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  • 251.
    Karakatsanis, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Olofsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Abdsaleh, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Simplifying Logistics and Avoiding the Unnecessary in Patients with Breast Cancer Undergoing Sentinel Node Biopsy. A Prospective Feasibility Trial of the Preoperative Injection of Super Paramagnetic Iron Oxide Nanoparticles2018In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 107, no 2, p. 130-137Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Sentinel node is routinely localized with the intraoperative use of a radioactive tracer, involving challenging logistics. Super paramagnetic iron oxide nanoparticle is a non-radioactive tracer with comparable performance that could allow for preoperative localization, would simplify the procedure, and possibly be of value in axillary mapping before neoadjuvant treatment. The current trial aimed to determine the a priori hypothesis that the injection of super paramagnetic iron oxide nanoparticles in the preoperative period for the localization of the sentinel node is feasible.

    METHODS: This is a prospective feasibility trial, conducted from 9 September 2014 to 22 October 2014 at Uppsala University Hospital. In all, 12 consecutive patients with primary breast cancer planned for resection of the primary and sentinel node biopsy were recruited. Super paramagnetic iron oxide nanoparticles were injected in the preoperative visit in the outpatient clinic. The radioactive tracer (99mTc) and the blue dye were injected perioperatively in standard fashion. A volunteer was injected with super paramagnetic iron oxide nanoparticles to follow the decline in the magnetic signal in the sentinel node over time. The primary outcome was successful sentinel node detection.

    RESULTS: Super paramagnetic iron oxide nanoparticles' detection after preoperative injection (3-15 days) was successful in all cases (100%). In the volunteer, axillary signal was presented for 4 weeks. No adverse effects were noted. Conclusion and relevance: Preoperative super paramagnetic iron oxide nanoparticles' injection is feasible and leads to successful detection of the sentinel node. That may lead to simplified logistics as well as the identification, sampling, and marking of the sentinel node in patients planned for neoadjuvant treatment.

  • 252. Karamanakos, Petros N.
    et al.
    Jaaskelainen, Juha E.
    Alafuzoff, Irina
    Department of Clinical Pathology, University Hospital, Kuopio, Finland.
    Pirinen, Elina
    Vanninen, Ritva
    Silvennoinen, Sanna
    Sankilampi, Ulla
    Immonen, Arto
    Malignant giant cell tumor in the posterior fossa of a neonate: case report2010In: Journal of Neurosurgery: Pediatrics, ISSN 1933-0707, E-ISSN 1933-0715, Vol. 5, no 3, p. 277-282Article in journal (Refereed)
    Abstract [en]

    Giant cell tumors (GCTs) of the bone are rare, usually benign but locally aggressive neoplasms that primarily occur in the epiphyses of long bones. They seldom develop in the cranium; when they do, they involve principally the sphenoid and temporal bones. These tumors usually affect young adults, and few reports in children have been published. Primary malignant GCTs of the skull are even more uncommon. The 3 published cases all involved adults over 40 years of age. Herein, the authors present a case of a highly aggressive primary malignant GCT of the posterior fossa in a 5-week old preterm infant. One month after the gross-total resection of the tumor found in the bone, the infant's condition rapidly deteriorated and she died. Magnetic resonance imaging and postmortem examination revealed a tumor larger than it had been before the operation, with expansion toward the brain. To the best of the authors' knowledge, this is the youngest patient reported with a primary malignant GCT of the skull, and actually the first case in a pediatric patient. In addition, the extremely high growth rate of the tumor in the postoperative period renders this case the most aggressive primary malignant GCT of the cranium described so far.

  • 253.
    Karawajczyk, Malgorzata
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Point-of-care instruments need to offer high levels of accuracy2017In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, no 10, article id 1707Article in journal (Other academic)
  • 254.
    Karlsson, Anna
    et al.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.;Reg Labs Reg Skane, Dept Pathol, Lund, Sweden..
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Veerla, Srinivas
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    La Fleur, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Jönsson, Mats
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Reuterswärd, Christel
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Planck, Maria
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.;Skane Univ Hosp, Dept Resp Med & Allergol, Lund, Sweden..
    Staaf, Johan
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification2017In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, no 8, p. 1257-1267Article in journal (Refereed)
    Abstract [en]

    Introduction: Large cell lung cancer (LCLC) and large cell neuroendocrine carcinoma (LCNEC) constitute a small proportion of NSCLC. The WHO 2015 classification guidelines changed the definition of the debated histological subtype LCLC to be based on immunomarkers for adenocarcinoma and squamous cancer. We sought to determine whether these new guidelines also translate into the transcriptional landscape of lung cancer, and LCLC specifically.

    Methods: Gene expression profiling was performed by using Illumina V4 HT12 microarrays (Illumina, San Diego, CA) on samples from 159 cases (comprising all histological subtypes, including 10 classified as LCLC WHO 2015 and 14 classified as LCNEC according to the WHO 2015 guidelines), with complimentary mutational and immunohistochemical data. Derived transcriptional phenotypes were validated in 199 independent tumors, including six WHO 2015 LCLCs and five LCNECs.

    Results: Unsupervised analysis of gene expression data identified a phenotype comprising 90% of WHO 2015 LCLC tumors, with characteristics of poorly differentiated proliferatiVe cancer, a 90% tumor protein p53 gene (TP53) mutation rate, and lack of well-known NSCLC oncogene driver alterations. Validation in independent data confirmed aggregation of WHO 2015 LCLCs in the specific phenotype. For LCNEC tumors, the unsupervised gene expression analysis suggested two different transcriptional patterns corresponding to a proposed genetic division of LCNEC tumors into SCLC-like and NSCLC-like cancer on the basis of TP53 and retinoblastoma 1 gene (RB1) alteration patterns.

    Conclusions: Refined classification of LCLC has implications for diagnosis, prognostics, and therapy decisions. Our molecular analyses support the WHO 2015 classification of LCLC and LCNEC tumors, which herein follow different tumorigenic paths and can accordingly be stratified into different transcriptional subgroups, thus linking diagnostic immunohistochemical staining driven classification with the transcriptional landscape of lung cancer.

  • 255.
    Karlsson, Mats G.
    et al.
    Department of Otorhinolaryngology, Örebro Medical Center Hospital, Örebro, Sweden; Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Davidsson, Åke
    Department of Otorhinolaryngology, Örebro Medical Center Hospital, Örebro, Sweden; Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Hellquist, H. B.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Quantitative computerized image analysis of immunostained lymphocytes: A methodological approach1994In: Pathology, Research and Practice, ISSN 0344-0338, E-ISSN 1618-0631, Vol. 190, no 8, p. 799-807Article in journal (Refereed)
    Abstract [en]

    A methodological approach by computerized image analysis to quantify immunostained objects in histological sections is described. We have investigated antibodies against CD4, CD8, CD20, CD23 and CD25 in frozen sections of human nasal mucosa; however, the methodology of standardization is of general validity. The study was designed particularly to investigate the following points: 1) light intensity, 2) the grey level for counter staining intensity, 3) the grey level threshold value for positive objects, 4) the minimal acceptable size of a positive object, 5) the influence of the brightness of the light on both the number and the area of objects. Furthermore, random sampling and determination of 6) the area per section, and 7) the number of histological sections to be measured per biopsy. Finally, a study of reproducibility of immunostaining intensity was performed. The influence of the different parameters mentioned above was studied and the values (eg. threshold value) for our particular setting of microscope, image analysis equipment, computer software etc, were defined. The method was then tested for intra- and interindividual variation which was found to be less than 5%. Correlation analysis of the reproducibility gave coefficients of correlation of 0.99, both concerning number of immunopositive objects and immunopositive area. We emphasize the importance of a highly standardized methodology if the numeric data obtained from computer assisted image analysis are to be more accurate than semiquantitative assessments by experienced observers. With a thorough standardization as described in this method it is possible to obtain numeric values, and data with low deviations, which are two obvious and important advantages.

  • 256.
    Karlsson, Mats G.
    et al.
    Departments of Pathology and Otorhionolaryngology, Medical Center Hospital, Örebro, Sweden.
    Davidsson, Åke
    Departments of Pathology and Otorhionolaryngology, Medical Center Hospital, Örebro, Sweden.
    Hellquist, Henrik B.
    Department of Pathology II, University Hospital, Linköping, Sweden.
    Increase in CD4+ and CD45RO+ memory T cells in the nasal mucosa of allergic patients1994In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 102, no 10, p. 753-758Article in journal (Refereed)
    Abstract [en]

    By means of immunocytochemistry we have investigated subsets of T lymphocytes in frozen sections of nasal mucosa from patients with seasonal allergic rhinitis and healthy control persons. All participants were subjected to time-course provocation during the non-pollen season, and samples were taken during provocation as well as during the natural pollen season. Computerized image analysis was applied for evaluation of the immunostained lymphocytes. CD45RO+ memory T cells outnumbered the remaining leukocyte populations in the mucosa of both allergic patients and controls on all occasions. During the repeat provocation there was no difference in numerical values, with respect to any of the five leukocyte subpopulations studied (CD4, CD8, CD25, CD45RA and CD45RO), between patients and controls. However, during continuous exposure in the pollen season a significant increase in CD4+ cells was observed in allergic patients compared to before provocation (p < 0.05). No changes were observed with respect to CD8+ and CD25+ cells. Similarly, an increase in CD45RO+ memory was found in allergic patients during the pollen season compared to the non-pollen season (p < 0.02). This latter finding was, however, only evident in the patients who did not use nasal corticosteroids. Hence the present investigation has demonstrated an allergen-induced increase in CD4+ and CD45RO+ memory T cells in the mucosa of allergic patients during the pollen season. These events may constitute a cellular basis for local continuous production of certain cytokines, particularly interleukin-4, which is essential for IgE synthesis.

