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  • 151.
    Blomberg, Carl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Nilsson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Holgersson, Georg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Edlund, Per
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Adwall, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Brattström, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Bergström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Randomized Trials of Systemic Medically-treated Malignant Mesothelioma: A Systematic Review2015In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 35, no 5, p. 2493-2501Article, review/survey (Refereed)
    Abstract [en]

    Malignant pleural mesothelioma (MPM) is a rare but aggressive malignancy mainly localized to the pleura. Malignant mesothelioma grows highly invasive into surrounding tissue and has a low tendency to metastasize. The median overall survival (OS) of locally advanced or metastatic disease without treatment is 4-13 months but, during recent years, improvement in survival has been achieved since treatment for patients with mesothelioma has improved with better palliative care, systemic medical treatment, surgery and improved diagnostics methods. The present review aims at describing available data from randomized trials considering systemic medical treatment for this patient category.

  • 152.
    Blomquist, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ronne Engström, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Borota, Ljubisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Gál, Gyula
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Montelius, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Grusell, Erik
    Isacsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Positive correlation between occlusion rate and nidus size of proton beam treated brain arteriovenous malformations (AVMs)2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 1, p. 105-112Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Proton beam radiotherapy of arteriovenous malformations (AVM) in the brain has been performed in Uppsala since 1991. An earlier study based on the first 26 patients concluded that proton beam can be used for treating large and medium sized AVMs that were considered difficult to treat with photons due to the risk of side effects. In the present study we analyzed the result from treating the subsequent 65 patients.

    MATERIAL AND METHODS: A retrospective review of the patients' medical records, treatment protocols and radiological results was done. Information about gender, age, presenting symptoms, clinical course, the size of AVM nidus and rate of occlusion was collected. Outcome parameters were the occlusion of the AVM, clinical outcome and side effects.

    RESULTS: The rate of total occlusion was overall 68%. For target volume 0-2cm(3) it was 77%, for 3-10 cm(3) 80%, for 11-15 cm(3) 50% and for 16-51 cm(3) 20%. Those with total regress of the AVM had significantly smaller target volumes (p < 0.009) higher fraction dose (p < 0.001) as well as total dose (p < 0.004) compared to the rest. The target volume was an independent predictor of total occlusion (p = 0.03). There was no difference between those with and without total occlusion regarding mean age, gender distribution or symptoms at diagnosis. Forty-one patients developed a mild radiation-induced brain edema and this was more common in those that had total occlusion of the AVM. Two patients had brain hemorrhages after treatment. One of these had no effect and the other only partial occlusion from proton beams. Two thirds of those presenting with seizures reported an improved seizure situation after treatment.

    CONCLUSION: Our observations agree with earlier results and show that proton beam irradiation is a treatment alternative for brain AVMs since it has a high occlusion rate even in larger AVMs.

  • 153. Blystad, I
    et al.
    Warntjes, Jbm
    Smedby, Örjan
    Landtblom, A-M
    Lundberg, P
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Synthetic MRI of the brain in a clinical setting2012In: Acta Radiologica, ISSN 0284-1851, E-ISSN 1600-0455, Vol. 53, no 10, p. 1158-1163Article in journal (Refereed)
    Abstract [en]

    Background

    Conventional magnetic resonance imaging (MRI) has relatively long scan times for routine examinations, and the signal intensity of the images is related to the specific MR scanner settings. Due to scanner imperfections and automatic optimizations, it is impossible to compare images in terms of absolute image intensity. Synthetic MRI, a method to generate conventional images based on MR quantification, potentially both decreases examination time and enables quantitative measurements.

    Purpose

    To evaluate synthetic MRI of the brain in a clinical setting by assessment of the contrast, the contrast-to-noise ratio (CNR), and the diagnostic quality compared with conventional MR images.

    Material and Methods

    Twenty-two patients had synthetic imaging added to their clinical MR examination. In each patient, 12 regions of interest were placed in the brain images to measure contrast and CNR. Furthermore, general image quality, probable diagnosis, and lesion conspicuity were investigated.

    Results

    Synthetic T1-weighted turbo spin echo and T2-weighted turbo spin echo images had higher contrast but also a higher level of noise, resulting in a similar CNR compared with conventional images. Synthetic T2-weighted FLAIR images had lower contrast and a higher level of noise, which led to a lower CNR. Synthetic images were generally assessed to be of inferior image quality, but agreed with the clinical diagnosis to the same extent as the conventional images. Lesion conspicuity was higher in the synthetic T1-weighted images, which also had a better agreement with the clinical diagnoses than the conventional T1-weighted images.

    Conclusion

    Synthetic MR can potentially shorten the MR examination time. Even though the image quality is perceived to be inferior, synthetic images agreed with the clinical diagnosis to the same extent as the conventional images in this study.

  • 154. Bockelman, Camilla
    et al.
    Engelmann, Bodil E.
    Kaprio, Tuomas
    Hansen, Torben F.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Risk of recurrence in patients with colon cancer stage II and III: A systematic review and meta-analysis of recent literature2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 1, p. 5-16Article, review/survey (Refereed)
    Abstract [en]

    Background. Adjuvant chemotherapy is established routine therapy for colon cancer (CC) patients with radically resected stage III and 'high-risk' stage II disease. The decision on recommending adjuvant chemotherapy, however, is based on data from older patient cohorts not reflecting improvements in pre-operative staging, surgery, and pathological examination. The aim is to review the current risk of recurrence in stage II and III patients and second, to estimate the relative importance of routinely assessed clinico-pathological variables. Methods. The PubMed/MEDLINE and the Cochrane databases were systematically searched for randomized controlled studies and observational studies published after 1 January 2005 with patients included after January 1995 on prognosis in surgically treated stage II and III CC patients. Results. Of 2596 studies identified, 37 met the inclusion criteria and 25 provided data for meta-analysis. The total patient sample size in the 25 studies reporting either disease-free (DFS) or recurrence-free survival was 15 559 in stage II and 18 425 in stage III. Five-year DFS for stage II patients operated without subsequent adjuvant chemotherapy was 81.4% [95% confidence interval (CI) 75.4-87.4; in studies with good/very good quality of reporting 82.7%, (95% CI 80.8-84.6)]. For stage II patients treated with adjuvant chemotherapy, the five-year DFS was 79.3% (95% CI 75.6-83.1). For stage III patients without chemotherapy, five-year DFS was 49.0% (95% CI 23.2-74.8) and for those treated with adjuvant chemotherapy, 63.6% (95% CI 59.3-67.9). The prognostic impact of commonly investigated clinico-pathological parameters, (pT-stage, pN-stage, differentiation, number of lymph nodes studied, MMR-status, and emergency surgery) were confirmed. Conclusions. In this meta-analysis, studies with good quality of reporting show a FIVE-year DFS of 82.7% for stage II CC without adjuvant chemotherapy, whereas the FIVE-year DFS is 63.8% for stage III CC with adjuvant chemotherapy. Due to insufficient reporting on treatment quality the presented DFS is likely an under-estimation of what is achieved at high-quality centers today.

