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  • 1.
    Jonsson, E
    et al.
    Quantify Research, Stockholm, Sweden.
    Hansson-Hedblom, A
    Quantify Research, Stockholm, Sweden.
    Ljunggren, Ö
    Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Åkesson, K
    Department of Clinical Sciences, Clinical and Molecular Osteoporosis Unit, Lund University, Malmö, Sweden.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Kanis, J A
    University of Sheffield, Sheffield, UK; Catholic University of Australia, Melbourne, Australia.
    Borgström, F
    Quantify Research, Stockholm; Karolinska Institutet, Stockholm, Sweden.
    A health economic simulation model for the clinical management of osteoporosis2018In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 29, no 3, p. 545-555Article in journal (Refereed)
    Abstract [en]

    The objective was to estimate the burden of osteoporosis in Sweden based on current clinical practice and the cost-effectiveness of improvements in the management of osteoporosis over the clinical management compared to current clinical practice. Results showed that better compliance to treatment guidelines is associated with better projected outcomes and cost-savings.

    INTRODUCTION: The purpose of this study is to estimate the burden of osteoporosis in Sweden based on current clinical practice and the cost-effectiveness of improvements in the management of osteoporosis over the clinical management compared to current clinical practice.

    METHODS: The analysis was carried out using a model that simulates the individual patients considered for pharmacological treatment during 1 year and their projected osteoporosis treatment pathway, quality-adjusted life years (QALYs) and costs over their remaining lifetime. All patients regardless of treatment or no treatment were simulated. Information on current management of osteoporosis in terms of patient characteristics and treatment patterns were derived from a Swedish osteoporosis research database based on national registers and patient records. Current (standard) clinical management was compared with alternative scenarios mirroring Swedish treatment guidelines.

    RESULTS: The national burden in terms of lost QALYs was estimated at 14,993 QALYs and the total economic cost at €776M. Scenario analyses showed that 382-3864 QALYs could be gained at a cost/QALY ranging from cost-saving to €31368, depending on the scenario. The margin of investment, i.e. the maximum amount that could be invested in the healthcare system to achieve these improvements up to the limit of the willingness to pay/QALY, was estimated at €199M on a population level (€3,634/patient).

    CONCLUSIONS: The analysis showed that better compliance to treatment guidelines is associated with better projected outcomes and cost-savings. From a cost-effectiveness perspective, there is also considerable room for investment to achieve these improvements in the management of osteoporosis.

  • 2.
    Mc Gowan, BM
    et al.
    Imperial College London.
    Stanley, SA
    Imperial College London.
    White, NE
    Imperial College London.
    Spångeus, Anna
    Imperial College London.
    Patterson, M
    Imperial College London.
    Thompson, EL
    Imperial College London.
    Smith, KL
    Imperial College London.
    Donovan, J
    Imperial College London.
    Gardiner, JV
    Imperial College London.
    Ghatei, MA
    Imperial College London.
    Bloom, SR
    Imperial College London.
    Hypothalamic mapping of orexigenic action and Fos-like immunoreactivity following relaxin-3 administration in male Wistar rats.2007In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 292, p. 913-919Article in journal (Refereed)
    Abstract [en]

      The insulin superfamily, characterized by common disulphide bonds, includes not only insulin but also insulin-like peptides such as relaxin-1 and relaxin-3. The actions of relaxin-3 are largely unknown, but recent work suggests a role in regulation of food intake. Relaxin-3 mRNA is highly expressed in the nucleus incertus, which has extensive projections to the hypothalamus, and relaxin immunoreactivity is present in several hypothalamic nuclei. In the rat, relaxin-3 binds and activates both relaxin family peptide receptor 1, which also binds relaxin-1, and a previously orphaned G protein-coupled receptor, RXFP3. These receptors are extensively expressed in the hypothalamus. The aims of these studies were twofold: 1) map the hypothalamic site(s) of the orexigenic action of relaxin-3 and 2) examine the site(s) of neuronal activation following central relaxin-3 administration. After microinjection into hypothalamic sites, human relaxin-3 (H3; 180 pmol) significantly stimulated 0- to 1-h food intake in the supraoptic nucleus (SON), arcuate nucleus (ARC), and the anterior preoptic area (APOA) [SON 0.4 ± 0.2 (vehicle) vs. 2.9 ± 0.5 g (H3), P < 0.001; ARC 0.7 ± 0.3 (vehicle) vs. 2.7 ± 0.2 g (H3), P < 0.05; and APOA 0.8 ± 0.1 (vehicle) vs. 2.2 ± 0.2 g (H3), P < 0.05]. Cumulative food intake was significantly increased 8 h following administration into the SON and 4 h into the APOA. A significant increase in Fos-like immunoreactivity was seen in the SON following central relaxin-3 administration. Relaxin-3 stimulates feeding in several hypothalamic nuclei, and these studies provide additional support for relaxin-3 as an important peptide in appetite regulation.

