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  • 51.
    Ahlstrom, Håkan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bergqvist, David
    Department of Surgical Sciences.
    Välgjord multicenterstudie ett skolexempel på hur ny medicinsk teknik bör utvärderas.1996In: Läkartidningen, Vol. 93, p. 3555-Article in journal (Other scientific)
  • 52.
    Ahlstrom, Håkan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Eriksson, Barbro
    Department of Medical Sciences.
    Bergstrom, Mats
    Bjurling, P
    Langstrom, Bengt
    Oberg, Kjell
    Department of Medical Sciences.
    Positron emission tomography in endocrine pancreatic tumors.1995In: Radiology, Vol. 195, p. 333-Article in journal (Refereed)
  • 53.
    Ahlstrom, Håkan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gehl, H-B
    Mn-DPDP as a pancreas specific contrast media for MRI.1997In: Acta Radiol., Vol. 38, p. 660-Article in journal (Refereed)
  • 54. Ahmed, Shahana
    et al.
    Thomas, Gilles
    Ghoussaini, Maya
    Healey, Catherine S.
    Humphreys, Manjeet K.
    Platte, Radka
    Morrison, Jonathan
    Maranian, Melanie
    Pooley, Karen A.
    Luben, Robert
    Eccles, Diana
    Evans, D. Gareth
    Fletcher, Olivia
    Johnson, Nichola
    dos Santos Silva, Isabel
    Peto, Julian
    Stratton, Michael R.
    Rahman, Nazneen
    Jacobs, Kevin
    Prentice, Ross
    Anderson, Garnet L.
    Rajkovic, Aleksandar
    Curb, J. David
    Ziegler, Regina G.
    Berg, Christine D.
    Buys, Saundra S.
    McCarty, Catherine A.
    Feigelson, Heather Spencer
    Calle, Eugenia E.
    Thun, Michael J.
    Diver, W. Ryan
    Bojesen, Stig
    Nordestgaard, Børge G.
    Flyger, Henrik
    Dörk, Thilo
    Schürmann, Peter
    Hillemanns, Peter
    Karstens, Johann H.
    Bogdanova, Natalia V.
    Antonenkova, Natalia N.
    Zalutsky, Iosif V.
    Bermisheva, Marina
    Fedorova, Sardana
    Khusnutdinova, Elza
    Kang, Daehee
    Yoo, Keun-Young
    Noh, Dong Young
    Ahn, Sei-Hyun
    Devilee, Peter
    van Asperen, Christi J.
    Tollenaar, R. A. E. M.
    Seynaeve, Caroline
    Garcia-Closas, Montserrat
    Lissowska, Jolanta
    Brinton, Louise
    Peplonska, Beata
    Nevanlinna, Heli
    Heikkinen, Tuomas
    Aittomäki, Kristiina
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Hopper, John L.
    Southey, Melissa C.
    Smith, Letitia
    Spurdle, Amanda B.
    Schmidt, Marjanka K.
    Broeks, Annegien
    van Hien, Richard R.
    Cornelissen, Sten
    Milne, Roger L.
    Ribas, Gloria
    González-Neira, Anna
    Benitez, Javier
    Schmutzler, Rita K.
    Burwinkel, Barbara
    Bartram, Claus R.
    Meindl, Alfons
    Brauch, Hiltrud
    Justenhoven, Christina
    Hamann, Ute
    Chang-Claude, Jenny
    Hein, Rebecca
    Wang-Gohrke, Shan
    Lindblom, Annika
    Margolin, Sara
    Mannermaa, Arto
    Kosma, Veli-Matti
    Kataja, Vesa
    Olson, Janet E.
    Wang, Xianshu
    Fredericksen, Zachary
    Giles, Graham G.
    Severi, Gianluca
    Baglietto, Laura
    English, Dallas R.
    Hankinson, Susan E.
    Cox, David G.
    Kraft, Peter
    Vatten, Lars J.
    Hveem, Kristian
    Kumle, Merethe
    Sigurdson, Alice
    Doody, Michele
    Bhatti, Parveen
    Alexander, Bruce H.
    Hooning, Maartje J.
    van den Ouweland, Ans M. W.
    Oldenburg, Rogier A.
    Schutte, Mieke
    Hall, Per
    Czene, Kamila
    Liu, Jianjun
    Li, Yuqing
    Cox, Angela
    Elliott, Graeme
    Brock, Ian
    Reed, Malcolm W. R.
    Shen, Chen-Yang
    Yu, Jyh-Cherng
    Hsu, Giu-Cheng
    Chen, Shou-Tung
    Anton-Culver, Hoda
    Ziogas, Argyrios
    Andrulis, Irene L.
    Knight, Julia A.
    Beesley, Jonathan
    Goode, Ellen L.
    Couch, Fergus
    Chenevix-Trench, Georgia
    Hoover, Robert N.
    Ponder, Bruce A. J.
    Hunter, David J.
    Pharoah, Paul D. P.
    Dunning, Alison M.
    Chanock, Stephen J.
    Easton, Douglas F.
    Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.22009In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 41, no 5, p. 585-590Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 x 10(-23)) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 x 10(-8)). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.

  • 55.
    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.

  • 56.
    Ahnesjö, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hårdemark, Björn
    Isacsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Montelius, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    The IMRT information process-mastering the degrees of freedom in external beam therapy2006In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 51, no 13, p. R381-402Article in journal (Refereed)
    Abstract [en]

    The techniques and procedures for intensity-modulated radiation therapy (IMRT) are reviewed in the context of the information process central to treatment planning and delivery of IMRT. A presentation is given of the evolution of the information based radiotherapy workflow and dose delivery techniques, as well as the volume and planning concepts for relating the dose information to image based patient representations. The formulation of the dose shaping process as an optimization problem is described. The different steps in the calculation flow for determination of machine parameters for dose delivery are described starting from the formulation of optimization objectives over dose calculation to optimization procedures. Finally, the main elements of the quality assurance procedure necessary for implementing IMRT clinically are reviewed.