  • 155. Bodei, Lisa
    et al.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kidd, Mark
    Prasad, Vikas
    Modlin, Irvin M
    The Status of Neuroendocrine Tumor Imaging: From Darkness to Light?2015In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 101, no 1, p. 1-17Article in journal (Refereed)
    Abstract [en]

    Diagnostic imaging plays a pivotal role in the diagnosis, staging, treatment selection and follow-up for neuroendocrine tumors. The available diagnostic strategies are morphologic imaging, including computed tomography, magnetic resonance imaging (MRI) and ultrasound techniques, and molecular imaging, including scintigraphy with 111In-pentetreotide and positron emission tomography with 68Ga-DOTA-peptides, 18F-DOPA and 11C-5-HTP. A combination of anatomic and functional techniques is routinely performed to optimize sensitivity and specificity. The introduction of diffusion-weighted MRI and dynamic contrast-enhanced techniques represents a promising advance in radiologic imaging, whereas new receptor-binding peptides, including somatostatin agonists and antagonists, represent the recent most favorable innovation in molecular imaging. Future development includes the short-term validation of these techniques, but in extension also a more comprehensive multilevel integration of biologic information pertaining to a specific tumor and patient, possibly encompassing genomic considerations, currently evolving as a new entity denoted ‘precision medicine'. The ideal is a diagnostic sequence that captures the global status of an individual's tumor and encompasses a multidimensional characterization of tumor location, metabolic performance and target identification. To date, advances in imagery have focused on increasing resolution, discrimination and functional characterization. In the future, the fusion of imagery with the parallel analysis of biological and genomic information has the potential to considerably amplify diagnosis.

  • 156.
    Bohl Kullberg, E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Edwards, Katarina
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Physical Chemistry.
    Capala, J
    Sjöberg, S
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Introductory experiments on ligand liposomes as delivery agents for boronneutron capture therapy2003In: International Journal of Oncology, ISSN 1019-6439, Vol. 23, no 2, p. 461-467Article in journal (Refereed)
    Abstract [en]

    Liposomes are, when coupled to receptor ligands, candidates for receptor mediated delivery of boron for tumour therapy since they have capacity to deliver large amounts of boron per receptor interaction. With EGF-liposomes we present a pegylated ligand liposome delivery vehicle, containing water soluble boronated phenanthridine, WSP1, or water soluble boronated acridine, WSA1, for EGFR targeting. In the case of WSA1 a ligand dependent uptake was obtained and the boron uptake was as good as if free WSA1 was given. No ligand dependent boron uptake was seen for WSP1 containing liposomes. Thus, WSA1 is a candidate for further studies. Approximately 10(5) boron atoms were in each liposome. A critical assessment indicates that after optimization up to 10(6) boron atoms can be loaded. Since it is known that, for therapeutic effect, approximately 10(8)-10(9) boron atoms are needed in a single tumour cell it is realized that 10(2)-10(3) receptor interactions are needed to meet the demand. Tests applying cultured glioma cells indicate, without optimization of the delivery conditions, a boron uptake in the ppm range, which is necessary for successful BNCT. Thus, it seems possible to kill micro-invasive tumour cells with targeted liposomes if the delivery conditions are optimal.

  • 157. Bolinder, Jan
    et al.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Metabolic Bone Diseases.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wilding, John
    Langkilde, Anna Maria
    Sugg, Jennifer
    Parikh, Shamik
    Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 3, p. 1020-1031Article in journal (Refereed)
    Abstract [en]

    Context:

    Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding.

    Objectives:

    Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components.

    Design and Setting:

    This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries.

    Patients:

    Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin.

    Intervention:

    Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk.

    Main Outcome Measures:

    Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated.

    Results:

    At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, −2.08 kg [95% confidence interval (CI) = −2.84 to −1.31; P < 0.0001]; waist circumference, −1.52 cm (95% CI = −2.74 to −0.31; P = 0.0143); FM, −1.48 kg (95% CI = −2.22 to −0.74; P = 0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI = 15.5 to 36.7; P < 0.0001); VAT, −258.4 cm3 (95% CI = −448.1 to −68.6; nominal P = 0.0084); SAT, −184.9 cm3 (95% CI = −359.7 to −10.1; nominal P = 0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%.

    Conclusions:

    Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.

  • 158.
    Bondza, Sina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Stenberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Nestor, Marika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Andersson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Björkeund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Conjugation Effects on Antibody-Drug Conjugates: Evaluation of Interaction Kinetics in Real Time on Living Cells2014In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 11, p. 4154-4163Article in journal (Refereed)
    Abstract [en]

    Antibody-drug conjugates (ADC) have shown promising effects in cancer therapy by combining the target specificity of an antibody with the toxicity of a chemotherapeutic drug. As the number of therapeutic antibodies is significantly larger than those used as ADCs, there is unused potential for more effective therapies. However, the conjugation of an additional molecule to an antibody may affect the interaction with its target, altering association rate, dissociation rate, or both. Any changes of the binding kinetics can have subsequent effects on the efficacy of the ADCs, thus the kinetics are important to monitor during ADC development and production. This paper describes a method for the analysis of conjugation effects on antibody binding to its antigen, using the instrument LigandTracer and a fluorescent monovalent anti-IgG binder denoted FIBA, which did not affect the interaction. All measurements were done in real time using living cells which naturally expressed the antigens. With this method the binding profiles of different conjugations of the therapeutic anti-EGFR antibody cetuximab and the anti-CD44v6 antibody fragment AbD15171 were evaluated and compared. Even comparatively small modifications of cetuximab altered the interaction with the epidermal growth factor receptor (EGFR). In contrast, no impact on the AbD15171-CD44v6 interaction was observed upon conjugation. This illustrates the importance to study the binding profile for each ADC combination, as it is difficult to draw any general conclusion about conjugation effects. The modification of interaction kinetics through conjugation opens up new possibilities when optimizing an antibody or an ADC, since the conjugations can be used to create a binding profile more apt for a specific clinical need.

  • 159.
    Borges, Joao Batista
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Costa, Eduardo L. V.
    Bergquist, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lucchetta, Luca
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Amato, Marcelo B. P.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lung Inflammation Persists After 27 Hours of Protective Acute Respiratory Distress Syndrome Network Strategy and Is Concentrated in the Nondependent Lung2015In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 43, no 5, p. E123-E132Article in journal (Refereed)
    Abstract [en]

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

  • 160.
    Borges, João Batista
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Costa, Eduardo L V
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Amato, Marcelo
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Early inflammation mainly affects normally and poorly aerated lung in experimental ventilator-induced lung injury2014In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 42, no 4, p. e279-e287Article in journal (Refereed)
    Abstract [en]

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

    DESIGN: Prospective laboratory investigation.

    SETTING: A university animal research laboratory.