  • 3.
    Rauma, Jussi
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences.
    Spångéus, Anna
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
    El-Salhy, Magdy
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology.
    Ghrelin cell density in the gastrointestinal tracts of animal models of human diabetes.2006In: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 21, no 1, p. 1-5Article in journal (Refereed)
    Abstract [en]

    Ghrelin cell density in the gastrointestinal tract of animal models of human diabetes type 1 and 2 was investigated. The animals used were non-obese diabetic (NOD) mice and obese diabetic mice. Ghrelin cells were detected by immunohistochemistry and quantified by computerized image analysis. Ghrelin-immunoreactive cells were detected in all animals studied. They were abundant in the oxyntic mucosa, patchy and few in the duodenum and rare in the colon. The density of ghrelin-immunoreactive cells decreased in diabetic, pre-diabetic NOD mice and in obese diabetic mice as compared to controls, though not statistically significant. It was concluded that the reduced density of ghrelin-immunoreactive cells in animal models of human diabetes type 1 and 2 might explain the slow gastric emptying and slow intestinal transit found in diabetes gastroenteropathy.

  • 4.
    Rejler, Martin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL. Linköping University, Department of Medical and Health Sciences, Internal Medicine.
    Tholstrup, Jörgen
    Department of Medicine, Hoglands Hospital in Eksjö, Sweden.
    Andersson-Gäre, Boel
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Improved population-based care: Implementing patient-and demand-directed care for inflammatory bowel disease and evaluating the redesign with a population-based registry2007In: Quality Management in Health Care, ISSN 1063-8628, E-ISSN 1550-5154, Vol. 16, no 1, p. 38-50Article in journal (Refereed)
    Abstract [en]

    The gastroenterology unit at the Höglands Hospital in Eksjö is responsible for the care of all 466 patients with inflammatory bowel disease (IBD) in a geographic area including approximately 115,000 inhabitants. In 2000, the frustration over an inadequate traditional outpatient clinic inspired us to redesign our outpatient unit to become more patient and demand directed. The redesign included the following: A direct telephone line for patients to a specialized nurse, available during working hours, appointments were scheduled in accordance with expected needs, and emergency appointments were available daily, traditional follow-ups of IBD patients were replaced by an annual telephone contact with a specialized nurse, the team agreed on a patient-centered value base for its work, and the redesign was monitored using clinical outcome measures reflecting 4 dimensions (see parentheses below) of the care in a "Value compass", quality of life (functional) and routine blood samples (clinical) were followed yearly and collected in a computerized IBD registry together with basic information about the patients, access and waiting lists together with patient satisfaction (satisfaction) are followed regularly, and ward utilization (financial) was registered. Our study shows that the new design offers a more efficient outpatient clinic in which waiting lists are markedly reduced although production rates remains the same. Utilization data show a significant decrease in comparison with national data, showing that the new care is economically favorable. The clinical results regarding anemia frequency in the IBD population are highly comparable with or even better than those found in the literature. We also show good results regarding quality of life where more than 88% of patients achieve set goals. In conclusion, our new patient- and demand-directed care seems to be more efficient and with clinical and quality-of-life results remaining on a high standard. ©2007Lippincott Williams & Wilkins, Inc.