  • 257.
    Karlsson, Mats G.
    et al.
    Departments of Pathology, Medical Center Hospital, Örebro, Sweden.
    Davidsson, Åke
    Departments of Otorhinolaryngology, Medical Center Hospital, Örebro, Sweden.
    Viale, Guiseppe
    Universitá degli Studi di Milano, Ospedale S. Paolo, Milan, Italy .
    Graziani, Daniela
    Universitá degli Studi di Milano, Ospedale S. Paolo, Milan, Italy .
    Hellquist, Henrik B.
    Departments of Pathology, Medical Center Hospital, Örebro, Sweden; Departments of Otorhinolaryngology, Medical Center Hospital, Örebro, Sweden.
    Nasal messenger RNA expression of interleukins 2, 4, and 5 in patients with allergic rhinitis1995In: Diagnostic molecular pathology (Print), ISSN 1052-9551, E-ISSN 1533-4066, Vol. 4, no 2, p. 85-92Article in journal (Refereed)
    Abstract [en]

    In nasal biopsies from 17 adult patients with seasonal allergic rhinitis and from 10 healthy controls, cytokines were analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR). The time-course study during winter included repeated local allergen provocation with subsequent nasal biopsies as well as biopsies taken during pollen season. The RT-PCR for CD44 yielded positive bands in 65 of 71 cases, in which cases mRNA for interleukins 2, 4, and 5 (IL-2, IL-4, and IL-5) were thus investigated by means of seminested PCR. IL-4 mRNA was found almost exclusively in the allergic patients. During provocation a significant increase in IL-4 was noticed compared with controls (p = 0.043). Equally, during the natural pollen season, IL-4 mRNA expression was significantly higher in patients not using nasal corticosteroids compared with those who did (p = 0.011). No differences in IL-2 or IL-5 were observed between the groups. These findings also indicate, together with earlier observations of T-cell activation, a phenotype switch toward T-helper 2 (Th2) cells, and the accumulation (homing) of these T cells in the nasal mucosa, that T cells constitute the main source for IL-4 in the nasal mucosa. Therefore, allergic patients have an increased synthesis of IL-4 when provoked with the allergen, and during natural pollen season this synthesis can be downregulated by corticosteroids. Furthermore, this study exemplifies the versatility of molecular biology in surgical pathology and that even low-copy-number cytokine mRNA can be examined in routinely snap-frozen surgical specimens.

  • 258.
    Karlsson, Mats G.
    et al.
    Department of Pathology, Örebro Medical Center, Örebro, Sweden.
    Hardell, Lennart
    Department of Oncology, Örebro Medical Center, Örebro, Sweden.
    Hallquist, Arne
    Stockholms Sjukhem, Stockholm, Sweden.
    No association between immunohistochemical expression of p53, c-erbB-2, Ki-67, estrogen and progesterone receptors in female papillary thyroid cancer and ionizing radiation1997In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 120, no 2, p. 173-177Article in journal (Refereed)
    Abstract [en]

    An association has previously been reported between exposure to medical diagnostic ionizing radiation and papillary thyroid cancer in women. To further evaluate potential mechanisms in carcinogenesis, the expression of p53, c-erbB-2, as well as Ki-67, estrogen and progesterone receptors were analyzed by immunohistochemistry in 19 women exposed to X-rays and for comparison in nine women without such reported exposure. They all had papillary thyroid cancer. No difference was found between these groups. The results of this study showed that p53, c-erbB-2, Ki-67, estrogen and progesterone receptors are not involved in papillary thyroid cancer associated with exposure to medical diagnostic ionizing radiation.

  • 259.
    Karlsson, Mats G.
    et al.
    Department of Pathology, Medical Center Hospital, Örebro, Sweden .
    Hellquist, H. B.
    Department of Pathology II, University Hospital, Linköping, Sweden.
    Endothelial adhesion molecules for nasal-homing T cells in allergy1996In: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 429, no 1, p. 49-54Article in journal (Refereed)
    Abstract [en]

    During the allergic reaction mucosal T cells are activated and a local increase in numbers occurs. In peripheral blood, a concomitant T cell activation and switch towards memory phenotype appears. E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 were studied in nasal mucosal biopsies taken during a time-course provocation study, including patients with seasonal allergic rhinitis and healthy controls. Allergic patients were also studied during the natural pollen season with particular attention to the influence of local corticosteroid treatment. Before provocation allergic patients and controls did not differ concerning the expression of endothelial adhesion molecules. However, the epithelial ICAM-1 expression was increased among allergics (P < 0.05). Repetitive allergen provocation induces an increased endothelial expression of VCAM-1 in allergic patients (P < 0.01). Similarly, VCAM-1 expression was increased during the natural pollen season (P < 0.05). Interestingly, the increased VCAM-1 expression was inhibited by the use of local corticosteroids. The present data demonstrate a putative integrin-VCAM-1 mechanism for selective homing of T memory cells to the allergic nasal mucosa and new in vivo effects of local corticosteroid treatment are demonstrated.

  • 260.
    Karlsson, Mats G.
    et al.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Hellquist, H. B.
    Phenotype switch and activation of T lymphocytes in patients with allergic rhinitis1994In: Journal for Oto-Rhino-Laryngology, ISSN 0301-1569, E-ISSN 1423-0275, Vol. 56, no 3, p. 166-172Article in journal (Refereed)
    Abstract [en]

    The peripheral blood of 17 patients with seasonal allergic rhinitis (birch pollen) and of 10 healthy subjects were analysed before and during a provocation study in the non-pollen season as well as during the pollen season. Analytical flow cytometry comprised a panel of monoclonal antibodies investigating helper/suppressor T cells, activated T cells, and naive/memory T helper cells. Allergic patients showed no increase in the amount of T lymphocytes but an increased proportion of CD4+ helper T cells early during pronounced exposure (provocation) but not during natural antigen exposure (pollen season). Allergic patients showed a significant increase in activated T cells during the non-pollen season compared with healthy subjects, and furthermore, the nasal allergen provocation induced an additional increase in activated T cells among allergics. The T cell activation mainly affected helper T cells (85%) rather than suppressor T cells. Furthermore, allergic patients showed a significant increase in naive T helper cells during the pollen season. The presence of a double-positive subpopulation indicates an activated T helper subpopulation that switches its phenotype from naive (CD45RA) to memory (CD29). The results indicate at least two important differences between patients with allergic rhinitis and healthy controls. In allergic patients T helper cells become activated upon allergen exposure, and circulate in the blood and switch their phenotype. These T cells have a potential homing tendency to the nasal mucosa. These two events do not occur in non-allergic individuals and may thus constitute new insights into the basic mechanisms of allergic rhinitis.

  • 261.
    Karlsson, Terese
    et al.
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    Kvarnbrink, Samuel
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    Holmlund, Camilla
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Henriksson, Roger
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    Johansson, Mikael
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    Hedman, Hakan
    Umea Univ, Dept Radiat Sci, Oncol, SE-90187 Umea, Sweden.
    LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease2018In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 125, p. 174-184Article in journal (Refereed)
    Abstract [en]

    Objectives: The human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises the integral membrane proteins LRIG1, LRIG2 and LRIG3. LRIG1 is frequently down-regulated in human cancer, and high levels of LRIG1 in tumor tissue are associated with favorable clinical outcomes in several tumor types including non-small cell lung cancer (NSCLC). Mechanistically, LRIG1 negatively regulates receptor tyrosine kinases and functions as a tumor suppressor. However, the details of the molecular mechanisms involved are poorly understood, and even less is known about the functions of LRIG2 and LRIG3. The aim of this study was to further elucidate the functions and molecular interactions of the LRIG proteins.

    Materials and methods: A yeast two-hybrid screen was performed using a cytosolic LRIG3 peptide as bait. In transfected human cells, co-immunoprecipitation and co-localization experiments were performed. Proximity ligation assay was performed to investigate interactions between endogenously expressed proteins. Expression levels of LMO7 and LIMCH1 in normal and malignant lung tissue were investigated using qRT-PCR and through in silico analyses of public data sets. Finally, a clinical cohort comprising 355 surgically treated NSCLC cases was immunostained for LMO7.

    Results: In the yeast two-hybrid screen, the two paralogous proteins LMO7 and LIMCH1 were identified as interaction partners to LRIG3. LMO7 and LIMCH1 co-localized and co-immunoprecipitated with both LRIG1 and LRIG3. Endogenously expressed LMO7 was in close proximity of both LRIG1 and LRIG3. LMO7 and LIMCH1 were highly expressed in normal lung tissue and down-regulated in malignant lung tissue. LMO7 immunoreactivity was shown to be a negative prognostic factor in LRIG1 positive tumors, predicting poor patient survival.

    Conclusion: These findings suggest that LMO7 and LIMCH1 physically interact with LRIG proteins and that expression of LMO7 is of clinical importance in NSCLC.

  • 262. Katsoulis, Joannis
    et al.
    Lang, Niklaus P
    Persson, G. Rutger
    University of Bern, Bern, Switzerland & University of Washington, Seattle, WA, USA.
    Proportional distribution of the red complex and its individual pathogens after sample storage using the checkerboard DNA-DNA hybridization technique.2005In: Journal of Clinical Periodontology, ISSN 0303-6979, E-ISSN 1600-051X, Vol. 32, no 6, p. 628-633Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Information on the impact of sample storage prior to analysis by DNA methods is limited.

    AIMS: To investigate the effect of microbial sample storage on bacterial detection and proportional distribution of the red complex and its individual pathogens.

    MATERIAL AND METHODS: Subgingival plaque samples were analysed by (1) immediate processing, (2) after storage at +4 degrees C for 6 weeks, (3) after storage at -20 degrees C for 6 months or (4) after storage at -20 degrees C for 12 months using the checkerboard DNA-DNA hybridization.