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

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

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

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

  • 161.
    Borges, João Batista
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Bohm, Stephan H
    Tusman, Gerardo
    Melo, Alexandre
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Park, Marcelo
    Costa, Eduardo L V
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Amato, Marcelo
    Regional Lung Perfusion estimated by Electrical Impedance Tomography in a piglet model of lung collapse2011In: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 112, no 1, p. 225-236Article in journal (Refereed)
    Abstract [en]

    The assessment of the regional match between alveolar ventilation and perfusion in critically ill patients requires simultaneous measurements of both parameters. Ideally, assessment of lung perfusion should be performed in real-time with an imaging technology which provides, through fast acquisition of sequential images, information about the regional dynamics or regional kinetics of an appropriate tracer. We present a novel electrical impedance tomography (EIT) based method that quantitatively estimates regional lung perfusion based on first-pass kinetics of a bolus of hypertonic saline contrast. Pulmonary blood flow was measured in six piglets during control and unilateral or bilateral lung collapse conditions. The first-pass kinetics method showed good agreement with the estimates obtained by single-photon-emission computerized tomography (SPECT). The mean difference (SPECT minus EIT) between fractional blood flow to lung areas suffering atelectasis was -0.6 %, with a standard deviation of 2.9 %. This method outperformed the estimates of lung perfusion based on impedance-pulsatility. In conclusion, we describe a novel method based on Electrical Impedance Tomography for estimating regional lung perfusion at the bedside. In both, healthy and injured lung conditions, the distribution of pulmonary blood flow as assessed by EIT agreed well with the one obtained by SPECT. The method proposed in this paper has the potential to contribute to a better understanding of the behavior of regional perfusion under different lung and therapeutic conditions.

  • 162.
    Borges, João Batista
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Ulin, Johan
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Ventilation Distribution Studies Comparing Technegas and "Gallgas" Using (GaCl3)-Ga-68 as the Label2011In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 52, no 2, p. 206-209Article in journal (Refereed)
    Abstract [en]

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

  • 163.
    Borota, Ljubisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Gál, Gyula
    Jonasson, Per
    Ridderheim, Per-Åke
    Successful treatment of a ruptured aneurysm at the vertebral artery-posterior inferior cerebellar artery junction and simultaneous treatment of the stenotic vertebral artery with a single flow-diverting stent: a case report2014In: Journal of Medical Case Reports, ISSN 1752-1947, E-ISSN 1752-1947, Vol. 8, p. 172-Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    This is the first report on the simultaneous successful treatment of a large ruptured saccular aneurysm and stenotic parent artery with a single flow-diverting stent.

    CASE PRESENTATION:

    We report the case of a 68-year-old Caucasian man with occlusion of the right vertebral artery and a ruptured aneurysm at the junction of the left posterior inferior cerebellar artery-left vertebral artery that was successfully treated by the deployment of a single flow-diverting stent in the stenotic left vertebral artery. Stent deployment was complicated by thrombotic occlusion of the basilar artery, which was successfully reopened. The patient recovered completely, and follow-up angiography at 4 months and 1 year showed patent vertebral artery with gradual shrinkage of the aneurysm.

    CONCLUSIONS:

    This report contributes to the literature on treatment of large ruptured aneurysms localized in stenotic arteries and in areas of the endocranium where a mass of embolic material in the aneurysm (coils) might compromise the circulation in the parent blood vessel or compress vital brain structures.

  • 164.
    Borota, Ljubisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Mahmoud, Ehab
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nyberg, Christoffer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Ekberg, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Combined percutaneous and transarterial devascularisation of juvenile nasopharyngeal angiofibroma with protection of internal carotid artery: A modification of the technique2015In: Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences, ISSN 1591-0199, Vol. 21, no 3, p. 390-396Article in journal (Refereed)
    Abstract [en]

    Juvenile nasal angiofibroma (JNA) is a hypervascularised, benign, but locally aggressive tumour that grows in the posterior, upper part of the nasal cavity and invades surrounding anatomical structures. The treatment of choice is surgical removal, but complete resection of the tumour can be hampered because of profuse perioperative bleeding. Preoperative embolisation of the tumour has been proposed as an effective method for prevention of perioperative bleeding, thereby shortening of the time of the operation. In this report of five cases, we describe successful preoperative devascularisation of the tumour by applying a modified method of direct intratumoural injection of the liquid embolic agent Onyx combined with protection of the internal carotid artery. The control of bleeding during the embolisation and occlusion of the maxillary or sphenopalatine artery was achieved by using a bi-luminal balloon catheter. Such use of the dual-lumen catheter in treatment of JNA has not been reported so far in the medical literature.

  • 165. Borzecka, Kinga
    et al.
    Plociennikowska, Agnieszka
    Björkelund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Sobota, Andrzej
    Kwiatkowska, Katarzyna
    CD14 Mediates Binding of High Doses of LPS but Is Dispensable for TNF-alpha Production2013In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, p. 824919-Article in journal (Refereed)
    Abstract [en]

    Activation of macrophages with lipopolysaccharide (LPS) involves a sequential engagement of serum LPS-binding protein (LBP), plasma membrane CD14, and TLR4/MD-2 signaling complex. We analyzed participation of CD14 in TNF-alpha production stimulated with 1-1000 ng/mL of smooth or rough LPS (sLPS or rLPS) and in sLPS binding to RAW264 and J744 cells. CD14 was indispensable for TNF-alpha generation induced by a low concentration, 1 ng/mL, of sLPS and rLPS. At higher doses of both LPS forms (100-1000 ng/mL), TNF-alpha release required CD14 to much lower extent. Among the two forms of LPS, rLPS-induced TNF-alpha production was less CD14-dependent and could proceed in the absence of serumas an LBP source. On the other hand, the involvement of CD14 was crucial for the binding of 1000 ng/mL of sLPS judging from an inhibitory effect of the anti-CD14 antibody. The binding of sLPS was also strongly inhibited by dextran sulfate, a competitive ligand of scavenger receptors (SR). In the presence of dextran sulfate, sLPS-induced production of TNF-alpha was upregulated about 1.6-fold. The data indicate that CD14 together with SR participates in the binding of high doses of sLPS. However, CD14 contribution to TNF-alpha production induced by high concentrations of sLPS and rLPS can be limited.

