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  • 1.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Perols, Anna
    Eriksson Karlström, Amelie
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Boschetti, Frederic
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Preclinical evaluation of anti-HER2 Affibody molecules site-specifically labeled with 111In using a maleimido derivative of NODAGA2012In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 39, no 4, p. 518-529Article in journal (Refereed)
    Abstract [en]

    Introduction

    Affibody molecules have demonstrated potential for radionuclide molecular imaging. The aim of this study was to synthesize and evaluate a maleimido derivative of the 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) for site-specific labeling of anti-HER2 Affibody molecule.

    Methods

    The maleimidoethylmonoamide NODAGA (MMA-NODAGA) was synthesized and conjugated to ZHER2:2395 Affibody molecule having a C-terminal cysteine. Labeling efficiency, binding specificity to and cell internalization by HER2-expressing cells of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 were studied. Biodistribution of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 and [111In-MMA-DOTA-Cys61]-ZHER2:2395 was compared in mice.

    Results

    The affinity of [MMA-NODAGA-Cys61]-ZHER2:2395 binding to HER2 was 67 pM. The 111In-labeling yield was 99.6%±0.5% after 30 min at 60°C. [111In-MMA-NODAGA-Cys61]-ZHER2:2395 bound specifically to HER2-expressing cells in vitro and in vivo. Tumor uptake of [111In-MMA-NODAGA-Cys61]-ZHER2:2395 in mice bearing DU-145 xenografts (4.7%±0.8% ID/g) was lower than uptake of [111In-MMA-DOTA-Cys61]-ZHER2:2395 (7.5%±1.6% ID/g). However, tumor-to-organ ratios were higher for [111In-MMA-NODAGA-Cys61]-ZHER2:2395 due to higher clearance rate from normal tissues.

    Conclusions

    MMA-NODAGA is a promising chelator for site-specific labeling of targeting proteins containing unpaired cysteine. Appreciable influence of chelators on targeting properties of Affibody molecules was demonstrated.

  • 2.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Wållberg, Helena
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Medical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Löfblom, John
    Larsson, Erik
    Strand, Sven-Erik
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Ståhl, Stefan
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors: preclinical assessment2014In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no 11, p. 1842-1848Article in journal (Refereed)
    Abstract [en]

    Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of 99mTc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide–based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate 188Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)–expressing tumors.

    Methods:

    ZHER2:V2 was labeled with 188Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.

    Results:

    Binding of 188Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that 188Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.

    Conclusion:

    188Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.

  • 3.
    Borges, Joao Batista
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Costa, Eduardo L. V.
    Bergquist, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lucchetta, Luca
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Amato, Marcelo B. P.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lung Inflammation Persists After 27 Hours of Protective Acute Respiratory Distress Syndrome Network Strategy and Is Concentrated in the Nondependent Lung2015In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 43, no 5, p. E123-E132Article in journal (Refereed)
    Abstract [en]

    Objective: PET with [F-18]fluoro-2-deoxy-D-glucose can be used to image cellular metabolism, which during lung inflammation mainly reflects neutrophil activity, allowing the study of regional lung inflammation in vivo. We aimed at studying the location and evolution of inflammation by PET imaging, relating it to morphology (CT), during the first 27 hours of application of protective-ventilation strategy as suggested by the Acute Respiratory Distress Syndrome Network, in a porcine experimental model of acute respiratory distress syndrome. Design: Prospective laboratory investigation. Setting: University animal research laboratory. Subjects: Ten piglets submitted to an experimental model of acute respiratory distress syndrome. Interventions: Lung injury was induced by lung lavages and 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressure and high inspiratory pressures. During 27 hours of controlled mechanical ventilation according to Acute Respiratory Distress Syndrome Network strategy, the animals were studied with dynamic PET imaging of [F-18]fluoro-2-deoxy-D-glucose at two occasions with 24-hour interval between them. Measurements and Main Results: [F-18]fluoro-2-deoxy-D-glucose uptake rate was computed for the total lung, four horizontal regions from top to bottom (nondependent to dependent regions) and for voxels grouped by similar density using standard Hounsfield units classification. The global lung uptake was elevated at 3 and 27 hours, suggesting persisting inflammation. In both PET acquisitions, nondependent regions presented the highest uptake (p = 0.002 and p = 0.006). Furthermore, from 3 to 27 hours, there was a change in the distribution of regional uptake (p = 0.003), with more pronounced concentration of inflammation in nondependent regions. Additionally, the poorly aerated tissue presented the largest uptake concentration after 27 hours. Conclusions: Protective Acute Respiratory Distress Syndrome Network strategy did not attenuate global pulmonary inflammation during the first 27 hours after severe lung insult. The strategy led to a concentration of inflammatory activity in the upper lung regions and in the poorly aerated lung regions. The present findings suggest that the poorly aerated lung tissue is an important target of the perpetuation of the inflammatory process occurring during ventilation according to the Acute Respiratory Distress Syndrome Network strategy.

  • 4.
    Borges, João Batista
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Costa, Eduardo L V
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Amato, Marcelo
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Early inflammation mainly affects normally and poorly aerated lung in experimental ventilator-induced lung injury2014In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 42, no 4, p. e279-e287Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The common denominator in most forms of ventilator-induced lung injury is an intense inflammatory response mediated by neutrophils. PET with [F]fluoro-2-deoxy-D-glucose can be used to image cellular metabolism, which, during lung inflammatory processes, mainly reflects neutrophil activity, allowing the study of regional lung inflammation in vivo. The aim of this study was to assess the location and magnitude of lung inflammation using PET imaging of [F]fluoro-2-deoxy-D-glucose in a porcine experimental model of early acute respiratory distress syndrome.

    DESIGN: Prospective laboratory investigation.

    SETTING: A university animal research laboratory.

    SUBJECTS: Seven piglets submitted to experimental ventilator-induced lung injury and five healthy controls.

    INTERVENTIONS: Lung injury was induced by lung lavages and 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressure and high inspiratory pressures. All animals were subsequently studied with dynamic PET imaging of [F]fluoro-2-deoxy-D-glucose. CT scans were acquired at end expiration and end inspiration.

    MEASUREMENTS AND MAIN RESULTS: [F]fluoro-2-deoxy-D-glucose uptake rate was computed for the whole lung, four isogravitational regions, and regions grouping voxels with similar density. Global and intermediate gravitational zones [F]fluoro-2-deoxy-D-glucose uptakes were higher in ventilator-induced lung injury piglets compared with controls animals. Uptake of normally and poorly aerated regions was also higher in ventilator-induced lung injury piglets compared with control piglets, whereas regions suffering tidal recruitment or tidal hyperinflation had [F]fluoro-2-deoxy-D-glucose uptakes similar to controls.

    CONCLUSIONS: The present findings suggest that normally and poorly aerated regions-corresponding to intermediate gravitational zones-are the primary targets of the inflammatory process accompanying early experimental ventilator-induced lung injury. This may be attributed to the small volume of the aerated lung, which receives most of ventilation.

