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  • 101.
    Eskelund, Christian W.
    et al.
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Kolstad, Arne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Jerkeman, Mats
    Univ Lund Hosp, Dept Oncol, Lund, Sweden..
    Raty, Riikka
    Univ Helsinki, Dept Haematol, Cent Hosp, Helsinki, Finland..
    Laurell, Anna
    Univ Uppsala Hosp, Dept Oncol, Uppsala, Sweden..
    Eloranta, Sandra
    Karolinska Inst, Clin Epidemiol Unit, Dept Med Solna, Stockholm, Sweden..
    Smedby, Karin E.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med Solna, Stockholm, Sweden..
    Husby, Simon
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Pedersen, Lone B.
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Andersen, Niels S.
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Eriksson, Mikael
    Univ Lund Hosp, Dept Oncol, Lund, Sweden..
    Kimby, Eva
    Karolinska Inst, Dept Haematol, Stockholm, Sweden..
    Bentzen, Hans
    Aarhus Univ Hosp, Dept Haematol, Aarhus, Denmark..
    Kuittinen, Outi
    Oulu Univ Hosp, Dept Radiotherapy & Oncol, Oulu, Finland..
    Lauritzsen, Grete F.
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Nilsson-Ehle, Herman
    Sahlgrens Univ Hosp, Sect Haematol & Coagulat Med, Gothenburg, Sweden..
    Ralfkiaer, Elisabeth
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Ehinger, Mats
    Univ Lund Hosp, Dept Pathol, Lund, Sweden..
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Uppsala Hosp, Dept Genet & Pathol, Uppsala, Sweden..
    Delabie, Jan
    Oslo Univ Hosp, Dept Pathol, Oslo, Norway..
    Karjalainen-Lindsberg, Marja-Liisa
    Univ Helsinki, Dept Pathol, Cent Hosp, Helsinki, Finland..
    Workman, Christopher T.
    Tech Univ Denmark, Dept Syst Biol, Lyngby, Denmark.;Univ Copenhagen, Dept Hlth Sci, Copenhagen, Denmark..
    Garde, Christian
    Tech Univ Denmark, Dept Syst Biol, Lyngby, Denmark.;Univ Copenhagen, Dept Hlth Sci, Copenhagen, Denmark..
    Elonen, Erkki
    Univ Helsinki, Dept Haematol, Cent Hosp, Helsinki, Finland..
    Brown, Peter
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Gronbaek, Kirsten
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Geisler, Christian H.
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau2016Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 175, nr 3, s. 410-418Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 114years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 127 and 85years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI-B) and the MIPI-B including mIR-18b expression (MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.

  • 102. Evang, J Arild
    et al.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi. Dept. of laboratory medicine/pathology Umeå university hospital.
    Melum, Espen
    Holm, Ruth
    Ramm-Pettersen, Jon
    Bollerslev, Jens
    Berg, Jens P
    HDAC2 expression and variable number of repeats in exon 1 of the HDAC2 gene in corticotroph adenomas2010Inngår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 73, nr 2, s. 229-235Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Alterations in protein expression of histone deacetylase 2 (HDAC2) have been demonstrated in various neoplasms, and lack of nuclear expression of HDAC2 has previously been shown in some human and canine corticotroph adenomas. This study aimed to examine HDAC2 expression in a Norwegian cohort of corticotroph adenomas, screen for exonic HDAC2 gene variants in the adenomas and correlate the results with clinical data.

    PATIENTS AND DESIGN: Forty-four patients with verified Cushing's disease or Nelson's syndrome, positive ACTH staining and tissue available for immunohistochemistry and/or DNA sequencing were included. Ninety-four controls were chosen from the Norwegian Bone Marrow Registry.

    RESULTS: Histone deacetylase 2 expression examined by immunohistochemistry was strongly reduced in 3/30 adenomas. There were no association between HDAC2 expression and clinical variables. A previously unidentified insertion of three bases in a region coding for a polyserine cluster in exon 1 of the HDAC2 gene was identified in 6/32 adenomas. No other mutations in HDAC2 exons were found. Examination of DNA extracted from peripheral blood confirmed germ-line origin of the exon 1 insertion. The same insertion was also found in 28/94 of the controls (i.e., not significantly different from the patients).