  • 166. Bosly, Andre
    et al.
    Grigg, Andrew
    Holte, Harald
    Gisselbrecht, Christian
    Radford, John
    Rossi, Andrea
    Lopez-Guillermo, Armando
    Trneny, Marek
    Sebban, Catherine
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    da Costa, Fernando Leal
    Colombat, Philippe
    Bron, Dominique
    Coiffier, Bertrand
    A Randomized Study of Interferon alpha-2b Versus No Treatment as Consolidation After High Dose Therapy and Autologous Stem Cell Transplantation for Patients With Relapsed Lymphoma2013In: The Oncologist, ISSN 1083-7159, E-ISSN 1549-490X, Vol. 18, no 11, p. 1189-1189Article in journal (Other academic)
    Abstract [en]

    Background. Patients with lymphoma who have experienced a first relapse or progression and have disease deemed sensitive to salvage chemotherapy nevertheless have a high likelihood of having a second relapse. To decrease the likelihood of a second relapse after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT), interferon (IFN) alpha-2b was given in a prospective randomized international trial. Methods. In this trial, 221 patients with varying histologic diagnoses (8 small lymphocytic, 37 follicular, 9 mantle, 90 diffuse large B-cell, 20 peripheral T-cell, 3 high-grade B-cell non-Hodgkin lymphoma, and 54 Hodgkin lymphoma) were randomly assigned to receive no further treatment (armA: 117 patients) or IFN alpha-2b, 3 MU three times weekly, for 18 months (arm B: 104 patients). Results. In arm B, 21 patients (20%) did not receive IFN alpha-2b because of early progression or absence of hematologic recovery, 29 patients (28%) completed the 18 months of treatment, and 54 patients (52%) interrupted treatment because of progression (23%) or toxicity (29%). Event-free survival and overall survival were not different between the two arms on an intent-to-treat analysis and also if analysis was restricted to patients who were a live and had not experienced disease progression three months after transplantation. The study was not sufficiently powered to evaluate effects in histologic subtypes. Conclusion. In this trial, post-autograft IFN alpha-2b did not improve outcomes in a heterogeneous group of patients with lymphoma.

  • 167.
    Botling, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lohr, Miriam
    Hellwig, Birte
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lambe, Mats
    Berglund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    König, André
    Fernandes, Oswaldo
    Karlsson, Mats
    Helenius, Gisela
    Karlsson, Christina
    Rahnenführer, Jörg
    Hengstler, Jan G
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis and tissue microarray validation2013In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, no 1, p. 194-204Article in journal (Refereed)
    Abstract [en]

    Background:

    Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multi-gene signatures in clinical practice is unclear and the biological importance of individual genes is difficult to assess as the published signatures virtually do not overlap

    Methods:

    Here we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data was used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level p<0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n=860).

    RESULTS:

    The meta-analysis revealed 14 genes that were significantly associated with survival (p<0.001) with a false discovery rate <1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from two independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.

    CONCLUSIONS:

    Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics.

  • 168. Braendengen, Morten
    et al.
    Tveit, Kjell Magne
    Bruheim, Kjersti
    Cvancarova, Milada
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Late patient-reported toxicity after preoperative radiotherapy or chemoradiotherapy in nonresectable rectal cancer: Results from a randomized phase III study2011In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 81, no 4, p. 1017-1024Article in journal (Refereed)
    Abstract [en]

    Purpose: Preoperative chemoradiotherapy (CRT) is superior to radiotherapy (RT) in locally advanced rectal cancer, but the survival gain is limited. Late toxicity is, therefore, important. The aim was to compare late bowel, urinary, and sexual functions after CRT or RT.

    Methods and Materials: Patients (N = 207) with nonresectable rectal cancer were randomized to preoperative CRT or RT (2 Gy x 25 +/- 5-fluorouracil/leucovorin). Extended surgery was often required. Self-reported late toxicity was scored according to the LENT SOMA criteria in a structured telephone interview and with questionnaires European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), International Index of Erectile Function (IIEF), and sexual function -vaginal changes questionnaire (SVQ).

    Results: Of the 105 patients alive in Norway and Sweden after 4 to 12 years of follow-up, 78 (74%) responded. More patients in the CRT group had received a stoma (73% vs. 52%, p = 0.09). Most patients without a stoma (7 of 12 in CRT group and 9 of 16 in RT group) had incontinence for liquid stools or gas. No stoma and good anal function were seen in 5 patients (11%) in the CRT group and in 11 (30%) in the RT group (p = 0.046). Of 44 patients in the CRT group, 12 (28%) had had bowel obstruction compared with 5 of 33 (15%) in the RT group (p = 0.27). One-quarter of the patients reported urinary incontinence. The majority of men had severe erectile dysfunction. Few women reported sexual activity during the previous month. However, the majority did not have concerns about their sex life.

    Conclusions: Fecal incontinence and erectile dysfunction are frequent after combined treatment for locally advanced rectal cancer. There was a clear tendency for the problems to be more common after CRT than after RT.

  • 169. Brauner, S.
    et al.
    Zhou, W.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Green, T. M.
    Folkersen, L.
    Ivanchenko, M.
    Lofstrom, B.
    Xu-Monette, Z. Y.
    Young, K. H.
    Pedersen, L. Moller
    Moller, M. Boe
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Enblad, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wahren-Herlenius, M.
    Reduced expression of TRIM21/Ro52 predicts poor prognosis in diffuse large B-cell lymphoma patients with and without rheumatic disease2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 278, no 3, p. 323-332Article in journal (Refereed)
    Abstract [en]

    ObjectiveTRIM21 (also known as Ro52) is an autoantigen in rheumatic disease and is predominantly expressed in leucocytes. Overexpression is associated with decreased proliferation, and the TRIM21 gene maps to a tumour suppressor locus. We therefore investigated the expression of TRIM21 in patients with diffuse large B-cell lymphoma (DLBCL) and its potential usefulness as a prognostic biomarker. Materials and methodsTRIM21 expression levels were assessed by immunohistochemistry in lymphoma biopsies from three cohorts of patients with DLBCL: 42 patients with rheumatic disease treated with a cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP)-like regimen, 76 CHOP-treated and 196 rituximab-CHOP-treated nonrheumatic patients. Expression was correlated with clinical and biomedical parameters. TRIM21 expression was assessed in relation to lymphocyte proliferation by quantitative PCR and correlated with H-3-thymidine incorporation and propidium iodine staining. ResultsTRIM21 expression levels differed in the lymphomas compared to normal lymphoid tissue, with reduced expression correlating with shorter overall survival in all three cohorts. In the two larger cohorts, progression-free survival was assessed and was also found to correlate with TRIM21 expression. The association was independent of commonly used clinical prognostic scores, lymphoma subtype and several previously reported prognostic biomarkers. In agreement with this clinical observation, we noted an inverse correlation between TRIM21 expression and proliferation of leucocytes invitro. ConclusionsWe show that loss of TRIM21 expression is associated with more aggressive lymphoma and increased proliferation, whereas maintenance of TRIM21 expression is associated with better prognosis in patients with DLBCL. Based on our findings, we suggest that TRIM21 should be considered as a novel biomarker for lymphoma characterization and for predicting patient survival.