  • 5.
    Borges, João Batista
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Ulin, Johan
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Ventilation Distribution Studies Comparing Technegas and "Gallgas" Using (GaCl3)-Ga-68 as the Label2011In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 52, no 2, p. 206-209Article in journal (Refereed)
    Abstract [en]

    Ventilation distribution can be assessed by SPECT with Technegas. This study was undertaken in piglets with different degrees of ventilation inhomogeneity to compare PET using Ga-68-labeled pseudogas or "Gallgas" with Technegas. Methods: Twelve piglets were studied in 3 groups: control, lobar obstruction, and diffuse airway obstruction. Two more piglets were assessed for lung volume (functional residual capacity). Results: In controls, SPECT and PET images showed an even distribution of radioactivity. With lobar obstruction, the absence of ventilation of the obstructed lobe was visible with both techniques. In diffuse airway obstruction, SPECT images showed an even distribution of radioactivity, and PET images showed more varied radioactivity over the lung. Conclusion: PET provides detailed ventilation distribution images and a better appreciation of ventilation heterogeneity. Gallgas with PET is a promising new diagnostic tool for the assessment of ventilation distribution.

  • 6.
    Bäckström, Gloria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Protons, other Light Ions, and 60Co Photons: Study of Energy Deposit Clustering via Track Structure Simulations2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Radiotherapy aims to sterilize cancer cells through ionization induced damages to their DNA whilst trying to reduce dose burdens to healthy tissues. This can be achieved to a certain extent by optimizing the choice of radiation to treat the patient, i.e. the types of particles and their energy based on their specific interaction patterns. In particular, the formation of complex clusters of energy deposits (EDs) increases with the linear energy transferred for a given particle. These differences cause variation in the relative biological effectiveness (RBE). The complexity of ED clusters might be related to complex forms of DNA damage, which are more difficult to repair and therefore prone to inactivate the cells. Hence, mapping of the number and complexity of ED clusters for different radiation qualities could aid to infer a surrogate measure substituting physical dose and LET as main predictors for the RBE .  

    In this work the spatial patterns of EDs at the nanometre scale were characterized for various energies of proton, helium, lithium and carbon ions. A track structure Monte Carlo code, LIonTrack, was developed to accurately simulate the light ion tracks in liquid water. The methods to emulate EDs at clinical dose levels in cell nucleus-sized targets for both 60Co photons and light ions were established, and applied to liquid water targets. All EDs enclosed in such targets were analyzed with a specifically developed cluster algorithm where clustering was defined by a single parameter, the maximum distance between nearest neighbour EDs. When comparing measured RBE for different radiation qualities, there are cases for which RBE do not  increase with LET but instead increase with the frequencies of high order ED clusters.

    A test surrogate-measure based on ED cluster frequencies correlated to parameters of experimentally determined cell survival. The tools developed in this thesis can facilitate future exploration of semi-mechanistic modelling of the RBE.

    List of papers
    1. Monte Carlo simulation and analysis of proton energy-deposition patterns in the Bragg peak
    Open this publication in new window or tab >>Monte Carlo simulation and analysis of proton energy-deposition patterns in the Bragg peak
    2008 (English)In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 53, no 11, p. 2857-75Article in journal (Refereed) Published
    Abstract [en]

    The spatial pattern of energy depositions is crucial for understanding the mechanisms that modify the relative biological effectiveness of different radiation qualities. In this paper, we present data on energy-deposition properties of mono-energetic protons (1-20 MeV) and their secondary electrons in liquid water. Proton-impact ionization was described by means of the Hansen-Kocbach-Stolterfoht doubly differential cross section (DDCS), thus modelling both the initial energy and angle of the emitted electron. Excitation by proton impact was included to account for the contribution of this interaction channel to the electronic stopping power of the projectile. Proton transport was implemented assuming track-segment conditions, whereas electrons were followed down to 50 eV by the Monte Carlo code PENELOPE. Electron intra-track energy-deposition properties, such as slowing-down and energy-imparted spectra of electrons, were calculated. Furthermore, the use of DDCSs enabled the scoring of electron inter-track properties. We present novel results for 1, 5 and 20 MeV single-proton-track frequencies of distances between the nearest inter- (e(-)-e(-), e(-)-H+) and intra-track (e(-)-e(-), e(-)-H+, H+-H+) energy-deposition events. By setting a threshold energy of 17.5 eV, commonly employed as a surrogate to discriminate for elementary damage in the DNA, the variation in these frequencies was studied as well. The energy deposited directly by the proton represents a large amount of the total energy deposited along the track, but when an energy threshold is adopted the relative contribution of the secondary electrons becomes larger for increasing energy of the projectile. We found that the frequencies of closest energy-deposition events per nanometre decrease with proton energy, i.e. for lower proton energies a denser ionization occurs, following the trend of the characteristic LET curves. In conclusion, considering the energy depositions due to the delta electrons and at the core of the track, 1 MeV protons have an intrinsic capability of generating about five times more dual depositions within the characteristic 2 nm of the DNA-chain structure than 20 MeV protons.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-103247 (URN)10.1088/0031-9155/53/11/007 (DOI)000256352000008 ()18460751 (PubMedID)
    Available from: 2009-05-15 Created: 2009-05-15 Last updated: 2017-12-13Bibliographically approved
    2. Limitations (and merits) of PENELOPE as a track-structure code
    Open this publication in new window or tab >>Limitations (and merits) of PENELOPE as a track-structure code
    Show others...
    2012 (English)In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 88, no 1-2, p. 66-70Article in journal (Refereed) Published
    Abstract [en]

    Purpose: To outline the limitations of PENELOPE (acronym of PENetration and Energy LOss of Positrons and Electrons) as a track-structure code, and to comment on modifications that enable its fruitful use in certain microdosimetry and nanodosimetry applications. Methods: Attention is paid to the way in which inelastic collisions of electrons are modelled and to the ensuing implications for microdosimetry analysis. Results: Inelastic mean free paths and collision stopping powers calculated with PENELOPE and two well-known optical-data models are compared. An ad hoc modification of PENELOPE is summarized where ionization and excitation of liquid water by electron impact is simulated using tables of realistic differential and total cross sections. Conclusions: PENELOPE can be employed advantageously in some track-structure applications provided that the default model for inelastic interactions of electrons is replaced by suitable tables of differential and total cross sections.

