015Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 56, nr 3Artikkel i tidsskrift (Annet vitenskapelig)
  • 207.
    Tilly, David
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Probabilistic treatment planning based on dose coverage: How to quantify and minimize the effects of geometric uncertainties in radiotherapy2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Traditionally, uncertainties are handled by expanding the irradiated volume to ensure target dose coverage to a certain probability. The uncertainties arise from e.g. the uncertainty in positioning of the patient at every fraction, organ motion and in defining the region of interests on the acquired images. The applied margins are inherently population based and do not exploit the geometry of the individual patient. Probabilistic planning on the other hand incorporates the uncertainties directly into the treatment optimization and therefore has more degrees of freedom to tailor the dose distribution to the individual patient. The aim of this thesis is to create a framework for probabilistic evaluation and optimization based on the concept of dose coverage probabilities. Several computational challenges for this purpose are addressed in this thesis.

    The accuracy of the fraction by fraction accumulated dose depends directly on the accuracy of the deformable image registration (DIR). Using the simulation framework, we could quantify the requirements on the DIR to 2 mm or less for a 3% uncertainty in the target dose coverage.

    Probabilistic planning is computationally intensive since many hundred treatments must be simulated for sufficient statistical accuracy in the calculated treatment outcome. A fast dose calculation algorithm was developed based on the perturbation of a pre-calculated dose distribution with the local ratio of the simulated treatment’s fluence and the fluence of the pre-calculated dose. A speedup factor of ~1000 compared to full dose calculation was achieved with near identical dose coverage probabilities for a prostate treatment.

    For some body sites, such as the cervix dataset in this work, organ motion must be included for realistic treatment simulation. A statistical shape model (SSM) based on principal component analysis (PCA) provided the samples of deformation. Seven eigenmodes from the PCA was sufficient to model the dosimetric impact of the interfraction deformation.

    A probabilistic optimization method was developed using constructs from risk management of stock portfolios that enabled the dose planner to request a target dose coverage probability. Probabilistic optimization was for the first time applied to dataset from cervical cancer patients where the SSM provided samples of deformation. The average dose coverage probability of all patients in the dataset was within 1% of the requested.

    Delarbeid
    1. Dose mapping sensitivity to deformable registration uncertainties in fractionated radiotherapy – applied to prostate proton treatments
    Åpne denne publikasjonen i ny fane eller vindu >>Dose mapping sensitivity to deformable registration uncertainties in fractionated radiotherapy – applied to prostate proton treatments
    2013 (engelsk)Inngår i: BMC Medical Physics, ISSN 1756-6649, E-ISSN 1756-6649, Vol. 13, nr 2Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background

    Calculation of accumulated dose in fractionated radiotherapy based on spatial mapping of the dose points generally requires deformable image registration (DIR). The accuracy of the accumulated dose thus depends heavily on the DIR quality. This motivates investigations of how the registration uncertainty influences dose planning objectives and treatment outcome predictions.

    A framework was developed where the dose mapping can be associated with a variable known uncertainty to simulate the DIR uncertainties in a clinical workflow. The framework enabled us to study the dependence of dose planning metrics, and the predicted treatment outcome, on the DIR uncertainty. The additional planning margin needed to compensate for the dose mapping uncertainties can also be determined. We applied the simulation framework to a hypofractionated proton treatment of the prostate using two different scanning beam spot sizes to also study the dose mapping sensitivity to penumbra widths.

    Results

    The planning parameter most sensitive to the DIR uncertainty was found to be the targetD95. We found that the registration mean absolute error needs to be ≤0.20 cm to obtain an uncertainty better than 3% of the calculated D95 for intermediate sized penumbras. Use of larger margins in constructing PTV from CTV relaxed the registration uncertainty requirements to the cost of increased dose burdens to the surrounding organs at risk.

    Conclusions

    The DIR uncertainty requirements should be considered in an adaptive radiotherapy workflow since this uncertainty can have significant impact on the accumulated dose. The simulation framework enabled quantification of the accuracy requirement for DIR algorithms to provide satisfactory clinical accuracy in the accumulated dose.

    Emneord
    Radiotherapy; Adaptive radiotherapy; Dose tracking; Dose mapping; Dose accumulation; Dose accumulation accuracy; Deformable image registration; Non-rigid image registration; Protons
    HSV kategori
    Forskningsprogram
    Medicinsk radiofysik
    Identifikatorer
    urn:nbn:se:uu:diva-224059 (URN)10.1186/1756-6649-13-2 (DOI)
    Tilgjengelig fra: 2014-04-30 Laget: 2014-04-30 Sist oppdatert: 2017-12-05bibliografisk kontrollert
    2. Fast dose algorithm for generation of dose coverage probability for robustness analysis of fractionated radiotherapy
    Åpne denne publikasjonen i ny fane eller vindu >>Fast dose algorithm for generation of dose coverage probability for robustness analysis of fractionated radiotherapy
    2015 (engelsk)Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 60, nr 14, s. 5439-5454Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A fast algorithm is constructed to facilitate dose calculation for a large number of randomly sampled treatment scenarios, each representing a possible realisation of a full treatment with geometric, fraction specific displacements for an arbitrary number of fractions. The algorithm is applied to construct a dose volume coverage probability map (DVCM) based on dose calculated for several hundred treatment scenarios to enable the probabilistic evaluation of a treatment plan.For each treatment scenario, the algorithm calculates the total dose by perturbing a pre-calculated dose, separately for the primary and scatter dose components, for the nominal conditions. The ratio of the scenario specific accumulated fluence, and the average fluence for an infinite number of fractions is used to perturb the pre-calculated dose. Irregularities in the accumulated fluence may cause numerical instabilities in the ratio, which is mitigated by regularisation through convolution with a dose pencil kernel.Compared to full dose calculations the algorithm demonstrates a speedup factor of ~1000. The comparisons to full calculations show a 99% gamma index (2%/2 mm) pass rate for a single highly modulated beam in a virtual water phantom subject to setup errors during five fractions. The gamma comparison shows a 100% pass rate in a moving tumour irradiated by a single beam in a lung-like virtual phantom. DVCM iso-probability lines computed with the fast algorithm, and with full dose calculation for each of the fractions, for a hypo-fractionated prostate case treated with rotational arc therapy treatment were almost indistinguishable.

    Emneord
    Radiotherapy dose calculation
    HSV kategori
    Forskningsprogram
    Fysik
    Identifikatorer
    urn:nbn:se:uu:diva-258095 (URN)10.1088/0031-9155/60/14/5439 (DOI)000357620400008 ()26118844 (PubMedID)
    Tilgjengelig fra: 2015-07-10 Laget: 2015-07-10 Sist oppdatert: 2018-01-11bibliografisk kontrollert
    3. Dose coverage calculation using a statistical shape model: applied to cervical cancer radiotherapy
    Åpne denne publikasjonen i ny fane eller vindu >>Dose coverage calculation using a statistical shape model: applied to cervical cancer radiotherapy
    Vise andre…
    2017 (engelsk)Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 62, nr 10, s. 4140-4159Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A comprehensive methodology for treatment simulation and evaluation of dose coverage probabilities is presented where a population based statistical shape model (SSM) provide samples of fraction specific patient geometry deformations.The learning data consists of vector fields from deformable image registration of repeated imaging giving intra-patient deformations which are mapped to an average patient serving as a common frame of reference. The SSM is created by extracting the most dominating eigenmodes through principal component analysis of the deformations from all patients. The sampling of a deformation is thus reduced to sampling weights for enough of the most dominating eigenmodes that describe the deformations.For the cervical cancer patient datasets in this work, we found seven eigenmodes to be sufficient to capture 90% of the variance in the deformations of the, and only three eigenmodes for stability in the simulated dose coverage probabilities. The normality assumption of the eigenmode weights was tested and found relevant for the 20 most dominating eigenmodes except for the first. Individualization of the SSM is demonstrated to be improved using two deformation samples from a new patient. The probabilistic evaluation provided additional information about the trade-offs compared to the conventional single dataset treatment planning.

    Emneord
    Radiotherapy, probabilistic, statistical shape model, principal component analysis, deformable image registration, cervix
    HSV kategori
    Forskningsprogram
    Medicinsk radiofysik
    Identifikatorer
    urn:nbn:se:uu:diva-304979 (URN)10.1088/1361-6560/aa64ef (DOI)000425818300003 ()28266348 (PubMedID)
    Tilgjengelig fra: 2016-10-11 Laget: 2016-10-11 Sist oppdatert: 2018-05-04bibliografisk kontrollert
    4. Probabilistic optimization of the dose coverage – applied to radiotherapy treatment planning of cervical cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Probabilistic optimization of the dose coverage – applied to radiotherapy treatment planning of cervical cancer
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Probabilistic (or robust) optimization is an alternative to margins for handling geometrical uncertainties in treatment planning of radiotherapy where the uncertainties are explicitly incorporated in the optimization through sampling of treatment scenarios. We present a probabilistic method based on statistical measures close to those behind conventional margin based planning. The dose planner requests a dose coverage to a specified probability, which the algorithm then attempts to fulfil.

    We define the Percentile UnderDosage (PUD) as a measure of the target minimum dose coverage probability, i.e. the dose coverage that a treatment plan meet or exceed to a given probability. Margin based planning commonly use the implicit probabilistic treatment criteria that the 90th PUD is at least 95% of the intended dose. For optimization we use the Expected Percentile UnderDosage (EPUD) defined as the average dose coverage below a given PUD. The EPUD is, in contrast to PUD, a convex measure and hence standard optimization techniques can be used to find the optimal treatment plan. We propose an iterative method where a treatment optimization is performed at each iteration and the EPUD tolerance is adjusted gradually until a desired PUD is met.

    We demonstrate our proposed probabilistic planning method for cervical cancer patients. The uncertainty caused by organ deformation is explicitly included in the probabilistic optimization where a statistical shape model is used to sample scenarios with different deformations. For all patients in this work, the iterative process of finding the EPUD tolerance converged in less than 10 iterations to within 0.1Gy of the requested PUD even though a conservative update scheme was used. The resulting estimated PUD was validated based on 1000 simulated scenarios not part of the optimization yielding an agreement within 1.2% of the requested PUD.

    HSV kategori
    Forskningsprogram
    Medicinsk radiofysik
    Identifikatorer
    urn:nbn:se:uu:diva-304982 (URN)
    Tilgjengelig fra: 2016-10-11 Laget: 2016-10-11 Sist oppdatert: 2016-10-11
  • 208.
    Tilly, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Fast dose algorithm for generation of dose coverage probability for robustness analysis of fractionated radiotherapy2015Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 60, nr 14, s. 5439-5454Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A fast algorithm is constructed to facilitate dose calculation for a large number of randomly sampled treatment scenarios, each representing a possible realisation of a full treatment with geometric, fraction specific displacements for an arbitrary number of fractions. The algorithm is applied to construct a dose volume coverage probability map (DVCM) based on dose calculated for several hundred treatment scenarios to enable the probabilistic evaluation of a treatment plan.For each treatment scenario, the algorithm calculates the total dose by perturbing a pre-calculated dose, separately for the primary and scatter dose components, for the nominal conditions. The ratio of the scenario specific accumulated fluence, and the average fluence for an infinite number of fractions is used to perturb the pre-calculated dose. Irregularities in the accumulated fluence may cause numerical instabilities in the ratio, which is mitigated by regularisation through convolution with a dose pencil kernel.Compared to full dose calculations the algorithm demonstrates a speedup factor of ~1000. The comparisons to full calculations show a 99% gamma index (2%/2 mm) pass rate for a single highly modulated beam in a virtual water phantom subject to setup errors during five fractions. The gamma comparison shows a 100% pass rate in a moving tumour irradiated by a single beam in a lung-like virtual phantom. DVCM iso-probability lines computed with the fast algorithm, and with full dose calculation for each of the fractions, for a hypo-fractionated prostate case treated with rotational arc therapy treatment were almost indistinguishable.