  • 5.
    Rejler, Martin
    et al.
    Highland Hospital Eksjö, Sweden .
    Tholstrup, Jorgen
    Highland Hospital Eksjö, Sweden .
    Andersson-Gare, Boel
    Jönköpings County Council, Sweden Jönköping University, Sweden .
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology.
    Low prevalence of anemia in inflammatory bowel disease: A population-based study in Sweden2012In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 47, no 8-9, p. 937-942Article in journal (Refereed)
    Abstract [en]

    Objective. Anemia is a well-known complication of inflammatory bowel disease (IBD) with a reported prevalence of 8.8-73.7%. However, knowledge is sparse about the anemia prevalence in a population-based cohort of patients affected by IBD. Materials and methods. The aim of this retrospective, descriptive, population-based study was to determine and analyze the prevalence of anemia for ambulatory (n = 485) as well as for hospitalized patients diagnosed with IBD in 2008 in the Highland Health Care District, Jonkopings County, Sweden. Results. The prevalence of anemia at the annual follow-up in the studied IBD population was 6%, 5% for patients with ulcerative colitis (UC), and 9% for those with Crohns disease (CD). There was a higher rate of anemia at the yearly check up in patients requiring inpatient care during the year. IBD patients, prescribed anti-TNF-alpha treatment, had a higher rate of anemia. Of the hospitalized UC and CD patients (n = 31), 35% and 50%, respectively, had anemia at admission and 6% and 4% had severe anemia (Hb andlt;100 g/L), respectively. Conclusions. The prevalence of anemia in this population was lower than reported previously, probably due to inclusion of all IBD patients in the area in combination with a proactive follow-up model. The prevalence of anemia in this IBD population was similar to the prevalence in the general population. This may indicate that efforts by health care professionals to prevent, identify, and treat anemia in the IBD population have been successful.

  • 6.
    Rejler, Martin
    et al.
    Highland Hospital, Eksjö, Sweden.
    Tholstrup, Jörgen
    Highland Hospital, Eksjö, Sweden.
    Elg, Mattias
    Linköping University, Department of Management and Engineering, Quality Technology and Management. Linköping University, The Institute of Technology.
    Spångéus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Andersson Gäre, Boel
    Jonköping University, Sweden.
    Framework for assessing quality of care for inflammatory bowel disease in Sweden2012In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 18, no 10, p. 1085-1092Article in journal (Refereed)
    Abstract [en]

    AIM: To create and apply a framework for quality assessment and improvement in care for inflammatory bowel disease (IBD) patients. less thanbrgreater than less thanbrgreater thanMETHODS A framework for quality assessment and improvement was created for IBD based on two generally acknowledged quality models. The model of Donabedian (Df) offers a logistical and productive perspective and the Clinical Value Compass (CVC) model adds a management and service perspective. The framework creates a pedagogical tool to understand the balance between the dimensions of clinical care (CVC) and the components of clinical outcome (Df). The merged models create a framework of the care process dimensions as a whole, reflecting important parts of the IBD care delivery system in a local setting. Clinical and organizational quality measures were adopted from clinical experience and the literature and were integrated into the framework. Data were collected at the yearly check-up for 481 IBD patients during 2008. The application of the quality assessment framework was tested and evaluated in a local clinical IBD care setting in Jonkoping County, Sweden. less thanbrgreater than less thanbrgreater thanRESULTS: The main outcome was the presentation of how locally-selected clinical quality measures, integrated into two complementary models to develop a framework, could be instrumental in assessing the quality of care delivered to patients with IBD. The selected quality measures of the framework noted less anemia in the population than previously reported, provided information about hospitalization rates and the few surgical procedures reported, and noted good access to the clinic. less thanbrgreater than less thanbrgreater thanCONCLUSION: The applied local quality framework was feasible and useful for assessing the quality of care delivered to IBD patients in a local setting.

  • 7.
    Shibre, Teshome
    et al.
    Addis Ababa University, Addis Ababa, Ethiopia.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Henriksson, Linda
    Negash, Alemayehu
    Jacobsson, Lars
    Traditional treatment of mental disorders in rural Ethiopia2008In: Ethiopian Medical Journal, ISSN 0014-1755, Vol. 46, no 1, p. 87-91Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: 

    Mental disorders are known to be as prevalent in Ethiopia as in other countries. Only 26 psychiatrists are working in the country with close to 80 million inhabitants. To this should be added clinics run by psychiatric nurses in most of the general hospitals. This means that still most of the mentally ill in the country are trected and cared for in a traditional way.

    OBJECTIVES: 

    This paper presents the situation regarding traditional treatment of mental illness in a rural area in central Ethiopia, Butajira, with a population of about 350,000 persons, predominantly Muslim.