    RESULTS: Proportional distribution of the red complex did not differ between the first three protocols. However, the total bacterial DNA for pathogens studied decreased significantly in protocols 3 and 4. Relative amounts of Tannerella forsythensis, Porphyromonas gingivalis and Treponema denticola remained stable in the second protocols and changed in an unpredictable way if stored for 6 or 12 months.

    CONCLUSIONS: Results from samples stored for maximum 6 months at -20 degrees C with high proportional amounts of the red complex and T. denticola may be used as an indicator of persistence. All bacterial samples for DNA extraction should be processed following a standardized storage protocol (i.e. samples stored at +4 degrees C for maximum 6 weeks) in order to get comparable qualitative and quantitative results for total DNA, bacterial complexes and individual pathogens. Most representative results are yielded if processing and hybridization could be performed immediately after sampling.

  • 263. Kerr, Keith M
    et al.
    Tsao, Ming-Sound
    Nicholson, Andrew G
    Yatabe, Yasushi
    Wistuba, Ignacio I
    Hirsch, Fred R
    Botling, Johan
    IASLC Pathology Committee.
    Programmed Death-Ligand 1 Immunohistochemistry in Lung Cancer: In what state is this art?2015In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, no 7, p. 985-989Article in journal (Refereed)
    Abstract [en]

    Therapeutic antibodies to programmed death receptor 1 (PD-1) and its ligand PD-L1 show promising clinical results. Anti-PD-L1 immunohistochemistry (IHC) may be a biomarker to select patients more likely to respond to these treatments. However, the development of at least four different therapeutics, each with a different anti-PD-L1 IHC assay, has raised concerns among pathologists and oncologists alike. This article reviews existing data on the IHC biomarker aspects of studies using these drugs in non-small-cell lung cancer (NSCLC) and considers the challenges ahead, should these drug/IHC assay combinations reach routine practice. For each the known biomarker assays in development, there is a different monoclonal IHC antibody clone, produced by one of two diagnostics companies. Each test requires proprietary staining platforms and uses different definitions of a "positive" test for PD-L1 expression, on tumor cells and, in one test, also on tumor infiltrating immune cells. There are still considerable gaps in our knowledge of the technical aspects of these tests, and of the biological implications and associations of PD-L1 expression in NSCLC, considering heterogeneity of expression, dynamic changes in expression, and prognostic implications among other factors. The International Association for the Study of Lung Cancer Pathology Committee raises the prospect of trying not only to harmonize and standardize testing for PD-L1 by IHC, at least at a technical level, but also, ideally, as a predictive marker, to facilitate availability of this test and a promising treatment for patients with NSCLC.

  • 264.
    Khassebaf, Jasmine
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hellmark, Bengt
    Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Davidsson, Sabina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Nilsdotter-Augustinsson, Åsa
    Division of Infectious Diseases, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Department of Infectious Diseases, County Council of Östergötland, Linköping, Sweden.
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Antibiotic susceptibility of Propionibacterium acnes isolated from orthopaedic implant-associated infections2015In: Anaerobe, ISSN 1075-9964, E-ISSN 1095-8274, Vol. 32, p. 57-62Article in journal (Refereed)
    Abstract [en]

    Introduction: Prosthetic joint infections (PJIs) caused by Propionibacterium acnes account for a larger proportion of the total number of PJIs than previously assumed and thus knowledge of the antimicrobial susceptibility patterns of P. acnes is of great value in everyday clinical practice.

    Materials and methods: Using Etest, the present study investigated the susceptibility of 55 clinical isolates of P. acnes, obtained from orthopaedic implant-associated infections of the knee joint (n = 5), hip joint (n = 17), and shoulder joint (n = 33), to eight antimicrobial agents: benzylpenicillin, clindamycin, metronidazole, fusidic acid, doxycycline, moxifloxacin, linezolid and rifampicin. Synergy testing was also conducted, in which rifampicin was combined with each of the remaining seven antibiotics.

    Results: All isolates (n = 55) were susceptible to most of the antibiotics tested, with the exception of 100% resistance to metronidazole, five (9.1%) isolates displaying decreased susceptibility to clindamycin, and one (1.8%) to moxifloxacin. None of the antimicrobial agents investigated were synergistic with each other when combined and nine isolates were antagonistic for various antimicrobial combinations. The majority of the antimicrobial combinations had an indifferent effect on the isolates of P. acnes. However, the combination of rifampicin and benzylpenicillin showed an additive effect on nearly half of the isolates.

    Conclusion: Almost all P. acnes, isolated from orthopaedic implant-associated infections, predominantly PJIs, were susceptible to the antibiotics tested, with the exception of complete resistance to metronidazole. Synergy test could not demonstrate any synergistic effect but additive effects were found when combining various antibiotics. Antagonistic effects were rare.

  • 265.
    Khezri, Banafsheh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Helmersson-Karlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Estimation of the possible economic effects of a sequential testing strategy with NT-proBNP before echocardiography in primary care2014In: Clinical Laboratory, ISSN 1433-6510, Vol. 60, no 7-8, p. 881-886Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The object of the study was to estimate the possible economic effects of a sequential testing strategy with NT-proBNP from a primary care payer perspective.

    METHODS:

    The study data were collected from primary care physicians in the County of Uppland from 2005 through 2012. Two different cut-off levels were used for negative NT-proBNP in the rule-out test: 300 and 400 pg/mL. The cost-effectiveness of the testing strategy was estimated through the short-term cost avoidance and reduction in demand for echocardiographies.

    RESULTS:

    The female patients were slightly older than the males. Based on the data from 2012, the estimated costs for NT-proBNP tests and echocardiographies per county were reduced by EUR 300000/100000 inhabitants with the 300 pg/mL cut-off and EUR 350000/100000 inhabitants with the 400 pg/mL.

    CONCLUSIONS:

    The use of NT-proBNP as a rule-out test in a sequential testing strategy reduced the cost for diagnostic work-up of primary care patients with suspected heart failure.

  • 266. Kimby, Eva
    et al.
    Östenstad, Björn
    Brown, Peter
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Erlanson, Martin
    Holte, Harald
    Linden, Ola
    Johansson, Ann-Sofie
    Ahlgren, Tomas
    Wader, Karin
    Wahlin, Björn Engelbrekt
    Delabie, Jan
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Two courses of four weekly infusions of rituximab with or without interferon-α2a: final results from a randomized phase III study in symptomatic indolent B-cell lymphomas2015In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, no 9, p. 2598-2607Article in journal (Refereed)
    Abstract [en]

    Patients with advanced CD20 + indolent lymphoma, requiring therapy, were randomized to rituximab (four weekly infusions of 375 mg/m(2)) or to rituximab combined with 5 weeks of interferon-α2a (IFN-α2a) (3-4.5 MIU daily) as priming. Responding patients were eligible for a second cycle with the same allocated treatment. In total, 156 patients were randomized to rituximab and 157 to rituximab + IFN-α2a. In the intention-to treat (ITT) population, 244 patients (78%) responded to cycle 1. After a second cycle the complete remission/complete remission unconfirmed (CR/CRu) rate was 41% with the combination versus 24% with monotherapy (p = 0.005). The median time to treatment failure (primary endpoint) in ITT patients was 28 vs. 21.5 months, respectively (p = 0.302). After a long median follow-up (61 months), 33% (42% of patients responding to cycle 1) were still failure-free with an overall survival rate of 88% and with no difference between the treatment groups. The trial was registered at ClinicalTrials.gov Identifier: NCT01609010.

  • 267.
    Kinch, Amelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Association between HLA-A1 and -A2 types and Epstein-Barr virus status of post-transplant lymphoproliferative disorder2016In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 57, no 10, p. 2351-2358Article in journal (Refereed)
    Abstract [en]

    The susceptibility to Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder (PTLD) may be affected by the human leukocyte antigen (HLA) type. We investigated HLA-A and HLA-B allele frequencies, focusing on HLA-A1 and -A2, in a population-based case series of EBV + (n = 60) and EBV- (n = 44) PTLD after solid organ transplantation. The proportion of EBV + PTLD was highest in HLA-A1 homozygotes (100%), lower in carriers of HLA-A1/AX (79%), HLA-A1/A2 (55%), HLA-A2/AX (54%), and lowest in HLA-A2 homozygotes (37%). HLA-A1 type was overrepresented (22% versus 7%, p = 0.05) and HLA-A2 type underrepresented (57% versus 80%, p = 0.01) in patients with EBV + compared with EBV - PTLD. EBV + PTLD in HLA-A1 carriers developed almost exclusively in already EBV-seropositive individuals. EBV status of PTLD was not related to any other HLA-A or HLA-B type. Our findings suggest that HLA-A1 carriers may have an increased risk of EBV + PTLD due to a decreased ability to control the latent EBV infection.

  • 268.
    Knight, Ann
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hjorton, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Smedby, Karin E
    Askling, Johan
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Leukemia and Myelodysplastic Syndrome in Granulomatosis with Polyangiitis: Subtypes, Clinical Characteristics, and Outcome2015In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 42, no 4, p. 690-694Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Previous studies have shown that patients with granulomatosis with polyangiitis (GPA) have an increased risk of hematological malignancies, especially leukemia. Our aim was to assess clinical characteristics and treatment of patients with GPA complicated by hematological malignancies with focus on leukemia and to describe these malignancies in more detail.

    METHODS: From the Swedish population-based patient register, all individuals with a diagnosis of GPA from 1964-2012 were identified (n = 3224). Through linkage with the Swedish Cancer Register, we searched for all cases of leukemia [International Classification of Diseases (ICD) 7: 204-207 and corresponding codes ICD 8-10] registered after the first discharge listing GPA. The GPA diagnosis was evaluated using the European Medical Association classification algorithm. To confirm the hematological malignancy, all diagnostic bone marrow samples were reclassified. Clinical data of both the GPA and hematological malignancy were collected from medical files.