  • 209.
    Tilly, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Grusell, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Probabilistic optimization of the dose coverage – applied to radiotherapy treatment planning of cervical cancerManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Probabilistic (or robust) optimization is an alternative to margins for handling geometrical uncertainties in treatment planning of radiotherapy where the uncertainties are explicitly incorporated in the optimization through sampling of treatment scenarios. We present a probabilistic method based on statistical measures close to those behind conventional margin based planning. The dose planner requests a dose coverage to a specified probability, which the algorithm then attempts to fulfil.

    We define the Percentile UnderDosage (PUD) as a measure of the target minimum dose coverage probability, i.e. the dose coverage that a treatment plan meet or exceed to a given probability. Margin based planning commonly use the implicit probabilistic treatment criteria that the 90th PUD is at least 95% of the intended dose. For optimization we use the Expected Percentile UnderDosage (EPUD) defined as the average dose coverage below a given PUD. The EPUD is, in contrast to PUD, a convex measure and hence standard optimization techniques can be used to find the optimal treatment plan. We propose an iterative method where a treatment optimization is performed at each iteration and the EPUD tolerance is adjusted gradually until a desired PUD is met.

    We demonstrate our proposed probabilistic planning method for cervical cancer patients. The uncertainty caused by organ deformation is explicitly included in the probabilistic optimization where a statistical shape model is used to sample scenarios with different deformations. For all patients in this work, the iterative process of finding the EPUD tolerance converged in less than 10 iterations to within 0.1Gy of the requested PUD even though a conservative update scheme was used. The resulting estimated PUD was validated based on 1000 simulated scenarios not part of the optimization yielding an agreement within 1.2% of the requested PUD.

  • 210.
    Tilly, David
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Elekta Instruments AB, Stockholm, Sweden.
    van de Schoot, Agustinus J A J
    Academic Medical Center, Univesity of Amsterdam, Amsterdam, The Netherlands.
    Grusell, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Bel, Arjan
    Academic Medical Center, Univesity of Amsterdam, Amsterdam, The Netherlands.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Dose coverage calculation using a statistical shape model: applied to cervical cancer radiotherapy2017Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 62, nr 10, s. 4140-4159Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A comprehensive methodology for treatment simulation and evaluation of dose coverage probabilities is presented where a population based statistical shape model (SSM) provide samples of fraction specific patient geometry deformations.The learning data consists of vector fields from deformable image registration of repeated imaging giving intra-patient deformations which are mapped to an average patient serving as a common frame of reference. The SSM is created by extracting the most dominating eigenmodes through principal component analysis of the deformations from all patients. The sampling of a deformation is thus reduced to sampling weights for enough of the most dominating eigenmodes that describe the deformations.For the cervical cancer patient datasets in this work, we found seven eigenmodes to be sufficient to capture 90% of the variance in the deformations of the, and only three eigenmodes for stability in the simulated dose coverage probabilities. The normality assumption of the eigenmode weights was tested and found relevant for the 20 most dominating eigenmodes except for the first. Individualization of the SSM is demonstrated to be improved using two deformation samples from a new patient. The probabilistic evaluation provided additional information about the trade-offs compared to the conventional single dataset treatment planning.

  • 211.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Grönroos, Tove J
    Turku PET Centre, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland; Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland.
    Yim, Cheng-Bin
    Turku PET Centre, University of Turku, Turku, Finland; Turku PET Centre, Åbo Akademi University, Turku, Finland.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Yue, Ying
    Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.
    Grimm, Sebastian
    Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.
    Rajander, Johan
    Turku PET Centre, Åbo Akademi University, Turku, Finland.
    Perols, Anna
    Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.
    Haaparanta-Solin, Merja
    Turku PET Centre, University of Turku, Turku, Finland; Department of Chemistry, University of Turku, Turku, Finland.
    Solin, Olof
    Turku PET Centre, University of Turku, Turku, Finland; Turku PET Centre, Åbo Akademi University, Turku, Finland; Department of Chemistry, University of Turku, Turku, Finland.
    Ferdani, Riccardo
    Washington University, St. Louis, MO, USA.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Anderson, Carolyn J
    Departments of Medicine, Radiology, Bioengineering and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15203, USA.
    Karlström, Amelie Eriksson
    Department of Protein Science, KTH Royal Institute of Technology, Stockholm, Sweden.
    Molecular design of radiocopper-labelled Affibody molecules2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, nr 1, artikkel-id 6542Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cu-CB-TE2A-GEEE-ZHER2:342 was 16 ± 6%ID/g and tumor-to-blood ratio was 181 ± 52. In conclusion, a combination of the cross-bridged CB-TE2A chelator and Gly-Glu-Glu-Glu spacer is preferable for radiocopper labelling of Affibody molecules and, possibly, other scaffold proteins having high renal re-absorption.

  • 212.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Yim, C.
    Turku PET Ctr, Turku, Finland.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Yue, Y.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Grimm, S.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Rajander, J.
    Turku PET Ctr, Turku, Finland.
    Perols, A.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Haaparanta-Solin, M.
    Turku PET Ctr, Turku, Finland.
    Grönroos, T. J.
    Turku PET Ctr, Turku, Finland.
    Solin, O.
    Turku PET Ctr, Turku, Finland.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Anderson, C.
    Univ Pittsburgh, Pittsburgh, PA USA.
    Karlström, A. Eriksson
    KTH Royal Inst Technol, Stockholm, Sweden.
    Optimal molecular design of radiocopper-labelled affibody molecules2017Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, s. S549-S549Artikkel i tidsskrift (Annet vitenskapelig)
  • 213.
    Tolmachev, Vladimir
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Yim, Cheng-Bin
    Univ Turku, Turku PET Ctr, POB 52, Turku 20521, Finland.;Abo Akad Univ, Turku PET Ctr, POB 52, Turku 20521, Finland..
    Rajander, Johan
    Abo Akad Univ, Turku PET Ctr, POB 52, Turku 20521, Finland..
    Perols, Anna
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, S-10691 Stockholm, Sweden..
    Karlstrom, Amelie Eriksson
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, S-10691 Stockholm, Sweden..
    Haaparanta-Solin, Merja
    Univ Turku, Turku PET Ctr, POB 52, Turku 20521, Finland.;Univ Turku, MediC Res Lab, FIN-20520 Turku, Finland..
    Gronroos, Tove J.
    Univ Turku, Turku PET Ctr, POB 52, Turku 20521, Finland.;Univ Turku, MediC Res Lab, FIN-20520 Turku, Finland.;Turku Univ Hosp, Dept Oncol & Radiotherapy, FIN-20520 Turku, Finland..
    Solin, Olof
    Univ Turku, Turku PET Ctr, POB 52, Turku 20521, Finland.;Abo Akad Univ, Turku PET Ctr, POB 52, Turku 20521, Finland.;Univ Turku, Dept Chem, Turku 20014, Finland..
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Comparative Evaluation of Anti-HER2 Affibody Molecules Labeled with Cu-64 Using NOTA and NODAGA2017Inngår i: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, s. 1-12Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Imaging using affi body molecules enables discrimination between breast cancer metastases with high and low expression of HER2, making appropriate therapy selection possible. This study aimed to evaluate if the longer half-life of Cu-64 (T-1/2 = 12.7h) would make Cu-64 a superior nuclide compared to Ga-68 for PET imaging of HER2 expression using affibody molecules. The synthetic ZHER2: S1 affibody molecule was conjugated with the chelators NOTA or NODAGA and labeled with Cu-64. The tumor-targeting properties of Cu-64-NOTA-ZHER2: S1 and Cu-64-NODAGA-ZHER2: S1 were evaluated and compared with the targeting properties of Ga-68-NODAGA-ZHER2: S1 in mice. Both 64 Cu-NOTA-ZHER2: S1 and Cu-64-NODAGA-ZHER2: S1 demonstrated specific targeting of HER2-expressing xenografts. At 2 h after injection of Cu-64-NOTA-ZHER2: S1, Cu-64-NODAGA-ZHER2: S1, and Ga-68-NODAGAZHER2: S1, tumor uptakes did not differ significantly. Renal uptake of Cu-64-labeled conjugateswas dramatically reduced at 6 and 24 h after injection. Notably, radioactivity uptake concomitantly increased in blood, lung, liver, spleen, and intestines, which resulted in decreased tumor-to-organ ratios compared to 2 h postinjection. Organ uptake was lower for Cu-64-NODAGA-ZHER2: S1. The most probable explanation for this biodistribution pattern was the release and redistribution of renal radiometabolites. In conclusion, monoamide derivatives of NOTA and NODAGA may be suboptimal chelators for radiocopper labeling of anti-HER2 affibody molecules and, possibly, other scaffold proteins with high renal uptake.