    METHODS: 

    All traditional healers in Butajira area were mapped by asking key informants. Twenty-four healers were so identified and interviewed about their perception of mental illness and the treatment they offer. Clients from the healers and patients from the local health centre were interviewed about their opinions on the service given.

    FINDINGS: 

    A majority of both clients and patients were satisfied with the consultation, but the clients of the healers were more satisfied than the patients in health centres.

    CONCLUSION: 

    As most persons with mental disorders are treated by traditional healers in rural Ethiopia and in most other developing countries it is important to do more comprehensive studies on the traditional treatment and to find ways of collaboration between traditional practice and modern medicine.

  • 8.
    Spångeus, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Wijkman, Magnus
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Lindström, Torbjörn
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Engvall, Jan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Östgren, Carl Johan
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Finspång, Primary Health Care in Finspång.
    Nyström, Fredrik H.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Toe brachial index in middle aged patients with diabetes mellitus type 2: Not just a peripheral issue2013In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 100, no 2, p. 195-202Article in journal (Refereed)
    Abstract [en]

    Aim

    To explore risk factors for peripheral arterial disease (PAD) as well as the association between toe blood pressure and subclinical and clinical central vascular disease in patients with type 2 diabetes.

    Method

    Toe brachial index (TBI) was cross-sectionally analyzed in 742 middle-aged (54–66 years) patients with type 2 diabetes as well as non-diabetic controls and related to other vascular measures (e.g. carotid intima media thickness (IMT), presence of carotid plaque, central arterial stiffness and left ventricular mass index) and previous cardiovascular events.

    Results

    A TBI ≤ 0.7 was seen in 22% of the patients but only one patient had severe TBI reduction (TBI ≤ 0.3). The corresponding figures in the controls were 13% and 0%, respectively. Mean TBI was significantly lower in patients with type 2 diabetes than in controls (0.81 ± 0.14 vs. 0.87 ± 0.15, p < 0.001). In patients with diabetes, a lower TBI was associated with increased central arterial stiffness (p < 0.001), IMT (p < 0.001) and carotid plaque (p < 0.001) as well as with decreasing glomerular filtration rate (p < 0.001). Lower TBI was found in patients with previous macrovascular ischemic events. Furthermore, TBI was negatively correlated with age (p < 0.001), diabetes duration (p < 0.001) and HbA1c (p = 0.01).

    Conclusion

    PAD, assessed with TBI, is common in a Swedish middle-aged diabetes type 2 cohort, affecting about one-fifth. As ankle pressure may be confounded by falsely high values in patients with diabetes due to media calcification we conclude that information about TBI may improve the risk evaluation regarding arteriosclerotic disease in both small and large vessels in type 2 diabetes.

  • 9.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Bojmar, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Bratthall, Charlotte
    Kalmar Hospital, Sweden.
    Messmer, Davorka
    University of Calif San Diego, CA USA.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    IL-1α Expression in Pancreatic Ductal Adenocarcinoma Affects the Tumor Cell Migration and Is Regulated by the p38MAPK Signaling Pathway2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8Article in journal (Refereed)
    Abstract [en]

    The interplay between the tumor cells and the surrounding stroma creates inflammation, which promotes tumor growth and spread. The inflammation is a hallmark for pancreatic adenocarcinoma (PDAC) and is to high extent driven by IL-1α. IL-1α is expressed and secreted by the tumor cells and exerting its effect on the stroma, i.e. cancer associated fibroblasts (CAF), which in turn produce massive amount of inflammatory and immune regulatory factors. IL-1 induces activation of transcription factors such as nuclear factor-κβ (NF-κβ), but also activator protein 1 (AP-1) via the small G-protein Ras. Dysregulation of Ras pathways are common in cancer as this oncogene is the most frequently mutated in many cancers. In contrast, the signaling events leading up to the expression of IL-1α by tumor cells are not well elucidated. Our aim was to examine the signaling cascade involved in the induction of IL-1α expression in PDAC. We found p38MAPK, activated by the K-Ras signaling pathway, to be involved in the expression of IL-1α by PDAC as blocking this pathway decreased both the gene and protein expression of IL-1α. Blockage of the P38MAPK signaling in PDAC also dampened the ability of the tumor cell to induce inflammation in CAFs. In addition, the IL-1α autocrine signaling regulated the migratory capacity of PDAC cells. Taken together, the blockage of signaling pathways leading to IL-1α expression and/or neutralization of IL-1α in the PDAC microenvironment should be taken into consideration as possible treatment or complement to existing treatment of this cancer.