    Keywords
    Radiation physics, Monte Carlo simulation, microdosimetry
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-168096 (URN)10.3109/09553002.2011.598209 (DOI)000298666000012 ()
    Available from: 2012-02-08 Created: 2012-02-06 Last updated: 2017-12-08Bibliographically approved
    3. Track structure of protons and other light ions in liquid water: Applications of the LIonTrack code at the nanometer scale
    Open this publication in new window or tab >>Track structure of protons and other light ions in liquid water: Applications of the LIonTrack code at the nanometer scale
    Show others...
    2013 (English)In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 40, no 6, p. 064101-Article in journal (Refereed) Published
    Abstract [en]

    Purpose: The LIonTrack (Light Ion Track) Monte Carlo (MC) code for the simulation of H+, He2+, and other light ions in liquid water is presented together with the results of a novel investigation of energy-deposition site properties from single ion tracks. Methods: The continuum distorted-wave formalism with the eikonal initial state approximation (CDW-EIS) is employed to generate the initial energy and angle of the electrons emitted in ionizing collisions of the ions with H2O molecules. The model of Dingfelder et al. ["Electron inelastic-scattering cross sections in liquid water," Radiat. Phys. Chem. 53, 1-18 (1998); " Comparisons of calculations with PARTRAC and NOREC: Transport of electrons in liquid water," Radiat. Res. 169, 584-594 (2008)] is linked to the general-purpose MC code PENELOPE/penEasy to simulate the inelastic interactions of the secondary electrons in liquid water. In this way, the extended PENELOPE/penEasy code may provide an improved description of the 3D distribution of energy deposits (EDs), making it suitable for applications at the micrometer and nanometer scales. Results: Single-ionization cross sections calculated with the ab initio CDW-EIS formalism are compared to available experimental values, some of them reported very recently, and the theoretical electronic stopping powers are benchmarked against those recommended by the ICRU. The authors also analyze distinct aspects of the spatial patterns of EDs, such as the frequency of nearest-neighbor distances for various radiation qualities, and the variation of the mean specific energy imparted in nanoscopic targets located around the track. For 1 MeV/u particles, the C6+ ions generate about 15 times more clusters of six EDs within an ED distance of 3 nm than H+. Conclusions: On average clusters of two to three EDs for 1 MeV/u H+ and clusters of four to five EDs for 1 MeV/u C6+ could be expected for a modeling double strand break distance of 3.4 nm.

    Keywords
    track structure of protons and light ions, spatial patterns of energy deposits, Monte Carlo code, CDW-EIS model
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-204126 (URN)10.1118/1.4803464 (DOI)000319889100042 ()
    Available from: 2013-07-22 Created: 2013-07-22 Last updated: 2017-12-06Bibliographically approved
    4. Spatial energy-deposit patterns generated by light ions and 60Co photons in cell nucleus-sized targets
    Open this publication in new window or tab >>Spatial energy-deposit patterns generated by light ions and 60Co photons in cell nucleus-sized targets
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-206314 (URN)
    Available from: 2013-08-30 Created: 2013-08-30 Last updated: 2014-03-06
  • 7.
    Bäckström, Gloria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Fernández-Varea, José Maria
    Universitat de Barcelona.
    Tilly, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Spatial energy-deposit patterns generated by light ions and 60Co photons in cell nucleus-sized targetsManuscript (preprint) (Other academic)
  • 8.
    Danfors, Torsten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Relative Cerbral Blood Flow Measurement using dynamic Flumazenil-PET may Replace Fluorodeoxyglucose-PET in Epilepsy Surgical Investigations2012Article in journal (Other academic)
  • 9.
    Dimopoulou, Angeliki
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Åslund, Per-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    A new technique for visualisation of complex renal calculi using Dual Energy CT and image merging, in the preoperative work-up of patients undergoing Percutaneous NephrolithotomyManuscript (preprint) (Other academic)
  • 10.
    Eklund, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Modeling silicon diode dose response factors for small photon fields2010In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 55, no 24, p. 7411-7423Article in journal (Refereed)
    Abstract [en]

    The dosimetry of small fields is important for the use of high resolution photon radiotherapy. Silicon diodes yield a high signal from a small detecting volume which makes them suitable for use in small fields and high dose gradients. Unshielded diodes used in large fields are known to give a varying dose response depending on the proportion of low energy scattered photons in the field. Response variations in small fields can be caused by both spectral variations, and disturbances of the local level of lateral electron equilibrium. We present a model that includes the effects from lack of charged particle equilibrium. The local spectra are calculated by use of fluence pencil kernels and divided into a low and a high energy component. The low energy part is treated with large cavity theory and the high energy part with the Spencer-Attix small cavity theory. Monte Carlo-derived correction factors are used to account for both the local level of electron equilibrium in the field, and deviations from this level in the silicon disk cavity. Results for field sizes ranging from 0.5 × 0.5 to 20 × 20 cm2 are compared to data from full Monte Carlo simulations and measurements. The achieved dose response accuracy is for the smallest fields 1-2%, and for larger fields 0.5%. Spectral variations were of little importance for the small field response, implying that volume averaging, and to some extent interface transient effects, are of importance for use of unshielded diodes in non-equilibrium conditions. The results indicate that diodes should preferably be designed to have the thin layer of active volume padded in between inactive layers of the silicon base material.

  • 11. Enger, Shirin A.
    et al.
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Verhaegen, Frank
    Beaulieu, Luc
    Dose to tissue medium or water cavities as surrogate for the dose to cell nuclei at brachytherapy photon energies2012In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 57, no 14, p. 4489-4500Article in journal (Refereed)
    Abstract [en]

    It has been suggested that modern dose calculation algorithms should be able to report absorbed dose both as dose to the local medium, D-m,D-m, and as dose to a water cavity embedded in the medium, D-w,D-m, using conversion factors from cavity theory. Assuming that the cell nucleus with its DNA content is the most important target for biological response, the aim of this study is to investigate, by means of Monte Carlo (MC) simulations, the relationship of the dose to a cell nucleus in a medium, D-n,D-m, to D-m,D-m and D-w,D-m, for different combinations of cell nucleus compositions and tissue media for different photon energies used in brachytherapy. As D-n,D-m is very impractical to calculate directly for routine treatment planning, while D-m,D-m and D-w,D-m are much easier to obtain, the questions arise which one of these quantities is the best surrogate for D-n,D-m and which cavity theory assumptions should one use for its estimate. The Geant4.9.4 MC code was used to calculate D-m,D-m, D-w,D-m and D-n,D-m for photon energies from 20 (representing the lower energy end of brachytherapy for Pd-103 or I-125) to 300 keV (close to the mean energy of Ir-192) and for the tissue media adipose, breast, prostate and muscle. To simulate the cell and its nucleus, concentric spherical cavities were placed inside a cubic phantom (10 x 10 x 10 mm(3)). The diameter of the simulated nuclei was set to 14 mu m. For each tissue medium, three different setups were simulated; (a) D-n,D-m was calculated with nuclei embedded in tissues (MC-D-n,D-m). Four different published elemental compositions of cell nuclei were used. (b) D-w,D-m was calculated with MC (MC-D-w,D-m) and compared with large cavity theory calculated D-w,D-m (LCT-D-w,D-m), and small cavity theory calculated D-w,D-m (SCT-D-w,D-m). (c) D-m,D-m was calculated with MC (MC-D-m,D-m). MC-D-w,D-m is a good substitute for MC-D-n,D-m for all photon energies and for all simulated nucleus compositions and tissue types. SCT-D-w,D-m can be used for most energies in brachytherapy, while LCT-D-w,D-m should only be considered for source spectra well below 50 keV, since contributions to the absorbed dose inside the nucleus to a large degree stem from electrons released in the surrounding medium. MC-D-m,D-m is not an appropriate substitute for MC-D-n,D-m for the lowest photon energies for adipose and breast tissues. The ratio of MC-D-m,D-m to MC-D-n,D-m for adipose and breast tissue deviates from unity by 34% and 15% respectively for the lowest photon energy (20 keV), whereas the ratio is close to unity for higher energies. For prostate and muscle tissue MC-D-m,D-m is a good substitute for MC-D-n,D-m. However, for all photon energies and tissue types the nucleus composition with the highest hydrogen content behaves differently than other compositions. Elemental compositions of the tissue and nuclei affect considerably the absorbed dose to the cell nuclei for brachytherapy sources, in particular those at the low-energy end of the spectrum. Thus, there is a need for more accurate data for the elemental compositions of tumours and healthy cells. For the nucleus compositions and tissue types investigated, MC-D-w,D-m is a good substitute to MC-D-n,D-m for all simulated photon energies. Whether other studied surrogates are good approximations to MC-D-n,D-m depends on the target size, target composition, composition of the surrounding tissue and photon energy.