  • 214.
    Trotter, Dinko E. Gonzalez
    et al.
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    Meng, Xiangjun
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    McQuade, Paul
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    Rubins, Daniel
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    Klimas, Michael
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    Zeng, Zhizhen
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    Connolly, Brett M.
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    Miller, Patricia J.
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    O'Malley, Stacey S.
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    Lin, Shu-An
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    Getty, Krista L.
    Merck & Co Inc, Screening & Prot Sci Dept, West Point, PA 19486 USA..
    Fayadat-Dilman, Laurence
    Merck & Co Inc, Biol Discovery, Palo Alto, CA USA..
    Liang, Linda
    Merck & Co Inc, Biol Discovery, Palo Alto, CA USA..
    Wahlberg, Elisabet
    Affibody AB, Solna, Sweden..
    Widmark, Olof
    Affibody AB, Solna, Sweden..
    Ekblad, Caroline
    Affibody AB, Solna, Sweden..
    Frejd, Fredrik Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Affibody AB, Solna, Sweden.
    Hostetler, Eric D.
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    Evelhoch, Jeffrey L.
    Merck & Co Inc, Translat Biomarkers Dept, West Point, PA 19486 USA..
    In Vivo Imaging of the Programmed Death Ligand 1 by F-18 PET2017Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 58, nr 11, s. 1852-1857Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Programmed death ligand 1 (PD-L1) is an immune regulatory ligand that binds to the T-cell immune check point programmed death 1. Tumor expression of PD-L1 is correlated with immune suppression and poor prognosis. It is also correlated with therapeutic efficacy of programmed death 1 and PD-L1 inhibitors. In vivo imaging may enable real-time follow-up of changing PD-L1 expression and heterogeneity evaluation of PD-L1 expression across tumors in the same subject. We have radiolabeled the PD-L1-binding Affibody molecule NOTA-Z(PD-L1_1) with F-18 and evaluated its in vitro and in vivo binding affinity, targeting, and specificity. Methods: The affinity of the PD-L1-binding Affibody ligand Z(PD-L1_1) was evaluated by surface plasmon resonance. Labeling was accomplished by maleimide coupling of NOTA to a unique cysteine residue and chelation of F-18-AlF. In vivo studies were performed in PD-L1-positive, PD-L1-negative, and mixed tumor-bearing severe combined immunodeficiency mice. Tracer was injected via the tail vein, and dynamic PET scans were acquired for 90 min, followed by gamma-counting biodistribution. Immunohistochemical staining with an antibody specific for anti-PD-L1 (22C3) was used to evaluate the tumor distribution of PD-L1. Immunohistochemistry results were then compared with ex vivo autoradiographic images obtained from adjacent tissue sections. Results: NOTA-Z(PD-L1_1) was labeled, with a radiochemical yield of 15.1% +/- 5.6%, radiochemical purity of 96.7% +/- 2.0%, and specific activity of 14.6 +/- 6.5 GBq/mu mol. Surface plasmon resonance showed a NOTA-conjugated ligand binding affinity of 1 nM. PET imaging demonstrated rapid uptake of tracer in the PD-L1-positive tumor, whereas the PD-L1-negative control tumor showed little tracer retention. Tracer clearance from most organs and blood was quick, with biodistribution showing prominent kidney retention, low liver uptake, and a significant difference between PD-L1-positive (percentage injected dose per gram [%ID/g] = 2.56 +/- 0.33) and -negative (% ID/g = 0.32 +/- 0.05) tumors (P = 0.0006). Ex vivo autoradiography showed excellent spatial correlation with immunohistochemistry in mixed tumors. Conclusion: Our results show that Affibody ligands can be effective at targeting tumor PD-L1 in vivo, with good specificity and rapid clearance. Future studies will explore methods to reduce kidney activity retention and further increase tumor uptake.

  • 215.
    Varasteh, Zohreh
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosenström, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Velikyan, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Rosestedt, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Lindeberg, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Larhed, Mats
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    The effect of macrocyclic chelators on the targeting properties of the 68Ga-labeled gastrin releasing peptide receptor antagonist PEG2-RM262015Inngår i: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 42, nr 5, s. 446-454Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction

    Overexpression of gastrin-releasing peptide receptors (GRPR) has been reported in several cancers. Bombesin (BN) analogs are short peptides with a high affinity for GRPR. Different BN analogs were evaluated for radionuclide imaging and therapy of GRPR-expressing tumors. We have previously investigated an antagonistic analog of BN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to NOTA via a PEG2 spacer (NOTA-PEG2-RM26) labeled with 68Ga, 111In and Al18F. 68Ga-labeled NOTA-PEG2-RM26 showed high tumor-to-organ ratios.

    Methods

    The influence of different macrocyclic chelators (NOTA, NODAGA, DOTA and DOTAGA) on the targeting properties of 68Ga-labeled PEG2-RM26 was studied in vitro and in vivo.

    Results

    All conjugates were labeled with generator-produced 68Ga with high yields and demonstrated high stability and specific binding to GRPR. The IC50 values of natGa-X-PEG2-RM26 (X = NOTA, DOTA, NODAGA, DOTAGA) were 2.3 ± 0.2, 3.0 ± 0.3, 2.9 ± 0.3 and 10.0 ± 0.6 nM, respectively. The internalization of the conjugates by PC-3 cells was low. However, the DOTA-conjugated analog demonstrated a higher internalization rate compared to other analogs. GRPR-specific uptake was found in receptor-positive normal tissues and PC-3 xenografts for all conjugates. The biodistribution of the conjugates was influenced by the choice of the chelator moiety. Although all radiotracers cleared rapidly from the blood, [68Ga]Ga-NOTA-PEG2-RM26 showed significantly lower uptake in lung, muscle and bone compared to the other analogs. The uptake in tumors (5.40 ± 1.04 %ID/g at 2 h p.i.) and the tumor-to-organ ratios (25 ± 3, 157 ± 23 and 39 ± 4 for blood, muscle and bone, respectively) were significantly higher for the NOTA-conjugate than the other analogs.

    Conclusions

    Chelators had a clear influence on the biodistribution and targeting properties of 68Ga-labeled antagonistic BN analogs. Positively charged [68Ga]Ga-NOTA-PEG2-RM26 provided a low kidney radioactivity uptake, high affinity, high tumor uptake and high image contrast.

  • 216.
    Velikyan, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Schweighoefer, Philip
    Eckert & Ziegler Eurotope GmbH, Berlin, Germany.
    Feldwisch, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Affibody AB, Solna, Sweden.
    Seemann, Johanna
    Eckert & Ziegler Eurotope GmbH, Berlin, Germany.
    Frejd, Fredrik Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Affibody AB, Solna, Sweden.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Diagnostic HER2-binding radiopharmaceutical, [Ga-68]Ga-ABY-025, for routine clinical use in breast cancer patients2019Inngår i: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 9, nr 1, s. 12-23Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 217.
    Velikyan, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wennborg, Anders
    Affibody AB, Solna.
    Feldwisch, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Affibody AB, Solna.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Good manufacturing practice production of [68Ga]Ga-ABY-025 for HER2 specific breast cancer imaging.2016Inngår i: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 6, nr 2, s. 135-153Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 218.
    Velikyan, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Wennborg, Anders
    Affibody AB, Solna, Sweden..
    Feldwisch, Joachim
    Affibody AB, Solna, Sweden..
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Good manufacturing practice compliant production of a Ga-68-labelled Affibody agent for breast cancer imaging: first-in-human2015Inngår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, s. S358-S358Artikkel i tidsskrift (Annet vitenskapelig)
  • 219.
    Villegas, Fernanda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Bäckström, Gloria
    Tilly, Nina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Energy deposition clustering as a functional radiation quality descriptor for modelling relative biological effectiveness2016Inngår i: Medical physics (Lancaster), ISSN 0094-2405, Vol. 43, nr 12, s. 6322-6335Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To explore the use of the frequency of the energy deposition (ED) clusters of different sizes (cluster order, CO) as a surrogate (instead of, e.g., LET) classification of the physical characteristics of ionizing radiation at a nanometer scale, to construct a framework for the calculation of relative biological effectiveness (RBE) with cell survival as endpoint.

    Methods: The frequency of cluster order f(CO) is calculated by sorting the ED sites generated with the Monte Carlo track structure code LIonTrack into clusters based on a single parameter called the cluster distance d(C) being the maximum allowed distance between two neighboring EDs belonging to a cluster. Published cell survival data parameterized with the linear-quadratic (LQ) model for V79 cells exposed to 15 different radiation qualities (including brachytherapy sources, proton, and carbon ions) were used as input to a fitting procedure, designed to determine a weighting function w(CO) that describes the capacity of a cluster of a certain CO to damage the cell's sensitive volume. The proposed framework uses both f(CO) and w(CO) to construct surrogate based functions for the LQ parameters a and beta from which RBE values can be derived.

    Results: The results demonstrate that radiation quality independent weights w(CO) exist for both the a and beta parameters. This enables the calculation of a values that correlate to their experimental counterparts within experimental uncertainties (relative residual of 15% for d(C) = 2.5 nm). The combination of both a and beta surrogate based functions, despite the higher relative residuals for beta values, yielded an RBE function that correlated to experimentally derived RBE values (relative residual of 16.5% for d(C) = 2.5 nm) for all radiation qualities included in this work.

    Conclusions: The f(CO) cluster characterization of ionizing radiation at a nanometer scale can effectively be used to calculate particle and energy dependent a and beta values to predict RBE values with potential applications to, e.g., treatment planning systems in radiotherapy. (C) 2016 American Association of Physicists in Medicine.

  • 220.
    Villegas, Fernanda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tilly, Nina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Elekta Instrument AB.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Target size variation in microdosimetric distributions and its impact on the linear-quadratic parameterization of cell survival.2018Inngår i: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 190, s. 504-512Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The linear-quadratic (LQ) parameterization of survival fraction SF(D) inherently assumes that all cells in a population get the same dose D, albeit the distribution of specific energy z over the individual cells f(z,D) can be very wide. From these microdosimetric distributions, which are target size dependent, we estimate the size of the cellular sensitive volume by analysing its influence on the LQ parameterization of cell survival. A Monte Carlo track structure code was used to simulate detailed tracks from a 60Co source as well as proton and carbon ions of various energies. From these tracks, f(z,D) distributions were calculated for spherical targets with diameters ranging from 10 nm to 12 µm. A cell survival function based on f(z,D) was fitted to published experimental LQ α values, revealing an intrinsic limitation that target size imposes on the usage of f(z,D) to describe the linear term of the LQ parameterization. The results indicate that such threshold volume arises naturally from the relationship between the particle´s probability of no-hit and the probability of cell survival. Further analysis led to the proposal of a radiobiological property yf,MID, defined as the mean lineal energy corresponding to the target size that allows equivalence between the mean inactivation dose (MID) and the mean specific energy z1.  The fact that z1 is an increasing continuous function of target size within the range of biological targets of interest in radiobiology, ensures the uniqueness of yf,MID for any radiation quality, thus, its potential usefulness in modelling. In conclusion, an accurate estimation of such threshold volumes may be useful for improving modelling of cell survival curves.

  • 221.
    Villegas, Fernanda
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tilly, Nina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för medicinsk strålfysik. Elekta Instrument AB, Box7593, SE-10393 Stockholm, Sweden.
    Bäckström, Gloria
    McGill Univ, Dept Oncol, Med Phys Unit, Montreal, PQ, Canada; McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ, Canada.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Corrigendum to ’Cluster pattern analysis of energy deposition sites for the brachytherapy sources 103Pd,125I,192Ir,137Cs and 60Co’, PMB 59 (2014) 5531-432016Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 61, nr 15, s. 5883-5886Artikkel i tidsskrift (Fagfellevurdert)
  • 222.
    Villegas Navarro, Fernanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Micro/nanometric Scale Study of Energy Deposition and its Impact on the Biological Response for Ionizing Radiation: Brachytherapy radionuclides, proton and carbon ion beams2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Research in radiotherapy for cancer treatment focuses on finding methods that can improve the compromise between tumour cell inactivation versus damage to the surrounding healthy tissue. As new radiation modalities such as proton therapy become accessible for everyday clinical practice, a better understanding of the variation in biological response of the tumour and healthy tissues would improve treatment planning to achieve optimal outcome. The development of radiobiological models capable of accurate predictions of biological effectiveness is needed.

    Existing radiation quality descriptors such as absorbed dose and LET are insufficient to explain variation in biological effectiveness for different treatment modalities. The stochastic nature of ionizing radiation creates discrete patterns of energy deposition (ED) sites which can now be analysed through sophisticated computer simulations (e.g. Monte Carlo track structure codes). This opens the possibility to develop a nanometre characterization of radiation quality based on the spatial cluster patterns of ED.

    The aim of this thesis is to investigate the track structure (ED spatial pattern) properties of several radiation qualities at a micro- and nanometric scale while exploring their influence in biological response through correlations with published experimental data. This work uses track structure data simulated for a set of 15 different radiation qualities: 4 commonly used brachytherapy sources, 6 different proton energies, 4 different carbon ion energies, and 60Co photons used as reference radiation for quantification of biological effectiveness.