  • 170. Brehmer, Marianne
    et al.
    Beckman, Mats O
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Three-dimensional computed tomography planning improves percutaneous stone surgery2014In: Scandinavian journal of urology, ISSN 2168-1813, Vol. 48, no 3, p. 316-323Article in journal (Refereed)
    Abstract [en]

    Objective

    Percutaneous nephrolithotripsy (PCNL) has become the gold standard for treatment of renal stones larger than 2 cm. To optimize the surgical procedure a method for meticulous preoperative three-dimensional computed tomography (3D-CT) planning was developed and analysed. The aim of this study was to evaluate how 3D-CT influenced the choice of access route and treatment outcome.

    Material and methods

    Patients planned for PCNL were included in a prospective study. Decision algorithms were studied and recorded before and after 3D-CT planning in a total of 35 patients.

    Results

    Thirty-one of the patients (88%) had a complex stone situation. The CT examinations resulted in change of access plan in 15 out of 28 patients, in addition to seven patients where access could not be planned without 3D-CT, totalling 22 out of 35 (63%). This resulted in 24 patients (69%) being stone free after a single PCNL session. Of these 24 patients, 22 (22/35 = 63%) were stone free with one dilated access track only. In 16 of the 24 patients (76%) who were stone free after one PCNL procedure, evaluation of the 3D-CT images had changed the initial preoperative planning (10 cases) or made planning possible (six cases). A few patients had thoracic complications but there were no cases with bleeding.

    Conclusions

    Preoperative planning of complex stone situations with 3D-CT had a significant impact on operative procedure, resulting in a low number of access punctures.

  • 171. Breugom, A. J.
    et al.
    van Gijn, W.
    Muller, E. W.
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    van den Broek, C. B. M.
    Fokstuen, T.
    Gelderblom, H.
    Kapiteijn, E.
    Leer, J. W. H.
    Marijnen, C. A. M.
    Martijn, H.
    Kranenbarg, E. Meershoek-Klein
    Nagtegaal, I. D.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Punt, C. J. A.
    Putter, H.
    Roodvoets, A. G. H.
    Rutten, H. J. T.
    Steup, W. H.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    van de Velde, C. J. H.
    Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial2015In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 26, no 4, p. 696-701Article in journal (Refereed)
    Abstract [en]

    Background: The discussion on the role of adjuvant chemotherapy for rectal cancer patients treated according to current guidelines is still ongoing. A multicentre, randomized phase III trial, PROCTOR-SCRIPT, was conducted to compare adjuvant chemotherapy with observation for rectal cancer patients treated with preoperative (chemo) radiotherapy and total mesorectal excision (TME). Patients and methods: The PROCTOR-SCRIPT trial recruited patients from 52 hospitals. Patients with histologically proven stage II or III rectal adenocarcinoma were randomly assigned (1: 1) to observation or adjuvant chemotherapy after preoperative (chemo) radiotherapy and TME. Radiotherapy consisted of 5 x 5 Gy. Chemoradiotherapy consisted of 25 x 1.8-2 Gy combined with 5-FU-based chemotherapy. Adjuvant chemotherapy consisted of 5-FU/LV (PROCTOR) or eight courses capecitabine (SCRIPT). Randomization was based on permuted blocks of six, stratified according to centre, residual tumour, time between last irradiation and surgery, and preoperative treatment. The primary end point was overall survival. Results: Of 470 enrolled patients, 437 were eligible. The trial closed prematurely because of slow patient accrual. Patients were randomly assigned to observation (n = 221) or adjuvant chemotherapy (n = 216). After a median follow-up of 5.0 years, 5-year overall survival was 79.2% in the observation group and 80.4% in the chemotherapy group [hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.62-1.39; P = 0.73]. The HR for disease-free survival was 0.80 (95% CI 0.60-1.07; P = 0.13). Five-year cumulative incidence for locoregional recurrences was 7.8% in both groups. Five-year cumulative incidence for distant recurrences was 38.5% and 34.7%, respectively (P = 0.39). Conclusion: The PROCTOR-SCRIPT trial could not demonstrate a significant benefit of adjuvant chemotherapy with fluoropyrimidine monotherapy after preoperative (chemo) radiotherapy and TME on overall survival, disease-free survival, and recurrence rate. However, this trial did not complete planned accrual.

  • 172.
    Briley Saebo, Karen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Bjørnerud, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Grant, Derek
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Berg, Trond
    Mörk Kindberg, Grete
    Hepatic cellular distribution and degradation of iron oxide nanoparticles following single intravenous injection in rats: implications for magnetic resonance imaging2004In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 316, no 3, p. 315-323Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to determine the cellular distribution and degradation in rat liver following intravenous injection of superparamagnetic iron oxide nanoparticles used for magnetic resonance imaging (NC100150 Injection). Relaxometric and spectrophotometric methods were used to determine the concentration of the iron oxide nanoparticles and their degradation products in isolated rat liver parenchymal, endothelial and Kupffer cell fractions. An isolated cell phantom was also constructed to quantify the effect of the degradation products on the loss of MR signal in terms of decreased transverse relaxation times, T2*. The results of this study show that iron oxide nanoparticles found in the NC100150 Injection were taken up and distributed equally in both liver endothelial and Kupffer cells following a single 5 mg Fe/kg body wt. bolus injection in rats. Whereas endothelial and Kupffer cells exhibited similar rates of uptake and degradation, liver parenchymal cells did not take up the NC100150 Injection iron oxide particles. Light-microscopy methods did, however, indicate an increased iron load, presumably as ferritin/hemosiderin, within the hepatocytes 24 h post injection. The study also confirmed that compartmentalisation of ferritin/hemosiderin may cause a significant decrease in the MRI signal intensity of the liver. In conclusion, the combined results of this study imply that the prolonged presence of breakdown product in the liver may cause a prolonged imaging effect (in terms of signal loss) for a time period that significantly exceeds the half-life of NC100150 Injection iron oxide nanoparticles in liver.

  • 173.
    Brooks, Samantha J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Burgos, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kempton, M J
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nordenskjöld, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nylander, Ruta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Late-life obesity is associated with smaller global and regional gray matter volumes: a voxel-based morphometric study2013In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 37, no 2, p. 230-236Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: 

    Obesity adversely affects frontal lobe brain structure and function. Here we sought to show that people who are obese versus those who are of normal weight over a 5-year period have differential global and regional brain volumes.

    DESIGN: 

    Using voxel-based morphometry, contrasts were done between those who were recorded as being either obese or of normal weight over two time points in the 5 years prior to the brain scan. In a post-hoc preliminary analysis, we compared scores for obese and normal weight people who completed the trail-making task.

    SUBJECTS: 

    A total of 292 subjects were examined following exclusions (for example, owing to dementia, stroke and cortical infarcts) from the Prospective Investigation of the Vasculature in Uppsala Seniors cohort with a body mass index of normal weight (<25 kg m−2) or obese (30 kg m−2).