  • 12. Fernandez-Varea, Jose M.
    et al.
    Gonzalez-Munoz, Gloria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Galassi, Mariel E.
    Wiklund, Kristin
    Lind, Bengt K.
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Tilly, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Limitations (and merits) of PENELOPE as a track-structure code2012In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 88, no 1-2, p. 66-70Article in journal (Refereed)
    Abstract [en]

    Purpose: To outline the limitations of PENELOPE (acronym of PENetration and Energy LOss of Positrons and Electrons) as a track-structure code, and to comment on modifications that enable its fruitful use in certain microdosimetry and nanodosimetry applications. Methods: Attention is paid to the way in which inelastic collisions of electrons are modelled and to the ensuing implications for microdosimetry analysis. Results: Inelastic mean free paths and collision stopping powers calculated with PENELOPE and two well-known optical-data models are compared. An ad hoc modification of PENELOPE is summarized where ionization and excitation of liquid water by electron impact is simulated using tables of realistic differential and total cross sections. Conclusions: PENELOPE can be employed advantageously in some track-structure applications provided that the default model for inelastic interactions of electrons is replaced by suitable tables of differential and total cross sections.

  • 13.
    Garske, Ulrike
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lessons on Tumour Response: Imaging during Therapy with Lu-177-DOTA-octreotate. A Case Report on a Patient with a Large Volume of Poorly Differentiated Neuroendocrine Carcinoma2012In: Theranostics, ISSN 1838-7640, Vol. 2, no 5, p. 459-471Article in journal (Refereed)
    Abstract [en]

    Favourable outcomes of peptide receptor radiotherapy (PRRT) of neuroendocrine tumours have been reported during the last years. Still, there are uncertainties on the radionuclides to be used, the treatment planning, and the indication in patients with a high proliferation rate. This case report describes a patient with a high tumour burden of poorly differentiated neuroendocrine carcinoma of unknown primary with a proliferation rate in liver metastases up to 50%, undergoing fractionated treatment with 7 cycles of Lu-177-DOTA-octreotate (7.4 GBq each) after disease progression on two different chemotherapy regiments. Based on initial staging scintigraphy, somatostatin receptor expression was very high. Longitudinal dosimetry studies during therapy indicated ongoing increases in tumour-to-organ ratios that coincided with an objective response. We conclude that fractionated therapy with Lu-177-DOTA-octreotate should be considered a treatment option also for those patients with large tumours, high proliferation, and high receptor expression.

  • 14.
    Garske, Ulrike
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Minor changes in effective half-life during fractionated 177Lu-Octreotate therapy2011In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 1, p. 86-96Article in journal (Refereed)
    Abstract [en]

    Fractionated (177)Lu-DOTA-octreotate therapy has been reported to be an effective treatment option for patients with generalized neuroendocrine tumors. In our clinic, full individual dosimetry is performed during the first therapy cycle, while dosimetry at later cycles is based on the 24 h uptake measurement assuming an unchanged effective half-life. Our aim was to evaluate this assumption and the variation in the 24 h uptake during therapy. Patients. Thirty patients, 13 women and 17 men, were included in the study. Methods. During the first therapy cycle the (177)Lu-concentration was measured with SPECT/CT over the abdomen at 24 h, 96 h and 168 h after infusion. The effective half-life was determined for the kidneys, liver and spleen. The procedure was repeated at cycle 4 or 5. Results. The median ratio between the effective half-lives of the latter and the first cycle was 0.97 and 1.01 for the right and left kidney, with a range of 0.89-1.01 (1st-3rd quartile) and 0.93-1.05, respectively. Discussion. The mean value of the ratios was slightly lower than one, indicating a tendency towards increased activity elimination during therapy. In individual patients, significant changes were found for all organs, often when a large tumor burden reduction occurred during treatment. Possible contributing factors appeared to be larger amounts of non-tumor bound tracer, improved organ function (kidneys), decrease of vessel obstruction (spleen), less scatter from large tumors and reduction of small metastases (liver and spleen). Conclusion. With most patients it is safe to estimate absorbed doses to kidneys, liver and spleen from 24 h activity concentration assuming an unchanged effective half-life during therapy. Patients with risk factors for kidney dysfunction need to be monitored in more detail. Simplified dosimetry based on the assumption of unchanged effective half-life can function as guidance to the number of therapy cycles an individual patient can tolerate.

  • 15.
    Grusell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Comment on "Impact of Dose and Sensitivity Heterogeneity on TCP''2015In: Computational & Mathematical Methods in Medicine, ISSN 1748-670X, E-ISSN 1748-6718, article id 682036Article in journal (Refereed)
  • 16.
    Grusell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Comments on 'The influence of dose heterogeneity on tumor control probability in fractionated radiation therapy'2013In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 58, no 18, p. 6585-6589Article in journal (Other academic)
    Abstract [en]

    By analyzing the radiobiological model, and the equations derived from the model, it is shown that the main results of the article 'The influence of dose heterogeneity on tumor control probability in fractionated radiation therapy' by Wiklund et al (2011 Phys. Med. Biol. 56 7585-600) are valid only under the condition that the dose to any cell is statistically independent of the dose to any other cell in the same fraction. This condition is in practice not fulfilled for radiotherapy. Hence the main results and most of the discussion are not applicable to fractionated radiation therapy.

  • 17.
    Grusell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    On the definition of absorbed dose2015In: Radiation Physics and Chemistry, ISSN 0969-806X, E-ISSN 1879-0895, Vol. 107, p. 131-135Article in journal (Refereed)
    Abstract [en]

    Purpose: The quantity absorbed dose is used extensively in all areas concerning the interaction of ionizing radiation with biological organisms, as well as with matter in general. The most recent and authoritative definition of absorbed dose is given by the International Commission on Radiation Units and Measurements (ICRU) in ICRU Report 85. However, that definition is incomplete. The purpose of the present work is to give a rigorous definition of absorbed dose. Methods: Absorbed dose is defined in terms of the random variable specific energy imparted. A random variable is a mathematical function, and it cannot be defined without specifying its domain of definition which is a probability space. This is not done in report 85 by the ICRU, mentioned above. Results: In the present work a definition of a suitable probability space is given, so that a rigorous definition of absorbed dose is possible. This necessarily includes the specification of the experiment which the probability space describes. In this case this is an irradiation, which is specified by the initial particles released and by the material objects which can interact with the radiation. Some consequences are discussed. Specific energy imparted is defined for a volume, and the definition of absorbed dose as a point function involves the specific energy imparted for a small mass contained in a volume surrounding the point. A possible more precise definition of this volume is suggested and discussed. Conclusions: The importance of absorbed dose motivates a proper definition, and one is given in the present work. No rigorous definition has been presented before. (C) 2014 Elsevier Ltd. All rights reserved.

