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  • 1.
    Ahlgren, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wållberg, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Tran, Thuy A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Hjertman, Magnus
    Affibody AB, Stockholm, Sweden.
    Abrahmsén, Lars
    Affibody AB, Stockholm, Sweden.
    Berndorff, Dietmar
    Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Germany.
    Dinkelborg, Ludger M.
    Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Germany.
    Cyr, John E.
    Global Drug Discovery, Bayer Schering Pharma AG, Berlin, Germany.
    Feldwisch, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine2009In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 50, no 5, p. 781-789Article in journal (Refereed)
    Abstract [en]

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

  • 2.
    Ahnesjö, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Eklund, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Rikner, Göran
    Rönnqvist, Camilla
    Grusell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Detector response modeling2009Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    A detector response correction arrangement and method is proposed for online determination of correction factors for arbitrary positions from arbitrary incident fluence distributions. As modern radiotherapy utilizes more of the available degrees of freedom of radiation machines, dosimetry has to be able to present reliable measurements for all these degrees of freedom. To determine correction factors online during measurement, Monte Carlo technique is used to precalculate fluence pencil kernels from a monodirectional beam to fully describe the particle fluence in an irradiated medium. Assuming that the particle fluence is not significantly altered by the introduction of a small detector volume, the fluence pencil kernels (212) can be integrated (214), and correction factors (216) determined, e.g. by Cavity Theory, in different positions for the detector material.

  • 3. Andersen, C. E.
    et al.
    Edmund, J. M.
    Medin, J.
    Grusell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Avdelningen för sjukhusfysik.
    Jain, M.
    Mattsson, S.
    Medical proton dosimetry using radioluminescence from aluminium oxide crystals attached to optical-fiber cables2007In: Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, ISSN 0168-9002, E-ISSN 1872-9576, Vol. 580, no 1, p. 466-468Article in journal (Refereed)
    Abstract [en]

    The prime objective of this study is to investigate if radioluminescence (RL) from carbon-doped aluminum oxide (Al2O3:C) crystals potentially can be used for absorbed dose-rate measurements during proton radiotherapy. The RL from two separate (2 mg) Al2O3:C crystals attached to optical-fiber cables were recorded during irradiations in water in a 175 MeV clinical proton beam. The RL response for low-LET protons in the plateau region of the Bragg curve was found to closely resemble that observed for a clinical 6 MV X-ray beam. An identical response was found in the Bragg peak (where the dose-averaged LET is about 4 keV/mu m) for absorbed doses less than 0.3 Gy. For doses in the range of 0.3-3Gy, we observed a significant decrease in luminescence efficiency with LET. At 3 Gy, the luminescence efficiency was about 60% in the Bragg-peak region. The study implies that the RL-signal from Al2O3:C could potentially be suitable for medical proton dosimetry in the 0-0.3 Gy range even without any LET-dependent correction factors.

  • 4.
    Eklund, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Avdelningen för sjukhusfysik.
    Modeling Silicon Diode Dose Response in Radiotherapy Fields using Fluence Pencil Kernels2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In radiotherapy, cancer is treated with ionizing radiation, most commonly bremsstrahlung photons from electrons of several MeV. Secondary electrons produced in photon-interactions results in dose deposition. The treatment response is low for low doses, raises sharply for normal treatment doses and saturates at higher doses. This response pattern applies to both eradication of tumors and to complications in healthy tissues. Well controlled treatments require accurate dosimetry since the uncertainty in delivered dose will be magnified 1 to 5 times in treatment response variations. Techniques that superpose many small radiation fields to concentrate the dose to a localized target are becoming increasingly used. A detector with high spatial resolution suitable for such fields is a silicon diode. To maintain the current accuracy of the dosimetric calibration of 1.5%, diode measurements relative to this calibration should preferably be possible at 0.5% accuracy level.

    The main limitation of silicon diodes is their over-response to low-energy photons. This problem has been adressed with the insertion of a high atomic number filter in diodes. For modeling diode detector response one must quantify the spectral variations in the irradiated medium resulting from variations of the beam parameters. This requires understanding of the particle transport and can be achieved by Monte Carlo simulations. However, the small dimensions of the detector geometry compared to surrounding medium makes a direct application of Monte Carlo impractical due to the large amount of CPU time necessary to reach statistically satisfactory results.

    In this work a fast method for spectra calculations is used, based on superposition of mono-energetic fluence pencil kernels. Building on this base a general model for silicon response functions in photon fields is developed. The incident photons are bipartitioned into a low and a high energy component. The high energy part is treated with the Spencer-Attic cavity theory while the low energy part and scattered photons are treated with large cavity theory. The deviations from electron equilibrium are investigated and handled with correction factors. The result is used to correct unshielded diode measurements, with an overall uncertainty less than 0.5%, except for very small fields where the precision is around 1-2%, thus eliminating the need for less predictable shielded diodes for measurements in photon fields.