    RESULTS: 

    People who were obese had significantly smaller total brain volumes and specifically, significantly reduced total gray matter (GM) volume (GMV) (with no difference in white matter or cerebrospinal fluid). Initial exploratory whole brain uncorrected analysis revealed that people who were obese had significantly smaller GMV in the bilateral supplementary motor area, bilateral dorsolateral prefrontal cortex (DLPFC), left inferior frontal gyrus and left postcentral gyrus. Secondary more stringent corrected analyses revealed a surviving cluster of GMV difference in the left DLPFC. Finally, post-hoc contrasts of scores on the trail-making task, which is linked to DLPFC function, revealed that obese people were significantly slower than those of normal weight.

    CONCLUSION: 

    These findings suggest that in comparison with normal weight, people who are obese have smaller GMV, particularly in the left DLPFC. Our results may provide evidence for a potential working memory mechanism for the cognitive suppression of appetite that may lower the risk of developing obesity in later life.

  • 174.
    Brooks, Samantha J
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Solstrand Dahlberg, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Swenne, Ingemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Aronsson, Marianne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Zarei, Sanaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lundberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jacobsson, Josefin A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Salonen-Ros, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Rosling, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Obsessive-compulsivity and working memory are associated with differential prefrontal cortex and insula activation in adolescents with a recent diagnosis of an eating disorder2014In: Psychiatry Research, ISSN 0165-1781, E-ISSN 1872-7123, Vol. 224, no 3, p. 246-253Article in journal (Refereed)
    Abstract [en]

    The role of rumination at the beginning of eating disorder (ED) is not well understood. We hypothesised that impulsivity, rumination and restriction could be associated with neural activity in response to food stimuli in young individuals with eating disorders (ED). We measured neural responses with functional magnetic resonance imaging (fMRI), tested working memory (WM) and administered the eating disorders examination questionnaire (EDE-Q), Barratt impulsivity scale (BIS-11) and obsessive-compulsive inventory (OCI-R) in 15 adolescent females with eating disorder not otherwise specified (EDNOS) (mean age 15 years) and 20 age-matched healthy control females. We found that EDNOS subjects had significantly higher scores on the BIS 11, EDE-Q and OCI-R scales. Significantly increased neural responses to food images in the EDNOS group were observed in the prefrontal circuitry. OCI-R scores in the EDNOS group also significantly correlated with activity in the prefrontal circuitry and the cerebellum. Significantly slower WM responses negatively correlated with bilateral superior frontal gyrus activity in the EDNOS group. We conclude that ruminations, linked to WM, are present in adolescent females newly diagnosed with EDNOS. These may be risk factors for the development of an eating disorder and may be detectable before disease onset.

  • 175. Brændengen, Morten
    et al.
    Hansson, Karl
    Radu, Calin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Siegbahn, Albert
    Jacobsson, Hans
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Delineation of gross tumor volume (GTV) for radiation treatment planning of locally advanced rectal cancer using information from MRI or FDG-PET/CT: a prospective study2011In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 81, no 4, p. e439-e445Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Accurate delineation of target volumes is important to maximize radiation dose to the tumor and minimize it to nontumor tissue. Computed tomography (CT) and magnetic resonance imaging (MRI) are standard imaging modalities in rectal cancer. The aim was to explore whether functional imaging with F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), combined with CT (FDG-PET/CT) gives additional information to standard pretreatment evaluation and changes the shape and size of the gross tumor volume (GTV).

    METHODS AND MATERIALS:

    From 2007 to 2009, 77 consecutive patients with locally advanced rectal cancer were prospectively screened for inclusion in the study at two university hospitals in Sweden, and 68 patients were eligible. Standard GTV was delineated using information from clinical examination, CT, and MRI (GTV-MRI). Thereafter, a GTV-PET was defined in the fused PET-CT, and the target volume delineations were compared for total volume, overlap, and mismatch. Pathologic uptake suspect of metastases was also registered.

    RESULTS:

    The median volume of GTV-MRI was larger than that of GTV-PET: 111 cm3 vs. 87 cm3 (p < 0.001). In many cases, the GTV-MRI contained the GTV defined on the PET/CT images as subvolumes, but when a GTV total was calculated after the addition of GTV-PET to GTV-MRI, the volume increased, with median 11% (range, 0.5–72%). New lesions were seen in 15% of the patients for whom PET/CT was used.

    CONCLUSIONS:

    FDG-PET/CT facilitates and adds important information to the standard delineation procedure of locally advanced rectal cancer, mostly resulting in a smaller GTV, but a larger total GTV using the union of GTV-MRI and GTV-PET. New lesions were sometimes seen, potentially changing the treatment strategy.

  • 176. Brændengen, Morten
    et al.
    Tveit, Kjell M
    Hjermstad, Marianne J
    Johansson, Hemming
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Brandberg, Yvonne
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Health-related quality of life (HRQoL) after multimodal treatment for primarily non-resectable rectal cancer: Long-term results from a phase III study2012In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, no 6, p. 813-819Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    A randomised study in non-resectable rectal cancer showed that preoperative chemoradiotherapy (CRT) resulted in better local control and disease-specific survival, but not overall survival than radiotherapy alone. The present paper presents long-term (>4years) health-related quality of life (HRQoL) and a comparison between the results and reference values from the Norwegian general population.

    MATERIAL AND METHODS:

    A total of 207 patients with primarily non-resectable rectal cancer were randomised to preoperative CRT (2Gyx25+5FU/leucovorin) or RT (2Gyx25) before surgery. HRQoL was assessed using EORTC QLQ-C30, completed at baseline and sent to all patients alive in Norway and Sweden (n=105) after a minimum of 4years post treatment. A difference of ⩾5 points on the 0-100 scales was considered clinically significant.

    RESULTS:

    Seventy-six (72%) patients answered at follow-up. No statistically significant differences between the CRT and RT groups appeared at follow-up, although clinically significant differences in social functioning, dyspnoea and diarrhoea were found. Over time, a clinically significant reduction in physical functioning was found in both groups. Moreover, reduced social functioning and less diarrhoea in the CRT group and better role functioning and more diarrhoea in the RT group were found. Comparisons between the study group and age and gender matched reference values indicate impaired social functioning and more diarrhoea among the patients.

    CONCLUSION:

    There were no statistically significant differences in HRQoL between the randomisation groups. In general, despite having impaired social functioning and more diarrhoea, patients reported HRQoL comparable with the reference population several years after treatment.