  • 57.
    Ahnesjö, Anders
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Onkologi.
    Weber, Lars
    Murman, Anders
    Saxner, Mikael
    Thorslund, Ingvar
    Traneus, Erik
    Beam modeling and verification of a photon beam multisource model.2005In: Medical Physics, ISSN 0094-2405, Vol. 32, no 6, p. 1722-37Article in journal (Refereed)
    Abstract [en]

    Dose calculations for treatment planning of photon beam radiotherapy require a model of the beam to drive the dose calculation models. The beam shaping process involves scattering and filtering that yield radiation components which vary with collimator settings. The necessity to model these components has motivated the development of multisource beam models. We describe and evaluate clinical photon beam modeling based on multisource models, including lateral beam quality variations. The evaluation is based on user data for a pencil kernel algorithm and a point kernel algorithm (collapsed cone) used in the clinical treatment planning systems Helax-TMS and Nucletron-Oncentra. The pencil kernel implementations treat the beam spectrum as lateral invariant while the collapsed cone involves off axis softening of the spectrum. Both algorithms include modeling of head scatter components. The parameters of the beam model are derived from measured beam data in a semiautomatic process called RDH (radiation data handling) that, in sequential steps, minimizes the deviations in calculated dose versus the measured data. The RDH procedure is reviewed and the results of processing data from a large number of treatment units are analyzed for the two dose calculation algorithms. The results for both algorithms are similar, with slightly better results for the collapsed cone implementations. For open beams, 87% of the machines have maximum errors less than 2.5%. For wedged beams the errors were found to increase with increasing wedge angle. Internal, motorized wedges did yield slightly larger errors than external wedges. These results reflect the increased complexity, both experimentally and computationally, when wedges are used compared to open beams.

  • 58. Ahrenstedt, O
    et al.
    Knutson, L
    Nilsson, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson-Ekdahl, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Odlind, B
    Hällgren, R
    Enhanced local production of complement components in the small intestines of patients with Crohn's disease.1990In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 322, no 19, p. 1345-1349Article in journal (Refereed)
    Abstract [en]

    There is evidence that complement components may be formed locally in inflammatory lesions containing monocytes and macrophages. To investigate the role of complement in Crohn's disease we measured jejunal-fluid concentrations of the complement components C4, C3, and factor B by perfusion of a closed segment of the jejunum in 22 patients with Crohn's disease thought to be limited to the terminal ileum. The mean (+/- SEM) jejunal-fluid C4 concentration was 2.0 +/- 0.3 mg per liter, significantly higher than the mean level in 35 healthy controls (0.7 +/- 0.1 mg per liter; P less than 0.001). The mean C3 concentration was 1.0 +/- 0.1 mg per liter in the patients and 0.7 +/- 0.1 mg per liter in the controls (P less than 0.05). The factor B levels were similar in the two groups. Calculated rates of intestinal secretion of these components showed differences of the same magnitude. Leakage of protein from plasma was not increased. The jejunal-fluid:serum ratios of these complement proteins indicated that their appearance in the lumen of the jejunum was due to at least in part to local mucosal synthesis. The increased jejunal secretion of C4, but not C3 or factor B, paralleled the clinical activity of Crohn's disease. Values were normal in first-degree relatives of the patients (n = 13), patients with celiac disease (n = 8), and patients with ulcerative colitis (n = 4). We conclude that increased secretion of complement by clinically unaffected jejunal tissue in patients with Crohn's disease reflects the systemic nature of this disorder and may be due to the stimulated synthesis of complement by activated intestinal monocytes and macrophages.

  • 59. Ahrén-Moonga, Jennie
    et al.
    Lekander, Mats
    von Blixen, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Holmgren, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    af Klinteberg, Britt
    Levels of Tumour Necrosis Factor-Alpha and Interleukin-6 in Severely Ill Patients with Eating Disorders2011In: Neuropsychobiology, ISSN 0302-282X, E-ISSN 1423-0224, Vol. 63, no 1, p. 8-14Article in journal (Refereed)
    Abstract [en]

    Background: The underlying pathophysiology of eating disorders (ED) is dependent on complex interactions between psychological, biological and social factors. The purpose of the present study was to examine a possible increase in cytokines indicating inflammation, as measured by tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in ED patients, and to explore possible relationships between cytokines and self-reported personality traits. Methods: Female patients with severe ED (n = 26) were recruited consecutively from an inpatient clinic and were compared to age-matched healthy females (n = 12). Commercial ELISA tests developed for the measurement of serum levels of TNF-alpha and IL-6 were employed. Personality traits were measured using Karolinska Scales of Personality. Results: The patient group displayed increased levels of the cytokine TNF-alpha and a tendency towards increased IL-6 levels. Spearman's rank correlation coefficient was used to examine possible relationships between levels of cytokines and personality traits. The results showed that IL-6 levels were positively related to both somatic and psychic anxiety and to aggression scales, such as irritability and suspicion. Increased levels of TNF-alpha, in turn, were significantly correlated with high scores on the depression-related anxiety scale Inhibition of Aggression. However, increased levels of cytokines in the ED group did not seem to be mainly associated with symptoms of depression. Conclusion: We cannot rule out the possibility that comorbid conditions in the group contribute to the higher cytokine values. Further studies need to explore the possible influence of cytokines on the severity of ED and whether this might be mediated or moderated by specific personality traits.

  • 60. Alarabi, A A
    et al.
    Nilsson, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wikström, B
    Danielson, B G
    Complement activation during tryptophan immunoadsorption treatment.1993In: Artificial Organs, ISSN 0160-564X, E-ISSN 1525-1594, Vol. 17, no 9, p. 782-786Article in journal (Refereed)
    Abstract [en]

    Antibodies against human lymphocyte antigens (HLA) are frequently seen among patients undergoing repeated renal transplantations. Graft survival can be improved by eliminating these antibodies by plasmapheresis before transplantation. In this study, we have tried a new extracorporeal procedure to remove the anti-HLA antibodies. An immunoadsorption column (IM-TR) with a matrix of polyvinyl alcohol (PVA) gel conjugated with a hydrophobic amino acid tryptophan was utilized. Previous results have shown that repeated IM-TR treatments are at least equally effective as plasmapheresis in reducing levels of specific immunoglobulins in treated patients. In this study, 7 HLA-immunized patients were treated before renal transplantation. Each patient was subjected to a total of 12 treatment sessions divided into 3 sessions per week. After each treatment session, the reduction of the immunoglobulins was less than what has been reported for plasmapheresis. This suggests that mechanisms other than immunoglobulin depletion are involved in the reduction of the total immunoglobulin levels. The IM-TR treatment resulted in a strong complement activation triggered by the alternative pathway. Since the adsorbed plasma was returned to the patient, exceedingly high levels of the activation fragment C3d (C3dg) were found in plasma during and after the treatment. We conclude that the extensive generation of C3dg may be one of the factors that plays a role in the reduction of the antibody levels since the C3dg fragment has been shown to down-regulate the immune response.