    RESULTS: Twenty-one cases were identified, all of myeloid origin, including 9 with myelodysplastic syndrome developing to acute myeloid leukemia (MDS-AML), 7 AML, 3 MDS, and 2 chronic myeloid leukemia. The median time from GPA diagnosis to hematological malignancy was 8 years (range 5-21). All patients had severe generalized GPA and had received high doses of cyclophosphamide (CYC; median cumulative dose 96.5 g). Cytopenia occurred in 76% of the patients prior to the hematological malignancy.

    CONCLUSION: The findings emphasize the longterm risk of leukemia and MDS in CYC-treated, severely ill patients with GPA. Cytopenia during the course of GPA may be a warning sign and warrants a liberal attitude toward bone marrow examination.

  • 269. Koivisto, Anne M
    et al.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Savolainen, Sakari
    Sutela, Anna
    Rummukainen, Jaana
    Kurki, Mitja
    Jääskeläinen, Juha E
    Soininen, Hilkka
    Rinne, Jaakko
    Leinonen, Ville
    Poor Cognitive Outcome in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus2013In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 72, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:: Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce. OBJECTIVE:: To elucidate the long-term cognitive condition of shunt-responsive iNPH patients. METHODS:: The follow-up data (Kuopio University Hospital NPH Registry) of 146 patients diagnosed with iNPH by clinical and radiological examination, 24-hour intraventricular pressure monitoring, frontal cortical biopsy, and response to the shunt were analyzed for signs of dementia. The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, and specified memory disorder criteria were used. Median follow-up was 4.8 years. RESULTS:: At the end of follow-up, 117 (80%) of the 146 iNPH patients had cognitive decline and 67 (46%) had clinical dementia. The most common clinical diagnoses were Alzheimer disease and vascular dementia. In multivariate analysis of the 146 iNPH patients, memory deficit as a first symptom before shunt (odds ratio [OR] 18.3; 95% confidence interval [CI] 1.9-175), male sex (OR 3.29; 95% CI 1.11-9.73), age (OR 1.17 year; 95% CI 1.07-1.28), and follow-up time (OR 1.20 year; 95% CI 1.02-1.40) predicted dementia. Interestingly, 8 (5%) iNPH patients had dementia without any signs of other neurodegenerative diseases in clinical, neuroradiological, or brain biopsy evaluation. These patients initially presented a full triad of symptoms, with gait disturbance being the most frequent initial symptom followed by deterioration in cognition. CONCLUSION:: The novel findings were (a) a significant risk of dementia in iNPH initially responsive to cerebrospinal fluid shunt, (b) cognitive impairment most commonly due to iNPH-related dementia followed by concurrent degenerative brain disease, and (c) a subgroup with dementia related to iNPH without comorbidities. ABBREVIATIONS:: Aβ, amyloid betaAD, Alzheimer diseaseCI, confidence intervalHPτ, hyperphosphorylated tauICP, intracranial pressureiNPH, idiopathic normal pressure hydrocephalusKUH, Kuopio University HospitalNPH, normal pressure hydrocephalusVaD, vascular dementia.

  • 270.
    Kollmer, Marius
    et al.
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Meinhardt, Katrin
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Haupt, Christian
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Liberta, Falk
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Wulff, Melanie
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Linder, Julia
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Handl, Lisa
    Univ Ulm, Inst Stochast, D-89081 Ulm, Germany..
    Heinrich, Liesa
    Hans Knoell Inst, Leibniz Inst Nat Prod Res & Infect Biol, D-07745 Jena, Germany..
    Loos, Cornelia
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Schmidt, Matthias
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Syrovets, Tatiana
    Univ Ulm, Inst Pharmacol Nat Prod & Clin Pharmacol, D-89081 Ulm, Germany..
    Simmet, Thomas
    Univ Ulm, Inst Pharmacol Nat Prod & Clin Pharmacol, D-89081 Ulm, Germany..
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Horn, Uwe
    Hans Knoell Inst, Leibniz Inst Nat Prod Res & Infect Biol, D-07745 Jena, Germany..
    Schmidt, Volker
    Univ Ulm, Inst Stochast, D-89081 Ulm, Germany..
    Walther, Paul
    Univ Ulm, Cent Electron Microscopy Facil, D-89081 Ulm, Germany..
    Faendrich, Marcus
    Univ Ulm, Inst Prot Biochem, D-89081 Ulm, Germany..
    Electron tomography reveals the fibril structure and lipid interactions in amyloid deposits2016In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 20, p. 5604-5609Article in journal (Refereed)
    Abstract [en]

    Electron tomography is an increasingly powerful method to study the detailed architecture of macromolecular complexes or cellular structures. Applied to amyloid deposits formed in a cell culture model of systemic amyloid A amyloidosis, we could determine the structural morphology of the fibrils directly in the deposit. The deposited fibrils are arranged in different networks, and depending on the relative fibril orientation, we can distinguish between fibril meshworks, fibril bundles, and amyloid stars. These networks are frequently infiltrated by vesicular lipid inclusions that may originate from the death of the amyloid-forming cells. Our data support the role of nonfibril components for constructing fibril deposits and provide structural views of different types of lipid-fibril interactions.

  • 271. Kolstad, Arne
    et al.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Jerkeman, Mats
    Grønbæk, Kirsten
    Elonen, Erkki
    Räty, Riikka
    Pedersen, Lone Bredo
    Loft, Annika
    Bogsrud, Trond Velde
    Kimby, Eva
    Hansen, Per Boye
    Fagerli, Unn Merete
    Nilsson-Ehle, Herman
    Lauritzsen, Grete Fossum
    Lehmann, Anne Kristine
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Karjalainen-Lindsberg, Marja-Liisa
    Ralfkiaer, Elisabeth
    Ehinger, Mats
    Delabie, Jan
    Bentzen, Hans
    Schildt, Jukka
    Kostova-Aherdan, Kamelia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Frederiksen, Henrik
    Brown, Peter de Nully
    Geisler, Christian H
    Nordic MCL-3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 123, no 19, p. 2953-2959Article in journal (Refereed)
    Abstract [en]

    The main objective of the MCL3 study was to improve outcome for patients not in CR before transplant by adding (90)Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen. 160 consecutive, untreated stage II-IV MCL patients < 66 years received rituximab (R)- maxi-CHOP alternating with R-high-dose Ara-C (6 cycles total), followed by high-dose BEAM or BEAC and autologous stem cell transplantation 2005-2009. Zevalin (0.4 mCi/kg) was given to responders in only CRu/PR prior to high-dose therapy. The overall response rate (ORR) pre-transplant was 97%. After a median follow-up of 4.4 years the outcome did not differ from that of the historic control, the MCL2 trial with the same treatment except for Zevalin. Overall (OS), event free (EFS), and progression-free survival (PFS) at 4 years were 78, 62 and 71%, respectively. For patients in CRu/PR before transplant who received Zevalin duration of response was shorter than in the CR group. Inferior PFS, EFS- and OS were predicted by PET-positivity pre-transplant and detectable minimal residual disease (MRD) before and after transplant. In conclusion, a positive PET prior to transplant and MRD are strong predictors of outcome. Late intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant.

  • 272.
    Kolstad, Arne
    et al.
    Oslo Univ Hosp, Radiumhospitalet, Dept Oncol, Oslo, Norway..
    Pedersen, Lone Bredo
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Eskelund, Christian W.
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Husby, Simon
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Gronbaek, Kirsten
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Jerkeman, Mats
    Skane Univ Hosp, Dept Oncol, Lund, Sweden..
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Raty, Riikka
    Univ Helsinki, Cent Hosp, Dept Hematol & Oncol, Helsinki, Finland..
    Elonen, Erkki
    Univ Helsinki, Cent Hosp, Dept Hematol & Oncol, Helsinki, Finland..
    Andersen, Niels Smedegaard
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Brown, Peter deNully
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Kimby, Eva
    Karolinska Inst, Dept Hematol, S-10401 Stockholm, Sweden..
    Bentzen, Hans
    Aarhus Univ Hosp, Dept Hematol, DK-8000 Aarhus, Denmark..
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden..
    Ehinger, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Karjalainen-Lindsberg, Marja-Liisa
    Skane Univ Hosp, Dept Pathol, Lund, Sweden..
    Delabie, Jan
    Helsinki Univ Cent Hosp, Dept Pathol, Helsinki, Finland..
    Ralfkiaer, Elisabeth
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark.;Oslo Univ Hosp, Dept Pathol, Oslo, Norway..
    Fagerli, Unn-Merete
    Copenhagen Univ Hosp, Rigshospitalet, Dept Pathol, Copenhagen, Denmark..
    Nilsson-Ehle, Herman
    St Olavs Univ Hosp, Dept Oncol, Trondheim, Norway..
    Lauritzsen, Grete Fossum
    Oslo Univ Hosp, Radiumhospitalet, Dept Oncol, Oslo, Norway..
    Kuittinen, Outi
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden. Oulu Univ Hosp, Dept Oncol, Oulu, Finland..
    Niemann, Carsten
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Geisler, Christian Hartman
    Copenhagen Univ Hosp, Rigshospitalet, Dept Hematol, Copenhagen, Denmark..
    Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years2017In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 23, no 3, p. 428-435Article in journal (Refereed)
    Abstract [en]

    The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rear-rangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (P <.0001). OS was 75% at 10 years and median not reached in the MRD-negative group, compared with only 35 months in the MRD-positive group (P <.0001). Of the 86 patients (47%) who remained in continuous molecular remission, 73% were still in clinical remission after 10 years. For all patients, the median time from ASCT to first molecular relapse was 55 months, with a continuous occurrence of late molecular relapses. Fifty-eight patients who experienced MRD relapse received rituximab as preemptive treatment on 1 or more occasions, and in this group, the median time from first molecular relapse to clinical relapse was 55 months. In most cases, rituximab converted patients to MRD negativity (87%), but many patients became MRD-positive again later during follow-up (69%). By multivariate analysis, high-risk Mantle Cell Lymphoma International Prognostic Index score and positive MRD status pre-ASCT predicted early molecular relapse. In conclusion, preemptive rituximab treatment converts patients to MRD negativity and likely postpones clinical relapse. Molecular monitoring offers an opportunity to select some patients for therapeutic intervention and to avoid unnecessary treatment in others. MRD-positive patients in the first analysis post-ASCT have a dismal prognosis and thus are in need of novel strategies.