  • 10.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Niklasson, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Druid, Henrik
    Department of Oncology-pathology, Karolinska Institutet, Stockholm, Sweden.
    Bratthall, Charlotte
    Division of Oncology, Kalmar hospital, Kalmar, Sweden.
    Messmer, Davorka
    Cancer Center, University of California San Diego, La Jolla, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Pancreatic cancer microenvironment has a high degree of inflammation and infiltrating immune cells in its stroma2010Manuscript (preprint) (Other academic)
    Abstract [en]

    Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, and other cellular components, which work together and create an inflammatory environment favoring tumor progression. The present study aimed to characterize the expression and location of immune cells and investigate inflammatory factors that influence pancreatic ductal adenocarcinoma (PDAC).

    Methods: qPCRs and immunohistological stainings were performed for inflammatory factors and immune cells localized in tumor tissues from patients with PDAC (N=30).

    Results: All PDAC tissues had significant increased levels of inflammatory and chemotactic factors such as IL-1α, COX-2, CXCL8, CCL2, and CCL20 as compared to controls. The PDAC stroma, i.e. the fibrosis surrounding the tumor, was the main producer of these factors with the exception of IL-1α, which was expressed by tumor cells and some infiltrating immune cells. The gene expression for immune cell specific markers CD163, CD1c, CD303, and CD8, corresponding to macrophages, myeloid dendritic cells (DCs), plasmacytoid DCs, and cytotoxic T lymphocytes (CTL), respectively, were all significantly increased in PDAC tissues. Immunostaining of the tumor tissue confirmed the elevated levels of infiltrating macrophages, DCs, mature DCs, and cytotoxic T lymphocytes (CTL). The different immune cells were in nearly all cases localized in the fibrotic tissue adjacent to tumor nests. Production of CXCL8 mRNA and protein by the stroma was dependent on the tumor expression of IL-1α. Of importance, we found a correlation in expression of the proinflammatory factor IL-1α and the PDAC patients’ survival time.

    Conclusion: PDAC cells seem to take advantage of IL-1α to create an inflammatory microenvironment with high degree of fibrosis and the ability to both recruit and activate immune cells and the level of inflammation in this environment influenced the clinical outcome for the patients. Therapies targeting the inflammation might be beneficial for the survival of patients with PDAC.

  • 11.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Niklasson, Lina
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Druid, Henrik
    Karolinska Institute.
    Bratthall, Charlotte
    Kalmar Hospital.
    Messmer, Davorka
    University of Calif San Diego.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    The Desmoplastic Stroma Plays an Essential Role in the Accumulation and Modulation of Infiltrated Immune Cells in Pancreatic Adenocarcinoma2011In: Clinical & Developmental Immunology, ISSN 1740-2522, E-ISSN 1740-2530, Vol. 2011, no 212810Article in journal (Refereed)
    Abstract [en]

    Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, which all work together and create an inflammatory environment favoring tumor progression. The present study aimed to investigate the role of the desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC) regarding expression of inflammatory factors and infiltration of immune cells and their impact on the clinical outcome. The PDAC tissues examined expressed significantly increased levels of immunomodulatory and chemotactic factors (IL-6, TGF beta, IDO, COX-2, CCL2, and CCL20) and immune cell-specific markers corresponding to macrophages, myeloid, and plasmacytoid dendritic cells (DCs) as compared to controls. Furthermore, short-time survivors had the lowest levels of DC markers. Immunostainings indicated that the different immune cells and inflammatory factors are mainly localized to the desmoplastic stroma. Therapies modulating the inflammatory tumor microenvironment to promote the attraction of DCs and differentiation of monocytes into functional DCs might improve the survival of PDAC patients.