    List of papers
    1. Fast modelling of spectra and stopping-power ratios using differentiated fluence pencil kernels
    Open this publication in new window or tab >>Fast modelling of spectra and stopping-power ratios using differentiated fluence pencil kernels
    2008 (English)In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 53, no 16, p. 4231-4247Article in journal (Refereed) Published
    Abstract [en]

    Modern radiotherapy steadily utilizes more of the available degrees of freedom provided by radiotherapy equipment, raising the need for the dosimetric methods to deliver reliable measurements for situations where the spectral properties of the radiation field may also vary. A kernel-based superposition method is presented for which the spectra from any field modulation can be instantly calculated, thus facilitating the determination of dosimetric quantities at arbitrary locations. A database of fluence pencil kernels describing the fluence resulting from point monodirectional monoenergetic beams incident onto a water phantom has been calculated with the PENELOPE-2005 Monte Carlo package. Spectra calculated by means of the kernels are presented for various 6 MV fields. The spectra have been used to investigate depth and lateral variations of water-to-air stopping-power ratios. Results show that the stopping-power ratio decreases with depth, and that this effect is more pronounced for small fields. These variations are clearly connected to spectral variations. For a 10 x 10 cm(2) field, the difference between the stopping-power ratio at 2.5 cm depth and 30 cm depth is less than 0.3% while for a 0.3 x 0.3 cm(2) field this difference is 0.7%. Ratios outside the field were found to be sensitive to the collimator leakage spectral variations.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-103245 (URN)10.1088/0031-9155/53/16/002 (DOI)000258144300003 ()18653924 (PubMedID)
    Available from: 2009-05-15 Created: 2009-05-15 Last updated: 2017-12-13Bibliographically approved
    2. Modeling silicon diode energy response factors for use in therapeutic photon beams
    Open this publication in new window or tab >>Modeling silicon diode energy response factors for use in therapeutic photon beams
    2009 (English)In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 54, no 20, p. 6135-6150Article in journal (Refereed) Published
    Abstract [en]

    Silicon diodes have good spatial resolution, which makes them advantageous over ionization chambers for dosimetry in fields with high dose gradients. However, silicon diodes overrespond to low-energy photons, that are more abundant in scatter which increase with large fields and larger depths. We present a cavity-theory-based model for a general response function for silicon detectors at arbitrary positions within photon fields. The model uses photon and electron spectra calculated from fluence pencil kernels. The incident photons are treated according to their energy through a bipartition of the primary beam photon spectrum into low- and high-energy components. Primary electrons from the high-energy component are treated according to Spencer–Attix cavity theory. Low-energy primary photons together with all scattered photons are treated according to large cavity theory supplemented with an energy-dependent factor K(E) to compensate for energy variations in the electron equilibrium. The depth variation of the response for an unshielded silicon detector has been calculated for 5 × 5 cm2, 10 × 10 cm2 and 20 × 20 cm2 fields in 6 and 15 MV beams and compared with measurements showing that our model calculates response factors with deviations less than 0.6%. An alternative method is also proposed, where we show that one can use a correlation with the scatter factor to determine the detector response of silicon diodes with an error of less than 3% in 6 MV and 15 MV photon beams.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-120550 (URN)10.1088/0031-9155/54/20/007 (DOI)000270563300007 ()19779220 (PubMedID)
    Available from: 2010-03-12 Created: 2010-03-12 Last updated: 2017-12-12Bibliographically approved
    3. Modeling silicon diode dose response factors for small photon fields
    Open this publication in new window or tab >>Modeling silicon diode dose response factors for small photon fields
    2010 (English)In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 55, no 24, p. 7411-7423Article in journal (Refereed) Published
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-120594 (URN)10.1088/0031-9155/55/24/002 (DOI)000284825200002 ()21098913 (PubMedID)
    Available from: 2010-03-15 Created: 2010-03-15 Last updated: 2017-12-12Bibliographically approved
    4. Spectral perturbations from silicon diode detector encapsulation and shielding in photon fields
    Open this publication in new window or tab >>Spectral perturbations from silicon diode detector encapsulation and shielding in photon fields
    2010 (English)In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 37, no 11, p. 6055-6060Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE

    Silicon diodes are widely used as detectors for relative dose measurements in radiotherapy. Generally two types of diode mountings are used. Plastic encapsulation is used for electron fields while the encapsulation for diodes intended for photon fields include a shield of high density material (typically tungsten). The purpose of the shield is to absorb low energy scattered photons to which a silicon diode over-responses. However, new models based on spectra calculations have been proposed for direct correction of the readout from unshielded (e.g.”electron”) diodes in photon fields. This raises the question whether it is correct to assume that the spectrum calculated for water is not disturbed by the detector encapsulation. This work aims at investigating the spectral effects of the encapsulation materials typical for typical silicon diodes used in radiotherapy clinics, including the effects of the shielding traditionally used for photon field diodes.

    METHOD

    The effects of detector encapsulation of an unshielded and a shielded commercial diode on the spectra at the silicon chip location are studied through Monte Carlo simulations with PENELOPE-2005. Variance reduction based on importance sampling and correlated sampling is applied to reduce the CPU-time needed for the simulations.

    RESULTS

    The use of variance reduction is proved to be efficient and to not introduce any significant bias of the results. Compared to reference spectra calculated in water, the encapsulation for an unshielded diode is demonstrated to not perturb the spectrum while tungsten shielded diode caused not only the desired decrease in low energy scattered photons but also a large increase of primary electrons of all energies. Measurements with a shielded diode in a 6MV photon beam proved that the shielding does not completely remove the field-size dependence of the detector response caused by the over response from low energy photons.

    CONCLUSIONS

    Spectra calculated for water can be directly used for modeling the response of silicon diodes with plastic only encapsulations. For photon dose measurements, an unshielded diode used together with appropriate corrections gives more accurate results than the traditionally used shielded diodes. Variance reduction for diode simulations can effectively be applied, however with great considerations considering choice of application.