    At a micrometre level, the behaviour of the microdosimetric spread in energy deposition for target sizes of the order of cell nuclei was analysed. The degree of the influence it had in the biological response was found to be negligible for photon sources but for protons and carbon ions the impact increased with decreasing particle energy suggesting it may be a confounding factor in biological response.

    Finally, this thesis outlines a framework for modelling the relative biological effectiveness based on the frequency distribution of cluster order as a surrogate for the nanometre classification for the physical properties of radiation quality. The results indicate that this frequency is a valuable descriptor of ionizing radiation. The positive correlation across the different types of ionizing radiation encourages further development of the framework by incorporating the behavior of the microdosimetric spread and expanding tests to other experimental datasets.

    Delarbeid
    1. Monte Carlo calculated microdosimetric spread for cell nucleus-sized targets exposed to brachytherapy 125I and 192Ir sources and 60Co cell irradiation
    Åpne denne publikasjonen i ny fane eller vindu >>Monte Carlo calculated microdosimetric spread for cell nucleus-sized targets exposed to brachytherapy 125I and 192Ir sources and 60Co cell irradiation
    2013 (engelsk)Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 58, nr 17, s. 6149-6162Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The stochastic nature of ionizing radiation interactions causes a microdosimetric spread in energy depositions for cell or cell nucleus-sized volumes. The magnitude of the spread may be a confounding factor in dose response analysis. The aim of this work is to give values for the microdosimetric spread for a range of doses imparted by 125I and 192Ir brachytherapy radionuclides, and for a 60Co source. An upgraded version of the Monte Carlo code PENELOPE was used to obtain frequency distributions of specific energy for each of these radiation qualities and for four different cell nucleus-sized volumes. The results demonstrate that the magnitude of the microdosimetric spread increases when the target size decreases or when the energy of the radiation quality is reduced. Frequency distributions calculated according to the formalism of Kellerer and Chmelevsky using full convolution of the Monte Carlo calculated single track frequency distributions confirm that at doses exceeding 0.08 Gy for 125I, 0.1 Gy for 192Ir, and 0.2 Gy for 60Co, the resulting distribution can be accurately approximated with a normal distribution. A parameterization of the width of the distribution as a function of dose and target volume of interest is presented as a convenient form for the use in response modelling or similar contexts.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-208046 (URN)10.1088/0031-9155/58/17/6149 (DOI)000323517700024 ()
    Forskningsfinansiär
    Swedish National Infrastructure for Computing (SNIC), p2011144
    Tilgjengelig fra: 2013-09-24 Laget: 2013-09-23 Sist oppdatert: 2017-12-06
    2. Reply to the comment on ‘Monte Carlo calculated microdosimetric spread for cell nucleus-sized targets exposed to brachytherapy 125I and 192Ir sources and 60Co cell irradiation’
    Åpne denne publikasjonen i ny fane eller vindu >>Reply to the comment on ‘Monte Carlo calculated microdosimetric spread for cell nucleus-sized targets exposed to brachytherapy 125I and 192Ir sources and 60Co cell irradiation’
    2016 (engelsk)Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 61, nr 13, s. 5103-5106Artikkel i tidsskrift, Editorial material (Fagfellevurdert) Published
    Abstract [en]

    A discrepancy between the Monte Carlo derived relative standard deviation sigma(rel)(z) (microdosimetric spread) and experimental data was reported by Villegas et al (2013 Phys. Med. Biol. 58 6149-62) suggesting wall effects as a plausible explanation. The comment by Lindborg et al (2015 Phys. Med. Biol. 60 8621-4) concludes that this is not a likely explanation. A thorough investigation of the Monte Carlo (MC) transport code used for track simulation revealed a critical bug. The corrected MC version yielded sigma(rel)(z) values that are now within experimental uncertainty. Other microdosimetric findings are hereby communicated.

    HSV kategori
    Forskningsprogram
    Medicinsk radiofysik
    Identifikatorer
    urn:nbn:se:uu:diva-279243 (URN)10.1088/0031-9155/61/13/5103 (DOI)000378094000023 ()
    Forskningsfinansiär
    Swedish National Infrastructure for Computing (SNIC), p2011144
    Tilgjengelig fra: 2016-02-29 Laget: 2016-02-29 Sist oppdatert: 2017-11-30bibliografisk kontrollert
    3. Microdosimetric spread for cell-sized targets exposed to 60Co, 192Ir and 125I sources
    Åpne denne publikasjonen i ny fane eller vindu >>Microdosimetric spread for cell-sized targets exposed to 60Co, 192Ir and 125I sources
    2015 (engelsk)Inngår i: Radiation Protection Dosimetry, ISSN 0144-8420, E-ISSN 1742-3406, Vol. 166, nr 1-4, s. 365-368Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The magnitude of the spread in specific energy deposition per cell may be a confounding factor in dose–response analysis motivating derivation of explicit data for the most common brachytherapy isotopes 125I and 192Ir, and for 60Co radiation frequently used as reference in RBE studies. The aim of this study is to analyse the microdosimetric spread as given by the frequency distribution of specific energy for a range of doses imparted by 125I, 192Ir and 60Co sources. An upgraded version of the Monte Carlo code PENELOPE was used for scoring energy deposition distributions in liquid water for each of the radiation qualities. Frequency distributions of specific energy were calculated according to the formalism of Kellerer and Chmelevsky. Results indicate that the magnitude of the microdosimetric spread increases with decreasing target size and decreasing energy of the radiation quality. Within the clinical relevant dose range (1 to 100 Gy), the spread does not exceed 4 % for 60Co, 5 % for 192Ir and 6 % for 125I. The frequency distributions can be accurately approximated with symmetrical normal distributions at doses down to 0.2 Gy for 60Co, 0.1 Gy for 192Ir and 0.08 Gy for 125I.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-259745 (URN)10.1093/rpd/ncv200 (DOI)000361806600075 ()
    Forskningsfinansiär
    Swedish National Infrastructure for Computing (SNIC), p2011144
    Tilgjengelig fra: 2015-08-11 Laget: 2015-08-11 Sist oppdatert: 2017-12-04
    4. Cluster pattern analysis of energy deposition sites for the brachytherapy sources 103Pd, 125I, 192Ir, 137Cs, and 60Co
    Åpne denne publikasjonen i ny fane eller vindu >>Cluster pattern analysis of energy deposition sites for the brachytherapy sources 103Pd, 125I, 192Ir, 137Cs, and 60Co
    2014 (engelsk)Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 59, nr 18, s. 5531-5543Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Analysing the pattern of energy depositions may help elucidate differences in the severity of radiation-induced DNA strand breakage for different radiation qualities. It is often claimed that energy deposition (ED) sites from photon radiation form a uniform random pattern, but there is indication of differences in RBE values among different photon sources used in brachytherapy. The aim of this work is to analyse the spatial patterns of EDs from 103Pd, 125I, 192Ir, 137Cs sources commonly used in brachytherapy and a 60Co source as a reference radiation. The results suggest that there is both a non-uniform and a uniform random component to the frequency distribution of distances to the nearest neighbour ED. The closest neighbouring EDs show high spatial correlation for all investigated radiation qualities, whilst the uniform random component dominates for neighbours with longer distances for the three higher mean photon energy sources (192Ir, 137Cs, and 60Co). The two lower energy photon emitters (103Pd and 125I) present a very small uniform random component. The ratio of frequencies of clusters with respect to 60Co differs up to 15% for the lower energy sources and less than 2% for the higher energy sources when the maximum distance between each pair of EDs is 2 nm. At distances relevant to DNA damage, cluster patterns can be differentiated between the lower and higher energy sources. This may be part of the explanation to the reported difference in RBE values with initial DSB yields as an endpoint for these brachytherapy sources.

    Emneord
    clusters, energy deposition sites, brachytherapy
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-235065 (URN)10.1088/0031-9155/59/18/5531 (DOI)000341381900022 ()25170775 (PubMedID)
    Forskningsfinansiär
    Swedish National Infrastructure for Computing (SNIC), p2011144
    Tilgjengelig fra: 2014-10-29 Laget: 2014-10-28 Sist oppdatert: 2017-12-05
    5. Corrigendum to ’Cluster pattern analysis of energy deposition sites for the brachytherapy sources 103Pd,125I,192Ir,137Cs and 60Co’, PMB 59 (2014) 5531-43
    Åpne denne publikasjonen i ny fane eller vindu >>Corrigendum to ’Cluster pattern analysis of energy deposition sites for the brachytherapy sources 103Pd,125I,192Ir,137Cs and 60Co’, PMB 59 (2014) 5531-43
    2016 (engelsk)Inngår i: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 61, nr 15, s. 5883-5886Artikkel i tidsskrift (Fagfellevurdert) Published
    HSV kategori
    Forskningsprogram
    Medicinsk radiofysik
    Identifikatorer
    urn:nbn:se:uu:diva-279246 (URN)10.1088/0031-9155/61/15/5883 (DOI)000384207500025 ()
    Forskningsfinansiär
    Swedish National Infrastructure for Computing (SNIC), p2011144
    Tilgjengelig fra: 2016-02-29 Laget: 2016-02-29 Sist oppdatert: 2017-11-30bibliografisk kontrollert
    6. Target size variation in microdosimetric distributions and its impact on the linear-quadratic parameterization of cell survival.
    Åpne denne publikasjonen i ny fane eller vindu >>Target size variation in microdosimetric distributions and its impact on the linear-quadratic parameterization of cell survival.
    2018 (engelsk)Inngår i: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 190, s. 504-512Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The linear-quadratic (LQ) parameterization of survival fraction SF(D) inherently assumes that all cells in a population get the same dose D, albeit the distribution of specific energy z over the individual cells f(z,D) can be very wide. From these microdosimetric distributions, which are target size dependent, we estimate the size of the cellular sensitive volume by analysing its influence on the LQ parameterization of cell survival. A Monte Carlo track structure code was used to simulate detailed tracks from a 60Co source as well as proton and carbon ions of various energies. From these tracks, f(z,D) distributions were calculated for spherical targets with diameters ranging from 10 nm to 12 µm. A cell survival function based on f(z,D) was fitted to published experimental LQ α values, revealing an intrinsic limitation that target size imposes on the usage of f(z,D) to describe the linear term of the LQ parameterization. The results indicate that such threshold volume arises naturally from the relationship between the particle´s probability of no-hit and the probability of cell survival. Further analysis led to the proposal of a radiobiological property yf,MID, defined as the mean lineal energy corresponding to the target size that allows equivalence between the mean inactivation dose (MID) and the mean specific energy z1.  The fact that z1 is an increasing continuous function of target size within the range of biological targets of interest in radiobiology, ensures the uniqueness of yf,MID for any radiation quality, thus, its potential usefulness in modelling. In conclusion, an accurate estimation of such threshold volumes may be useful for improving modelling of cell survival curves.