  • 18.
    Honarvar, Hadis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Garousi, Javad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gunneriusson, E.
    Hoiden-Guthenberg, I.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Frejd, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Imaging of CAIX-expressing xenografts in vivo using 99mTc-HEHEHE-Z09781 Affibody molecule2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S176-S176, article id OP071Article in journal (Other academic)
  • 19. La Tessa, C.
    et al.
    Berger, T.
    Kaderka, R.
    Schardt, D.
    Körner, C.
    Ramm, U.
    Licher, J.
    Matsufuji, N.
    Dahlgren, Christina Vallhagen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Lomax, T.
    Reitz, G.
    Durante, M.
    Out-of-field dose studies with an anthropomorphic phantom: Comparison of X-rays and particle therapy treatments2012In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 105, no 1, p. 133-138Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Characterization of the out-of-field dose profile following irradiation of the target with a 3D treatment plan delivered with modern techniques. Methods: An anthropomorphic RANDO phantom was irradiated with a treatment plan designed for a simulated 5×2×5cm 3 tumor volume located in the center of the head. The experiment was repeated with all most common radiation treatment types (photons, protons and carbon ions) and delivery techniques (Intensity Modulated Radiation Therapy, passive modulation and spot scanning). The measurements were performed with active diamond detector and passive thermoluminescence (TLD) detectors to investigate the out-of-field dose both inside and outside the phantom. Results: The highest out-of-field dose values both on the surface and inside the phantom were measured during the treatment with 25 MV photons. In the proximity of the Planned Target Volume (PTV), the lowest lateral dose profile was observed for passively modulated protons mainly because of the presence of the collimator in combination with the chosen volume shape. In the far out-of-field region (above 100 mm from the PTV), passively modulated ions were characterized by a less pronounced dose fall-off in comparison with scanned beams. Overall, the treatment with scanned carbon ions delivered the lowest dose outside the target volume. Conclusions: For the selected PTV, the use of the collimator in proton therapy drastically reduced the dose deposited by ions or photons nearby the tumor. Scanning modulation represents the optimal technique for achieving the highest dose reduction far-out-of-field.

  • 20.
    Lattuada, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Hård af Segerstad, Carl
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Evaluating abdominal oedema during experimental sepsis using an isotope technique2012In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 32, no 3, p. 197-204Article in journal (Refereed)
    Abstract [en]

    Purpose: Abdominal oedema is common in sepsis. A technique for the study of such oedema may guide in the fluid regime of these patients.

    Procedures: We modified a double-isotope technique to evaluate abdominal organ oedema and fluid extravasation in 24 healthy or endotoxin-exposed (septic) piglets. Two different markers were used: red blood cells (RBC) labelled with Technetium99m (99mTc) and Transferrin labelled with Indium111 (111In). Images were acquired on a dual-head gamma camera. Microscopic evaluation of tissue biopsies was performed to compare data with the isotope technique.

    Results: No 99mTc activity was measured in the plasma fraction in blood sampled after labelling. Similarly, after molecular size gel chromatography, 111In activity was exclusively found in the high molecular fraction of the plasma. Extravasation of transferrin, indicating the degree of abdominal oedema, was 4 06 times higher in the LPS group compared to the healthy controls (P< 0 0001). Abdominal free fluid, studied in 3 animals, had as high 111In activity as in plasma, but no 99mTc activity. Intestinal lymphatic vessel size was higher in LPS (3 7 +/- 1 1 lm) compared to control animals (0 6 + 0 2 lm; P< 0 001) and oedema correlated to villus diameter (R 2 = 0 918) and lymphatic diameter (R 2 = 0 758). A correlation between a normalized index of oedema formation (NI) and intra-abdominal pressure (IAP) was also found: NI = 0 46* IAP) 3 3 (R2 = 0 56).

    Conclusions: The technique enables almost continuous recording of abdominal oedema formation and may be a valuable tool in experimental research, with the potential to be applied in the clinic.

  • 21.
    Lubberink, Mark
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Herzog, Hans
    Quantitative imaging of I-124 and Y-86 with PET2011In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 38, p. 10-18Article, review/survey (Refereed)
    Abstract [en]

    The quantitative accuracy and image quality of positron emission tomography (PET) measurements with I-124 and Y-86 is affected by the prompt emission of gamma radiation and positrons in their decays, as well as the higher energy of the emitted positrons compared to those emitted by F-18. PET scanners cannot distinguish between true coincidences, involving two 511-keV annihilation photons, and coincidences involving one annihilation photon and a prompt gamma, if the energy of this prompt gamma is within the energy window of the scanner. The current review deals with a number of aspects of the challenge this poses for quantitative PET imaging. First, the effect of prompt gamma coincidences on quantitative accuracy of PET images is discussed and a number of suggested corrections are described. Then, the effect of prompt gamma coincidences and the increased singles count rates due to gamma radiation on the count rate performance of PET is addressed, as well as possible improvements based on modification of the scanner's energy windows. Finally, the effect of positron energy on spatial resolution and recovery is assessed. The methods presented in this overview aim to overcome the challenges associated with the decay characteristics of I-124 and Y-86. Careful application of the presented correction methods can allow for quantitatively accurate images with improved image contrast.

  • 22.
    Lubberink, Mark
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Avdelningen för sjukhusfysik.
    Wong, Yeun Ying
    Raijmakers, Pieter G. H. M.
    Schuit, Robert C.
    Luurtsema, Gert
    Boellaard, Ronald
    Knaapen, Paul
    Vonk-Noordegraaf, Anton
    Lammertsma, Adriaan A.
    Myocardial Oxygen Extraction Fraction Measured Using Bolus Inhalation of O-15-Oxygen Gas and Dynamic PET2011In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 52, no 1, p. 60-66Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to determine the accuracy of oxygen extraction fraction (OEF) measurements using a dynamic scan protocol after bolus inhalation of O-15(2). The method of analysis was optimized by investigating potential reuse of myocardial blood flow (MBF), perfusable tissue fraction, and blood and lung spillover factors derived from separate O-15-water and (CO)-O-15 scans. Methods: Simulations were performed to assess the accuracy and precision of OEF for a variety of models in which different parameters from O-15-water and (CO)-O-15 scans were reused. Reproducibility was assessed in 8 patients who underwent one 10-min dynamic scan after bolus injection of 1.1 GBq of O-15-water, two 10-min dynamic scans after bolus inhalation of 1.4 GBq of O-15(2), and a 6-min static scan after bolus inhalation of 0.8 GBq of (CO)-O-15 for region-of-interest definition. Results: Simulations showed that accuracy and precision were lowest when all parameters were determined from the O-15(2) scan. The optimal accuracy and precision of OEF were obtained when fixing MBF, perfusable tissue fraction, and blood spillover to values derived from a O-15-water scan and estimating spillover from the pulmonary gas volume using an attenuation map. Optimal accuracy and precision were confirmed in the patient study, showing an OEF test-retest variability of 13% for the whole myocardium. Correction of spillover from pulmonary gas volume requires correction of the lung time-activity curve for pulmonary blood volume, which could equally well be obtained from a O-15-water rather than (CO)-O-15 scan. Conclusion: Measurement of OEF is possible using bolus inhalation of O-15(2) and a dynamic scan protocol, with optimal accuracy and precision when other relevant parameters, such as MBF, are derived from an additional O-15-water scan.