    Keywords
    silicone diode; photon spectra; detector response
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-120602 (URN)10.1118/1.3501316 (DOI)000283747600051 ()
    Available from: 2010-03-15 Created: 2010-03-15 Last updated: 2017-12-12Bibliographically approved
    5. Detector response modeling
    Open this publication in new window or tab >>Detector response modeling
    Show others...
    2009 (English)Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    A detector response correction arrangement and method is proposed for online determination of correction factors for arbitrary positions from arbitrary incident fluence distributions. As modern radiotherapy utilizes more of the available degrees of freedom of radiation machines, dosimetry has to be able to present reliable measurements for all these degrees of freedom. To determine correction factors online during measurement, Monte Carlo technique is used to precalculate fluence pencil kernels from a monodirectional beam to fully describe the particle fluence in an irradiated medium. Assuming that the particle fluence is not significantly altered by the introduction of a small detector volume, the fluence pencil kernels (212) can be integrated (214), and correction factors (216) determined, e.g. by Cavity Theory, in different positions for the detector material.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-120609 (URN)
    Patent
    US US2009090870 (A1) (2009-04-09)
    Available from: 2010-03-15 Created: 2010-03-15 Last updated: 2012-05-29Bibliographically approved
  • 5.
    Eklund, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics. 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 Oncology, Radiology and Clinical Immunology, 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 energy response factors for use in therapeutic photon beams2009In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 54, no 20, p. 6135-6150Article in journal (Refereed)
    Abstract [en]

    Silicon diodes have good spatial resolution, which makes them advantageous over ionization chambers for dosimetry in fields with high dose gradients. However, silicon diodes overrespond to low-energy photons, that are more abundant in scatter which increase with large fields and larger depths. We present a cavity-theory-based model for a general response function for silicon detectors at arbitrary positions within photon fields. The model uses photon and electron spectra calculated from fluence pencil kernels. The incident photons are treated according to their energy through a bipartition of the primary beam photon spectrum into low- and high-energy components. Primary electrons from the high-energy component are treated according to Spencer–Attix cavity theory. Low-energy primary photons together with all scattered photons are treated according to large cavity theory supplemented with an energy-dependent factor K(E) to compensate for energy variations in the electron equilibrium. The depth variation of the response for an unshielded silicon detector has been calculated for 5 × 5 cm2, 10 × 10 cm2 and 20 × 20 cm2 fields in 6 and 15 MV beams and compared with measurements showing that our model calculates response factors with deviations less than 0.6%. An alternative method is also proposed, where we show that one can use a correlation with the scatter factor to determine the detector response of silicon diodes with an error of less than 3% in 6 MV and 15 MV photon beams.

  • 6. Engfeldt, Torun
    et al.
    Tran, Thuy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Feldwisch, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Abrahmsen, Lars
    Wennborg, Anders
    Karlström, Amelie Eriksson
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    99mTc-chelator engineering to improve tumour targeting properties of a HER2-specific Affibody molecule2007In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 34, no 11, p. 1843-1853Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Monitoring HER2 expression is crucial for selection of breast cancer patients amenable to HER2-targeting therapy. The Affibody molecule Z(HER2:342) binds to HER2 with picomolar affinity and enables specific imaging of HER2 expression. Previously, Z(HER2:342) with the additional N-terminal mercaptoacetyl-glycyl-glycyl-glycyl (maGGG) sequence was labelled with (99m)Tc and demonstrated specific targeting of HER2-expressing xenografts. However, hepatobiliary excretion caused high radioactivity accumulation in the abdomen. We investigated whether the biodistribution of Z(HER2:342) can be improved by substituting glycyl residues in the chelating sequence with more hydrophilic seryl residues. METHODS: The Affibody molecule Z(HER2:342), carrying the chelators mercaptoacetyl-glycyl-seryl-glycyl (maGSG), mercaptoacetyl-glycyl-D: -seryl-glycyl [maG(D-S)G] and mercaptoacetyl-seryl-seryl-seryl (maSSS), were prepared by peptide synthesis and labelled with (99m)Tc. The differences in the excretion pathways were evaluated in normal mice. The tumour targeting capacity of (99m)Tc-maSSS-Z(HER2:342) was studied in nude mice bearing SKOV-3 xenografts and compared with the capacity of radioiodinated Z(HER2:342). RESULTS: A shift towards renal excretion was obtained when glycine was substituted with serine in the chelating sequence. The radioactivity in the gastrointestinal tract was reduced threefold for the maSSS conjugate in comparison with the maGGG conjugate 4 h post injection (p.i.). The tumour uptake of (99m)Tc-maSSS-Z(HER2:342) was 11.5 +/- 0.5% IA/g 4 h p.i., and the tumour-to-blood ratio was 76. The pharmacokinetics and uptake characteristics of technetium-labelled Z(HER2:342) were better than those of radioiodinated Z(HER2:342). CONCLUSION: The introduction of serine residues in the chelator results in better tumour imaging properties of the Affibody molecule Z(HER2:342) compared with glycyl-containing chelators and is favourable for imaging of tumours and metastases in the abdominal area.

  • 7.
    Hansson, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Garske, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Graf, Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Single-photon emission computed tomography for prediction of treatment results in sequential intraperitoneal chemotherapy at peritoneal carcinomatosis2012In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140Article in journal (Refereed)
    Abstract [en]

    Background:

    Cytoreductive surgery and intraperitoneal chemotherapy (IPC) treatment can improve survival in peritoneal carcinomatosis. One of the reasons for failure of sequential postoperative intraperitoneal chemotherapy (SPIC) is lack of distribution of the chemotherapy in the peritoneal cavity. The primary aim of this study was to evaluate single-photon emission computed tomography (SPECT) as a predictor of successful SPIC treatment and prognosis. A secondary aim was to assess the relationship between SPECT, feasibility of SPIC, and clinical variables.

    Methods:

    Fifty-one patients (mean age 52 years, range 14-74, 20 women) were treated with Cytoreductive surgery and SPIC. SPECT studies with intraperitoneal (i.p.) Technetium-99 via a Port-a-Cath (PaC) were performed before the second course of treatment. The i.p. distribution was registered as a detected volume (DV) at four different threshold settings (1, 2, 5, and 10%) of the global maximum intensity of the SPECT examination. A calculation model for SPECT and clinical variables was tested.