    HSV kategori
    Forskningsprogram
    Medicinsk radiofysik
    Identifikatorer
    urn:nbn:se:uu:diva-279210 (URN)10.1667/RR15089.1 (DOI)000452084900006 ()
    Forskningsfinansiär
    Swedish National Infrastructure for Computing (SNIC), p2011144
    Tilgjengelig fra: 2016-02-29 Laget: 2016-02-29 Sist oppdatert: 2019-01-21bibliografisk kontrollert
    7. Energy deposition clustering as a functional radiation quality descriptor for modelling relative biological effectiveness
    Åpne denne publikasjonen i ny fane eller vindu >>Energy deposition clustering as a functional radiation quality descriptor for modelling relative biological effectiveness
    2016 (engelsk)Inngår i: Medical physics (Lancaster), ISSN 0094-2405, Vol. 43, nr 12, s. 6322-6335Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose: To explore the use of the frequency of the energy deposition (ED) clusters of different sizes (cluster order, CO) as a surrogate (instead of, e.g., LET) classification of the physical characteristics of ionizing radiation at a nanometer scale, to construct a framework for the calculation of relative biological effectiveness (RBE) with cell survival as endpoint.

    Methods: The frequency of cluster order f(CO) is calculated by sorting the ED sites generated with the Monte Carlo track structure code LIonTrack into clusters based on a single parameter called the cluster distance d(C) being the maximum allowed distance between two neighboring EDs belonging to a cluster. Published cell survival data parameterized with the linear-quadratic (LQ) model for V79 cells exposed to 15 different radiation qualities (including brachytherapy sources, proton, and carbon ions) were used as input to a fitting procedure, designed to determine a weighting function w(CO) that describes the capacity of a cluster of a certain CO to damage the cell's sensitive volume. The proposed framework uses both f(CO) and w(CO) to construct surrogate based functions for the LQ parameters a and beta from which RBE values can be derived.

    Results: The results demonstrate that radiation quality independent weights w(CO) exist for both the a and beta parameters. This enables the calculation of a values that correlate to their experimental counterparts within experimental uncertainties (relative residual of 15% for d(C) = 2.5 nm). The combination of both a and beta surrogate based functions, despite the higher relative residuals for beta values, yielded an RBE function that correlated to experimentally derived RBE values (relative residual of 16.5% for d(C) = 2.5 nm) for all radiation qualities included in this work.

    Conclusions: The f(CO) cluster characterization of ionizing radiation at a nanometer scale can effectively be used to calculate particle and energy dependent a and beta values to predict RBE values with potential applications to, e.g., treatment planning systems in radiotherapy. (C) 2016 American Association of Physicists in Medicine.

    Emneord
    RBE, Monte Carlo track structure, linear-quadratic model, energy deposition clusters
    HSV kategori
    Forskningsprogram
    Medicinsk radiofysik
    Identifikatorer
    urn:nbn:se:uu:diva-279240 (URN)10.1118/1.4966033 (DOI)000390237200012 ()
    Forskningsfinansiär
    Swedish National Infrastructure for Computing (SNIC), p2011144Swedish Radiation Safety Authority
    Tilgjengelig fra: 2016-02-29 Laget: 2016-02-29 Sist oppdatert: 2017-11-30bibliografisk kontrollert
  • 223.
    Vlachogiannis, Pavlos
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Gudjonsson, Olafur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Montelius, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Grusell, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Isacsson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Nilsson, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Blomquist, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hypofractionated high-energy proton-beam irradiation is an alternative treatment for WHO grade I meningiomas2017Inngår i: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 159, nr 12, s. 2391-2400Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radiation treatment is commonly employed in the treatment of meningiomas. The aim of this study was to evaluate the effectiveness and safety of hypofractionated high-energy proton therapy as adjuvant or primary treatment for WHO grade I meningiomas. A total of 170 patients who received irradiation with protons for grade I meningiomas between 1994 and 2007 were included in the study. The majority of the tumours were located at the skull base (n = 155). Eighty-four patients were treated post subtotal resection, 42 at tumour relapse and 44 with upfront radiotherapy after diagnosis based on the typical radiological image. Irradiation was given in a hypofractionated fashion (3-8 fractions, usually 5 or 6 Gy) with a mean dose of 21.9 Gy (range, 14-46 Gy). All patients were planned for follow-up with clinical controls and magnetic resonance imaging scans at 6 months and 1, 2, 3, 5, 7 and 10 years after treatment. The median follow-up time was 84 months. Age, gender, tumour location, Simpson resection grade and target volume were assessed as possible prognostic factors for post-irradiation tumour progression and radiation related complications. The actuarial 5- and 10-year progression-free survival rates were 93% and 85% respectively. Overall mortality rate was 13.5%, while disease-specific mortality was 1.7% (3/170 patients). Older patients and patients with tumours located in the middle cranial fossa had a lower risk for tumour progression. Radiation-related complications were seen in 16 patients (9.4%), with pituitary insufficiency being the most common. Tumour location in the anterior cranial fossa was the only factor that significantly increased the risk of complications. Hypofractionated proton-beam radiation therapy may be used particularly in the treatment of larger World Health Organisation grade I meningiomas not amenable to total surgical resection. Treatment is associated with high rates of long-term tumour growth control and acceptable risk for complications.

  • 224.
    von Witting, Emma
    et al.
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindbo, Sarah
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Oroujeni, Maryam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Hober, Sophia
    KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Selection of the optimal macrocyclic chelators for labeling with 111In and 68Ga improves contrast of HER2 imaging using engineered scaffold protein ADAPT62019Inngår i: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 140, s. 109-120Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radionuclide molecular imaging is a promising tool that becomes increasingly important as targeted cancer therapies are developed. To ensure an effective treatment, a molecular stratification of the cancer is a necessity. To accomplish this, visualization of cancer associated molecular abnormalities in vivo by molecular imaging is the method of choice. ADAPTs, a novel type of small protein scaffold, have been utilized to select and develop high affinity binders to different proteinaceous targets. One of these binders, ADAPT6 selectively interacts with human epidermal growth factor 2 (HER2) with low nanomolar affinity and can therefore be used for its in vivo visualization. Molecular design and optimization of labeled anti-HER2 ADAPT has been explored in several earlier studies, showing that small changes in the scaffold affect the biodistribution of the domain. In this study, we evaluate how the biodistribution properties of ADAPT6 is affected by the commonly used maleimido derivatives of the macrocyclic chelators NOTA, NODAGA, DOTA and DOTAGA with the aim to select the best variants for SPECT and PET imaging. The different conjugates were labeled with 111In for SPECT and 68Ga for PET. The acquired data show that the combination of a radionuclide and a chelator for its conjugation has a strong influence on the uptake of ADAPT6 in normal tissues and thereby gives a significant variation in tumor-toorgan ratios. Hence, it was concluded that the best variant for SPECT imaging is 111In-(HE)3DANS-ADAPT6-GSSC-DOTA while the best variant for PET imaging is 68Ga-(HE)3DANS-ADAPT6-GSSC-NODAGA.

  • 225.
    Vorobyeva, Anzhelika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Westerlund, K.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Al-Ramadan, Afkar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Karlström, A. Eriksson
    KTH Royal Inst Technol, Stockholm, Sweden.
    Feasibility of Z Domain-Mediated Conjugation of PNA to Antibodies for Radionuclide Pretargeting2017Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 44, s. S559-S560Artikkel i tidsskrift (Annet vitenskapelig)
  • 226.
    Vorobyeva, Anzhelika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Bragina, O.
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Tomsk, Russia.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Shulga, A.
    Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow, Russia.
    Proshkina, G.
    Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow, Russia.
    Chernov, V.
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Tomsk, Russia; Natl Res Tomsk Polytech Univ, Tomsk, Russia.
    Deyev, S.
    Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow, Russia; Natl Res Tomsk Polytech Univ, Tomsk, Russia; Natl Res Nucl Univ MEPhI, Moscow, Russia.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Evaluation of Radioiodine and Technetium-Labeled DARPin 9_29 for Molecular Imaging of HER2 Expression in Cancer Using SPECT2018Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, nr Supplement 1, s. S678-S679Artikkel i tidsskrift (Annet vitenskapelig)
  • 227.
    Vorobyeva, Anzhelika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Bragina, Olga
    Russian Acad Sci, Canc Res Inst, Nucl Med Dept, Tomsk Natl Res Med Ctr, Tomsk, Russia.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Shulga, Alexey
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia.
    Proshkina, Galina
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia.
    Chernov, Vladimir
    Russian Acad Sci, Canc Res Inst, Nucl Med Dept, Tomsk Natl Res Med Ctr, Tomsk, Russia;Natl Res Tomsk Polytech Univ, Tomsk, Russia.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Deyev, Sergey
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia;Natl Res Tomsk Polytech Univ, Tomsk, Russia;Natl Res Nucl Univ MEPhI, Bionanophoton Lab, Inst Engn Phys Biomed PhysBio, Moscow, Russia.
    Comparative Evaluation of Radioiodine and Technetium-Labeled DARPin 9_29 for Radionuclide Molecular Imaging of HER2 Expression in Malignant Tumors2018Inngår i: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, artikkel-id 6930425Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High expression of human epidermal growth factor receptor 2 (HER2) in breast and gastroesophageal carcinomas is a predictive biomarker for treatment using HER2-targeted therapeutics (antibodies trastuzumab and pertuzumab, antibody-drug conjugate trastuzumab DM1, and tyrosine kinase inhibitor lapatinib). Radionuclide molecular imaging of HER2 expression might permit stratification of patients for HER2-targeting therapies. In this study, we evaluated a new HER2-imaging probe based on the designed ankyrin repeat protein (DARPin) 9_29. DARPin 9_29 was labeled with iodine-125 by direct radioiodination and with [Tc-99m] Tc(CO)(3) using the C-terminal hexahistidine tag. DARPin 9_29 preserved high specificity and affinity of binding to HER2-expressing cells after labeling. Uptake of [I-125] I-DARPin 9_29 and [Tc-99m] Tc(CO)(3)-DARPin 9_29 in HER2-positive SKOV-3 xenografts in mice at 6 h after injection was 3.4 +/- 0.7 % ID/g and 2.9 +/- 0.7 % ID/g, respectively. This was significantly (p < 0.00005) higher than the uptake of the same probes in HER2-negative Ramos lymphoma xenografts, 0.22 +/- 0.09 % ID/g and 0.30 +/- 0.05 % ID/g, respectively. Retention of [I-125] I-DARPin 9_29 in the lung, liver, spleen, and kidneys was appreciably lower compared with [Tc-99m] Tc(CO)(3)-DARPin 9_29, which resulted in significantly (p < 0.05) higher tumor-to-organ ratios. The biodistribution data were confirmed by SPECT/CT imaging. In conclusion, radioiodine is a preferable label for DARPin 9_29.