  • 12.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Spangeus, Anna
    Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences.
    Messmer, Davorka
    University of California.
    Emilsson, Johan
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Falkmer, Ursula
    Jonköping Hospital.
    Falkmer, Sture
    Jonköping Hospital.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Pancreatic adenocarcinoma exerts systemic effects on the peripheral blood myeloid and plasmacytoid dendritic cells: an indicator of disease severity?2010In: BMC CANCER, ISSN 1471-2407, Vol. 10, no 87Article in journal (Refereed)
    Abstract [en]

    Background: Dendritic cells (DCs) isolated from tumor bearing animals or from individuals with solid tumors display functional abnormalities and the DC impairment has emerged as one mechanism for tumor evasion from the control of the immune system. Ductal pancreatic adenocarcinoma (PDAC), the most common pancreatic cancer, is recognized as a very aggressive cancer type with a mortality that almost matches the rate of incidence. Methods: We examined the systemic influence ductal pancreatic adenocarcinoma ( PDAC) exerted on levels of peripheral blood DCs and inflammatory mediators in comparison to the effects exerted by other pancreatic tumors, chronic pancreatitis, and age-matched controls. Results: All groups examined, including PDAC, had decreased levels of myeloid DCs (MDC) and plasmacytoid DCs (PDC) and enhanced apoptosis in these cells as compared to controls. We found elevated levels of PGE2 and CXCL8 in subjects with PDAC, and chronic pancreatitis. Levels of these inflammatory factors were in part restored in PDAC after tumor resection, whereas the levels of DCs were impaired in the majority of these patients similar to 12 weeks after tumor removal. Our results prove that solid pancreatic tumors, including PDAC, systemically affect blood DCs. The impairments do not seem to be tumor-specific, since similar results were obtained in subjects with chronic pancreatitis. Furthermore, we found that PDAC patients with a survival over 2 years had significant higher levels of blood DCs compared to patients with less than one year survival. Conclusions: Our findings points to the involvement of inflammation in the destruction of the blood MDCs and PDCs. Furthermore, the preservation of the blood DCs compartment in PDAC patients seems to benefit their ability to control the disease and survival.

  • 13.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Messmer, Davorka
    University of California San Diego, CA 92093, USA.
    Larsson, Marie
    University of California San Diego, CA 92093, USA.
    Semi Mature Blood Dendritic Cells Exist in Patients with Ductal Pancreatic Adenocarcinoma Owing to Inflammatory Factors Released from the Tumor2010In: PLOS ONE, ISSN 1932-6203, Vol. 5, no 10Article in journal (Refereed)
    Abstract [en]

    Background: Much evidence exists regarding the fact that blood DCs, both myeloid DCs (MDCs) and plasmacytoid DCs (PDCs), are negatively affected in different types of cancer, with both reduced numbers and impaired functionality. Functional impairment of DCs in patients with pancreatic ductal adenocarcinoma (PDAC), may contribute to the poor clinical outcome. The aim of this study was to examine the effects PDAC had on blood DCs and elucidate the underlying mechanism responsible for the DC impairment. Methodology/Principal Findings: We examined the systemic influence PDAC exerted on blood DCs by ex vivo measuring numerous activation and maturation markers expressed on these cells. Furthermore, the effect patient plasma and the inflammatory factors CXCL8 and PGE(2) had on purified MDCs and PDCs from healthy donors was assessed and compared to the DCs existing in PDAC patients. We found a partial maturation of the blood MDCs and PDCs in PDAC patients with significantly enhanced expression of CD83, CD40, B7H3, PDL-1, CCR6, and CCR7 and decreased expression of ICOSL, and DCIR. These changes lead to impairment in their immunostimulatory function. Furthermore, chronic pancreatitis gave rise to DCs with similar semi-mature phenotype as seen in PDAC. Low expression of ICOSL was associated with poor prognosis. We found that the mechanism underlying this semi-maturation of DCs was inflammatory factors existing in the PDAC patients plasma. Of note, PGE2, which is elevated PDAC patient plasma, was one contributing factor to the changes seen in MDCs and PDCs phenotype. Conclusion/Significance: Our findings point to a role for the systemic inflammation in transforming blood MDCs and PDCs into semi-mature cells in PDAC patients and we show a correlation between maturation status and clinical outcome. Thus, means to preserve a functional blood DC compartment in PDAC patients by diminishing the inflammation could facilitate their ability to control the disease and improve survival.