    Results:

    The DV measured in the SPECT examination predicted the number of subsequent SPIC courses. The highest correlation (R=0.45) for DV was in the 2% threshold setting. Patients with a DV2% lower than mean reached two SPIC courses and patients with a DV2% higher than mean reached six SPIC course. Height correlated to higher DV and a higher number of SPIC courses. Patients with a height lower than mean reached a DV2% at 3930 ml and patients higher than mean reached a DV2% at 5507 ml. A taller person could tolerate more SPIC courses (R=0.28) and patients with a height higher than mean reached six SPIC courses; patients with a height lower than mean reached four courses. There was no correlation between DV and survival.

    Conclusion:

    The feasibility of performing SPIC without further surgical intervention can be predicted by SPECT, and it might therefore be an instrument to select which patients should preferably be treated with alternative therapy.

  • 8. Kampa, Naruepon
    et al.
    Lord, Peter
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Avdelningen för sjukhusfysik.
    Hoppe, Astrid
    Effects of measurement of plasma activity input on normalization of glomerular filtration rate to plasma volume in dogs2007In: Veterinary Radiology & Ultrasound, ISSN 1058-8183, E-ISSN 1740-8261, Vol. 48, no 6, p. 585-593Article in journal (Refereed)
    Abstract [en]

    Glomerular filtration rate (GFR) normalized to body fluid volumes to adjust for differing body size and conformation is more physiologically correct than a relationship with body weight (BW). GFR can be normalized to plasma volume by a renographic method that uses the Rutland-Patlak plot with plasma activity and kidney activity inputs. A plasma time-activity curve is obtained from a region of interest (ROI) of the left ventricle (LV), the size of which is in theory not critical. The aims of the study were to evaluate the effect of different LV ROI sizes, the effect of extravascular activity in the thorax over the LV ROI, and different time intervals for the semilogarithmic LV plot. Seventy-two scintigrams were used, with three different-sized automatic and a manual LV ROI, all with and without subtracting extravascular activity, and with LV curve time intervals of 30-120 s and 60-240 s. GFR/plasma volume was not affected by LV ROI sizes but significantly affected by extravascular activity subtraction and different time intervals. Subtracting extravascular activity from the LV ROI did not improve precision, but increased variability caused by different LV ROI sizes and time intervals chosen for the LV plot. The ROI for measuring extravascular activity apparently contained a considerable and variable intravascular component, which when subtracted, created noisy and unreliable LV curves. Manual LV ROI, without extravascular subtraction, and a time interval for LV input between 1 and 4 min are recommended as they gave the least variability determined by statistical analysis. With these methods, normal individual GFR/plasma volume in normal beagle dogs was 29.2 +/- 6.5 ml/min/l.

  • 9.
    Kozian, Alf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Schilling, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Fredén, Filip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Avdelningen för sjukhusfysik.
    Röcken, Christoph
    Institute of Pathology, Charite University Hospital, Berlin, Germany.
    Strang, Christof
    Department of Anaesthesiology and Intensive Care Medicine, Otto-von-Guericke-University Magdeburg, Germany.
    Hachenberg, Thomas
    Department of Anaesthesiology and Intensive Care Medicine, Otto-von-Guericke-University Magdeburg, Germany.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    One-lung ventilation induces hyperperfusion and alveolar damage in the ventilated lung: an experimental study2008In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 100, no 4, p. 549-559Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: One-lung ventilation (OLV) increases mechanical stress in the lung and affects ventilation and perfusion (V, Q). There are no data on the effects of OLV on postoperative V/Q matching. Thus, this controlled study evaluates the influence of OLV on V/Q distribution in a pig model using a gamma camera technique [single-photon emission computed tomography (SPECT)] and relates these findings to lung histopathology after OLV. METHODS: Eleven anaesthetized and ventilated pigs (V(T)=10 ml kg(-1), Fio2=0.40, PEEP=5 cm H2O) were studied. After lung separation, OLV and thoracotomy were performed in seven pigs (OLV group). During OLV and in a two-lung ventilation (TLV), control group (n=4) ventilation settings remained unchanged. SPECT with (81m)Kr (ventilation) and (99m)Tc-labelled macro-aggregated albumin (perfusion) was performed before, during, and 90 min after OLV/TLV. Finally, lung tissue samples were harvested and examined for alveolar damage. RESULTS: OLV affected ventilation and haemodynamic variables, but there were no differences between the OLV group and the control group before and after OLV/TLV. SPECT revealed an increase of perfusion in the dependent lung compared with baseline (49-56%), and a corresponding reduction of perfusion (51-44%) in non-dependent lungs after OLV. No perfusion changes were observed in the control group. This resulted in increased low V/Q regions and a shift of V/Q areas to 0.3-0.5 (10(-0.5)-10(-0.3)) in dependent lungs of OLV pigs and was associated with an increased diffuse alveolar damage score. CONCLUSIONS: OLV in pigs results in a substantial V/Q mismatch, hyperperfusion, and alveolar damage in the dependent lung and may thus contribute to gas exchange impairment after thoracic surgery.