  • 273. Kostjukovits, Svetlana
    et al.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pekkinen, Minna
    Klemetti, Paula
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Taskinen, Mervi
    Makitie, Outi
    Decreased telomere length in children with cartilage-hair hypoplasia2017In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 54, no 5, p. 365-370Article in journal (Refereed)
    Abstract [en]

    Background Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia caused by RMRP (RNA component of mitochondrial RNA processing endoribonuclease) gene mutations. Manifestations include short stature, variable immunodeficiency, anaemia and increased risk of malignancies, all of which have been described also in telomere biology disorders. RMRP interacts with the telomerase RT (TERT) subunit, but the influence of RMRP mutations on telomere length is unknown. We measured relative telomere length (RTL) in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical and laboratory features. Methods The study cohort included 48 patients with CHH with homozygous (n=36) or compound heterozygous RMRP mutations (median age 38.2 years, range 6.0-70.8 years), 86 relatives (74 with a heterozygous RMRP mutation) and 94 unrelated healthy controls. We extracted DNA from peripheral blood, sequenced the RMRP gene and measured RTL by qPCR. Results Compared with age-matched and sex-matched healthy controls, median RTL was significantly shorter in patients with CHH (n=40 pairs, 1.05 vs 1.21, p=0.017), but not in mutation carriers (n=48 pairs, 1.16 vs 1.10, p=0.224). RTL correlated significantly with age in RMRP mutation carriers (r=-0.482, p < 0.001) and non-carriers (r=-0.498, p<0.001), but not in patients (r=-0.236, p=0.107). In particular children (< 18 years) with CHH had shorter telomeres than controls (median RTL 1.12 vs 1.26, p=0.008). In patients with CHH, RTL showed no correlation with genotype, clinical or laboratory characteristics. Conclusions Telomere length was decreased in children with CHH. We found no correlation between RTL and clinical or laboratory parameters.

  • 274. Kovacs, Gabor G
    et al.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Preface.2017In: Handbook of Clinical Neurology, ISSN 0072-9752, E-ISSN 2212-4152, Vol. 145, article id ixArticle in journal (Refereed)
  • 275.
    Kovacs, Gabor G
    et al.
    Institute of Neurology, Medical University of Vienna, Vienna, Austria.
    Ferrer, Isidro
    Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, Spain.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Concomitant pathologies II: neurodegenerative conditions2015In: Neuropathology of neurodegenerative diseases A practical guide / [ed] Gabor G Kovacs, Cambridge University Press, 2015, p. 292-298Chapter in book (Refereed)
    Abstract [en]

    Introduction The term “mixed or concomitant” pathologies in neurodegenerative disease means that, in addition to the hallmark lesions of a neurodegenerative disease entity, further pathological alterations can be observed in the same brain. The term mixed pathology was originally used when describing accompanying vascular pathology. Later, Lewy body pathology was also described as concomitant pathology when seen together with other neurodegenerative diseases. Currently, we classify neurodegenerative diseases according to the predominant protein that shows pathological depositions in the brain. During the diagnostic process, detecting hallmark lesions of a certain disease, like neuritic plaques in the cortex, spongiform change in the cortex, globose tangles in the brainstem nuclei or Lewy bodies in the brainstem or cortex, can lead to negligence of further lesions or performance of further stains. However, deposition of multiple proteins, in addition to co-occurrence of non-neurodegenerative pathology (e.g. vascular, metabolic), is a frequent event. In fact, overlapping neurodegeneration may be more the rule than the exception. This concept is supported by observations in genetic forms of neurodegenerative disorders where various proteins may show pathological deposits in the same brain [1–3]. Complex constellations of clinical symptoms (movement disorders and cognitive decline) may associate with the accompanying presence of diverse neurodegenerative disorders. There are several factors determining overlap between neurodegenerative disorders as proposed by Armstrong et al. [4]): (i) historical factors, which means that the original descriptions of key disorders were based on the descriptions of relatively small numbers of cases; furthermore, the original investigators interpreted these as ‘syndromes’ rather than distinct diseases; (ii) disease heterogeneity; (iii) age-related changes;(iv) apolipoprotein ɛ genotype, especially in cases with significant Aβ deposition but without further features of Alzheimer’s disease (AD); (v) co-occurrence of common diseases, like AD and Parkinson’s disease (PD), as both are more likely to occur in the elderly and thus are more likely to co-occur.

  • 276. Kovacs, Gabor G
    et al.
    Rozemuller, Annemieke J M
    van Swieten, John C
    Gelpi, Ellen
    Majtenyi, Katalin
    Al-Sarraj, Safa
    Troakes, Claire
    Bódi, István
    King, Andrew
    Hortobágyi, Tibor
    Esiri, Margaret M
    Ansorge, Olaf
    Giaccone, Giorgio
    Ferrer, Isidre
    Arzberger, Thomas
    Bogdanovic, Nenad
    Nilsson, Tatjana
    Leisser, Irene
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Ironside, James W
    Kretzschmar, Hans
    Budka, Herbert
    Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: A study of the BrainNet Europe Consortium2013In: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 39, no 2, p. 166-178Article in journal (Refereed)
    Abstract [en]

    Aims: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurons. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. Methods: We evaluated immunoreactivity for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. Results: Mean age at death was 68.2 years (range 49 to 96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of FTD, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein immunoreactivity was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurons. Aβ immunoreactivity was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. Conclusions: 1) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; 2) even minor deviation from these morphological criteria suggests a different disorder; and 3) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.

  • 277. Kovacs, Gabor G.
    et al.
    Wagner, Uta
    Dumont, Benoit
    Pikkarainen, Maria
    Osman, Awad A.
    Streichenberger, Nathalie
    Leisser, Irene
    Verchère, Jérémy
    Baron, Thierry
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Budka, Herbert
    Perret-Liaudet, Armand
    Lachmann, Ingolf
    An antibody with high reactivity for disease-associated α-synuclein reveals extensive brain pathology2012In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 124, no 1, p. 37-50Article in journal (Refereed)
    Abstract [en]

    α-Synuclein is the major protein associated with Lewy body dementia, Parkinson's disease and multiple system atrophy. Since α-synuclein is present in the brain in physiological conditions as a presynaptic protein, it is crucial to characterize disease-associated modifications to develop an in vivo biomarker. With the aim to develop antibodies showing high specificity and sensitivity for disease-associated α-synuclein, synthetic peptides containing different amino acid sequences were used for immunization of mice. After generation of α-synuclein aggregates, ELISA and immunoblotting were used to test the specificity of antibodies. Tissue microarray sections originating from different human α-synucleinopathies were used to compare immunostaining with other, commercially available antibodies. Immunization of mice with the peptide TKEGVVHGVATVAE (amino acid 44-57 of α-synuclein) resulted in the generation of a monoclonal antibody (5G4), which was able to bind aggregated α-synuclein preparation in sandwich ELISA or coated on magnetic beads. 5G4 proved to be superior to other antibodies in comparative immunohistochemical studies by revealing more widespread and distinct α-synuclein pathology. Immunoblotting of human brain tissue revealed an additional band seen in dementia with Lewy bodies, whereas the band representing monomeric α-synuclein was very weak or lacking. In summary, the 5G4 antibody is most promising for re-evaluation of archival material and may offer new perspective for the development of in vivo diagnostic assays for detecting disease-associated α-synuclein in body fluids.

  • 278. Kuusisto, E
    et al.
    Kauppinen, T
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Use of p62/SQSTM1 antibodies for neuropathological diagnosis.2008In: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 34, no 2, p. 169-80Article in journal (Refereed)
    Abstract [en]

    The demonstration of proteinaceous inclusions in the brain is the key step in the pathological diagnosis of degenerative dementias. The diversity of these diseases has necessitated the use of a panel of (immuno)stains to visualize all suspect pathologies, elevating diagnostic costs. Immunodetection of p62 (sequestosome 1), an abundant constituent in diverse pathological inclusions, holds the potential for a broad-specificity, high-contrast inclusion label. In the brain, pathological p62-positive aggregates comprise both cytoplasmic and nuclear types in neurones and glia, with abnormal tau, alpha-synuclein, TAR DNA-binding protein 43 or polyglutamine proteins as primary components. We therefore set out to evaluate the performance of p62 antibodies for diagnostic immunohistochemistry. We optimized the application conditions and compared the staining profiles of eight commercial p62 antibodies with each other and with reference immunostains, using 2-mm tissue multiarrays representing the major tauo- and synucleinopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). The lesions were best visualized using monoclonal antibodies, displaying most types of hallmark inclusions with excellent contrast. Expanding the list of p62-containing aggregates, we demonstrated p62 in tufted astrocytes, coiled bodies, astrocytic plaques, and variform neocortical inclusions and pathological processes in FTLD-U. Polyclonal antibodies exhibited lower sensitivities with variable background levels. We also noted more subtle p62-immunoreactive features lacking overt disease associations. Emphasizing the importance of proper antibody and epitope unmasking methods for maximum sensitivity, we recommend p62 immunodetection as a screening stain for diagnostic practice.