  • 61.
    Alarabi, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Backman, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wikstrom, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Sjoberg, O
    Department of Oncology, Radiology and Clinical Immunology.
    Tufveson, G
    Department of Surgical Sciences.
    Plasmapheresis in HLA-immunosensitized patients prior to kidney transplantation1997In: J Artific Organs, Vol. 20, p. 51-Article in journal (Refereed)
  • 62.
    Alarabi, A
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Backman, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wikstrom, B
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Sjoberg, O
    Department of Oncology, Radiology and Clinical Immunology.
    Tufveson, G
    Department of Surgical Sciences.
    Pretransplantation plasmapheresis in HLA-sensitized patients: five years experience.1995In: Transplant Proc, Vol. 27, p. 3448Other (Other scientific)
  • 63. Albertsson, Maria
    et al.
    Johansson, B.
    Friesland, S.
    Kadar, L.
    Letocha, H.
    Frykholm, G.
    Wagenius, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer2007In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 24, no 4, p. 407-412Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The purpose of these studies was to compare efficacy and toxicity of docetaxel alone with the combination of gemcitabine and docetaxel for treatment of metastatic esophageal carcinoma. PATIENTS AND METHODS: These studies enrolled patients with histopathologically verified squamous cell carcinoma or adenocarcinoma of the esophagus or cardia. Between March 1997 and June 1999, 52 patients were enrolled in the initial Phase II study (Study 1). They were scheduled for treatment with docetaxel 100 mg/m2 every third week as a 1-h infusion. The second Phase II study between September 2000 and March 2003 included 65 patients (Study II). They were given docetaxel 30 mg/m2, administered as a 30-min i.v. infusion weekly for four times, followed by 2 weeks of rest, and gemcitabine starting with a dose of 750 mg/m2 (if well-tolerated 1,000 mg/m2) on days 1 and 15, followed by 3 weeks of rest. A new cycle began on day 36. Patients were premedicated with betamethasone 8 mg p.o. on the evening before, and 8 mg i.v. 30-60 min before the docetaxel infusion. Response was confirmed by computed tomography and assessed at 12 and 24 weeks. Toxicity was assessed according to WHO scales. RESULTS: In study I, 38 out of the 52 enrolled patients were valuable. Two patients experienced complete remission (CR) (5%), 10 patients partial remission (PR) (26%), nine patients stable disease (SD) (24%), and 17 patients showed progressive disease (PD) (45%). Toxicity mainly involved leukopenia, which in some cases required hospitalization and treatment with antibiotics. In Study II, 46 out of the 65 enrolled patients (70%) were assessable. Out of these, three patients (7%) had CR, eight patients (17%) had PR, 10 patients (22%) had SD, and 25 (54%) PD. Overall response was 24% while an additional 22% showed stable disease. Toxicity mainly consisted of leucopenia and pain. CONCLUSION: Docetaxel as a single agent is active in esophageal cancer, both in treatment naive and in previously treated patients with recurrent disease. The overall response rate was 31%, with a good-safety profile. The addition of gemcitabine is well tolerated, but adds no efficacy. Weekly administration of docetaxel may be less effective. It demonstrates moderate efficacy and the doses used provide an acceptable safety profile.

  • 64. Aldulaymi, Bahir
    et al.
    Byström, Per
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Christensen, Ib J.
    Brunner, Nils
    Nielsen, Hans J.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    High Plasma TIMP-1 and Serum CEA Levels during Combination Chemotherapy for Metastatic Colorectal Cancer Are Significantly Associated with Poor Outcome2010In: Oncology, ISSN 0030-2414, E-ISSN 1423-0232, Vol. 79, no 1-2, p. 144-149Article in journal (Refereed)
    Abstract [en]

    Objective: To evaluate whether combination chemotherapy leads to early changes in plasma TIMP-1 and serum carcinoembryonic antigen (CEA) levels in patients with metastatic colorectal cancer (mCRC), and whether such changes relate to subsequent objective response, time to progression (TTP) and overall survival. Materials and Methods: Eighty-eight patients with mCRC were included. Blood samples were collected before initiation and after 2, 4 and 6 weeks of treatment with an irinotecan-5-fluorouracil combination. Plasma TIMP-1 and serum CEA levels were determined by validated ELISA platforms. The first response evaluation was performed after 8 weeks of chemotherapy. Results: Median plasma TIMP-1 and serum CEA levels did not change significantly during 6 weeks of treatment. High plasma TIMP-1 and high serum CEA levels before treatment and at weeks 2, 4 and 6 were related to poor objective response. Moreover, high levels of plasma TIMP-1 before treatment and at weeks 2 and 4 were significantly associated with short TTP, while high levels of serum CEA at week 4 were significantly associated with short TTP. Finally, high levels of plasma TIMP- 1 before and during treatment were significantly associated with poor overall survival; p < 0.0001 in all 4 determinations. A similar association between serum CEA and overall survival could only be demonstrated before treatment. Conclusion: Median plasma TIMP-1 or serum CEA levels do not change significantly during the first 6 weeks of chemotherapy for mCRC. The results indicate that plasma TIMP-1 in particular and serum CEA may be valuable biomarkers even in samples collected during treatment with chemotherapy.