  • 10.
    Lundin, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Graf, Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Garske, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nilsson, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Segmental colonic transit studies: Comparison of a radiological and a scintigraphic method2007In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 9, no 4, p. 344-351Article in journal (Refereed)
    Abstract [en]

    Objective: Colonic transit studies are used to diagnose slow transit constipation (STC) and to evaluate segmental colonic transit before segmental or subtotal colectomy. The aim of the study was to compare a single X-ray radio-opaque marker method with a scintigraphic technique to assess total and segmental colonic transit in patients with STC. Methods: Thirty-one female patients (median age 46 years) with severe constipation and a prolonged or borderline prolonged colonic transit time on radio-opaque marker study were included in the study. They were subsequently investigated with 111 Indium-DTPA colonic transit scintigraphy, with a median time between the investigations of 4(range 1-27) months. Normal values of healthy female controls were used for comparison. Results: There was no difference between the two methods interms of prolonged or normal total colonic transit time. Twenty-nine of 31 female patients had a prolonged transit time only in one or two segments on the marker study. On scintigraphy, the transit time was prolonged for patients in the left (P < 0.05 to P < 0.001), but not in the right colon. With respect to prolonged or normal segmental transit time, there was a significant difference between the two methods only in the descending colon (P = 0.02). However, the results varied considerably for individual patients. Conclusion: Segmental colonic delay was a common finding. The two methods gave similar results for groups of patients, except in the descending colon. The variation of the results for individuals suggests that a repeated transit test may improve the assessment of total and segmental transit.

  • 11. Nyholm, Tufve
    et al.
    Olofsson, Jörgen
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Karlsson, Mikael
    Photon pencil kernel parameterisation based on beam quality index2006In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 78, no 3, p. 347-351Article in journal (Refereed)
    Abstract [en]

    Background and purpose

    New treatment techniques in radiotherapy employ increasing dose calculation complexity in treatment planning. For an adequate check of the results coming from a modern treatment planning system, clinical tools with almost the same degree of generality and accuracy as the planning system itself are needed. To fulfil this need we propose a photon pencil kernel parameterization based on a minimum of input data that can be used for phantom scatter calculations. Through scatter integration the pencil kernel model can calculate common parameters, such as TPR or phantom scatter factors, used in various dosimetric QA (quality assurance) procedures.

    Material and methods

    The proposed model originates from an already published radially parameterized pencil kernel. A depth parameterization of the pencil kernel parameters has been introduced, based on a large database containing commissioned beam data for a commercial treatment planning system. The entire pencil kernel model demands only one photon beam quality index, TPR20,10, as input.

    Results

    By comparing the dose calculation results to the extensive experimental data set in the database, it has been possible to make a thorough analysis of the resulting accuracy. The errors in calculated doses, normalized to the reference geometry, are in most cases smaller than 2%.

    Conclusions

    The investigation shows that a pencil kernel model based only on TPR20,10 can be used for dosimetric verification purposes in megavoltage photon beams at depths below the range of contaminating electrons.

  • 12. Olofsson, Jörgen
    et al.
    Nyholm, Tufve
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Avdelningen för sjukhusfysik.
    Karlsson, Mikael
    Optimization of photon beam flatness for radiation therapy2007In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 52, no 6, p. 1735-1746Article in journal (Refereed)
    Abstract [en]

    In this work, we investigate the relation between lateral fluence/dose distributions and photon beam uniformity, possibly identifying ways to improve these characteristics. The calculations included treatment head scatter properties associated with three common types of linear accelerators in order to study their impact on the results. For 6 and 18 MV photon beams the lateral fluence distributions were optimized with respect to the resulting calculated flatness, as defined by the International Electrotechnical Commission (IEC), at 10 cm depth in six different field sizes. The limits proposed by IEC for maximum dose ratios ('horns') at the depth of dose maximum have also been accounted for in the optimization procedure. The conclusion was that typical head scatter variations among different types of linear accelerators have a very limited effect on the optimized results, which implies that the existing differences in measured off-axis dose distributions are related to non-equivalent optimization objectives. Finally, a comparison between the theoretically optimized lateral dose distributions and corresponding dose measurements for the three investigated accelerator types was performed. Although the measured data generally fall within the IEC requirements the optimized distributions show better results overall for the evaluated uniformity parameters, indicating that there is room for improved flatness performance in clinical photon beams.

  • 13.
    Orlova, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Nilsson, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Wikman, Maria
    KTH Sthlm.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Ståhl, Stefan
    KTH Sthlm.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Comparative in vivo evaluation of technetium and iodine labels on an anti-HER2 affibody for single-photon imaging of HER2 expression in tumors2006In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 47, no 3, p. 512-519Article in journal (Refereed)
    Abstract [en]

    In vivo diagnosis with cancer-specific targeting agents that have optimal characteristics for imaging is an important development in treatment planning for cancer patients. Overexpression of the HER2 antigen is high in several types of carcinomas and has predictive and prognostic value, especially for breast cancer. A new type of targeting agent, the Affibody molecule, was described recently. An Affibody dimer, His6-(ZHER2:4)2 (15.4 kDa), binds to HER2 with an affinity of 3 nmol/L and might be used for the imaging of HER2 expression. The use of 99mTc might improve the availability of the labeled conjugate, and Tc(I)-carbonyl chemistry enables the site-specific labeling of the histidine tag on the Affibody molecule. The goals of the present study were to prepare 99mTc-labeled His6-(ZHER2:4)2 and to evaluate its targeting properties compared with the targeting properties of 125I-4-iodobenzoate-His6-(ZHER2:4)2 [125I-His6-(ZHER2:4)2]. METHODS: The labeling of His6-(ZHER2:4)2 with 99mTc was performed with an IsoLink kit. The specificity of 99mTc-His6-(ZHER2:4)2 binding to HER2 was evaluated in vitro with SK-OV-3 ovarian carcinoma cells. The comparative biodistributions of 99mTc-His6-(ZHER2:4)2 and 125I-His6-(ZHER2:4)2 in tumor-bearing BALB/c nu/nu mice were determined. RESULTS: The labeling yield for 99mTc-His6-(ZHER2:4)2 was approximately 60% (50 degrees C), and the radiochemical purity was greater than 97%. The conjugate was stable during storage and under histidine and cysteine challenges and demonstrated receptor-specific binding. The biodistribution study demonstrated tumor-specific uptake levels (percentage injected activity per gram of tissue [%IA/g]) of 2.6 %IA/g for 99mTc-His6-(ZHER2:4)2 and 2.3 %IA/g for 125I-His6-(ZHER2:4)2 at 4 h after injection. Both conjugates provided clear imaging of SK-OV-3 xenografts at 6 h after injection. The tumor-to-nontumor ratios were much more favorable for the radioiodinated Affibody. CONCLUSION: The use of Tc(I)-carbonyl chemistry enabled us to prepare a stable, site-specifically labeled 99mTc-His6-(ZHER2:4)2 conjugate that was able to bind to HER2-expressing cells in vitro and in vivo. The indirectly radioiodinated conjugate provided better tumor-to-liver ratios. The labeling of Affibody molecules with 99mTc should be investigated further.