  • 23.
    Mitran, Bogdan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Altai, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Hofstrom, C.
    Honarvar, Hadis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Graslund, T.
    Evaluation of 99mTc-ZIGF1R:4551-GGGC Affibody Molecule, a New Construct for Imaging the Insulin-like Growth Factor Type 1 Receptor Expression2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S440-S440, article id P288Article in journal (Other academic)
  • 24. Nyström, Håkan
    et al.
    Blomqvist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Høyer, Morten
    Montelius, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Muren, Ludvig Paul
    Nilsson, Per
    Taheri-Kadkhoda, Zahra
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Particle therapy: a next logical step in the improvement of radiotherapy2011In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 50, no 6, p. 741-744Article in journal (Refereed)
  • 25.
    Orlova, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Hofström, Camilla
    Strand, Joanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Andersson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gräslund, Torbjörn
    [99mTc(CO)3]+-(HE)3-ZIGF1R:4551, a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours2013In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no 3, p. 439-449Article in journal (Refereed)
    Abstract [en]

    Purpose

    Radionuclide imaging of insulin-like growth factor type 1 receptor (IGF-1R) expression in tumours might be used for selection of patients who would benefit from IGF-1R-targeted therapy. We have previously shown the feasibility of IGF-1R imaging using the Affibody molecule 111In-DOTA-His6-ZIGF1R:4551. The use of 99mTc instead of 111In should improve sensitivity and resolution of imaging, and reduce the dose burden to patients. We hypothesized that inclusion of a HEHEHE tag instead of a His6 tag in ZIGF1R:4551 would permit its convenient purification using IMAC, enable labelling with [99mTc(CO)3]+, and improve its biodistribution.

    Methods

    ZIGF1R:4551 was expressed with a HEHEHE tag in the N terminus. The resulting (HE)3-ZIGF1R:4551 construct was labelled with [99mTc(CO)3]+. Targeting of IGF-1R-expressing cells using [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 was evaluated in vitro and in vivo.

    Results

    (HE)3-ZIGF1R:4551 was stably labelled with 99mTc with preserved specific binding to IGF-1R-expressing DU-145 prostate cancer cells in vitro. In mice, [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 accumulated in IGF-1R-expressing organs (pancreas, stomach, lung and salivary gland). [99mTc(CO)3]+-(HE)3-ZIGF1R:4551 demonstrated 3.6-fold lower accumulation in the liver and spleen than 111In-DOTA-ZIGF1R:4551. In NMRI nu/nu mice with DU-145 prostate cancer xenografts, the tumour uptake was 1.32 ± 0.11 %ID/g and the tumour-to-blood ratio was 4.4 ± 0.3 at 8 h after injection. The xenografts were visualized using a gamma camera 6 h after injection.

    Conclusion

    99mTc(CO)3]+-(HE)3-ZIGF1R:4551 is a promising candidate for visualization of IGF-1R expression in malignant tumours.

  • 26.
    Radu, Calin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Norrlid, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Braendengen, Morten
    Department of Oncology, Oslo University Hospital, Oslo, Norway.
    Hansson, Karl
    Department of Diagnostic Radiology, Karolinska University Hospital Solna and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm.
    Isacsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patientsManuscript (preprint) (Other academic)
  • 27. Rosik, Daniel
    et al.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Malmberg, Jennie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Eriksson Karlström, Amelie
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Direct comparison of In-111-labelled two-helix and three-helix Affibody molecules for in vivo molecular imaging2012In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 39, no 4, p. 693-702Article in journal (Refereed)
    Abstract [en]

    Radiolabelled Affibody molecules have demonstrated a potential for visualization of tumour-associated molecular targets. Affibody molecules (7 kDa) are composed of three alpha-helices. Recently, a smaller two-helix variant of Affibody molecules (5.1 kDa) was developed. The aim of this study was to compare two- and three-helix HER2-targeting Affibody molecules directly in vivo. The three-helix Affibody molecule ABY-002 and the two-helix Affibody molecule PEP09239 were labelled with In-111 at the N-termini via DOTA chelator. Tumour-targeting properties were directly compared at 1 and 4 h after injection in mice bearing SKOV-3 xenografts with high HER2 expression and LS174T xenografts with low HER2 expression. The dissociation constants (K (D)) for HER2 binding were 78 pM for the three-helix Affibody molecule and 2.1 nM for the two-helix Affibody molecule. In-111-PEP09239 cleared more rapidly from the blood. In xenografts with high HER2 expression, the uptake of In-111-ABY-002 was significantly higher than that of In-111-PEP09239. The tumour-to-blood ratio was higher for In-111-PEP09239 at 4 h after injection, while there was no significant difference in other tumour-to-organ ratios. The tumour uptake of In-111-ABY-002 was eightfold higher than that of In-111-PEP09239 in xenografts with low expression. Tumour-to-blood ratios were equal in this case, but other tumour-to-organ ratios were appreciably higher for the three-helix variant. For tumours with high HER2 expression, two-helix HER2-targeting Affibody molecules can provide higher tumour-to-blood ratio at the cost of lower tumour uptake. In the case of low expression, both tumour uptake and tumour-to-organ ratios are appreciably higher for three-helix than for two-helix HER2-targeting Affibody molecules.

  • 28.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Dosimetry of Radionuclide Therapy with 177Lu-octreotate2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In radionuclide therapy it is still common to administer standard activities or to scale administered activity with blunt parameters such as body weight or surface area. This is not ideal because, due to considerable variation in kinetics, large safety margins have to be applied to avoid radiation damage to healthy organs, which causes under-treatment of many patients. To base the administered activity on individual dosimetry, as in other therapy modalities using ionizing radiation, will essentially solve this problem. However, dosimetry in radionuclide therapy is resource-demanding and debilitating for the patient because it involves a number of measurements to determine the kinetics of the therapy radionuclide and needs to be optimized for clinical feasibility.

    First, the ability to measure radioactivity distributions of radionuclides for therapy was investigated. SPECT measurements of 177Lu, which was later used clinically, showed good spatial resolution and a reasonable quantitative accuracy.

    A new method to calculate absorbed dose to solid risk organs and tumours was developed and applied in the clinic. Kinetic data were obtained by repeated SPECT measurements. Radiation concentration determined in small volumes of interest could then be multiplied by a constant to obtain absorbed dose because it was shown that cross-fire was negligible in organs with high activity concentration. The new dosimetry method, compared to other methods, was found to give better results with less effort. In addition, a method to calculate absorbed dose to bone marrow was developed and clinically implemented.

    In 200 patients, individual kinetics and absorbed dose were studied and variations were found to be large. Kidney was the dose-limiting organ in almost all patients (98.5%). Keeping the kidney dose < 23Gy, about half of the patients could receive 5, or up to 10 treatments instead of the stipulated 4.