  • 228.
    Vorobyeva, Anzhelika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Schulga, Alexey
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia.
    Konovalova, Elena
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia.
    Guler, Rezan
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Lofblom, John
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Sandström, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Chernov, Vladimir
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Nucl Med Dept, Tomsk, Russia.
    Bragina, Olga
    Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Nucl Med Dept, Tomsk, Russia.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Deyev, Sergey M.
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow, Russia;Natl Res Tomsk Polytech Univ, Tomsk, Russia;Natl Res Nucl Univ MEPhI, Inst Engn Phys Biomed PhysBio, Bionanophoton Lab, Moscow, Russia.
    Optimal composition and position of histidine-containing tags improves biodistribution of Tc-99m-labeled DARP in G32019Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikkel-id 9405Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radionuclide molecular imaging of HER2 expression in disseminated cancer enables stratification of patients for HER2-targeted therapies. DARP in G3, a small (14 kDa) engineered scaffold protein, is a promising probe for imaging of HER2. We hypothesized that position (C- or N-terminus) and composition (hexahistidine or (HE)(3)) of histidine-containing tags would influence the biodistribution of [Tc-99m]Tc(CO)(3)-labeled DARP in G3. To test the hypothesis, G3 variants containing tags at N-terminus (H-6-G3 and (HE)(3)-G3) or at C-terminus (G3-H-6 and G3-(HE)(3)) were labeled with [Tc-99m]Tc(CO)(3). Labeling yield, label stability, specificity and affinity of the binding to HER2, biodistribution and tumor targeting properties of these variants were compared side-by-side. There was no substantial influence of position and composition of the tags on binding of [Tc-99m]Tc(CO)(3)-labeled variants to HER2. The specificity of HER2 targeting in vivo was confirmed. The tumor uptake in BALB/c nu/nu mice bearing SKOV3 xenografts was similar for all variants. On the opposite, there was a strong influence of the tags on uptake in normal tissues. The tumor-to-liver ratio for [Tc-99m]Tc(CO)(3)-(HE)(3)-G3 was three-fold higher compared to the hexahistidine-tag containing variants. Overall, [Tc-99m]Tc(CO)(3)-(HE)(3)-G3 variant provided the highest tumor-to-lung, tumor-to-liver, tumor-to-bone and tumor-to-muscle ratios, which should improve sensitivity of HER2 imaging in these common metastatic sites.

  • 229.
    Vorobyeva, Anzhelika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Schulga, Alexey
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow 117997, Russia.
    Konovalova, Elena
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow 117997, Russia.
    Güler, Rezan
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Garousi, Javad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Rinne, Sara S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Löfblom, John
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Deyev, Sergey
    Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow 117997, Russia;Natl Res Nucl Univ MEPhI, Inst Engn Phys Biomed PhysBio, Bionanophoton Lab, Moscow 115409, Russia;Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Nucl Med Dept, Tomsk 634050, Russia.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Comparison of tumor-targeting properties of directly and indirectly radioiodinated designed ankyrin repeat protein (DARPin) G3 variants for molecular imaging of HER22019Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 54, nr 4, s. 1209-1220Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Evaluation of human epidermal growth factor receptor 2 (HER2) expression levels in breast and gastroesophageal cancer is used for the stratification of patients for HER2-targeting therapies. The use of radionuclide molecular imaging may facilitate such evaluation in a non-invasive way. Designed ankyrin repeat proteins (DARPins) are engineered scaffold proteins with high potential as probes for radionuclide molecular imaging. DARPin G3 binds with high affinity to HER2 and may be used to visualize this important therapeutic target. Studies on other engineered scaffold proteins have demonstrated that selection of the optimal labeling approach improves the sensitivity and specificity of radionuclide imaging. The present study compared two methods of labeling G3, direct and indirect radioiodination, to select an approach providing the best imaging contrast. G3-H-6 was labeled with iodine-124, iodine-125 and iodine-131 using a direct method. A novel construct bearing a C-terminal cysteine, G3-GGGC, was site-specifically labeled using [I-125]I-iodo-[(4-hydroxyphenyl)ethyl]maleimide (HPEM). The two radiolabeled G3 variants preserved binding specificity and high affinity to HER2-expressing cells. The specificity of tumor targeting in vivo was demonstrated. Biodistribution comparison of [I-131]I-G3-H-6 and [I-125]I-HPEM-G3-GGGC in mice, bearing HER2-expressing SKOV3 xenografts, demonstrated an appreciable contribution of hepatobiliary excretion to the clearance of [I-125]I-HPEM-G3-GGGC and a decreased tumor uptake compared to [I-131]I-G3-H-6. The direct label provided higher tumor-to-blood and tumor-to-organ ratios compared with the indirect label at 4 h post-injection. The feasibility of high contrast PET/CT imaging of HER2 expression in SKOV3 xenografts in mice using [I-124]I-G3-H-6 was demonstrated. In conclusion, direct radioiodination is the preferable approach for labeling DARPin G3 with iodine-123 and iodine-124 for clinical single photon emission computed tomography and positron emission tomography imaging.

  • 230.
    Vorobyeva, Anzhelika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Schulga, Alexey
    Russian Acad Sci, Mol Immunol Lab, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia.
    Rinne, Sara S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Günther, Tyran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Deyev, Sergey
    Russian Acad Sci, Mol Immunol Lab, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia;Natl Res Nucl Univ MEPhI, Inst Engn Phys Biomed PhysBio, Bionanophoton Lab, Moscow 115409, Russia;Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Nucl Med Dept, Tomsk 634050, Russia.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Indirect Radioiodination of DARPin G3 Using N-succinimidyl-Para-Iodobenzoate Improves the Contrast of HER2 Molecular Imaging2019Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, nr 12, artikkel-id 3047Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radionuclide molecular imaging of human epidermal growth factor receptor 2 (HER2) in breast and gastroesophageal cancer might be used to stratify patients for HER2-targeted therapy as well as monitor treatment response and disease progression. Designed ankyrin repeat proteins (DARPins) are small engineered scaffold proteins with favorable properties for molecular imaging. Herein we compared two methods for labeling the anti-HER2 DARPin (HE)(3)-G3, direct and indirect radioiodination. We hypothesized that the use of N-succinimidyl-para-iodobenzoate (SPIB) for radioiodination would facilitate the clearance of radiometabolites and improve the contrast of imaging. Both radiolabeled (HE)(3)-G3 variants preserved their binding specificity and high affinity to HER2-expressing cells. The specificity of tumor targeting in vivo was also demonstrated. A biodistribution comparison of [I-125]I-(HE)(3)-G3 and [I-125]I-PIB-(HE)(3)-G3, in mice bearing HER2 expressing SKOV3 xenografts, showed rapid clearance of [I-125]I-PIB-(HE)(3)-G3 from normal organs and tissues and low accumulation of activity in organs with NaI-symporter expression. Both radiolabeled (HE)(3)-G3 variants had equal tumor uptake. Consequently, the indirect label provided higher tumor-to-blood and tumor-to-organ ratios compared with the direct label. Comparative Single Photon Emission Computed Tomography (SPECT)/CT imaging of HER2 expression in SKOV3 xenografts, using both radiolabeled DARPins, demonstrated the superior imaging contrast of the indirect label. Indirect radioiodination of (HE)(3)-G3 using SPIB could be further applied for SPECT and PET imaging with iodine-123 and iodine-124.

  • 231.
    Vorobyeva, Anzhelika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Westerlund, K.
    KTH Royal Inst Technol, Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Rinne, Sara S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Karlström, A. Eriksson
    KTH Royal Inst Technol, Stockholm, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Development of a PET Imaging Approach for Selection of Patients for Affibody-Based PNA-Mediated Pretargeted Radionuclide Therapy2018Inngår i: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 45, nr Supplement 1, s. S104-S104Artikkel i tidsskrift (Annet vitenskapelig)
  • 232.
    Vorobyeva, Anzhelika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Westerlund, Kristina
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Rinne, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala Univ Hosp, Med Imaging Ctr, Uppsala, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Sci Life Lab, Uppsala, Sweden.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Karlström, Amelie Eriksson
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, Stockholm, Sweden.
    Development of an optimal imaging strategy for selection of patients for affibody-based PNA-mediated radionuclide therapy2018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 9643Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 233. Wang, Ruoxi
    et al.
    Pittet, Patrick
    Ribouton, Julien
    Lu, Guo-Neng
    Galvan, Jean-Marc
    Jalade, Patrice
    Balosso, Jacques
    Ahnesjo, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Bi-Crystal compensation method for the over-response of solid-state dosimetry2014Inngår i: Materials and Applications for Sensors and Transducers III, 2014, Vol. 605, s. 540-543Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Solid-state dosimetry employs highly sensitive semiconductors such as Gallium Nitride (GaN) and Silicon (Si), but they have a common drawback of over response compared to tissues for low-energy scattered photons, which induces inacceptable errors for radiotherapy application. To tackle this issue, we propose a compensation method consisting in using two different materials of dosimetric interest with different atomic numbers. Their responses are denoted as SC1 and SC2. The response ratio SC1/water as a function of the ratio SC1/SC2 exhibits a monotonic curve that can serve as reference to compensate the over-response of SC1. To validate this method, we have studied the dosimetric response of GaN (0.1 mm(3)) and Si crystals (2.5 mm(3)) by simulations, using a validated model based on the general cavity theory in a homogeneous water phantom. The dosimetric response of GaN and Si calculated using the model has errors within 2.5% compared to measured data. The local fluence spectra have been obtained by convolution of pencil beam kernel built by Monte Carlo simulations for different clinical irradiation conditions with field size (from 5x5 cm(2) up to 20x20 cm(2)) at depth in the phantom (from 2 cm to 25 cm). The obtained results confirm a monotone relationship between GaN/water dose ratio and GaN/Si dose ratio. The reference curve is independent of irradiation conditions (field size, dosimeter position...), and allows determination of compensation value by identification.

  • 234.
    Wennstig, A. K.
    et al.
    Umea Univ, Sundsvall Hosp, Dept Oncol, Dept Surg & Perioperat Sci Surg, Sundsvall, Sweden..
    Garmo, H.
    Kings Coll London, Sch Canc & Pharmaceut Sci, TOUR, London, England.;Reg Canc Ctr, SE-75185 Uppsala, Sweden..
    Isacsson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Gagliardi, G.
    Karolinska Univ Hosp, Dept Med Radiat Phys & Nucl Med, SE-17176 Stockholm, Sweden..
    Rintela, N.
    Karolinska Univ Hosp, Dept Med Radiat Phys & Nucl Med, SE-17176 Stockholm, Sweden..
    Lagerqvist, B.
    Uppsala Univ, Dept Med Sci, SE-75185 Uppsala, Sweden..
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Kings Coll London, Sch Canc & Pharmaceut Sci, TOUR, London, England..
    Blomqvist, C.
    Orebro Univ, Univ Hosp, Dept Oncol, SE-70182 Orebro, Sweden..
    Sund, M.
    Umea Univ, Dept Surg & Perioperat Sci Surg, SE-90185 Umea, Sweden..
    Nilsson, G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    The relationship between radiation doses to coronary arteries and later intervention requiring coronary stenosis in breast cancer2018Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 92, s. S61-S62Artikkel i tidsskrift (Annet vitenskapelig)
  • 235.
    Wennstig, Anna-Karin
    et al.
    Umea Univ, Dept Surg & Perioperat Sci, Surg, SE-90185 Umea, Sweden;Sundsvall Hosp, Dept Oncol, SE-85186 Sundsvall, Sweden.
    Garmo, Hans
    Kings Coll London, Sch Canc & Pharmaceut Sci, TOUR, London, England;Reg Canc Ctr, SE-75185 Uppsala, Sweden.
    Isacsson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Gagliardi, Giovanna
    Karolinska Univ Hosp, Dept Med Radiat Phys & Nucl Med, SE-17176 Stockholm, Sweden.
    Rintelä, Niina
    Karolinska Univ Hosp, Dept Med Radiat Phys & Nucl Med, SE-17176 Stockholm, Sweden.
    Lagerqvist, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Kings Coll London, Sch Canc & Pharmaceut Sci, TOUR, London, England.
    Blomqvist, Carl
    Orebro Univ, Univ Hosp, Dept Oncol, SE-70182 Orebro, Sweden.
    Sund, Malin
    Umea Univ, Dept Surg & Perioperat Sci, Surg, SE-90185 Umea, Sweden.
    Nilsson, Greger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Gavle Cent Hosp, Dept Oncol, SE-80107 Gavle, Sweden;Visby Hosp, Dept Oncol, SE-62184 Visby, Sweden.
    The relationship between radiation doses to coronary arteries and location of coronary stenosis requiring intervention in breast cancer survivors2019Inngår i: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 14, artikkel-id 40Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: To assess the relationship between radiation doses to the coronary arteries (CAs) and location of a coronary stenosis that required intervention after three-dimensional conformal radiotherapy (3DCRT) for breast cancer (BC).