  • 14.
    Orlova, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Pehrson, Rikard
    Lindborg, Malin
    Tran, Thuy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Nilsson, Fredrik Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wennborg, Anders
    Abrahmsén, Lars
    Feldwisch, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Synthetic affibody molecules: a novel class of affinity ligands for molecular imaging of HER2-expressing malignant tumors2007In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 67, no 5, p. 2178-2186Article in journal (Refereed)
    Abstract [en]

    The Affibody molecule Z(HER2:342-pep2), site-specifically and homogeneously conjugated with a 1,4,7,10-tetra-azacylododecane-N,N',N'',N'''-tetraacetic acid (DOTA) chelator, was produced in a single chemical process by peptide synthesis. DOTA-Z(HER2:342-pep2) folds spontaneously and binds HER2 with 65 pmol/L affinity. Efficient radiolabeling with >95% incorporation of (111)In was achieved within 30 min at low (room temperature) and high temperatures (up to 90 degrees C). Tumor uptake of (111)In-DOTA-Z(HER2:342-pep2) was specific for HER2-positive xenografts. A high tumor uptake of 23% injected activity per gram tissue, a tumor-to-blood ratio of >7.5, and high-contrast gamma camera images were obtained already 1 h after injection. Pretreatment with Herceptin did not interfere with tumor targeting, whereas degradation of HER2 using the heat shock protein 90 inhibitor 17-allylamino-geldanamycin before administration of (111)In-DOTA-Z(HER2:342-pep2) obliterated the tumor image. The present results show that radiolabeled synthetic DOTA-Z(HER2:342-pep2) has the potential to become a clinically useful radiopharmaceutical for in vivo molecular imaging of HER2-expressing carcinomas.

  • 15.
    Orlova, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Tran, Thuy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Engfeldt, Torun
    Eriksson Karlström, Amelie
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pre-clinical evaluation of [111In]-benzyl-DOTA-Z(HER2:342), a potential agent for imaging of HER2 expression in malignant tumors2007In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 20, no 3, p. 397-404Article in journal (Refereed)
    Abstract [en]

    Imaging of expression of human epidermal growth factor receptor type 2 (HER2) in breast carcinomas may help to select patients eligible for trastuzumab therapy. The Affibody molecule Z(HER2:342) is a small (7-kDa) non-immunoglobulin affinity protein, which binds to HER2 with a picomolar affinity. Previously, a benzyl-DTPA conjugate of Z(HER2:342) was labeled with 111In and demonstrated good targeting in murine xenografts. We considered that the use of the macrocyclic chelator DOTA could increase the label stability and enhance a choice of nuclides, which could be used as a label for Z(HER2:342). The goal of this study was the preparation and pre-clinical evaluation of the indium-111- labeled DOTA-derivative of Z(HER2:342). Isothiocyanate-benzyl-DOTA was coupled to recombinant Z(HER2:342), and the conjugate was efficiently labeled with 111In at 60 degrees C. The specificity of 111In-benzyl-DOTA-Z(HER2:342) binding to HER2 was confirmed in vitro using HER2-expressing breast carcinoma BT474 and ovarian carcinoma SKOV-3 cell lines. Biodistribution of 111In-benzyl-DOTA-Z(HER2:342) was performed in nude mice bearing LS174T xenografts and compared directly with the biodistribution of 111In-benzyl-DTPA-Z(HER2:342). In vivo, 111In-benzyl-DOTA-Z(HER2:342) demonstrated quick clearance from blood and non-specific organs except the kidneys. Four hours post injection (pi), the tumor uptake of 111In-benzyl-DOTA-Z(HER2:342) (4.4+/-1.0% IA/g) was specific and the tumor-to-blood ratio was 23. The use of benzyl-DTPA provided higher tumor-to-blood and tumor-to-liver ratios. gamma-camera imaging showed clear visualization of HER2-expressing xenografts using 111In-benzyl-DOTA-Z(HER2:342). 111In-benzyl-DOTA-Z(HER2:342) has a potential for imaging of HER2 expression in malignant tumors.

  • 16.
    Sandström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Garske, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Individualized dosimetry in patients undergoing therapy with Lu-177-DOTA-D-Phe(1)-Tyr(3)-octreotate2010In: 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)
    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.