  • 279.
    Källberg, Linnéa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Evaluation of lithium-heparintube analyses performance2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Today, some kind of laboratory results is required for around 70% of the diagnostics and follow-ups for diseases. In many of the cases the time from sampling to a result is very critical. Therefore the discussion of how to improve this situation has begun. For many analyses serum has been the routine choice for a long time but now it is disputed. After blood collection in a serum tube it is essential to wait 30-60 minutes before centrifugation and analysis of the sample, a long time for someone in an acute state. Other problems like post centrifugation clots of fibrin causing false results or time-consuming reruns of the sample have also been reported. These problems have initiated the laboratory in Hudiksvall’s hospital to find out an alternative to the common serum sampling.In this report, the differences between serum and lithium heparin plasma for 31 analyses has been evaluated. Paired blood samples, one serum and one plasma, were collected for routine, hormonal and for tumor markers analyses and analyzed in a Cobas c501, e411 or e601 (ROCHE). The results of the analyzed samples were compared to each other by statistical analysis.The results prove that serum and lithium heparin plasma is equal for ALT, GGT, NT-proBNP, FT3, FT4, cobalamin, LH, prolactin, TSH, CA19-9, CEA and PSA. The results also prove that serum and lithium heparin plasma is not equal for 19 other analyses. Therefore, a shift between different types of sampling is not to be recommended without further evaluations.

  • 280. Kämäläinen, Anna
    et al.
    Viswanathan, Jayashree
    Natunen, Teemu
    Helisalmi, Seppo
    Kauppinen, Tarja
    Pikkarainen, Maria
    Pursiheimo, Juha-Pekka
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Kivipelto, Miia
    Haapasalo, Annakaisa
    Soininen, Hilkka
    Herukka, Sanna-Kaisa
    Hiltunen, Mikko
    GRN Variant rs5848 Reduces Plasma and Brain Levels of Granulin in Alzheimer's Disease Patients.2013In: Journal of Alzheimer's disease : JAD, ISSN 1875-8908, Vol. 33, no 1, p. 23-7Article in journal (Refereed)
    Abstract [en]

    Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer's disease (AD). Here, we report that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Similarly, the mRNA levels of granulin were decreased with respect to A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Our findings suggest that the A allele of rs5848 is functionally relevant by reducing the expression of granulin.

  • 281.
    La Fleur, Linnea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Boura, Vanessa F.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Alexeyenko, Andrey
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden;Natl Bioinformat Infrastruct Sweden, Sci Life Lab, Solna, Sweden.
    Berglund, Anders
    Epistat, Uppsala, Sweden.
    Ponten, Victor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mattsson, Johanna Sofia Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Djureinovic, Dijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Persson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Brunnström, Hans
    Lund Univ, Skane Univ Hosp, Div Pathol, Lund, Sweden.
    Isaksson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Brandén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Koyi, Hirsh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson, Mikael C. I.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Botling, Johan
    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 and experimental pathology.
    Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 7, p. 1741-1752Article in journal (Refereed)
    Abstract [en]

    Tumor-associated macrophages (TAMs) are attractive targets for immunotherapy. Recently, studies in animal models showed that treatment with an anti-TAM antibody directed against the scavenger receptor MARCO resulted in suppression of tumor growth and metastatic dissemination. Here we investigated the expression of MARCO in relation to other macrophage markers and immune pathways in a non-small cell lung cancer (NSCLC) cohort (n=352). MARCO, CD68, CD163, MSR1 and programmed death ligand-1 (PD-L1) were analyzed by immunohistochemistry and immunofluorescence, and associations to other immune cells and regulatory pathways were studied in a subset of cases (n=199) with available RNA-seq data. We observed a large variation in macrophage density between cases and a strong correlation between CD68 and CD163, suggesting that the majority of TAMs present in NSCLC exhibit a protumor phenotype. Correlation to clinical data only showed a weak trend toward worse survival for patients with high macrophage infiltration. Interestingly, MARCO was expressed on a distinct subpopulation of TAMs, which tended to aggregate in close proximity to tumor cell nests. On the transcriptomic level, we found a positive association between MARCO gene expression and general immune response pathways including strong links to immunosuppressive TAMs, T-cell infiltration and immune checkpoint molecules. Indeed, a higher macrophage infiltration was seen in tumors expressing PD-L1, and macrophages residing within tumor cell nests co-expressed MARCO and PD-L1. Thus, MARCO is a potential new immune target for anti-TAM treatment in a subset of NSCLC patients, possibly in combination with available immune checkpoint inhibitors.

  • 282.
    La Fleur, Linnéa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Falk-Sörqvist, Elin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Smeds, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berglund, Anders
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mattsson, Johanna SM
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Brandén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Dept. of Respiratory Medicine, Gävle Hospital, Gävle.
    Koyi, Hirsh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Dept. of Respiratory Medicine, Gävle Hospital, Gävle.
    Isaksson, Johan
    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 and experimental pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Dept. of Respiratory Medicine, Gävle Hospital, Gävle.
    Brunnström, Hans
    Nilsson, Mats
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moens, Lotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK112019In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 130, p. 50-58Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.

    MATERIALS AND METHODS: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.

    RESULTS: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.

    CONCLUSION: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.

  • 283. Lafuente, Jose Vicente
    et al.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Patnaik, Ranjana
    Muresanu, Dafin Fior
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Diabetes Exacerbates Nanoparticles Induced Brain Pathology2012In: CNS & Neurological Disorders: Drug Targets, ISSN 1871-5273, E-ISSN 1996-3181, Vol. 11, no 1, p. 26-39Article, review/survey (Refereed)
    Abstract [en]

    Long term exposure of nanoparticles e.g., silica dust (SiO2) from desert environments, or engineered nanoparticles from metals viz., Cu, Al or Ag from industry, ammunition, military equipment and related products may lead to adverse effects on mental health. However, it is unclear whether these nanoparticles may further adversely affect human health in cardiovascular or metabolic diseases e.g., hypertension or diabetes. It is quite likely that in diabetes or hypertension where the body immune system is already compromised there will be greater adverse effects following nanoparticles exposure on human health as compared to their exposure to healthy individuals. Previous experiments from our laboratory showed that diabetic or hypertensive animals are more susceptible to heat stress-induced neurotoxicity. Furthermore, traumatic injury to the spinal cord in SiO2 exposed rats resulted in exacerbation of cord pathology. However, whether nanoparticles such as Cu, Ag or SiO2 exposure will lead to enhanced neurotoxicity in diabetic animals are still not well investigated. Previous data from our laboratory showed that Cu or Ag intoxication (50 mg/kg, i.p. per day for 7 days) in streptozotocine induced diabetic rats exhibited enhanced neurotoxicity and exacerbation of sensory, motor and cognitive function as compared to normal animals under identical conditions. Thus the diabetic animals showed exacerbation of regional blood-brain barrier (BBB) disruption, edema formation and cell injuries along with greater reduction in the local cerebral blood flow (CBF) as compared to normal rats. These observations suggest that diabetic animals are more vulnerable to nanoparticles induced brain damage than healthy rats. The possible mechanisms and functional significance of these findings are discussed in this review largely based on our own investigations.

  • 284. Laiterä, Tiina
    et al.
    Paananen, Jussi
    Helisalmi, Seppo
    Sarajärvi, Timo
    Huovinen, Joel
    Laitinen, Marjo
    Rauramaa, Tuomas
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Remes, Anne M
    Soininen, Hilkka
    Haapasalo, Annakaisa
    Jääskeläinen, Juha E
    Leinonen, Ville
    Hiltunen, Mikko
    Effects of Alzheimer's Disease-Associated Risk Loci on Amyloid-β Accumulation in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients2017In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 55, no 3, p. 995-1003Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition featuring characteristic symptoms, ventriculomegaly, and normal or slightly elevated cerebrospinal fluid pressure. In Alzheimer's disease (AD) patients, diffuse aggregates of amyloid-β (Aβ) and neurofibrillary hyperphosphorylated tau are detected in the neocortex of the brain, while similar accumulation of Aβ is also detected in iNPH. Recent genome-wide association studies have identified several novel risk loci for AD, potentially affecting Aβ-related cellular processes. Apart from the apolipoprotein E ɛ4 allele (APOE4), the risk effect of single loci is low, emphasizing the importance of the polygenic risk score approach when assessing the combined effects.

    OBJECTIVE: To study the effects of AD-associated individual and polygenic risk score of single nucleotide polymorphisms (SNPs) on the accumulation of Aβ in the brain samples of iNPH patients.

    METHODS: A sample set of frontal cortex biopsies from 188 iNPH patients were divided into two groups according to the Aβ pathology. After the genotyping of the AD-associated risk loci, polygenic risk score was calculated for each iNPH patient and subsequently analyzed in relation to Aβ deposition.

    RESULTS: Apart from the APOE4, none of the SNPs revealed a statistically significant effect on the accumulation of Aβ in iNPH. Also, the non-APOE4 polygenic risk score did not associate with Aβ deposition.

    CONCLUSION: Novel AD-associated risk genes have no significant effect on Aβ accumulation in the brain of iNPH patients. However, APOE4 affects the Aβ deposition in the brain of iNPH and AD patients in a similar manner.