  • 14.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
    Välilä, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Druid, Henrik
    Department of Oncology-pathology, Karolinska Institutet, Stockholm, Sweden.
    Falkmer, Sture
    Department of Clinical Pathology, County Hospital Ryhov, Jönköping, Sweden.
    Falkmer, Ursula
    Department of Oncology, County Hospital Ryhov, Jönköping, Sweden.
    Messmer, Davorka
    Cancer Center, University of California San Diego, La Jolla, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    IL-1α Sustains the Inflammation in Human Pancreatic Cancer Microenvironment by Targeting Cancer Associated Fibroblasts2010Manuscript (preprint) (Other academic)
    Abstract [en]

    The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic with an extensive interaction between the stroma and tumor cells. Our aim for this study was to delineate the cross-talk between PDAC and cancer-associated fibroblasts (CAFs) with focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effect cross talk between primary PDAC and CAF cell lines propagated from tumors had on the creation and sustenance of an inflammatory environment and what factors that were involved in establishing the inflammation.

    The coculture of PDAC and CAF cell lines, propagated from tumor tissues, enhanced the levels of inflammatory factors including IL-1α, IL-6, CXCL8, VEGFA, CCL20, and COX-2. The production of these factors correlated with the expression detected in vivo in PDAC tissues. The key producers of nearly all inflammatory factors were the CAFs and not the tumor cells.

    IL-1α was produced by the tumor cell lines, whereas almost all IL-1RI was expressed by CAFs thus corresponding to their in vivo expression profile in PDAC tissues, indicating a role for the IL-1 signaling cascade in a tumor favorable microenvironment. Neutralization of the IL-1α pathway efficiently diminished the cross talk induced production of inflammatory factors, both in stroma and tumor cells. These data suggest that the cross-talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one contributing factor in the formation of the inflammatory tumor environment and we propose that the neutralization of IL-1α pathway might be a potential therapy for this cancer.

  • 15.
    Tjomsland, Vegard
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Välilä, Johanna
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Borch, Kurt
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Druid, Henrik
    Department of Oncology – Pathology, Karolinska Institutet, Stockholm.
    Falkmer, Sture
    Department of Clinical Pathology, County Hospital Ryhov, Jönköping.
    Falkmer, Ursula
    Department of Oncology, Aalborg University Hospital, Aalborg, Denmark.
    Messmer, Davorka
    Moores Cancer Center, University California San Diego, La Jolla, CA, USA.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Interleukin 1α sustains the expression of inflammatory factors in human pancreatic cancer microenvironment by targeting cancer-associated fibroblasts2011In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 13, no 8, p. 664-675Article in journal (Refereed)
    Abstract [en]

    The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic with an extensive interaction between the stroma and tumor cells. The aim for this study was to delineate the cross-talk between PDAC and cancer-associated fibroblasts (CAFs) with focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effects of the cross-talk between primary PDAC and CAF cell lines on the creation and sustenance of the inflammatory tumor microenvironment in pancreatic cancer. The coculture of primary PDAC and CAF cell lines enhanced the levels of inflammatory factors including IL-1á, IL-6, CXCL8, VEGFA, CCL20, and COX-2. CAFs were superior to tumor cells regarding the production of most inflammatory factors and tumor cell associated IL-1á was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1á to the active IL-1 receptor (IL-1R1) expressed predominantly by CAFs. Furthermore, we found a positive correlation between IL-1á and CXCL8 expression levels in PDAC tissues and correlation between IL-1á expression and the clinical outcome of the patients. This confirmed an important role for the IL-1 signaling cascade in the creation and sustenance of a tumor favorable microenvironment. Neutralization of the IL-1á signaling efficiently diminished the cross-talk induced production of inflammatory factors. These data suggest that the cross-talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one essential factor in the formation of the inflammatory tumor environment and we propose that neutralization of the IL-1á signaling might be a potential therapy for this cancer.

  • 16.
    Woisetschläger, Mischa
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Radiology in Linköping.
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Model for improved correlation of BMD values between abdominal routine Dual energy CT data and DXA scans2018In: European Journal of Radiology, ISSN 0720-048X, E-ISSN 1872-7727, Vol. 99, p. 76-81Article in journal (Refereed)
    Abstract [en]

    Background

    Osteoporosis is a common but underdiagnosed and undertreated disease causing severe morbidity and economic burden. The gold standard for detection of osteoporosis is DXA (dual energy x-ray absorptiometry), which is a dedicated examination for osteoporosis. Dual energy CT (DECT) examinations are increasingly used in daily routine for a wide variety of diagnoses. In the present study, we wanted to examine whether vBMD (volume bone mass density) could be evaluated as a side product in non-contrast as well as contrast phases as well as to evaluate a correction model taking known shortcomings for DXA into account.