  • 17.
    Strang, Christof M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Fredén, Filip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Avdelningen för sjukhusfysik.
    Hachenberg, T.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Ventilation-perfusion distributions and gas exchange during carbon dioxide-pneumoperitoneum in a porcine model2010In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 105, no 5, p. 691-697Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: /st> Carbon dioxide (CO(2))-pneumoperitoneum (PP) of 12 mm Hg increases arterial oxygenation, but it also promotes collapse of dependent lung regions. This seeming paradox prompted the present animal study on the effects of PP on ventilation-perfusion distribution (V/Q) and gas exchange. METHODS: /st> Fourteen anaesthetized pigs were studied. In seven pigs, single photon emission computed tomography (SPECT) was used for spatial analysis of ventilation and perfusion distributions, and in another seven pigs, multiple inert gas elimination technique (MIGET) was used for detailed analysis of V/Q matching. SPECT/MIGET and central haemodynamics and pulmonary gas exchange were recorded during anaesthesia before and 60 min after induction of PP. RESULTS: /st> SPECT during PP showed no or only poorly ventilated regions in the dependent lung compared with the ventilation distribution during anaesthesia before PP. PP was accompanied by redistribution of blood flow away from the non- or poorly ventilated regions. V/Q analysis by MIGET showed decreased shunt from 9 (sd 2) to 7 (2)% after induction of PP (P<0.05). No regions of low V/Q were seen either before or during PP. Almost no regions of high V/Q developed during PP (1% of total ventilation). Pa(o(2)) increased from 33 (1.2) to 35.7 (3.2) kPa (P<0.01) and arterial to end-tidal Pco(2) gradient (Pae'(co(2))) increased from 0.3 (0.1) to 0.6 (0.2) kPa (P<0.05). CONCLUSIONS: /st> Perfusion was redistributed away from dorsal, collapsed lung regions when PP was established. This resulted in a better V/Q match. A possible mechanism is enhanced hypoxic pulmonary vasoconstriction.

  • 18.
    Tolmachev, Vladimir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Friedman, Mikaela
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Eriksson, Tove L.
    Rosik, Daniel
    Hodik, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Ståhl, Stefan
    Frejd, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Affibody molecules for epidermal growth factor receptor targeting in vivo: aspects of dimerization and labeling chemistry2009In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 50, no 2, p. 274-283Article in journal (Refereed)
    Abstract [en]

    Noninvasive detection of epidermal growth factor receptor (EGFR) expression in malignant tumors by radionuclide molecular imaging may provide diagnostic information influencing patient management. The aim of this study was to evaluate a novel EGFR-targeting protein, the ZEGFR:1907 Affibody molecule, for radionuclide imaging of EGFR expression, to determine a suitable tracer format (dimer or monomer) and optimal label. METHODS: An EGFR-specific Affibody molecule, ZEGFR:1907, and its dimeric form, (ZEGFR:1907)2, were labeled with 111In using benzyl-diethylenetriaminepentaacetic acid and with 125I using p-iodobenzoate. Affinity and cellular retention of conjugates were evaluated in vitro. Biodistribution of radiolabeled Affibody molecules was compared in mice bearing EGFR-expressing A431 xenografts. Specificity of EGFR targeting was confirmed by comparison with biodistribution of non-EGFR-specific counterparts. RESULTS: Head-to-tail dimerization of the Affibody molecule improved the dissociation rate. In vitro, dimeric forms demonstrated superior cellular retention of radioactivity. For both molecular set-ups, retention was better for the 111In-labeled tracer than for the radioiodinated counterpart. In vivo, all conjugates accumulated specifically in xenografts and in EGFR-expressing tissues. The retention of radioactivity in tumors was better in vivo for dimeric forms; however, the absolute uptake values were higher for monomeric tracers. The best tracer, 111In-labeled ZEGFR:1907, provided a tumor-to-blood ratio of 100 (24 h after injection). CONCLUSION: The radiometal-labeled monomeric Affibody molecule ZEGFR:1907 has a potential for radionuclide molecular imaging of EGFR expression in malignant tumors.

  • 19.
    Tolmachev, Vladimir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    A HER2-binding Affibody molecule labelled with 68Ga for PET imaging: direct in vivo comparison with the 111In-labelled analogue2010In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 37, no 7, p. 1356-1367Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Overexpression of HER2 receptors is a prognostic and predictive biomarker in breast cancer and a number of other malignancies. Radionuclide molecular imaging of HER2 overexpression may influence patient management making treatment more personalized. Earlier, (111)In-DOTA-Z(HER2:342-pep2) (ABY-002) Affibody molecule demonstrated excellent imaging of HER2-expressing xenografts in mice shortly after injection. The use of the positron-emitting nuclide (68)Ga instead of (111)In might increase both the sensitivity of HER2 imaging and accuracy of expression quantification. The goal of this study was to prepare and characterize (68)Ga-labelled ABY-002. METHODS: (68)Ga labelling of ABY-002 was optimized. In vitro cell binding and procession of (68)Ga-ABY-002 was evaluated. Biodistribution and tumour targeting of (68)Ga-ABY-002 and (111)In-ABY-002 was compared in vivo by paired-label experiments. RESULTS: ABY-002 was incubated with (68)Ga at 90 degrees C for 10 min resulting in a radiochemical labelling yield of over 95%. Capacity for specific binding to HER2-expressing cells was retained. In vivo, both (68)Ga-ABY-002 and (111)In-ABY-002 demonstrated specific targeting of SKOV-3 xenografts and high-contrast imaging. Background radioactivity in blood, lungs, gastrointestinal tract and muscle fell more rapidly for (68)Ga-ABY-002 compared with (111)In-ABY-002 favouring imaging shortly after injection. For (68)Ga-ABY-002, a tumour uptake of 12.4 +/- 3.8%ID/g and a tumour to blood ratio of 31 +/- 13 were achieved at 2 h post-injection. CONCLUSION: (68)Ga-ABY-002 is easy to label and provides high-contrast imaging within 2 h after injection. This makes it a promising candidate for clinical molecular imaging of HER2 expression in malignant tumours.