    List of papers
    1. Performance of coincidence imaging with long-lived positron emitters as an alternative to dedicated PET and SPECT
    Open this publication in new window or tab >>Performance of coincidence imaging with long-lived positron emitters as an alternative to dedicated PET and SPECT
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    2004 (English)In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 49, no 24, p. 5419-32Article in journal (Refereed) Published
    Abstract [en]

    An important application of quantitative imaging in nuclear medicine is the estimation of absorbed doses in radionuclide therapy. Depending on the radionuclide used for therapy, quantitative imaging of the kinetics of the therapeutic radiopharmaceutical could be done using planar imaging, SPECT or PET. Since many nuclear medicine departments have a gamma camera system that is also suitable for coincidence imaging, the performance of these systems with respect to quantitative imaging of PET isotopes that could be of use in radionuclide dosimetry is of interest. We investigated the performance of a gamma camera with coincidence imaging capabilities with 99mTc, 111In, 18F and 76Br and a dedicated PET system with 18F and 76Br, using a single standard set of phantom measurements. Here, 76Br was taken as a typical example of prompt gamma-emitting PET isotopes that are applicable in radionuclide therapy dosimetry such as 86Y and 124I. Image quality measurements show comparable image contrasts for 76Br coincidence imaging and 111In SPECT. Although the spatial resolution of coincidence imaging is better than single photon imaging, the contrast obtained with 76Br is not better than that with 99mTc or 111In because of the prompt gamma involved. Additional improvements are necessary to allow for quantitative coincidence imaging of long-lived, prompt gamma producing positron emitters.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-72947 (URN)10.1088/0031-9155/49/24/002 (DOI)15724533 (PubMedID)
    Available from: 2005-09-26 Created: 2005-09-26 Last updated: 2017-12-14Bibliographically approved
    2. Individualized dosimetry in patients undergoing therapy with Lu-177-DOTA-D-Phe(1)-Tyr(3)-octreotate
    Open this publication in new window or tab >>Individualized dosimetry in patients undergoing therapy with Lu-177-DOTA-D-Phe(1)-Tyr(3)-octreotate
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    2010 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 37, no 2, p. 212-225Article in journal (Refereed) Published
    Abstract [en]

    In recent years, targeted radionuclide therapy with [Lu-177-DOTA(0), Tyr(3)]octreotate for neuroendocrine tumours has yielded promising results. This therapy may be further improved by using individualized dosimetry allowing optimization of the absorbed dose to the tumours and the normal organs. The aim of this study was to investigate the feasibility and reliability of individualized dosimetry based on SPECT in comparison to conventional planar imaging. Attenuation-corrected SPECT data were analysed both by using organ-based volumes of interest (VOIs) to obtain the total radioactivity in the organ, and by using small VOIs to measure the tissue radioactivity concentration. During the first treatment session in 24 patients, imaging was performed 1, 24, 96 and 168 h after [Lu-177-DOTA(0), Tyr(3)]octreotate infusion. Absorbed doses in non tumour-affected kidney, liver and spleen were calculated and compared for all three methods (planar imaging, SPECT organ VOIs, SPECT small VOIs). Planar and SPECT dosimetry were comparable in areas free of tumours, but due to overlap the planar dosimetry highly overestimated the absorbed dose in organs with tumours. Furthermore, SPECT dosimetry based on small VOIs proved to be more reliable than whole-organ dosimetry. We conclude that SPECT dosimetry based on small VOIs is feasible and more accurate than conventional planar dosimetry, and thus may contribute towards optimising targeted radionuclide therapy.

    Keywords
    Neuroendocrine tumours, Individualized dosimetry, Targeted radionuclide therapy, [Lu-177-DOTA(0), Tyr(3)]Octreotate
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-138035 (URN)10.1007/s00259-009-1216-8 (DOI)000274293900003 ()19727718 (PubMedID)
    Available from: 2010-12-16 Created: 2010-12-16 Last updated: 2017-12-11Bibliographically approved
    3. Minor changes in effective half-life during fractionated 177Lu-Octreotate therapy
    Open this publication in new window or tab >>Minor changes in effective half-life during fractionated 177Lu-Octreotate therapy
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    2011 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 1, p. 86-96Article in journal (Refereed) Published
    Abstract [en]

    Fractionated (177)Lu-DOTA-octreotate therapy has been reported to be an effective treatment option for patients with generalized neuroendocrine tumors. In our clinic, full individual dosimetry is performed during the first therapy cycle, while dosimetry at later cycles is based on the 24 h uptake measurement assuming an unchanged effective half-life. Our aim was to evaluate this assumption and the variation in the 24 h uptake during therapy. Patients. Thirty patients, 13 women and 17 men, were included in the study. Methods. During the first therapy cycle the (177)Lu-concentration was measured with SPECT/CT over the abdomen at 24 h, 96 h and 168 h after infusion. The effective half-life was determined for the kidneys, liver and spleen. The procedure was repeated at cycle 4 or 5. Results. The median ratio between the effective half-lives of the latter and the first cycle was 0.97 and 1.01 for the right and left kidney, with a range of 0.89-1.01 (1st-3rd quartile) and 0.93-1.05, respectively. Discussion. The mean value of the ratios was slightly lower than one, indicating a tendency towards increased activity elimination during therapy. In individual patients, significant changes were found for all organs, often when a large tumor burden reduction occurred during treatment. Possible contributing factors appeared to be larger amounts of non-tumor bound tracer, improved organ function (kidneys), decrease of vessel obstruction (spleen), less scatter from large tumors and reduction of small metastases (liver and spleen). Conclusion. With most patients it is safe to estimate absorbed doses to kidneys, liver and spleen from 24 h activity concentration assuming an unchanged effective half-life during therapy. Patients with risk factors for kidney dysfunction need to be monitored in more detail. Simplified dosimetry based on the assumption of unchanged effective half-life can function as guidance to the number of therapy cycles an individual patient can tolerate.

    Keywords
    Absorbed dose, Neuroendocrine tumour, 177Lu-octreotate
    National Category
    Cancer and Oncology
    Research subject
    Physics; Oncology; Radiology
    Identifiers
    urn:nbn:se:uu:diva-158969 (URN)10.3109/0284186X.2011.618511 (DOI)000298002000012 ()21961497 (PubMedID)
    Available from: 2011-09-19 Created: 2011-09-19 Last updated: 2017-12-08Bibliographically approved
    4. Absorbed doses to kidney and bone marrow in 200 patients undergoing therapy with 177Lu-DOTA-D-Phe1-Tyr3-octreotate
    Open this publication in new window or tab >>Absorbed doses to kidney and bone marrow in 200 patients undergoing therapy with 177Lu-DOTA-D-Phe1-Tyr3-octreotate
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    177Lu-octreotate, Absorbed dose, Neuroendocrine tumour
    National Category
    Cancer and Oncology
    Research subject
    Physics; Oncology; Radiology
    Identifiers
    urn:nbn:se:uu:diva-158971 (URN)
    Available from: 2011-09-19 Created: 2011-09-19 Last updated: 2011-11-04
  • 29.
    Sandström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Avdelningen för sjukhusfysik.
    Garske, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Avdelningen för sjukhusfysik.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Avdelningen för sjukhusfysik.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Absorbed doses to kidney and bone marrow in 200 patients undergoing therapy with 177Lu-DOTA-D-Phe1-Tyr3-octreotateManuscript (preprint) (Other academic)
  • 30.
    Sandström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Garske-Román, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment2013In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 1, p. 33-41Article in journal (Refereed)
    Abstract [en]