    Methods

    A total of 20 patients, i.e. 79 vertebrae (one excluded due to vertebral fracture), mean age 71 years (range 43–85) with a mean BMI (body mass index) of 26 (range 17–33) were examined with both abdominal/pelvic DECT as well as DXA. Furthermore, aortic calcium was measured as well as the presence of osteoarthritis of the spine (OAS) and osteoarthritis in facet joints (OAF) with a 5-grade scaling system.

    Results

    A significant correlation was found between DXA BMD and vBMD from DECT with no contrast (WNC) (r = 0.424, p = 0.001), and with venous contrast (WVC) (r = 0.402, p < 0.001), but no significant correlation was found with arterial contrast (WAC). Using multivariate linear regression with DXA BMD as dependent, two models were created combining DECT WNC, aortic calciumscore (ACS), OAS and BMI yielding an R2 = 0.616 (model 1) and replacement of WNC to WVC a R2 = 0.612 (model 2). The Pearson correlation between DXA and predictive DXA BMD value of model 1 was r = 0.785 (p < 0.001) and model 2 r = 0.782 (p < 0.001).

    Conclusion

    There is a correlation between DXA BMD and DECT in non-contrast and venous contrast scans but not in arterial scans. The correlation is further improved by quantifying the degree of different confounding factors (osteoarthritis of the spine, body mass index and aortic calcium score) and taking these into account in an explanatory model. Future software solutions with DECT data as input data might be able to automatically measure the BMD in the trabecular bone as well as measuring the confounding factors automatically in order to obtain spinal DXA comparable BMD values.

  • 17.
    Woisetschläger, Mischa
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Spångeus, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Model for improved correlation of BMD values between abdominal routine dual-energy CT data and DXA scans2018Conference paper (Other academic)
    Abstract [en]

    Background:

    Osteoporosis is a common but underdiagnosed and undertreated disease causing severe morbidity and economic burden. The gold standard for detection of osteoporosis is DXA (dual energy x-ray absorptiometry), which is a dedicated examination for osteoporosis. Dual energy CT (DECT) examinations are increasingly used in daily routine for a wide variety of diagnoses. In the present study, we wanted to examine whether vBMD (volume bone mass density) could be evaluated as a side product in non-contrast as well as contrast phases as well as to evaluate a correction model taking known shortcomings for DXA into account. 

    Methods:

    A total of 20 patients, i.e. 79 vertebrae (one excluded due to vertebral fracture), mean age 71 years (range 43 – 85) with a mean BMI (body mass index) of 26 (range 17 – 33) were examined with both abdominal/pelvic DECT as well as DXA.  Furthermore, aortic calcium was measured as well as the presence of osteoarthritis of the spine (OAS) and osteoarthritis in facet joints (OAF) with a 5-grade scaling system. 

    Results:

    A significant correlation was found between DXA BMD and vBMD from DECT without with no contrast (WNC) (r=0.424, p=0.001), and with venous contrast (WVC) (r=0.402, p<0.001), but no significant correlation was found with arterial contrast (WAC). Using multivariate linear regression with DXA BMD as dependent, two models were created combining DECT WNC, aortic calciumscore (ACS), OAS and BMI yielding an R2 = 0.616 (model 1) and replacement of WNC to WVC a R2 = 0.612 (model 2).  The Pearson correlation between DXA and predictive DXA BMD value of model 1 was r = 0.785 (p<0.001) and model 2 r = 0.782 (p<0.001).

    Conclusion:

    There is a correlation between DXA BMD and DECT in non-contrast and venous contrast scans but not in arterial scans. The correlation is further improved by quantifying the degree of different confounding factors (osteoarthritis of the spine, body mass index and aortic calcium score) and taking these into account in an explanatory model. Future software solutions with DECT data as input data might be able to automatically measure the BMD in the trabecular bone as well as measuring the confounding factors automatically in order to obtain spinal DXA comparable BMD values.

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