  • 177. Bujko, Krzysztof
    et al.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Adjuvant chemotherapy for rectal cancer2014In: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 15, no 6, p. E194-E195Article in journal (Refereed)
  • 178.
    Bulenga, T. N.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Selvaraju, Ram Kumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Asplund, Veronika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Velikyan, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Eriksson, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Dosimetry of 68Ga and 177Lu labeled Exendin4-impact on feasibility of repeated PET imaging and radiotherapy2014In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 41, no S2, p. S293-S293, article id OP607Article in journal (Other academic)
  • 179.
    Buratovic, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Sundell-Bergman, Synnöve
    Sveriges lantbruksuniversitet, Fakulteten för naturresurser och lantbruksvetenskap, Institutionen för Mark och miljö.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Effects of fractionated low dose exposure to gamma radiation and the interaction with nicotine on behaviour in miceManuscript (preprint) (Other academic)
  • 180.
    Buratovic, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Sundell-Bergman, Synnöve
    Sveriges lantbruksuniversitet, Fakulteten för naturresurser och lantbruksvetenskap, Institutionen för Mark och miljö.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Coexposure to gamma-radiation and nicotine during a critical period of neonatal brain development can excarebate cognitive defects in adult mice2014Conference paper (Refereed)
  • 181.
    Buratovic, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Sundell-Bergman, Synnöve
    Sveriges lantbruksuniversitet, Fakulteten för naturresurser och lantbruksvetenskap, Institutionen för Mark och miljö.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Cognitive defects and tau protein alterations in adult mice following neonatal low dose co-exposure to radiation and ketamine2014Conference paper (Refereed)
  • 182.
    Buratovic, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Sundell-Bergman, Synnöve
    Sveriges lantbruksuniversitet, Fakulteten för naturresurser och lantbruksvetenskap, Institutionen för Mark och miljö.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Exposure to a single dose of ionising radiation during brain development can cause cognitive defects and increased levels of tau in mice2012Conference paper (Refereed)
    Abstract [en]

    Ionising radiation (IR) is widely used in the medical field for treating tumours, including tumours in the central nervous system, and for imaging techniques such as computed tomography (CT). There is a lack of knowledge and increasing concern about effects and consequences from low dose exposure during critical phases of perinatal and/or neonatal brain development compared to prenatal irradiation. It is known that IR causes neurotoxicological and neurobehavioural defects in mammals. Further, an epidemiological study has suggested that low doses of IR to the human brain during infancy can have a negative effect on cognitive abilities in adulthood. The rapid brain growth spurt (BGS) occurs in humans as well as mice. In humans the BGS starts during the third trimester of pregnancy and continues throughout the first two years of life. In mouse and rat the BGS is neonatal, spanning the first 3-4 weeks of life. The BGS is characterized by maturation of axonal and dendritic outgrowth, establishment of neural connections and acquisition of many new motor and sensory abilities. By using the neonatal mouse as an animal model we are able to study the effect of IR during early periods of brain development and which consequences it has for the adult animal. Disturbances in development caused by nicotine, MeHg, PCBs and PBDEs have previously been shown to alter adult spontaneous behaviour and/or neuroprotein levels in mice.

    Neonatal NMRI male mice were irradiated (0; 0.35 and 0.5 Gy) at one single occasion on postnatal day 10. Mice serving as controls were placed in plastic dishes for a time-period corresponding to the irradiation. Spontaneous behaviour was tested in a novel home environment at 2- and 4-months of age and parameters observed were locomotion, rearing and total activity. Analyses of important neuroprotein levels were performed on 6-month-old control and 0.5 Gy irradiated mice.

    Spontaneous behaviour test (locomotion, rearing, total activity revealed a significantly deranged behaviour in 2- and 4-month old mice irradiated with 0.35 or 0.5 Gy in a dose-response related manner, when compared to controls. The behavioural alterations were manifested as a reduced activity during at the beginning of the observational period and a higher activity at the end of the observational period. Analyses of the neuroprotein tau, which in human medicine is used as a biomarker for Alzheimer’s disease, showed a significantly higher level in mice irradiated with 0.5 Gy compared to controls. This demonstrates that a single dose of gamma radiation, given at a defined critical time period during brain development, is sufficient to cause persistently reduced cognitive functions and increased levels of tau in mice.   

  • 183.
    Buratovic, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Sundell-Bergman, Synnöve
    Sveriges lantbruksuniversitet, Fakulteten för naturresurser och lantbruksvetenskap, Institutionen för Mark och miljö.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Neonatal exposure to a single low dose of ionising radiation causes persistent disruptions in cognitive abilities and increased levels of tau in mice2013Conference paper (Other academic)
    Abstract [en]

    Ionising radiation (IR) is extensively used in the medical field for treatment and diagnostics. Concern has been raised about possible negative consequences from low dose exposure to IR during critical phases of perinatal and/or neonatal brain development. The brain growth spurt, which is characterized by maturation of axonal and dendritic outgrowth, establishment of neural connections and acquisition of new motor and sensory abilities, occurs perinatally in humans and neonatally in mice. By using the neonatal mouse as an animal model we are able to study the effect of IR during early periods of brain development and which consequences it has for the adult animal.

    Neonatal NMRI mice were irradiated (0; 0.35 and 0.5 Gy) at one single occasion on postnatal day 10. At 2- and 4-months of age, spontaneous behaviour was tested in a novel home environment and parameters observed were locomotion, rearing and total activity. Analyses of important neuroproteins in cerebral cortex were performed 24h following irradiation (0 and 0.5 Gy) and at 6-months of age.

    Observations of spontaneous behaviour revealed a significantly deranged behaviour in 2- and 4-month old mice of both sexes irradiated with 0.35 or 0.5 Gy in a dose response related manner. The observed reduced activity during the beginning of the test period and increased activity at the end of the test period indicates a lack of habituation capacity and disrupted cognitive functions. Neuroprotein analyses of cerebral cortex 24h after irradiation and at 6-months of age showed a significantly increased level of tau in mice irradiated with 0.5 Gy compared to controls. This demonstrates that a single dose of IR, given at a defined critical period during brain development, is sufficient to cause persistently reduced cognitive functions and increased levels of tau in mice. 

  • 184.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Fagius, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bilateral and recurrent optic neuritis in multiple sclerosis2011In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 123, no 3, p. 207-210Article in journal (Refereed)
    Abstract [en]

    Objective - To assess the frequency of bilateral and recurrent optic neuritis (ON) in multiple sclerosis (MS) and to compare these results with epidemiological data of ON in neuromyelitis optica (NMO) and recurrent ON without other signs of disease. Methods - We identified 472 patients with diagnosis of MS from the Swedish Multiple Sclerosis Register. These patients were evaluated for the presence of ON and whether the ON was the presenting symptom of MS; unilateral or bilateral; monophasic or recurrent. Results - Twenty-one percent presented with ON as their first manifestation of MS. The proportion of patients developing a second attack of ON before demonstration of other manifestations of MS was 5.5% and the frequency of recurrent bilateral ON as the presenting symptom was 3.8%. Only two patients presented with simultaneously appearing bilateral ON corresponding to 0.42%. Conclusion - Recurrent ON, whether unilateral or bilateral, is a common presentation of MS. As MS is a much more common disease than NMO, care must be taken when evaluating the work-up of patients with recurrent ON. In some cases repeated MRI and lumbar punctures are warranted to improve diagnostic accuracy, even in the presence of the serological marker NMO-IgG.