    The organs at risk in radionuclide therapy with 177Lu-octreotate are the bone marrow and the kidneys. The primary aim of this study was to develop an individualized dosimetry protocol for the bone marrow. The secondary aim was to identify those patients, undergoing fractionated therapy with 7.4 GBq/cycle, who first reached an accumulated dose of either 2 Gy to the bone marrow or 23 Gy to the kidneys. Methods: Two hundred patients with metastatic neuroendocrine tumors with high somatostatin receptor expression were included. After the administration of 7.4 GBq of 177Lu-octreotate, blood samples were drawn 6 times within the first 24 h. In 50 patients, additional blood samples were obtained at 96 and 168 h. Moreover, urine was collected from 30 patients during the first 24 h. Planar whole-body and SPECT/CT images over the abdomen were acquired at 24, 96, and 168 h after the infusion. Calculation of the absorbed radiation dose to the bone marrow was based on blood and urinary activity curves combined with organ-based analysis of the whole-body images. The absorbed dose to the kidney was calculated from the pharmacokinetic data obtained from SPECT/CT. Results: For a single cycle of 7.4 GBq, the absorbed dose to the bone marrow and the kidney ranged from 0.05 to 0.4 Gy and from 2 to 10 Gy, respectively. In 197 of 200 patients, the kidneys accumulated an absorbed dose of 23 Gy before the bone marrow reached 2 Gy. Between 2 and 10 cycles of 177Lu-octreotate could be administered before the upper dose limit for the individual patient was reached. Conclusion: A method based on repeated whole-body imaging in combination with blood and urinary activity data over time was developed to determine the absorbed dose to the bone marrow. The dose-limiting organ was the kidney in 197 of 200 patients. In 50% of the patients, more than 4 cycles of 7.4 GBq of 177Lu-octreotate could be administered, whereas 20% of the subjects were treated with fewer than 4 cycles. Individualized absorbed dose calculation is essential to optimize the therapy.

  • 31.
    Sandström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Garske-Roman, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Comparative Biodistribution and Radiation Dosimetry of Ga-68-DOTATOC and Ga-68-DOTATATE in Patients with Neuroendocrine Tumors2013In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, no 10, p. 1755-1759Article in journal (Refereed)
    Abstract [en]

    Ga-68-DOTATOC and Ga-68-DOTATATE are 2 radiolabeled somatostatin analogs for in vivo diagnosis of neuroendocrine tumors with PET. The aim of the present work was to measure their comparative biodistribution and radiation dosimetry. Methods: Ten patients diagnosed with neuroendocrine tumors were included. Each patient underwent a 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 3 h after injection of each tracer on consecutive days. Absorbed doses were calculated using OLINDA/EXM 1.1. Results: Data from 9 patients could be included in the analysis. Of the major organs, the highest uptake at 1, 2, and 3 h after injection was observed in the spleen, followed by kidneys and liver. For both tracers, the highest absorbed organ doses were seen in the spleen and urinary bladder wall, followed by kidney, adrenals, and liver. The absorbed doses to the liver and gallbladder wall were slightly but significantly higher for Ga-68-DOTATATE. The total effective dose was 0.021 +/- 0.003 mSv/MBq for both tracers. Conclusion: The effective dose for a typical 100-MBq administration of Ga-68-DOTATATE and Ga-68-DOTATOC is 2.1 mSv for both tracers. Therefore, from a radiation dosimetry point of view, there is no preference for either tracer for PET/CT evaluation of somatostatin receptor-expressing tumors.

  • 32.
    Sjöberg, Carl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Multi-atlas based segmentation using probabilistic label fusion with adaptive weighting of image similarity measures2013In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, E-ISSN 1872-7565, Vol. 110, no 3, p. 308-319Article in journal (Refereed)
    Abstract [en]

    Label fusion multi-atlas approaches for image segmentation can give better segmentation results than single atlas methods. We present a multi-atlas label fusion strategy based on probabilistic weighting of distance maps. Relationships between image similarities and segmentation similarities are estimated in a learning phase and used to derive fusion weights that are proportional to the probability for each atlas to improve the segmentation result. The method was tested using a leave-one-out strategy on a database of 21 pre-segmented prostate patients for different image registrations combined with different image similarity scorings. The probabilistic weighting yields results that are equal or better compared to both fusion with equal weights and results using the STAPLE algorithm. Results from the experiments demonstrate that label fusion by weighted distance maps is feasible, and that probabilistic weighted fusion improves segmentation quality more the stronger the individual atlas segmentation quality depends on the corresponding registered image similarity. The regions used for evaluation of the image similarity measures were found to be more important than the choice of similarity measure.

  • 33.
    Strang, Christof M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Ebmeyer, U.
    Maripuu, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Hachenberg, T.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Improved ventilation-perfusion matching by abdominal insufflation (pneumoperitoneum) with CO2 but not with air2013In: Minerva Anestesiologica, ISSN 0375-9393, E-ISSN 1827-1596, Vol. 79, no 6, p. 617-625Article in journal (Refereed)
    Abstract [en]

    Background. Pneumoperitoneum (PP) by CO2-insufflation causes atelectasis however with maintained or even improved oxygenation. We studied the effect of abdominal insufflation by carbon dioxide (CO2) and air on gas exchange during PP. Methods. Twenty-seven anesthetized pigs were studied during PP with insufflations to 12 mmHg by either 1/CO2, 2/ air or 3/CO2 during intravenous nitroprusside infusion (SNP) (N.=9 in each group). In 3 pigs in each group, gamma camera technique (SPECT) was used to study ventilation and perfusion distributions, in another 6 pigs an inert-gas technique (MIGET) was used for assessing ventilation-perfusion matching (V-A/Q). Measurements were made during anesthesia before and after 60 minutes of PP. Results. CO2-PP caused a shift of blood flow away from dependent, non-ventilated (atelectatic) to ventilated regions. Air-PP caused smaller, and SNP-PP even less shift of lung blood flow. Shunt decreased luring CO2-PP (6+/-1% compared to baseline 9+/-2%, P<0.05), did not change during Air-PP (10+/-2%) and increased during SNP-PP (16+/-2%, P<0.05). PaO2 increased from baseline 35+/-2 to 41+/-3 kPa during CO2-PP and decreased to 32+/-3 kPa during Air-PP and to 27+/-3 kPa during SNP-PP (P<0.05 for all three comparisons). PaCO2 increased during CO2- and SNP-PP. Conclusion. CO2-PP enhanced the shift of blood flow towards better ventilated areas of the lung compared to Air-PP and SNP blunted the effects seen with CO2-PP. SNP may thus have blunted and CO2 potentiated vasoconstriction, by hypoxic pulmonary vasoconstriction or another mechanism.

  • 34.
    Thuy, Tran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.