  • 65.
    Alemany, Montserrat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Stenborg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Terent, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sonninen, Pirkko
    Röntgenavdelningen, Åbo universitetssjukhus, Åbo, Finland.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Coexistence of microhemorrhages and acute spontaneous brain hemorrhage: correlation with signs of microangiopathy and clinical data2006In: Radiology, ISSN 0033-8419, E-ISSN 1527-1315, Vol. 238, no 1, p. 240-7Article in journal (Refereed)
    Abstract [en]

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

  • 66.
    Alemany Ripoll, Montserrat
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    MRI Diagnosis of Intracranial Hemorrhage: Experimental and Clinical Studies2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

  • 67.
    Alemany Ripoll, Montserrat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gustafsson, O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Siösteen, B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Olsson, Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    MR follow-up of small experimental intracranial haemorrhages from hyperacute to subacute phase2002In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 43, no 1, p. 2-9Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To compare pulse sequences in revealing intracranial bleeding from the hyperacute to subacute phase. MATERIAL AND METHODS: We injected 0.3-1 ml of autologous blood into the brain of 8 rabbits. MR imaging was performed immediately after haematoma creation and then at determined intervals up to 9-12 days. All images were analysed by two observers. After the last MR investigation, the brain was fixed in formalin. The last MR images were compared to the fixed brain sections and to the histologic findings. RESULTS: T2*-weighted GE sequences, both conventional spoiled and echoplanar sequences, revealed the intraparenchymal haematomas as hypointensities in all but 1 case, which was negative from the second day onward (a rabbit with 0.3 ml blood injected). The signal patterns remained unchanged during the follow-up. The haematoma sizes and shapes corresponded well to gross pathology. Blood in the cerebrospinal fluid (CSF) space was detected with T2*-weighted GE sequences in a great majority of the examinations during the first 2 days. The cases with the smallest injected volume of blood were negative. SE sequences were rather insensitive. The FLAIR sequence often revealed blood in CSF spaces but not in the brain. CONCLUSION: T2*-weighted GE sequences are capable of revealing very small intraparenchymal haemorrhages from the hyperacute to the subacute phase, and blood in CSF spaces during at least the first 2 days.

  • 68.
    Alemany Ripoll, Montserrat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Experimental intracerebral and subarachnoid/intraventricular haemorrhages2002In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 43, no 5, p. 464-73Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To compare the detectability of small experimental intracranial haemorrhages on MR imaging at 0.5 T and 1.5 T, from hyperacute to subacute stages. MATERIAL AND METHODS: 1 ml of autologous blood was injected into the brain of 15 rabbits to create intraparenchymal haematomas. Since the blood partially escaped into the cerebrospinal fluid (CSF) spaces, detectability of subarachnoid and intraventricular blood was also evaluated. MR imaging at 0.5 T and at 1.5 T was repeated up to 14 days, including T1-, proton density- and T2-weighted (w) spin-echo (SE), FLAIR and T2*-w gradient echo (GE) pulse sequences. The last MR investigation was compared to the formalin-fixed brain sections in 7 animals. RESULTS: The intraparenchymal haematomas were best revealed with T2*-w GE sequences, with 100% of sensitivity at 1.5 T and 90-95% at 0.5 T. Blood in the CSF spaces was significantly (p < 0.05) better detected at 1.5 T with T2*-w GE sequences and detected best during the first 2 days. The next most sensitive sequence for intracranial blood was FLAIR. SE sequences were rather insensitive. CONCLUSION: 1.5 T equipment is superior to 0.5 T in the detection of intracranial haemorrhages from acute to subacute stages. T2*-w GE sequences account for this result but other sequences are also needed for a complete examination.

  • 69.
    Alemany Ripoll, Montserrat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Stenborg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sonninen, Pirkko
    Terent, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Detection and appearance of intraparenchymal haematomas of the brain at 1.5 T with spin-echo, FLAIR and GE sequences: poor relationship to the age of the haematoma2004In: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 46, no 6, p. 435-43Article in journal (Refereed)
    Abstract [en]

    The specific appearance of blood related to time at T1- and T2-weighted spin-echo (SE) sequences is generally accepted; thus, these sequences are classically used for estimating the age of haematomas. Magnetic resonance imaging at 1.5 T, including T1- and T2-weighted SE fluid-attenuated inversion recovery (FLAIR) and T2*-weighted gradient-echo (GE) sequences, was performed on 82 intraparenchymal haematomas (IPHs) and 15 haemorrhagic infarcts (HIs) in order to analyse the appearance at different stages and with different sequences, and to investigate how reliably the age of hematomas can be estimated. The IPHs had been previously detected by CT, were spontaneous ( n=72) or traumatic ( n=10) in origin and were of different sizes (2 mm to 7 cm) and ages (from 7.5 h to 4 years after acute haemorrhagic event). The age of the lesion was calculated from the moment when clinical symptoms started or the traumatic event occurred. The 15 patients with HIs were patients with ischaemic stroke in whom there was either a suspicion of haemorrhagic transformation on CT, or haemorrhage was detected as an additional finding on MR performed for other indications. Patients with conditions that could affect the SI of blood, such as anticoagulant therapy or severe anaemia, were excluded. The signal intensity pattern of the lesions was analysed and related to their ages without prior knowledge of the clinical data. All lesions were detected with T2*-weighted GE. T1-weighted SE missed 13 haematomas and T2-weighted SE and FLAIR sequences missed five. Haemorrhagic transformation was missed in three infarcts by T1-, T2-weighted SE and FLAIR. The signal pattern on FLAIR was identical to that on T2-weighted SE. For all sequences, a wide variety of signal patterns, without a clear relationship to the age of the haematomas, was observed. There was a poor relationship between the real MR appearance of IPHs and the theoretical appearance on SE sequences. T2*-weighted GE was effective for detecting small bleedings but was not useful for estimating the age of a lesion. The FLAIR does not provide any more information than T2-weighted SE.

  • 70. Alexanderson, Camilla
    et al.
    Stener-Victorin, Elisabet
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Nilsson, Staffan
    Levin, Max
    Cajander, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lönn, Lars
    Lönn, Malin
    Holmäng, Agneta
    A single early postnatal estradiol injection affects morphology and gene expression of the ovary and parametrial adipose tissue in adult female rats2010In: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 122, no 1-3, p. 82-90Article in journal (Refereed)
    Abstract [en]

    Events during early life can affect reproductive and metabolic functions in adulthood. We evaluated the programming effects of a single early postnatal estradiol injection (within 3h after birth) in female rats. We assessed ovarian and parametrial adipose tissue morphology, evaluated gene expression related to follicular development and adipose tissue metabolism, and developed a non-invasive volumetric estimation of parametrial adipose tissue by magnetic resonance imaging. Estradiol reduced ovarian weight, increased antral follicle size and number of atretic antral follicles, and decreased theca interna thickness in atretic antral follicles. Adult estradiol-injected rats also had malformed vaginal openings and lacked corpora lutea, confirming anovulation. Estradiol markedly reduced parametrial adipose tissue mass. Adipocyte size was unchanged, suggesting reduced adipocyte number. Parametrial adipose tissue lipoprotein lipase activity was increased. In ovaries, estradiol increased mRNA expression of adiponectin, complement component 3, estrogen receptor alpha, and glucose transporter 3 and 4; in parametrial adipose tissue, expression of complement component 3 was increased, expression of estrogen receptor alpha was decreased, and expression of leptin, lipoprotein lipase, and hormone-sensitive lipase was unaffected. These findings suggest that early postnatal estradiol exposure of female rats result in long-lasting effects on the ovary and parametrial adipose tissue at adult age.