    CONCLUSIONS: Strongly reduced HDAC2 protein expression was confirmed in a small portion of corticotroph tumours. Mutations in HDAC2 exons are unlikely to play an important role in the development of corticotroph adenomas.

  • 103. Evang, Johan Arild
    et al.
    Berg, Jens Petter
    Casar-Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Lekva, Tove
    Kringen, Marianne Kristiansen
    Ramm-Pettersen, Jon
    Bollerslev, Jens
    Reduced levels of E-cadherin correlate with progression of corticotroph pituitary tumours2011Inngår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 75, nr 6, s. 811-818Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES:

    Loss of E-cadherin is an important marker of epithelial tumour progression. The aims of this study were to explore whether E-cadherin expression and localization correlate to corticotroph tumour progression, relate the expression of the E-cadherin gene (CDH1) to immunohistochemical E-cadherin staining pattern, and study whether the E-cadherin levels were correlated to methylation status of the CDH1 promoter region.

    DESIGN:

    Immunohistochemical analyses of E-cadherin protein were performed, as was RT-qPCR of the CDH1 and the POMC genes. Methylation pattern of the promoter region of CDH1 was measured using pyrosequencing of bisulfite-treated DNA.

    PATIENTS:

    Forty-five patients operated at a tertiary referral centre in Oslo, Norway. Adenoma tissue sections and RNA samples from patients with verified Cushing's disease or Nelson's syndrome were collected.

    MEASUREMENTS:

    Expression of E-cadherin mRNA and protein in pituitary corticotroph adenomas and average percentage of methylated cytosines in a cytosine-phosphate-guanosine island of the CDH1 promoter.

    RESULTS:

    Correlations were observed between tumour progression and both nuclear expression of E-cadherin and reduced CDH1 mRNA. The E-cadherin expression was not determined by the methylation pattern of the CDH1 promoter.

    CONCLUSIONS:

    Corticotroph tumour progression was associated with reduced expression of the epithelial marker E-cadherin.

  • 104.
    Falk Delgado, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Fahlström, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Nilsson, Markus
    Lund Univ, Bioimaging Ctr, Lund, Sweden..
    Berntsson, Shala G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Zetterling, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Libard, Sylwia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    van Westen, Danielle
    Lund Univ, Clin Sci Lund, Diagnost Radiol, Lund, Sweden..
    Lätt, Jimmy
    Skane Univ Healthcare, Dept Imaging & Funct, Lund, Sweden..
    Smits, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Diffusion kurtosis imaging of gliomas grades II and III: a study of perilesional tumor infiltration, tumor grades and subtypes at clinical presentation2017Inngår i: Radiology and Oncology, ISSN 1318-2099, E-ISSN 1581-3207, Vol. 51, nr 2, s. 121-129Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Diffusion kurtosis imaging (DKI) allows for assessment of diffusion influenced by microcellular structures. We analyzed DKI in suspected low-grade gliomas prior to histopathological diagnosis. The aim was to investigate if diffusion parameters in the perilesional normal-appearing white matter (NAWM) differed from contralesional white matter, and to investigate differences between glioma malignancy grades II and III and glioma subtypes (astrocytomas and oligodendrogliomas).

    Patients and methods. Forty-eight patients with suspected low-grade glioma were prospectively recruited to this institutional review board-approved study and investigated with preoperative DKI at 3T after written informed consent. Patients with histologically proven glioma grades II or III were further analyzed (n=35). Regions of interest (ROIs) were delineated on T2FLAIR images and co-registered to diffusion MRI parameter maps. Mean DKI data were compared between perilesional and contralesional NAWM (student's t-test for dependent samples, Wilcoxon matched pairs test). Histogram DKI data were compared between glioma types and glioma grades (multiple comparisons of mean ranks for all groups). The discriminating potential for DKI in assessing glioma type and grade was assessed with receiver operating characteristics (ROC) curves.

    Results. There were significant differences in all mean DKI variables between perilesional and contralesional NAWM (p=< 0.000), except for axial kurtosis (p=0.099). Forty-four histogram variables differed significantly between glioma grades II (n=23) and III (n=12) (p=0.003-0.048) and 10 variables differed significantly between ACs (n=18) and ODs (n=17) (p=0.011-0.050). ROC curves of the best discriminating variables had an area under the curve (AUC) of 0.657-0.815.