    Methods: The study population consisted of 182 women treated for BC in Sweden between 1992 and 2012. All women received 3DCRT and subsequently underwent coronary angiography due to a suspected coronary event. CA segments were delineated in the patient's original planning-CT and radiation doses were recalculated based on the dose distribution of the original radiotherapy (RT) plan. The location of the CA stenosis that required intervention was identified from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Logistic regression analysis was used to assess the relationship between CA radiation doses and risk of a later coronary intervention at this specific location.

    Results: The odds ratio (OR) varied by radiation dose to the mid left anterior descending artery (LAD) (p=0.005). Women receiving mean doses of 1-5 Gray (Gy) to the mid LAD had an adjusted OR of 0.90 (95% CI 0.47-1.74) for a later coronary intervention compared to women receiving mean doses of 0-1Gy to the mid LAD. In women receiving mean doses of 5-20Gy to the mid LAD, an adjusted OR of 1.24 (95% CI 0.52-2.95) was observed, which increased to an OR of 5.23 (95% CI 2.01-13.6) for mean doses over 20Gy, when compared to women receiving mean doses of 0-1Gy to the mid LAD.

    Conclusions: In women receiving conventional 3DCRT for BC between 1992 and 2012, radiation doses to the LAD remained high and were associated with an increased requirement of coronary intervention in mid LAD. The results support that the LAD radiation dose should be considered in RT treatment planning and that the dose should be kept as low as possible. Minimising the dose to LAD is expected to diminish the risk of later radiation-induced stenosis.

  • 236.
    Westerlund, Kristina
    et al.
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden..
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Konijnenberg, Mark
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Oroujeni, Maryam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Atterby, Christina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    de Jong, Marion
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Eriksson Karlström, Amelie
    KTH Royal Inst Technol, Dept Prot Sci, Stockholm, Sweden..
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Radionuclide Therapy of HER2-Expressing Human Xenografts Using Affibody-Based Peptide Nucleic Acid-Mediated Pretargeting: In Vivo Proof of Principle2018Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, nr 7, s. 1092-1098Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are small proteins engineered using a nonanti-body scaffold. Radiolabeled Affibody molecules are excellent imaging probes, but their application to radionuclide therapy has been prevented by high renal reabsorption. The aim of this study was to test the hypothesis that Affibody-based peptide nucleic acid (PNA)-mediated pretargeted therapy of human epidermal growth factor receptor 2 (HER2)-expressing cancer extends survival without accompanying renal toxicity.

    Methods: A HER2-targeting Affibody molecule ligated with an AGTCGTGATGTAGTC PNA hybridization probe (Z(HER2:342)-SR-HP1) was used as the primary pretargeting agent. A complementary AGTCGTGATGTAGTC PNA conjugated to the chelator DOTA and labeled with the radionuclide Lu-177 (Lu-177-HP2) was used as the secondary agent. The influence of different factors on pretargeting was investigated. Experimental radionuclide therapy in mice bearing SKOV-3 xenografts was performed in 6 cycles separated by 7 d.

    Results: Optimal tumor targeting was achieved when 16 MBq/3.5 mu g (0.65 nmol) of Lu-177-HP2 was injected 16 h after injection of 100 mu g (7.7 nmol) of Z(HER2:342)-SR-HP1. The calculated absorbed dose to tumors was 1,075 mGy/MBq, whereas the absorbed dose to kidneys was 206 mGy/MBq and the absorbed dose to blood (surrogate of bone marrow) was 4 mGy/MBq. Survival of mice was significantly longer (P < 0.05) in the treatment group (66 d) than in the control groups treated with the same amount of Z(HER2:342)-SR-HP1 only (37 d), the same amount and activity of Lu-177-HP2 only (32 d), or phosphate-buffered saline (37 d).

    Conclusion: The studied pretargeting system can deliver an absorbed dose to tumors appreciably exceeding absorbed doses to critical organs, making Affibody-based PNA-mediated pretargeted radionuclide therapy highly attractive.

  • 237. Westerlund, Kristina
    et al.
    Honarvar, Hadis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Norrström, Emily
    Strand, Joanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Eriksson Karlström, Amelie
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Increasing the Net Negative Charge by Replacement of DOTA Chelator with DOTAGA Improves the Biodistribution of Radiolabeled Second-Generation Synthetic Affibody Molecules2016Inngår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, nr 5, s. 1668-1678Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A promising strategy to enable patient stratification for targeted therapies is to monitor the target expression in a tumor by radionuclide molecular imaging. Affibody molecules (7 kDa) are nonimmunoglobulin scaffold proteins with a 25-fold smaller size than intact antibodies. They have shown an apparent potential as molecular imaging probes both in preclinical and clinical studies. Earlier, we found that hepatic uptake can be reduced by the incorporation of negatively charged purification tags at the N-terminus of Affibody molecules. We hypothesized that liver uptake might similarly be reduced by positioning the chelator at the N-terminus, where the chelator-radionuclide complex will provide negative charges. To test this hypothesis, a second generation synthetic anti-HER2 ZHER2:2891 Affibody molecule was synthesized and labeled with (111)In and (68)Ga using DOTAGA and DOTA chelators. The chelators were manually coupled to the N-terminus of ZHER2:2891 forming an amide bond. Labeling DOTAGA-ZHER2:2891 and DOTA-ZHER2:2891 with (68)Ga and (111)In resulted in stable radioconjugates. The tumor-targeting and biodistribution properties of the (111)In- and (68)Ga-labeled conjugates were compared in SKOV-3 tumor-bearing nude mice at 2 h postinjection. The HER2-specific binding of the radioconjugates was verified both in vitro and in vivo. Using the DOTAGA chelator gave significantly lower radioactivity in liver and blood for both radionuclides. The (111)In-labeled conjugates showed more rapid blood clearance than the (68)Ga-labeled conjugates. The most pronounced influence of the chelators was found when they were labeled with (68)Ga. The DOTAGA chelator gave significantly higher tumor-to-blood (61 ± 6 vs 23 ± 5, p < 0.05) and tumor-to-liver (10.4 ± 0.6 vs 4.5 ± 0.5, p < 0.05) ratios than the DOTA chelator. This study demonstrated that chelators may be used to alter the uptake of Affibody molecules, and most likely other scaffold-based imaging probes, for improvement of imaging contrast.

  • 238. Westerlund, Kristina
    et al.
    Honarvar, Hadis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Eriksson Karlström, Amelie
    Design, Preparation, and Characterization of PNA-Based Hybridization Probes for Affibody-Molecule-Mediated Pretargeting2015Inngår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 26, nr 8, s. 1724-1736Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In radioimmunotherapy, the contrast between tumor and normal tissue can be improved by using a pretargeting strategy with a primary targeting agent, which is conjugated to a recognition tag, and a secondary radiolabeled molecule binding specifically to the recognition tag. The secondary molecule is injected after the targeting agent has accumulated in the tumor and is designed to have a favorable biodistribution profile, with fast clearance from blood and low uptake in normal tissues. In this study, we have designed and evaluated two complementary peptide nucleic acid (PNA)-based probes for specific and high-affinity association in vivo. An anti-HER2 Affibody-PNA chimera, ZHER2:342-SR-HP1, was produced by a semisynthetic approach using sortase A catalyzed ligation of a recombinantly produced Affibody molecule to a PNA-based HP1-probe assembled using solid-phase chemistry. A complementary HP2 probe carrying a DOTA chelator and a tyrosine for dual radiolabeling was prepared by solid-phase synthesis. Circular dichroism (CD) spectroscopy and UV thermal melts showed that the probes can hybridize to form a structured duplex with a very high melting temperature (Tm), both in HP1:HP2 and in ZHER2:342-SR-HP1:HP2 (Tm = 86-88 °C), and the high binding affinity between ZHER2:342-SR-HP1 and HP2 was confirmed in a surface plasmon resonance (SPR)-based binding study. Following a moderately fast association (1.7 × 10(5) M(-1) s(-1)), the dissociation of the probes was extremely slow and <5% dissociation was observed after 17 h. The equilibrium dissociation constant (KD) for ZHER2:342-SR-HP1:HP2 binding to HER2 was estimated by SPR to be 212 pM, suggesting that the conjugation to PNA does not impair Affibody binding to HER2. The biodistribution profiles of (111)In- and (125)I-labeled HP2 were measured in NMRI mice, showing very fast blood clearance rates and low accumulation of radioactivity in kidneys and other organs. The measured radioactivity in blood was 0.63 ± 0.15 and 0.41 ± 0.15%ID/g for (125)I- and (111)In-HP2, respectively, at 1 h p.i., and at 4 h p.i., the kidney accumulation of radioactivity was 0.17 ± 0.04%ID/g for (125)I-HP2 and 3.83 ± 0.39%ID/g for (111)In-HP2. Taken together, the results suggest that a PNA-based system has suitable biophysical and in vivo properties and is a promising approach for pretargeting of Affibody molecules.

  • 239.
    Westerlund, Kristina
    et al.
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, S-10691 Stockholm, Sweden.
    Vorobyeva, Anzhelika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Mitran, Bogdan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Theranostics.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Karlström, Amelie Eriksson
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Prot Sci, S-10691 Stockholm, Sweden.
    Altai, Mohamed
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Site-specific conjugation of recognition tags to trastuzumab for peptide nucleic acid-mediated radionuclide HER2 pretargeting2019Inngår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 203, s. 73-85Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pretargeting is a promising strategy to reach high imaging contrast in a shorter time than by targeting with directly radiolabeled monoclonal antibodies (mAbs). One of problems in pretargeting is a site-specific, reproducible and uniform conjugation of recognition tags to mAbs. To solve this issue we propose a photoconjugation to covalently couple a recognition tag to a mAb via a photoactivatable Z domain. The Z-domain, a 58-amino acid protein derived from the IgG-binding B-domain of Staphylococcus aureus protein A, has a well-characterized binding site in the Fc portion of IgG. We tested the feasibility of this approach using pretargeting based on hybridization between peptide nucleic acids (PNAs). We have used photoconjugation to couple trastuzumab with the PNA-based hybridization probe, HP1. A complementary [Co-57]Co-labeled PNA hybridization probe ([Co-57]Co-HP2) was used as the secondary targeting probe. In vitro studies demonstrated that trastuzumab-ZHP1 bound specifically to human epidermal growth factor receptor 2 (HER2)-expressing cells with nanomolar affinity. The binding of the secondary [Co-57]Co-HP2 probe to trastuzumab-PNA-pretreated cells was in the picomolar affinity range. A two-fold increase in SKOV-3 tumor targeting was achieved when [Co-57]Co-HP2 (0.7 nmol) was injected 48 h after injection of trastuzumab-ZHP1 (0.5 nmol) compared with trastuzumab-ZHP1 alone (0.8 +/- 0.2 vs. 0.33 +/- 0.06 %ID/g). Tumor accumulation of [Co-57]Co-HP2 was significantly reduced by pre-saturation with trastuzumab or when no trastuzumab-ZHP1 was preinjected. A tumor-to-blood uptake ratio of 1.5 +/- 0.3 was achieved resulting in a clear visualization of HER2-expressing xenografts as confirmed by SPECT imaging. In conclusion, the feasibility of stable site-specific coupling of a PNA-based recognition tag to trastuzumab and successful pretargeting has been demonstrated. This approach can hopefully be used for a broad range of mAbs and recognition tags.