  • 71.
    Almqvist, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Targeted Therapy of Colorectal Cancer: Preclinical Evaluation of a Radiolabelled Antibody2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Targeted radiotherapy (TRT) of cancer is a promising approach that enables selective treatment of tumour cells, while sparing normal tissue. The humanized monoclonal antibody A33 (huA33) is a potential targeting agent for TRT of colorectal cancer, since its antigen is expressed in more than 95 % of all colorectal carcinomas. The aim of this thesis was to evaluate the therapeutic potential of the two huA33-based TRT-conjugates, 177Lu-huA33, and 211At-huA33.

    The conjugates 177Lu-huA33, and 211At-huA33, bound specifically to colorectal cancer cells, both in vitro and in vivo. A dose dependent cytotoxic effect of 211At-huA33 was also demonstrated in vitro. From a therapeutic perspective, both conjugates had a favourable biodistribution in tumour-bearing nude mice, with high tumour uptake and a low uptake in normal organs (with the exception of an expected thyroid uptake of 211At). After injection of 211At-huA33, the blood absorbed a slightly higher dose than the tumour, but for 177Lu-huA33, the tumour received a 12 times higher dose than blood. Two days after intravenous injection of 177Lu-huA33 in tumour-bearing mice, the tumours could be clearly visualised by gamma camera imaging, with very low interference from normal tissue radioactivity. In an experimental therapy study, also performed in tumour-bearing mice, there was an excellent therapeutic effect of 177Lu-huA33. About 50 % of the treated animals were tumour free 140 days after injection of 177Lu-huA33, while none of the non-radioactive controls survived beyond 20 days after injection of treatment substances.

    In conclusion, this thesis demonstrates that the therapeutic conjugates 177Lu-huA33, and 211At-huA33, are promising targeting agents that might help improve therapy of colorectal cancer.

    List of papers
    1.
    The record could not be found. The reason may be that the record is no longer available or you may have typed in a wrong id in the address field.
    2. Biodistribution of At-211-Labeled humanized monoclonal antibody A33
    Open this publication in new window or tab >>Biodistribution of At-211-Labeled humanized monoclonal antibody A33
    Show others...
    2007 (English)In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 22, no 4, p. 480-487Article in journal (Refereed) Published
    Abstract [en]

    Radioimmunotherapy (RIT) could be a possible adjuvant treatment method for patients with colorectal carcinoma. The A33 antigen is a promising RIT target, as it is highly and homogenously expressed in 95% of all colorectal carcinomas. In this study, the humanized monoclonal antibody A33 (huA33), targeting the A33 antigen, was labeled with the therapeutic nuclide 211At, and the biodistribution and in vivo targeting ability of the conjugate was investigated in an athymic mouse xenograft model. There was an accumulation of 211At in tumor tissue over time, but no substantial accumulation was seen in any organ apart from the skin and thyroid, indicating no major release of free 211At in vivo. At all time points, the uptake of 211At-huA33 was higher in tumor tissue than in most organs, and at 8 hours postinjection (p.i.), no organ had a higher uptake than tumor tissue. The tumor-to-blood ratio of 211At-huA33 increased with time, reaching 2.5 after 21 hours p.i. The highest absorbed dose was found in the blood, but the tumor received a higher dose than any organ other than the thyroid. An in vivo blocking experiment showed that 211At-huA33 binds specifically to human tumor xenografts in athymic mice. In conclusion, the favorable biodistribution and specific in vivo targeting ability of 211At-huA33 makes it a potential therapeutic agent for the RIT of metastatic colorectal carcinoma.

    Keywords
    A33, monoclonal antibody, At-211, radioimmunotherapy, biodistribution
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-17038 (URN)10.1089/cbr.2007.349 (DOI)000249320800003 ()17803442 (PubMedID)
    Available from: 2008-06-16 Created: 2008-06-16 Last updated: 2017-12-08Bibliographically approved
    3. In vitro and in vivo characterization of 177Lu‑huA33: A radioimmunoconjugate against colorectal cancer
    Open this publication in new window or tab >>In vitro and in vivo characterization of 177Lu‑huA33: A radioimmunoconjugate against colorectal cancer
    Show others...
    2006 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 33, no 8, p. 991-998Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: The humanized monoclonal antibody A33 (huA33) is a potential targeting agent against colorectal carcinoma since the A33 antigen is highly and homogenously expressed in >95% of all colorectal cancers, both primary tumors and metastases. The aim of this study was to determine the biodistribution and tumor-targeting ability of (177)Lu-labeled huA33. METHODS: huA33 was labeled with the beta-emitting therapeutic nuclide (177)Lu using the chelator CHX-A"-DTPA, and the properties of the (177)Lu-CHX-A"-huA33 ((177)Lu-huA33) conjugate was determined both in vitro and in vivo in a biodistribution study in nude mice xenografted with colorectal SW1222 tumor cells. RESULTS: The (177)Lu-huA33 conjugate bound specifically to colorectal cancer cells in vitro (with a K(D) value of 2.3+/-0.3 nM, determined by a saturation assay) and in vivo. The tumor uptake of (177)Lu-huA33 was very high, peaking at 134+/-21%ID/g 72 h postinjection (pi). Normal tissue uptake was low; radioactivity concentration in blood (which had the second highest radioactivity concentration) was lower than in tumor at all time points studied (8 h to 10 days). The tumor-to-blood ratio increased with time, reaching 70+/-30, 10 days pi. Throughout the study, the uptake of (177)Lu in bone (known to accumulate free (177)Lu) was low, and the fraction of protein-bound (177)Lu in plasma samples was high (95% to 99%). This indicates high stability of the (177)Lu-huA33 conjugate in vivo. CONCLUSION: The (177)Lu-huA33 conjugate shows a very favorable biodistribution, with an impressively high tumor uptake and high tumor-to-organ ratios, indicating that the conjugate may be suitable for radioimmunotherapy of colorectal cancer.