  • 285.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    What can we learn from studies on regional differences in the utilization of laboratory tests?2011In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, no 4, p. 225-226Article in journal (Refereed)
  • 286.
    Larsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Breimer, Lars
    Örebro Universitet.
    Anpassa utredningen av diabetes hos patienter med invandrarbakgrund.2018In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 115, p. FFIZ-FFIZArticle in journal (Refereed)
  • 287.
    Larsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Breimer, Lars
    Örebro Universiet.
    Bra att läkare inte stirrar sig blinda på HbA1c2019In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 116, p. FIEW-Article in journal (Other academic)
  • 288.
    Larsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Anne-Li
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Bodolea, Constantin
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid2015In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 76, no 2, p. 514-518Article in journal (Refereed)
    Abstract [en]

    Cytokines and chemokines regulate many functions in the body including the brain. The interactions between adipose tissue and the central nervous system (CNS) are important for the regulation of energy balance. CNS function is also influenced by age. The aim of the present study was to investigate the effects of body mass index (BMI) and age on cytokine and chemokine levels in cerebrospinal fluid. Cerebrospinal fluid samples (n=89) were collected from patients undergoing routine surgical procedures. The samples were analyzed using the multiplex proximity extension assay (PEA) in which 92 different cytokines are measured simultaneously using minute sample volume. We found no significant correlations between age and cytokine levels for any of the studied markers. In contrast, at a false discovery rate of 10%, 19 markers were significantly associated with BMI (in decreasing significance: FGF-5, ADA, Beta-NGF, CD40, IL-10RB, CCL19, TGF-alpha, SIRT2, TWEAK, SCF, CSF-1, 4E-BP1, DNER, LIF-R, STAMPB, CXCL10, CXCL6, VEGF-A and CX3CL1). This study reveals a clear effect of BMI on cytokine and chemokine levels in cerebrospinal fluid.

  • 289.
    Larsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Greig-Pylypczuk, Roman
    Huisman, Albert
    The state of point-of-care testing: a european perspective2015In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 120, no 1, p. 1-10Article, review/survey (Refereed)
    Abstract [en]

    Abstract Point-of-care testing (POCT) refers to any diagnostic test administered outside the central laboratory at or near the location of the patient. By performing the sample collection and data analysis steps in the same location POCT cuts down on transport and processing delays, resulting in the rapid feedback of test results to medical decision-makers. Over the past decades the availability and use of POCT have steadily increased in Europe and throughout the international community. However, concerns about overall utility and the reliability of benefits to patient care have impeded the growth of POCT in some areas. While there is no agreed-upon standard for how success should be judged, the increases in speed and mobility provided by POCT can lead to substantial advantages over traditional laboratory testing. When properly utilized, POCT has been shown to yield measurable improvements in patient care, workflow efficiency, and even provide significant financial benefits. However, important organizational and quality assurance challenges must be addressed with the implementation of POCT in any health care environment. To ensure maximal benefits it may be necessary to evaluate critically and restructure existing clinical pathways to capitalize better on the rapid test turnaround times provided by POCT.

  • 290.
    Larsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Nordin, Gunnar
    För kort ”bäst före-datum” ett hot mot patientsäkerheten2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, article id C9A6Article in journal (Other (popular science, discussion, etc.))
  • 291.
    Larsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ridefelt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Pediatric reference intervals for liver markers derived from healthy community-based subjects will improve diagnostic interpretation in children and adolescents2018In: Journal of Laboratory and Precision Medicine, ISSN 2519-9005, Vol. 3, p. 2-Article in journal (Refereed)
  • 292.
    Larsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ridefelt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Reference intervals for parathyroid hormone for 70-year-old males and females: exclusion of individuals from the reference interval based on sex, calcium, diabetes, cardiovascular diseases or reduced kidney function has limited effects on the interval2015In: Annals of Clinical Biochemistry, ISSN 0004-5632, E-ISSN 1758-1001, Vol. 52, no 1, p. 39-43Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A problem when producing reference intervals for elderly individuals is that they often suffer from a number of diseases and they are most often on medication. If all such persons are excluded, there is a risk that the residual subgroup may not be representative of the population, we therefore wanted to compare the effects different exclusion criteria has on the reference intervals.

    METHODS: We measured parathyroid hormone (PTH), calcium, albumin and cystatin C in a cohort of 70-year-old males and females (n = 1003). Reference intervals for PTH for males and females were calculated for the entire population and after exclusion of persons with calcium >2.60 mmol/L, calcium >2.51 mmol/L, diabetes, reduced glomerular filtration rate (GFR), and cardiovascular diseases.

    RESULTS: The calculated PTH reference interval 16 (CI 14-17) to 94 (CI 87-101) ng/L. Exclusion of study subjects resulted in smaller reference sample groups, but the reference limits remained within the 90% confidence intervals of the original reference limits. The selections thus had a very limited effect on the calculated reference interval for PTH.

    CONCLUSIONS: Exclusion of elderly individuals with high calcium concentrations, diabetes, reduced GFR or cardiovascular disease has little effect on the reference interval for PTH. It is better not to exclude these individuals, as it will provide a broader base for the reference interval.

  • 293.
    Larsson, Gabriella Lillsunde
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    HPV testing of biobanked liquid-based cytology: a validation study2016In: International Journal of Biological Markers, ISSN 0393-6155, E-ISSN 1724-6008, Vol. 31, no 2, p. E218-E223Article in journal (Refereed)
    Abstract [en]

    Introduction: The aim of the study was to investigate whether biobanked liquid-based cytology (LBC) vaginal samples could be reanalyzed for the biomarkers HPV DNA and mRNA without loss of sensitivity.

    Methods: One hundred LBC samples with ASCUS or CIN1 were tested for HPV DNA and mRNA before and after biobanking. DNA analysis targeted the viral genes E6 and E7, 12 high-risk and 2 low-risk HPV types together with the human control gene HBB, using real-time PCR. The Aptima HPV assay was used for mRNA analysis of 14 high-risk HPV types.

    Results: With Aptima there was 84% agreement between results before and after biobanking. The sensitivity and specificity were 0.79 (95% CI, 0.68-0.88) and 0.94 (95% CI, 0.80-0.99), respectively. With the DNA-based method, the agreement between results was 87%, the sensitivity 0.85 (95% CI, 0.75-0.92) and the specificity 0.95 (95% CI, 0.77-1.00). Both methods presented a significant difference between positive results before and after biobanking; McNemar test: p = 0.004, p = 0.003, Cohen's kappa: 0.67 (95% CI, 0.53-0.81), 0.68 (95% CI, 0.52-0.84). Cycle threshold values for the DNA method were higher for all genotypes after biobanking, except for HPV-59. Some loss of sensitivity was seen after biobanking but the concordance between HPV detection before and after biobanking was good for both evaluated methods.

    Conclusions: Biobanking of LBC vaginal samples offers a good platform for HPV testing and could be extended to further molecular analyses. However, in order to ensure a valid test result a larger portion needs to be analyzed from the biobanked sample.

  • 294.
    Leander, Ellinor
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Artidentifiering av mögelsvamp med MALDI-TOF MS2018Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    Rapid and accurate species identification is crucial for successful treatment of fungal infections, especially among immunosuppressed patients. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is used routinely at clinical laboratories to identify characteristic protein patterns of bacteria and yeast by the interpretation of protein spectra in a database for accurate species identification. The hard cell wall of the mold and the heterogeneous growth with varying protein expression due to maturation, complicates identification with MALDI-TOF MS. The potential benefits of this method compared to microscopy as traditional method are shortened turn-around times, safer species identification of more species that is independent on subjective morphological assessment. The purpose of the study was to investigate whether MALDI-TOF MS could be adapted and used for the identification of molds in clinical routine diagnostics. Four reference strains (Aspergillus niger, A.fumigatus, A.terreus, A.flavus) and a clinical isolate (A.terreus) were examined. The preparation methods (I) complete formic acid extraction, (II) direct application and (III) suspension in distilled water were used for analysis of spores and frontmycelium from younger and older mold cultures. Two different masspektradatabases for species identification were compared; routine database BDAL and the specialized mold database, Filamentous Fungi Library. Also the collecting technique of mold prior to analysis with MALDI-TOF MS was evaluated. Sometimes, the species identification improved after extraction of mold cultures, while in other cases direct application was sufficient. Cultures with a lot of spores tended to give slightly more species identifications in BDAL regardless of the age of cultures. Filamentous Fungi Library, in some cases, tended to improve the performance compared to BDAL for younger cultures. More studies are required to evaluate and optimize MALDI-TOF MS as a method of mold identification.

  • 295. Leinonen, Ville
    et al.
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Aalto, Sargo
    Suotunen, Timo
    Savolainen, Sakari
    Någren, Kjell
    Tapiola, Tero
    Pirttilä, Tuula
    Rinne, Jaakko
    Jääskeläinen, Juha E
    Soininen, Hilkka
    Rinne, Juha O
    Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh Compound B.2008In: Archives of Neurology, ISSN 0003-9942, E-ISSN 1538-3687, Vol. 65, no 10, p. 1304-9Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To compare carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) findings in patients with and without Alzheimer disease lesions in frontal cortical biopsy specimens.

    DESIGN: Cross-sectional study of [11C]PiB PET findings in patients with or without beta-amyloid (Abeta) aggregates in frontal cortical biopsy specimens.

    SETTING: Two university hospitals in Finland. Patients Ten patients who had undergone intraventricular pressure monitoring with a frontal cortical biopsy (evaluated for Abeta aggregates and hyperphosphorylated tau) for suspected normal-pressure hydrocephalus.

    INTERVENTIONS: [11C]PiB PET and evaluation for cognitive impairment using a battery of neuropsychological tests.

    MAIN OUTCOME MEASURES: Immunohistochemical evaluation for Abeta aggregates and hyperphosphorylated tau in the frontal cortical biopsy specimen and [11C]PiB PET.

    RESULTS: In patients with Abeta aggregates in the frontal cortical biopsy specimen, PET imaging revealed higher [11C]PiB uptake (P < .05) in the frontal, parietal, and lateral temporal cortices and in the striatum as compared with the patients without frontal Abeta deposits.

    CONCLUSIONS: Our study supports the use of noninvasive [11C]PiB PET in the assessment of Abeta deposition in the brain. Large prospective studies are required to verify whether [11C]PiB PET will be a diagnostic aid, particularly in early Alzheimer disease.