    Conclusions. Mean DKI variables in perilesional NAWM differ significantly from contralesional NAWM, suggesting altered microstructure by tumor infiltration not depicted on morphological MRI. Histogram analysis of DKI data identifies differences between glioma grades and subtypes.

  • 105.
    Fall, Tove
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hedman, Anna
    Karolinska Institutet.
    Pershagen, Göran
    Karolinska Institutet.
    Andolf, Ellika
    Karolinska Institutet.
    Almqvist, Catarina
    Karolinska Institutet.
    Helmersson-Karlqvist, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Reference Intervals for Fecal Calprotectin in Pregnant Women Using a Particle Enhanced Turbidimetric Assay2019Inngår i: Clinical Laboratory, ISSN 1433-6510, Vol. 65, nr 7, s. 1293-1297Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Fecal calprotectin is widely used as a marker for inflammatory bowel diseases (IBD). IBD often affects women during their reproductive years, but there are no established reference intervals during pregnancy. The aim of the present study was to define reference values during pregnancy and in the postpartum period to allow comparisons between patient results and reference values.

    METHODS: Fecal samples were collected from 84 healthy females during pregnancy week 26 to 28 and a second sample was collected six months after delivery. The samples were weighed, extracted, and centrifugated to remove debris. The extracted samples were then analyzed on a chemistry analyzer using a particle enhanced turbidimetric immunoassay reagent.

    RESULTS: The calculated reference interval during pregnancy was < 127 μg/g (90% confidence interval, 90 - 164 μg/g) and the corresponding reference interval during the postpartum period was < 143 μg/g (60 - 226 μg/g). There were no significant statistical differences between F-calprotectin values analyzed at the two sampling times.

    CONCLUSIONS: The reference values are slightly higher than the cutoff values of 50 - 100 μg/g often used as General cutoff for fecal calprotectin.

  • 106. Fend, Falko
    et al.
    Cabecadas, José
    Gaulard, Philippe
    Jaffe, Elaine S
    Kluin, Philip
    Kuzu, Isinsu
    Peterson, Loann
    Wotherspoon, Andrew
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Early lesions in lymphoid neoplasia: Conclusions based on the Workshop of the XV. Meeting of the European Association of Hematopathology and the Society of Hematopathology, in Uppsala, Sweden2012Inngår i: Journal of hematopathology, ISSN 1865-5785, Vol. 5, nr 3, s. 169-199Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The increasing use of immunophenotypic and molecular techniques on lymphoid tissue samples without obvious involvement by malignant lymphoma has resulted in the increased detection of "early" lymphoid proliferations, which show some, but not all the criteria necessary for a diagnosis of malignant lymphoma. In most instances, these are incidental findings in asymptomatic individuals, and their biological behaviour is uncertain. In order to better characterize these premalignant conditions and to establish diagnostic criteria, a joint workshop of the European Association for Haematopathology and the Society of Hematopathology was held in Uppsala, Sweden, in September 2010. The panel reviewed and discussed more than 130 submitted cases and reached consensus diagnoses. Cases representing the nodal equivalent of monoclonal B-cell lymphocytosis (MBL) were discussed, as well as the "in situ" counterparts of follicular lymphoma (FL) and mantle cell lymphoma (MCL), topics that also stimulated discussions concerning the best terminology for these lesions. The workshop also addressed the borderland between reactive hyperplasia, and clonal proliferations such as pediatric marginal zone lymphoma and pediatric FL, which may have very limited capacity for progression. Virus-driven lymphoproliferations in the grey zone between reactive lesions and manifest malignant lymphoma were covered. Finally, early manifestations of T-cell lymphoma, both nodal and extranodal, and their mimics were addressed. This workshop report summarizes the most important conclusions concerning diagnostic features, as well as proposals for terminology and classification of early lymphoproliferations and tries to give some practical guidelines for diagnosis and reporting.

  • 107. Feodoroff, Benjamin
    et al.
    Lauhio, Anneli
    Ellström, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Rautelin, Hilpi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    A Nationwide Study of Campylobacter jejuni and Campylobacter coli Bacteremia in Finland over a 10-Year Period, 1998-2007, with Special Reference to Clinical Characteristics and Antimicrobial Susceptibility2011Inngår i: Clinical Infectious Diseases, ISSN 1058-4838, E-ISSN 1537-6591, Vol. 53, nr 8, s. e99-e106Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Campylobacter bacteremia is an uncommon condition, usually diagnosed in elderly and immunocompromised patients.