    Keywords
    Antibody, A33 antigen, 177Lu, Colorectal cancer
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97087 (URN)10.1016/j.nucmedbio.2006.09.003 (DOI)000242840500007 ()17127172 (PubMedID)
    Available from: 2008-04-23 Created: 2008-04-23 Last updated: 2017-12-14Bibliographically approved
    4. Therapy of colorectal cancer xenografts in nude mice using 177Lu labelled humanized antibody A33
    Open this publication in new window or tab >>Therapy of colorectal cancer xenografts in nude mice using 177Lu labelled humanized antibody A33
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-97088 (URN)
    Available from: 2008-04-23 Created: 2008-04-23 Last updated: 2010-01-13Bibliographically approved
  • 72.
    Almqvist, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Sjöström, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Jensen, Holger J.
    Danmark.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    In vitro characterization of 211 At-labeled antibody A33: a potential therapeutic agent against metastatic colorectal carcinoma2005In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 20, no 5, p. 514-523Article in journal (Refereed)
    Abstract [en]

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

  • 73.
    Almqvist, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Steffen, Ann-Charlott
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Jensen, Holger
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Biodistribution of At-211-Labeled humanized monoclonal antibody A332007In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 22, no 4, p. 480-487Article in journal (Refereed)
    Abstract [en]

    Radioimmunotherapy (RIT) could be a possible adjuvant treatment method for patients with colorectal carcinoma. The A33 antigen is a promising RIT target, as it is highly and homogenously expressed in 95% of all colorectal carcinomas. In this study, the humanized monoclonal antibody A33 (huA33), targeting the A33 antigen, was labeled with the therapeutic nuclide 211At, and the biodistribution and in vivo targeting ability of the conjugate was investigated in an athymic mouse xenograft model. There was an accumulation of 211At in tumor tissue over time, but no substantial accumulation was seen in any organ apart from the skin and thyroid, indicating no major release of free 211At in vivo. At all time points, the uptake of 211At-huA33 was higher in tumor tissue than in most organs, and at 8 hours postinjection (p.i.), no organ had a higher uptake than tumor tissue. The tumor-to-blood ratio of 211At-huA33 increased with time, reaching 2.5 after 21 hours p.i. The highest absorbed dose was found in the blood, but the tumor received a higher dose than any organ other than the thyroid. An in vivo blocking experiment showed that 211At-huA33 binds specifically to human tumor xenografts in athymic mice. In conclusion, the favorable biodistribution and specific in vivo targeting ability of 211At-huA33 makes it a potential therapeutic agent for the RIT of metastatic colorectal carcinoma.

  • 74.
    Almqvist, Ylva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Steffen, Ann-Charlott
    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.
    Divgi, Chaitanya R.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    In vitro and in vivo characterization of 177Lu‑huA33: A radioimmunoconjugate against colorectal cancer2006In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 33, no 8, p. 991-998Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: The humanized monoclonal antibody A33 (huA33) is a potential targeting agent against colorectal carcinoma since the A33 antigen is highly and homogenously expressed in >95% of all colorectal cancers, both primary tumors and metastases. The aim of this study was to determine the biodistribution and tumor-targeting ability of (177)Lu-labeled huA33. METHODS: huA33 was labeled with the beta-emitting therapeutic nuclide (177)Lu using the chelator CHX-A"-DTPA, and the properties of the (177)Lu-CHX-A"-huA33 ((177)Lu-huA33) conjugate was determined both in vitro and in vivo in a biodistribution study in nude mice xenografted with colorectal SW1222 tumor cells. RESULTS: The (177)Lu-huA33 conjugate bound specifically to colorectal cancer cells in vitro (with a K(D) value of 2.3+/-0.3 nM, determined by a saturation assay) and in vivo. The tumor uptake of (177)Lu-huA33 was very high, peaking at 134+/-21%ID/g 72 h postinjection (pi). Normal tissue uptake was low; radioactivity concentration in blood (which had the second highest radioactivity concentration) was lower than in tumor at all time points studied (8 h to 10 days). The tumor-to-blood ratio increased with time, reaching 70+/-30, 10 days pi. Throughout the study, the uptake of (177)Lu in bone (known to accumulate free (177)Lu) was low, and the fraction of protein-bound (177)Lu in plasma samples was high (95% to 99%). This indicates high stability of the (177)Lu-huA33 conjugate in vivo. CONCLUSION: The (177)Lu-huA33 conjugate shows a very favorable biodistribution, with an impressively high tumor uptake and high tumor-to-organ ratios, indicating that the conjugate may be suitable for radioimmunotherapy of colorectal cancer.

  • 75.
    Almqvist, Ylva
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Tolmachev, Vladimir
    Lundqvist, Hans
    Sundin, Anders
    Therapy of colorectal cancer xenografts in nude mice using 177Lu labelled humanized antibody A33Manuscript (Other academic)
  • 76.
    Alparslan, Leyla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Chiodo, Christopher P.
    Lateral ankle instability: MR imaging of associated injuries and surgical treatment procedures2008In: Seminars in Musculoskeletal Radiology, ISSN 1089-7860, E-ISSN 1098-898X, Vol. 12, no 4, p. 346-58Article in journal (Refereed)
    Abstract [en]

    Chronic ankle instability has been defined as the development of recurrent ankle sprains and persistent symptoms after initial lateral ankle sprain. The diagnosis of ankle instability is usually established on the patient's history, physical examination, and radiographic assessment. Patients have signs of both functional and mechanical instability, and the repetitive, chronic nature of the injury may lead to intra-articular and periarticular pathologies. This article discusses the incidence, etiology, and magnetic resonance (MR) imaging of these pathologies, reviews the surgical treatment procedures for lateral ankle instability, and presents the postoperative MR imaging findings.