  • 20.
    Tran, Thuy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Sivaev, Igor
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Avdelningen för sjukhusfysik.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Comparison of benzoate- and dodecaborate-based linkers for attachment of radioiodine to HER2-targeting Affibody ligand2007In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 19, no 3, p. 485-493Article in journal (Refereed)
    Abstract [en]

    The use of radionuclide molecular imaging enables the selection of patients for treatment using molecular medicine. Preclinical studies have demonstrated that a novel low-molecular-weight affinity ligand, Affibody molecule Z(HER2:342) can image the expression of HER2 with high sensitivity and specificity in tumour xenografts and has a potential for the selection of patients for treatment using Herceptin or other anti-HER2 medicine. In this study, we performed a comparative evaluation of two possible linkers for radioiodination of the Affibody molecule Z(HER2:342), 4-iodobenzoate (PIB) and [4-isothiocyanatobenzyl)-amino]-undecahydro-closo-dodecaborate (DABI). It was shown that the use of DABI makes it possible to obtain radioiodinated Z(HER2:342) with preserved capacity for selective binding to HER2-expressing cells. There was no difference between 125I-PIB-Z(HER2:342) and 125I-DABI-Z(HER2:342) in cellular retention of radioactivity after interrupted incubation with radiolabelled Affibody ligands. In vivo, the biodistribution of 125I-PIB-Z(HER2:342) was characterized by a high tumour uptake at 4 h pi (12.7+/-4.6% IA/g) and a quick clearance from blood and normal organs. The tumour uptake of 125I-DABI-Z(HER2:342) was appreciably lower (2.7+/-1.2% IA/g), and a high uptake of this conjugate in the liver was observed. A gamma-camera experiment (at 6 h pi) demonstrated that the use of 125I-PIB-Z(HER2:342) provided a much better contrast of imaging HER2-expressing xenografts than the use of 125I-DABI-Z(HER2:342). In conclusion, 125I-PIB-Z(HER2:342) is superior to 125I-DABI-Z(HER2:342) as an agent for imaging HER2 expression in vivo.

  • 21. Waldeland, Einar
    et al.
    Hole, Eli Olaug
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Grusell, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Avdelningen för sjukhusfysik.
    Sagstuen, Einar
    Malinen, Eirik
    Radical formation in lithium formate EPR dosimeters after irradiation with protons and nitrogen ions2010In: Radiation Research, ISSN 0033-7587, E-ISSN 1938-5404, Vol. 174, no 2, p. 251-257Article in journal (Refereed)
    Abstract [en]

    Radical formation in polycrystalline lithium formate monohydrate after irradiation with gamma rays, protons and nitrogen ions at room temperature was studied by continuous-wave electron paramagnetic resonance (EPR) spectroscopy. The linear energy transfer (LET) of the various radiation beams was 0.2, 0.7-3.9 and 110-164 keV/microm for gamma rays, protons and nitrogen ions, respectively. Doses between 5 and 20 Gy were given. The EPR reading (the area under the EPR absorption resonance) increased linearly with dose for all types of radiation. As the LET increased, the relative effectiveness (the EPR reading per dose relative to that for gamma rays) decreased, while the EPR line width increased. Track structure theory and modeling of detector effectiveness predicted the dosimeter response observed after proton and nitrogen-ion irradiation. A semi-empirical line broadening model including dipolar spin-spin interactions was developed that explained the dependence of the line width on LET. The findings indicate that the local radical density in lithium formate is increased after high-LET irradiation.

  • 22.
    Wållberg, Helena
    et al.
    Affibody AB, Stockholm, Sweden.
    Ahlgren, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Section of Medical Physics.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys61]-ZHER2:2395-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors2010In: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 12, no 1, p. 54-62Article in journal (Refereed)
    Abstract [en]

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

  • 23.
    Zhu, Timothy C.
    et al.
    University of Pennsylvania.
    Ahnesjö, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Avdelningen för sjukhusfysik.
    Lam, Kwok Leung
    Li, X. Allen
    Ma, Chang-Ming Charlie
    Palta, Jatinder R.
    Sharpe, Michael B.
    Thomadsen, Bruce
    Tailor, Ramesh C.
    Report of AAPM Therapy Physics Committee Task Group 74: In-air output ratio, Sc, for megavoltage photon beams2009In: Medical physics (Lancaster), ISSN 0094-2405, Vol. 36, no 11, p. 5261-5291Article, review/survey (Refereed)
    Abstract [en]

    The concept of in-air output ratio (Sc) was introduced to characterize how the incident photon fluence per monitor unit (or unit time for a Co-60 unit) varies with collimator settings. However, there has been much confusion regarding the measurement technique to be used that has prevented the accurate and consistent determination of Sc. The main thrust of the report is to devise a theoretical and measurement formalism that ensures interinstitutional consistency of Sc. The in-air output ratio, Sc, is defined as the ratio of primary collision water kerma in free-space, Kp, per monitor unit between an arbitrary collimator setting and the reference collimator setting at the same location. Miniphantoms with sufficient lateral and longitudinal thicknesses to eliminate electron contamination and maintain transient electron equilibrium are recommended for the measurement of Sc. The authors present a correction formalism to extrapolate the correct Sc from the measured values using high-Z miniphantom. Miniphantoms made of high-Z material are used to measure Sc for small fields (e.g., IMRT or stereotactic radiosurgery). This report presents a review of the components of Sc, including headscatter, source-obscuring, and monitor-backscattering effects. A review of calculation methods (Monte Carlo and empirical) used to calculate Sc for arbitrary shaped fields is presented. The authors discussed the use of Sc in photon dose calculation algorithms, in particular, monitor unit calculation. Finally, a summary of Sc data (from RPC and other institutions) is included for QA purposes.

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