  • 185.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fransson, Moa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Loskog, Angelica S I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zetterberg, Henrik
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Svenningsson, Anders
    Fagius, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Mangsbo, Sara M
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The cerebrospinal fluid cytokine signature of multiple sclerosis: A homogenous response that does not conform to the Th1/Th2/Th17 convention2014In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 277, no 1-2, p. 153-159Article in journal (Refereed)
    Abstract [en]

    In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS). To this end, cerebrospinal fluid from patients with MS was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Increased levels of CCL22, CXCL10 and sCD40L characterized relapsing-remitting MS patients with the presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of relapsing-remitting MS patients irrespectively of the presence of gadolinium-enhancing lesions. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses.

  • 186.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svensson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Fransson, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Zetterberg, Henrik
    Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden..
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Svenningsson, Anders
    Department of Pharmacology and Clinical Neuroscience, Umeå University and University Hospital of Northern Sweden, Umeå, Sweden..
    Fagius, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Mangsbo, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The cerebrospinal fluid cytokine signature of multiple sclerosis: a homogenous response that does not conform to the Th1/Th2/Th17 conventionManuscript (preprint) (Other academic)
    Abstract [en]

    In this cross-sectional study, we wanted to identify key cytokines characteristic of different stages of multiple sclerosis (MS) that could be used as an outcome measure in clinical trials. To this end, cerebrospinal fluid from a cohort of patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) was investigated with a multiplexed fluorescent bead-based immunoassay. In total 43 cytokines were assessed and related to clinical and imaging data. Cerebrospinal fluid from a separate confirmatory cohort was used to validate cytokines pertinent to SPMS. Increased levels of CCL22, CXCL10 and sCD40L characterized RRMS patients with presence of gadolinium-enhancing lesions; decreased CCL2 and increased CXCL1 and CCL5 were typical of RRMS patients irrespectively of presence of gadolinium-enhancing lesions. IL-15 and IL-27 were increased in SPMS patients, but non-significantly in the confirmation cohort. These homogenous patterns of cytokine activation do not conform to conventional Th1/Th2/Th17 responses.

  • 187.
    Burman, Joachim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Zetterberg, H
    Sahlgrenska Academy, University of Gothenburg.
    Fransson, Moa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Loskog, Angelica SI.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Fagius, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Assessing tissue damage in multiple sclerosis: a biomarker approach2014In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404, Vol. 130, no 2, p. 81-89Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS.

    MATERIALS AND METHODS:

    Cerebrospinal fluid from 44 patients with relapsing-remitting MS, 20 with secondary progressive MS and 15 controls were investigated with ELISA to determine levels of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp). Patients underwent MRI of the brain and spinal cord, and gadolinium enhancing lesions, T1 lesions and T2 lesions were counted.

    RESULTS:

    Patients in clinical relapse and patients with nonsymptomatic gadolinium enhancing lesions had high levels of MBP and NFL, indicating ongoing damage to oligodendrocytes and axons. The level of MBP dropped quickly within a week from the onset of a relapse, whereas NFL remained elevated for several weeks and GFAp slowly rose during the course of a relapse. Relapsing-remitting MS patients without gadolinium enhancing lesions had values of MBP, NFL and GFAp similar to controls, while patients with secondary progressive disease had moderately increased values of all biomarkers.

    CONCLUSIONS:

    Analysis of MBP, NFL and GFAp provides direct means to measure tissue damage and is a useful addition to our methods for evaluation of MS.

  • 188. Byström, Per
    et al.
    Berglund, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Garske, Ulrike Garske
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jacobsson, H.
    Sundin, Anders
    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 Radiology, Oncology and Radiation Science, Radiology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Frödin, J-E.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Early prediction of response to first-line chemotherapy by sequential [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with advanced colorectal cancer2009In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 20, no 6, p. 1057-1061Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To evaluate [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), for early evaluation of response to palliative chemotherapy and for prediction of long-term outcome, in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In a randomized trial, patients with mCRC received irinotecan-based combination chemotherapy. FDG-PET was carried out before treatment and after two cycles in 51 patients at two centers. Visual changes in tumor FDG uptake and changes measured semi-automatically, as standard uptake values (SUVs), were compared with radiological response after four and eight cycles. RESULTS: The mean baseline SUV for all tumor lesions per patient was higher in nonresponders than in responders (mean 7.4 versus 5.6, P = 0.02). There was a strong correlation between metabolic response (changes in SUV) and objective response (r = 0.57, P = 0.00001), with a sensitivity of 77% and a specificity of 76%. There was no significant correlation between metabolic response and time to progression (P = 0.5) or overall survival (P = 0.1). CONCLUSIONS: Although metabolic response assessed by FDG-PET reflects radiological tumor volume changes, the sensitivity and specificity are too low to support the routine use of PET in mCRC. Furthermore, PET failed to reflect long-term outcome and can, thus, not be used as surrogate end point for hard endpoint benefit.

  • 189.
    Byström, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Evaluation of predictive markers for patients with advanced colorectal cancer2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 7, p. 849-859Article in journal (Refereed)
    Abstract [en]

    Background.

    To evaluate the predictive and prognostic value of serum and plasma tumor markers, in comparison with clinical and biomedical parameters for response rate (RR), progression-free survival (PFS) and overall survival (OS) among patients with metastatic colorectal cancer (mCRC) treated with combination chemotherapy.

    Material and methods.

    One-hundred and six patients with mCRC from three centers, part of a multicenter study, received irinotecan with the Nordic bolus 5-fluorouracil (5-FU) and folinic acid schedule (FLIRI) or the de Gramont schedule (Lv5FU2-IRI). Blood samples for CEA, CA19-9, TPA, TIMP-1, SAA, transthyretin and CRP were taken at baseline and after two, four and eight weeks of treatment. Tumor marker levels at baseline and longitudinally were compared with responses evaluated (CT/MRI) after two and four months of treatment. The correlations to RR, PFS and OS were evaluated with regression analyses.

    Results.

    A significant correlation to OS was seen for baseline levels of all markers. In multivariate analyses with clinical parameters, TPA, CRP, SAA and TIMP-1 provided independent information. The baseline values of CEA, TPA and TIMP-1 were also significantly correlated to PFS and TPA to RR. Changes during treatment, i.e. the slope gave with the exception of CA19-9 for OS less information about outcomes. The best correlation to response was seen for CEA, CA19-9 and TPA with AUC values of 0.78, 0.83 and 0.79, respectively, using a combined model based upon an interaction between the slope and the baseline value.

    Conclusions.

    Baseline tumor markers together with clinical parameters provide prognostic information about survival in patients with mCRC. The ability of the individual tumor markers to predict treatment response and PFS is limited. Changes in marker levels during the first two months of treatment are less informative of outcome.

  • 190.
    Byström, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sorbye, H
    Tveit, KM
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Health-related quality of life in patients with metastatic colorectal cancer receiving palliative combination chemotherapy2012Article in journal (Refereed)
  • 191.
    Bäckström, Gloria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Protons, other Light Ions, and 60Co Photons: Study of Energy Deposit Clustering via Track Structure Simulations2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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