  • 77.
    Altai, Mohamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Tumour Targeting using Radiolabelled Affibody Molecules: Influence of Labelling Chemistry2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Affibody molecules are promising candidates for targeted radionuclide-based imaging and therapy applications. Optimisation of targeting properties would permit the in vivo visualization of cancer-specific surface receptors with high contrast. In therapy, this may increase the ratio of radioactivity uptake between tumour and normal tissues.  This thesis work is based on 5 original research articles (papers I-V) and focuses on optimisation of targeting properties of anti-HER2 affibody molecules by optimising the labelling chemistry.

    Paper I and II report the comparative evaluation of the anti-HER2 ZHER2:2395 affibody molecule site specifically labelled with 111In (suitable for SPECT imaging) and 68Ga (suitable for PET imaging) using the thiol reactive derivatives of DOTA and NODAGA as chelators. The incorporation of different macrocyclic chelators and labelling with different radionuclides modified the biodistribution properties of affibody molecules. This indicates that the labelling strategy may have a profound effect on the targeting properties of radiotracers and must be carefully optimized.

    Paper III reports the study of the mechanism of renal reabsorption of anti-HER2 ZHER2:2395 affibody molecule. An unknown receptor (not HER2) is suspected to be responsible for the high reabsorption of ZHER2:2395 molecules in the kidneys.

    Paper IV reports the optimization and development of in vivo targeting properties of 188Re-labelled anti-HER2 affibody molecules. By using an array of peptide based chelators, it was found that substitution of one amino acid by another or changing its position can have a dramatic effect on the biodistribution properties of 188Re-labelled affibody molecules. This permitted the selection of –GGGC chelator whichdemonstrated the lowest retention of radioactivity in kidneys compared to other variants and showed excellent tumour targeting properties.

    Paper V reports the preclinical evaluation of 188Re-ZHER2:V2 as a potential candidate for targeted radionuclide therapy of HER2-expressing tumours. In vivo experiments in mice along with dosimetry assessment in both murine and human models revealed that future human radiotherapy studies using 188Re-ZHER2:V2 may be feasible.

    It would be reasonable to believe that the results of optimisation of anti-HER2 affibody molecules summarized in this thesis can be of importance for the development of other scaffold protein-based targeting agents.

    List of papers
    1. Preclinical evaluation of anti-HER2 Affibody molecules site-specifically labeled with 111In using a maleimido derivative of NODAGA
    Open this publication in new window or tab >>Preclinical evaluation of anti-HER2 Affibody molecules site-specifically labeled with 111In using a maleimido derivative of NODAGA
    Show others...
    2012 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 39, no 4, p. 518-529Article in journal (Refereed) Published
    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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-164424 (URN)10.1016/j.nucmedbio.2011.10.013 (DOI)000303790600008 ()22172396 (PubMedID)
    Available from: 2012-05-04 Created: 2011-12-20 Last updated: 2017-12-07Bibliographically approved
    2. Influence of Nuclides and Chelators on Imaging Using Affibody Molecules: Comparative Evaluation of Recombinant Affibody Molecules Site-Specifically Labeled with 68Ga and 111In via Maleimido Derivatives of DOTA and NODAGA
    Open this publication in new window or tab >>Influence of Nuclides and Chelators on Imaging Using Affibody Molecules: Comparative Evaluation of Recombinant Affibody Molecules Site-Specifically Labeled with 68Ga and 111In via Maleimido Derivatives of DOTA and NODAGA
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    2013 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 24, no 6, p. 1102-1109Article in journal (Refereed) Published
    Abstract [en]

    Accurate detection of cancer-associated molecular abnormalities in tumors could make cancer treatment more personalized. Affibody molecules enable high contrast imaging of tumor-associated protein expression shortly after injection. The use of the generator-produced positron-emitting radionuclide 68Ga should increase sensitivity of HER2 imaging. The chemical nature of radionuclides and chelators influences the biodistribution of Affibody molecules, providing an opportunity to further increase the imaging contrast. The aim of the study was to compare maleimido derivatives of DOTA and NODAGA for site-specific labeling of a recombinant ZHER2:2395 HER2-binding Affibody molecule with 68Ga. DOTA and NODAGA were site-specifically conjugated to the ZHER2:2395 Affibody molecule having a C-terminal cysteine and labeled with 68Ga and 111In. All labeled conjugates retained specificity to HER2 in vitro. Most of the cell-associated activity was membrane-bound with a minor difference in internalization rate. All variants demonstrated specific targeting of xenografts and a high tumor uptake. The xenografts were clearly visualized using all conjugates. The influence of chelator on the biodistribution and targeting properties was much less pronounced for 68Ga than for 111In. The tumor uptake of 68Ga-NODAGA-ZHER2:2395 and 68Ga-DOTA-ZHER2:2395 and tumor-to-blood ratios at 2 h p.i. did not differ significantly. However, the tumor-to-liver ratio was significantly higher for 68Ga-NODAGA- ZHER2:2395 (8 ± 2 vs 5.0 ± 0.3) offering the advantage of better liver metastases visualization. In conclusion, influence of chelators on biodistribution of Affibody molecules depends on the radionuclides and reoptimization of labeling chemistry is required when a radionuclide label is changed.

    National Category
    Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-203054 (URN)10.1021/bc300678y (DOI)000320898900030 ()23705574 (PubMedID)
    Note

    De två (2) första författarna delar förstaförfattarskapet.

    Available from: 2013-07-02 Created: 2013-07-02 Last updated: 2018-01-11Bibliographically approved
    3. In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors
    Open this publication in new window or tab >>In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors
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    2013 (English)In: Cancer Biotherapy and Radiopharmaceuticals, ISSN 1084-9785, E-ISSN 1557-8852, Vol. 28, no 3, p. 187-195Article in journal (Refereed) Published
    Abstract [en]

    Affibody molecules (6-7 kDa) are a new class of small robust three-helical scaffold proteins. Radiolabeled subnanomolar anti-HER2 affibody Z(HER2:342) was developed for imaging of HER2 expression in tumors, and a clinical study has demonstrated that the In-111- and Ga-68-labeled affibody molecules can efficiently detect HER2 expressing metastases in breast cancer patients. However, a significant renal accumulation of radioactivity after systemic injection of a radiolabeled anti-HER2 affibody conjugate is observed. The aim of this study was to investigate the mechanism of renal reabsorption of anti-HER2 affibody at the molecular level. Renal accumulation of radiolabeled anti-HER2 affibody molecules was studied in a murine model and in vitro using opossum-derived proximal tubule (OK) cells. It was found that kidney reabsorption of affibody molecule was not driven by megalin/cubilin. Amino acids in the target-binding side of affibody molecule were involved in binding to OK cells. On OK cells, two types of receptors for anti-HER2 affibody molecule were found: K-D1 = 0.8 nM, B-max1 = 71,500 and K-D2 = 9.2 nM, B-max2 = 367,000. The results of the present study indicate that affibody molecule and other scaffold-based targeting proteins with a relatively low kidney uptake can be selected using in vitro studies with tubular kidney cells.