  • 240.
    Wiesinger, Florian
    et al.
    GE Healthcare, Freisinger Landstr 50, D-85748 Munich, Germany.
    Bylund, Mikael
    Umea Univ, Umea, Sweden.
    Yang, Jaewon
    UCSF, San Francisco, CA USA.
    Kaushik, Sandeep
    GE Global Res, Bangalore, Karnataka, India.
    Shanbhag, Dattesh
    GE Global Res, Bangalore, Karnataka, India.
    Ahn, Sangtae
    GE Global Res, Niskayuna, NY USA.
    Jonsson, Joakim H.
    Umea Univ, Umea, Sweden.
    Lundman, Josef A.
    Umea Univ, Umea, Sweden.
    Hope, Thomas
    UCSF, San Francisco, CA USA.
    Nyholm, Tufve
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Umea Univ, Umea, Sweden.
    Larson, Peder
    UCSF, San Francisco, CA USA.
    Cozzini, Cristina
    GE Healthcare, Freisinger Landstr 50, D-85748 Munich, Germany.
    Zero TE-based pseudo-CT image conversion in the head and its application in PET/MR attenuation correction and MR-guided radiation therapy planning2018Inngår i: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 80, nr 4, s. 1440-1451Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To describe a method for converting Zero TE (ZTE) MR images into Xray attenuation information in the form of pseudo-CT images and demonstrate its performance for (1) attenuation correction (AC) in PET/MR and (2) dose planning in MR-guided radiation therapy planning (RTP). Methods: Proton density-weighted ZTE images were acquired as input for MRbased pseudo-CT conversion, providing (1) efficient capture of short-lived bone signals, (2) flat soft-tissue contrast, and (3) fast and robust 3D MR imaging. After bias correction and normalization, the images were segmented into bone, soft-tissue, and air by means of thresholding and morphological refinements. Fixed Hounsfield replacement values were assigned for air (-1000 HU) and soft-tissue (142 HU), whereas continuous linear mapping was used for bone. Results: The obtained ZTE-derived pseudo-CT images accurately resembled the true CT images (i. e., Dice coefficient for bone overlap of 0.73 +/- 0.08 and mean absolute error of 123 +/- 25 HU evaluated over the whole head, including errors from residual registration mismatches in the neck and mouth regions). The linear bone mapping accounted for bone density variations. Averaged across five patients, ZTE-based AC demonstrated a PET error of -0.04 +/- 1.68% relative to CT-based AC. Similarly, for RTP assessed in eight patients, the absolute dose difference over the target volume was found to be 0.23 +/- 0.42%. Conclusion: The described method enables MR to pseudo-CT image conversion for the head in an accurate, robust, and fast manner without relying on anatomical prior knowledge. Potential applications include PET/MR-AC, and MR-guided RTP.

  • 241.
    Wikström, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Isacsson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Bengt, Johansson
    Örebro University Hospital, Department of Oncology.
    Lennernäs, Bo
    Örebro University Hospital, Department of Oncology.
    Magnetic Resonance Compatibility of a Transponder Aimed for Radiotherapy Positioning – A Phantom Study2017Inngår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 37, nr 9, s. 4993-4996Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background/Aim: Electromagnetic Positioning Systems (EMP) is a new position-ing technique in four-dimensional radiotherapy. Patients with implanted transponders may be referred for magnetic resonance imaging (MRI) making it important to establish the MR safety.

    Materials and Methods: Oranges were prepared with transponders and imaged on a 3T MR scanner with different sequences. Computed tomography (CT) was performed as comparison. MR artifacts were assessed. An estimation of the maximum transponder de-flection force and heating was made.

    Results: The mean measured displacement of transponders was 0.1 mm (range=0.03-0.3 mm). Artifacts were observed adjacent to transponders using all sequences. The deflection force on the transponder in the gantry was less than 38 mN. No heating was observed.

    Conclusion: The absence of any substantial movement, the weak measured deflection force and absence of observed heating speaks for the safe use of MR imaging with transponder 3T. Local artefacts makes evaluation impossible adjacent to transponders.

  • 242.
    Wikström, Kenneth
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Isacsson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Nilsson, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Reproducibility of heart and thoracic wall positionin repeated deep inspiration breath holds forradiotherapy of left-sided breast cancer patients2018Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, nr 10, s. 1318-1324Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Deep inspiration breath hold (DIBH) for radiotherapy of left-sided breast cancer patientscan effectively move the heart away from the target and reduce the heart dose compared to treatmentsin free breathing. This study aims to investigate the positional reproducibility of heart edge(HE) and thoracic wall (TW) during repeated DIBHs.

    Material and methods: At three occasions, 11 left-sided breast cancer patients were CT imaged during6 minutes of repeated DIBHs with 60 cine CT series. The series were evenly distributed over threebed positions and for each bed position, the heart edge associated maximum heart distance (MHD)and thoracic wall-associated maximum lung distance (MLD) from a reference line were retrospectivelyanalyzed. The high temporal resolution of the CT series enabled intrinsic heart movements to beresolved from breath hold variations. A body surface laser scanning system continuously extracted thethorax height and displayed it in a pair of goggles for patient feedback. To check for ‘fake-breathing’movements, e.g. that the patient lifts its back from the couch to reach DIBH, the couch-to-spine distancewas also measured in all CT series.

    Results: The analysis was done for 1432 cine CTs captured during 292 breath holds. The DIBH movedthe heart on average 15mm in medial direction compared with free breathing. For the three bed positionsstudied, the mean value of the max range, across all patients, was between 11–13mm for theMHD and 4–8mm for the MLD. The MHD variation due to breath hold variation was twice as large asthe MHD variation due to intrinsic heart movement. The couch-to-spine distance varied less than3mm for all fractions, i.e., no fake-breathing was discovered.

    Conclusions: The heart edge and thoracic wall reproducibility was high in relation to the medial heartdisplacement induced by the DIBH.

  • 243.
    Zetterström, Andreas
    et al.
    Kontigo Care AB, Pavel Snickares Grand 12, S-75320 Uppsala, Sweden.
    Hämäläinen, Markku D.
    Kontigo Care AB, Pavel Snickares Grand 12, S-75320 Uppsala, Sweden.
    Karlberg, Elin
    Uppsala Univ Hosp, Innovat Akad, S-75185 Uppsala, Sweden.
    Winkvist, Maria
    Kontigo Care AB, Pavel Snickares Grand 12, S-75320 Uppsala, Sweden.
    Söderquist, Marcus
    Kontigo Care AB, Pavel Snickares Grand 12, S-75320 Uppsala, Sweden.
    Öhagen, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Andersson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Ridgeview Instruments AB, Skillsta 4, S-74020 Vange, Sweden.
    Nyberg, Fred
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Maximum Time Between Tests: A Digital Biomarker to Detect Therapy Compliance and Assess Schedule Quality in Measurement-Based eHealth Systems for Alcohol Use Disorder2019Inngår i: Alcohol and Alcoholism, ISSN 0735-0414, E-ISSN 1464-3502, Vol. 54, nr 1, s. 70-72Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: To evaluate, in a breathalyzer-based eHealth system, whether the time-based digital biomarker maximum time between tests' (MTBT) brings valuable information on alcohol consumption patterns as confirmed by correlation with blood phosphatidyl ethanol (PEth), serum carbohydrate deficient transferrin (CDT) and timeline follow-back data.

    Method: Data on 54 patients in follow-up for treatment of alcohol use disorder were analysed.

    Results: The model of weekly averages of 24-log transformed MTBT adequately described timeline follow-back data (P < 0.0001, R = 0.27-0.38, n = 650). Significant correlations were noted between MTBT and PEth (P < 0.0001, R = 0.41, n = 148) and between MTBT and CDT (P < 0.0079, R = 0.22, n = 120).

    Conclusions: The time-based digital biomarker maximum time between tests' described here has the potential to become a generally useful metric for all scheduled measurement-based eHealth systems to monitor test behaviour and compliance, factors important for dosing' of eHealth systems and for early prediction and interventions of lapse/relapse.

  • 244.
    Åström, Lennart
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Grusell, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Uppsala universitet, The Svedberg-laboratoriet.
    Sandin, Fredrik
    Regional Cancer Center Uppsala-Örebro (RCC), Uppsala, Sweden.
    Turesson, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. Kings Coll London, Fac Life Sci & Med, London, England.
    Two decades of high dose rate brachytherapy with external beam radiotherapy for prostate cancer2018Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 127, nr 1, s. 81-87Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: High-dose-rate brachytherapy (HDR-BT) has optimal prerequisites in radiotherapy of prostate cancer (PC) with a conformal dose distribution and high doses per fraction giving a biological dose escalation. We report the outcome after HDR-BT and external beam radiotherapy (EBRT) after 20 years of experience.

    Material and methods: The study includes 623 patients, median age of 66 years, treated from 1995 to 2008 and a median follow up of 11 years (range 2–266 months). Androgen deprivation therapy was given to 429 patients (69%). The HDR-BT was given with two 10 Gy fractions and the EBRT with 2 Gy fractions to 50 Gy.

    Results: The 10-year PC-specific survival was 100%, 92%, 91%, and 75% for low-, intermediate-, high- and very high-risk patients respectively, and the 10-year probability of PSA relapse was 0%, 21%, 33%, and 65% respectively. The 10-year actuarial prevalence for ≥grade 2 GU- and GI-toxicities were 28% and 12% respectively and for ≥grade 3, 4% and 1% respectively. Urethral stricture was the most frequent GU complication with a 10-year actuarial incidence of 10%. Treatment without dose constraints for the urethra conferred a higher incidence 18%, compared to 5% after 2003 (p < 0.001). Sixteen patients experienced grade 4 GU toxicity, of which 13 were treated before 2003. No grade 4 rectal toxicity was seen.

    Conclusion: The combination of EBRT and HDR-BT with adequate dose constraints to risk organs provides satisfactory long-term tumour control even in high-risk patients. GI toxicity stabilised but GU toxicity progressed during the 10-year follow up.

2345 201 - 244 of 244
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