  • 296. Leinonen, Ville
    et al.
    Koivisto, Anne M
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Pyykkö, Okko T
    Rummukainen, Jaana
    von Und Zu Fraunberg, Mikael
    Jääskeläinen, Juha E
    Soininen, Hilkka
    Rinne, Jaakko
    Savolainen, Sakari
    Cortical Brain Biopsy in Long-Term Prognostication of 468 Patients with Possible Normal Pressure Hydrocephalus2012In: Neuro-degenerative diseases, ISSN 1660-2862, Vol. 10, no 1-4, p. 166-169Article in journal (Refereed)
    Abstract [en]

    Normal pressure hydrocephalus (NPH) can be alleviated by cerebrospinal fluid shunting but the differential diagnosis and patient selection are challenging. Intraventricular intracranial pressure monitoring as part of the diagnostic workup as well as shunting enable to obtain cortical brain biopsies to detect amyloid-β (Aβ) and hyperphosphorylated tau (HPτ), the hallmark lesions of Alzheimer's disease (AD). In possible NPH, Aβ alone indicates an increased risk of AD and when present with HPτ probable AD, but the effect of those brain lesions on survival is not known. The aim of this study was to evaluate the predictive value of brain biopsy for the long-term outcome of possible NPH. Between 1991 and 2006, the Neurosurgery Department of the Kuopio University Hospital evaluated 468 patients for possible NPH by intraventricular intracranial pressure monitoring and frontal cortical brain biopsy immunostained against Aβ and HPτ. All patients were followed up until the end of 2008 (n = 201) or death (n = 267) with a median follow-up of 4.6 years (range 0-17). Logistic regression analysis with Cox models was applied. Out of the 468 cases, Aβ was detected in 197 (42%) cortical biopsies, and together with HPτ in 44 (9%). Aβ alone indicated increased risk of AD and with HPτ probable AD, but it did not affect survival. Vascular aetiology was the most frequent cause of death. Cortical biopsy findings indicate that NPH is at present a heterogeneous syndrome and has notable overlapping with AD. Brain biopsy did not predict survival but may open a novel research window to study the pathobiology of neurodegeneration.

  • 297.
    Lewin, Nongnit
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hosp, Sweden.
    Luetragoon, Thitiya
    Ryhov Hosp, Sweden; Naresuan Univ, Thailand.
    Andersson, Bengt-Åke
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hosp, Sweden.
    Oliva, Delmy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Ryhov Hosp, Sweden.
    Nilsson, Mats
    Ryhov Hosp, Sweden.
    Strandeus, Michael
    Ryhov Hosp, Sweden.
    Lofgren, Sture
    Ryhov Hosp, Sweden.
    Rutqvist, Lars-Erik
    Swedish Match AB, Sweden.
    Lewin, Freddi
    Ryhov Hosp, Sweden.
    The Influence of Single Nucleotide Polymorphisms and Adjuvant Radiotherapy on Systemic Inflammatory Proteins, Chemokines and Cytokines of Patients With Breast Cancer2019In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 39, no 3, p. 1287-1292Article in journal (Refereed)
    Abstract [en]

    Independently of tumour and treatment modulation, the host immune response status plays an important role in the clinical outcome of patients with cancer. The influence of single nucleotide polymorphisms (SNPs) and adjuvant radiotherapy (RT) on the systemic immune response status of patients with breast cancer was investigated. Materials and Methods: Eighty-six female patients recovering from breast cancer surgery were investigated. As a control cohort, 82 healthy female blood donors were used. Blood-based SNPs, plasma C-reactive protein (CRP), cytokines and chemokines were analyzed for this purpose. Results: Independently of tumour stage and hormone receptor status, dysregulation of plasma CRP, chemokine (C-C motif) ligand 4 (CCL4) and interleukin 2 (IL2), but not CCL5, CCL2, platelet-derived growth factor, IL6, IL10, IL12, interferon-gamma or tumour necrosis factor alpha were detected in the patients when compared to controls. The extent of alteration in plasma levels of CRP and IL2 patients was significantly associated with SNPs in CRP rs1800947 and IL2 rs6822844, respectively. These SNPs had no influence on the levels of corresponding plasma biomarkers in the healthy controls. Adjuvant RT reduced plasma CRP and CCL5 levels in patients with regards to CRP rs1800947CC, CCL5 rs2107538GG and CCL5 rs2280789AA sequences. Conclusion: Dysregulation of immune responses, as indicated by plasma levels of CRP, CCL4 and IL2 were found in patients with breast cancer despite the removal of the tumour mass. The benefit of adjuvant RT, as indicated by reduced plasma amounts of inflammatory protein CRP and chemokine CCL5 were based on the SNPs of the patients. Analyses of blood-based SNPs, plasma CRP, IL2 and CCL5 are low cost, rapid and can be carried out using general laboratory facilities while requiring only a peripheral blood sample. The possibility of using these blood-based biomarkers as an indicator of patient immune status for selection of individual patient treatment warrants further investigation.

  • 298. Li, Hui-xiang
    et al.
    Zh, Suo
    Zhang, Yun-han
    Risberg, Bjørn
    Karlsson, Mats G
    Örebro University Hospital, Örebro, Sweden.
    Nesland, Jahn M.
    [Expressions of thymidine phosphorylase, thymidylate synthase and dihydropyrimidine dehydrogenase in breast cancer and their correlations with prognosis]2004In: Zhonghua zhong liu za zhi [Chinese journal of oncology], ISSN 0253-3766, Vol. 26, no 11, p. 669-672Article in journal (Refereed)
    Abstract [en]

    Objective: To study the expression of thymidine phosphorylase (TP), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) mRNA in breast cancer and its correlation with prognosis.

    Methods: Expression levels of TP, TS and DPD mRNA in 86 micro-selected breast cancer tissues and 9 normal breast tissues were detected by real-time quantitative PCR.

    Results: The median expression levels of TP, TS and DPD mRNA in tumor tissue and in normal tissues were 16.54, 0.38, 2.47 and 11.75, 0.25, 8.33, respectively, there were no significant differences (P >0.05). The expression levels of TP, TS and DPD mRNA showed no association with tumor size, lymph node metastasis, pathological grade and clinical stage, except that of DPD showed a negative association with patients' ages. There was no significant difference in disease-free survival or overall survival between the patients with high and low TP or DPD mRNA levels. Disease-free survival tends to be better in the patients with low TS mRNA level than those with high TS mRNA, but the difference was not significant (P=0.069), while the overall survival showed a statistically difference (59.00 month and 70.30 month) (P=0.0496).

    Conclusion: The expression level of TS mRNA may serve as a prognostic marker for breast cancer patients.

  • 299.
    Li, M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Li, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Marx, J
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Scaling of motility speed and its temperature sensitivity in mammals representing a 5,500-fold difference in body size2011In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 202, no 4, p. 671-681Article in journal (Refereed)
    Abstract [en]

    Aim: 

    The predictions of scaling of skeletal muscle shortening velocity made by A.V. Hill 60-years ago have proven to be remarkably accurate at the cellular level. The current investigation looks to extend the study of scaling of contractile speed to the level of the molecular motor protein myosin at both physiological and unphysiological low temperatures.

    Methods: 

    A single muscle cell in vitro motility assay to test myosin function, i.e. myosin extracted from short single muscle fibre segments, was used in four species representing a 5 500-fold difference in body mass (rat, man, horse and rhinoceros) at temperatures ranging from 15 to 35 °C.

    Results: 

    The in vitro motility speed increased as the temperature of the assay increased, but a more profound effect was observed on the slower isoforms, narrowing the relative differences between fast and slow myosin heavy chain (MyHC) isoforms at physiological temperature in all species. The in vitro motility speed varied according to MyHC isoform within each species: I < IIa < IIx < IIb, but the expected scaling relationship within orthologous myosin isoforms was not observed at any temperature.

    Conclusion: 

    The scaling effect of body size and limb length on shortening velocity at the muscle fibre level, i.e. the decreasing shortening velocity associated with increasing body weight and limb length, was not confirmed at the motor protein level when including mammals of very large size. Thus, other factors than myosin structure and function appear to cause this scaling effect and thin filament isoform expression or myofilament lattice spacing are forwarded as alternative underlying factors.

  • 300.
    Libard, Sylwia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Cerjan, Dijana
    Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Characteristics of the tissue section that influence the staining outcome in immunohistochemistry2019In: Histochemistry and Cell Biology, ISSN 0948-6143, E-ISSN 1432-119X, Vol. 151, no 1, p. 91-96Article in journal (Refereed)
    Abstract [en]

    Immunohistochemistry (IHC) is influenced by several factors such as cold ischemia time, fixative, fixation time, paraffin, storage time, antibody, antigen retrieval technique and detection systems. In the setting of post-mortem tissue, not only post-mortem delay, but also agonal state is of interest. Here, we assessed an additional variable, i.e., the thickness of the section, and noted that this variable also influenced the IHC outcome. This is of significance when the extent of labelling is a parameter to be assessed, for example when assigning a stage or grade of a disease. Furthermore, when assessing brain tissue with neurons, soma measuring from 4 to 100 µm, various cellular compartments composed of different proteins are localised in sections measuring 4 or 7 µm. Thus, what is seen in a 7-µm-thick section might be lacking in a 4-µm-thick section. Lack of information regarding the molecular size of commercial antibodies is also disturbing as this parameter might influence the distribution of the molecule in the three-dimensional section. The choice of antibody to be used and the staining methodology have been acknowledged being of significance for IHC outcome; however, neither sections thickness or the molecular weight has been discussed sufficiently. IHC has been shown to be an unpredictable technique used for assessment of tissue. This emphasises the need for detailed methodological descriptions in publications, the need to acknowledge and to harmonize all eventual pitfalls related to this methodology.

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