    Keywords
    affibody molecules, HER2, OK cells, megalin, renal reabsorption
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-200076 (URN)10.1089/cbr.2012.1304 (DOI)000317478200002 ()
    Note

    De två (2) första författarna delar förstaförfattarskapet.

    Available from: 2013-05-23 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
    4. Selection of an optimal cysteine-containing peptide-based chelator for labeling of Affibody molecules with 188-Re
    Open this publication in new window or tab >>Selection of an optimal cysteine-containing peptide-based chelator for labeling of Affibody molecules with 188-Re
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    2013 (English)In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 40, no Suppl. 2, p. S219-S220Article in journal, Meeting abstract (Other academic) Published
    Abstract [en]

    Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of 188Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all 188Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The 188Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of 188Re-ZHER2:V2 (3.1±0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental 188Re-ZHER2:2395 (172±32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of 188Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.

    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-211592 (URN)10.1007/s00259-013-2535-3 (DOI)000325853400417 ()
    Conference
    Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Lyon 19-23 oktober 2013.
    Available from: 2013-12-03 Created: 2013-11-27 Last updated: 2017-12-06Bibliographically approved
    5. 188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors: preclinical assessment
    Open this publication in new window or tab >>188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors: preclinical assessment
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    2014 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, no 11, p. 1842-1848Article in journal (Refereed) Published
    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.

    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-211593 (URN)10.2967/jnumed.114.140194 (DOI)000344209200015 ()25278516 (PubMedID)
    Available from: 2013-12-03 Created: 2013-11-27 Last updated: 2017-12-06Bibliographically approved
  • 78. Alvegård, T A
    et al.
    Bauer, H
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Rydholm, A
    Smeland, S
    The Scandinavian Sarcoma Group--background, organization and the SSG Register--the first 25 years.2004In: Acta Orthop Scand Suppl, ISSN 0300-8827, Vol. 75, no 311, p. 1-7Article in journal (Other scientific)
  • 79. Amara, Umme
    et al.
    Flierl, Michael A.
    Rittirsch, Daniel
    Klos, Andreas
    Chen, Hui
    Acker, Barbara
    Brueckner, Uwe B.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Gebhard, Florian
    Lambris, John D.
    Huber-Lang, Markus
    Molecular Intercommunication between the Complement and Coagulation Systems2010In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 185, no 9, p. 5628-5636Article in journal (Refereed)
    Abstract [en]

    The complement system as well as the coagulation system has fundamental clinical implications in the context of life-threatening tissue injury and inflammation. Associations between both cascades have been proposed, but the precise molecular mechanisms remain unknown. The current study reports multiple links for various factors of the coagulation and fibrinolysis cascades with the central complement components C3 and C5 in vitro and ex vivo. Thrombin, human coagulation factors (F) XIa, Xa, and IXa, and plasmin were all found to effectively cleave C3 and C5. Mass spectrometric analyses identified the cleavage products as C3a and C5a, displaying identical molecular weights as the native anaphylatoxins C3a and C5a. Cleavage products also exhibited robust chemoattraction of human mast cells and neutrophils, respectively. Enzymatic activity for C3 cleavage by the investigated clotting and fibrinolysis factors is defined in the following order: FXa > plasmin > thrombin > FIXa > FXIa > control. Furthermore, FXa-induced cleavage of C3 was significantly suppressed in the presence of the selective FXa inhibitors fondaparinux and enoxaparin in a concentration-dependent manner. Addition of FXa to human serum or plasma activated complement ex vivo, represented by the generation of C3a, C5a, and the terminal complement complex, and decreased complement hemolytic serum activity that defines exact serum concentration that results in complement-mediated lysis of 50% of sensitized sheep erythrocytes. Furthermore, in plasma from patients with multiple injuries (n = 12), a very early appearance and correlation of coagulation (thrombin-antithrombin complexes) and the complement activation product C5a was found. The present data suggest that coagulation/fibrinolysis proteases may act as natural C3 and C5 convertases, generating biologically active anaphylatoxins, linking both cascades via multiple direct interactions in terms of a complex serine protease system. The Journal of Immunology, 2010, 185: 5628-5636.

  • 80.
    Amini, Hashem
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Raiend, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    The Clinical Impact of Fetal Magnetic Resonance Imaging on Management of CNS Anomalies in the Second Trimester of Pregnancy2010In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 89, no 12, p. 20p. 1571-1581Article in journal (Refereed)
    Abstract [en]

    Objectives: To evaluate the additional information of second trimester magnetic resonance imaging (MRI) compared to ultrasound in fetuses with identified or suspected CNS anomalies and to study the clinical impact of the information on pregnancy management.

    Design: Prospective study during 2004-2007. The fetal MRI examination was planned to be performed within three days after the ultrasound.

    Setting: Uppsala University hospital.    

    Subjects: Twenty-nine pregnant women where second trimester ultrasound identified or suspected fetal CNS anomalies.

    Main outcome measures: Evaluation of the additional information gained from MRI and the consequence it had on pregnancy management.

    Results: The mean interval between ultrasound and MRI was 1.6 days (range 0 –7). In 18 fetuses (62 %)  MRI verified the ultrasound diagnosis but provided no additional information, while in 8 (28 %) MRI gave additional information without changing the management. In 3 (10 %), MRI provided additional information that changed the management of the pregnancy. Two of these women were obese.

    Conclusions: Fetal MRI in the second trimester might be a clinically valuable adjunct to ultrasound for the evaluation of CNS anomalies, especially when ultrasound is inconclusive due to maternal obesity.

     

  • 81.
    Amini, Hashem
    et al.