    Methods: Blood culture isolates and clinical information were collected for patients with diagnoses of Campylobacter jejuni or Campylobacter coli bacteremia in Finland from 1998 through 2007. Bacterial species were identified by means of polymerase chain reaction analysis, and minimal inhibitory concentrations for ciprofloxacin, clindamycin, doxycycline, erythromycin, gentamicin, meropenem, and metronidazole were determined with an agar dilution method. Medical records and mortality data within 1 year after the bacteremic episode were reviewed.

    Results: The study included 76 patients (median age, 46 years), for whom bacterial isolates (C. jejuni in 73, C. coli in 3) and clinical information were available. Most patients (70%) had no significant underlying diseases. The majority (82%) of the isolates were susceptible for all antimicrobial agents tested. However, antimicrobial therapy seemed to have only a limited effect, because no differences could be detected between patients with appropriate empirical antimicrobial treatment and those with delayed appropriate, inappropriate, or no antimicrobial therapy, either in the duration of hospitalization (median, 4 days for both groups) or in attributable mortality. The outcome of the infection was severe in 4 patients infected with C. jejuni; 2 died within 30 days, spondylodiscitis developed in 1, and Guillain-Barré syndrome developed in 1.

    Conclusions: C. jejuni and C. coli bacteremia occurred mainly in moderately young individuals without severe underlying diseases. The bacterial isolates were predominantly susceptible to antimicrobial agents, and the outcome of the disease was typically good, regardless of appropriate or inappropriate antimicrobial treatment given in the hospital.

  • 108.
    Feresiadou, Amalia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Casar Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Oldfors, Carola Hedberg
    Univ Gothenburg, Inst Biomed, Dept Pathol & Genet, Gothenburg, Sweden..
    Stålberg, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Oldfors, Anders
    Univ Gothenburg, Inst Biomed, Dept Pathol & Genet, Gothenburg, Sweden..
    Tubular aggregates in congenital myasthenic syndrome2018Inngår i: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 28, nr 2, s. 174-175Artikkel i tidsskrift (Annet vitenskapelig)
  • 109.
    Ferrandis, Maria-José
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Rydén, Ingvar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Lindahl, Tomas L
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Ruling out cardiac failure: Cost-benefit analysis of a sequential testing strategy with NT-proBNP before echocardiography2013Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 118, nr 2, s. 75-79Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives

    To estimate the possible economic benefit of a sequential testing strategy with NT-proBNP to reduce the number of echocardiographies.

    Methods

    Retrospective study in a third-party payer perspective. The costs were calculated from three Swedish counties: Blekinge, Östergötland, and Uppland. Two cut-off levels of NT-proBNP were used: 400 and 300 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 estimated costs for NT-proBNP tests and echocardiographies per county were reduced by 33%-36% with the 400 pg/mL cut-off and by 28%-29% with the 300 pg/mL cut-off. This corresponded to a yearly cost reduction of approximately €2-5 million per million inhabitants in these counties.

    Conclusion

    The use of NT-proBNP as a screening test could substantially reduce the number of echocardiographies in the diagnostic work-up of patients with suspected cardiac failure, as well as the associated costs.

  • 110. Fougner, Stine L
    et al.
    Casar Borota, Olivera
    Oslo University.
    Berg, Jens Petter
    Hald, John K
    Ramm-Pettersen, Jon
    Bollerslev, Jens
    The clinical response to somatostatin analogues in acromegaly correlates to the somatostatin receptor subtype 2a protein expression of the adenoma.2008Inngår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 68, nr 3, s. 458-65Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: Reduced expression of the somatostatin receptor subtype 2 (SSTR2) has been suggested as an explanation for the poor response to octreotide in acromegaly, but studies correlating levels of SSTR2 mRNA to octreotide efficacy have been contradictory. Some studies have found better responses to somatostatin analogues in G-protein alpha subunit (Gsalpha) mutation (gsp oncogene)-positive adenomas. The aim of this study was to determine adenoma SSTR2a protein expression and gsp status in a large group of patients with acromegaly, and relate this to the clinical effect of octreotide.

    PATIENTS: Seventy-one patients were included. All underwent transsphenoidal surgery, 23 patients after preoperative octreotide treatment.

    MEASUREMENTS: The adenoma SSTR2a expression was examined by immunohistochemistry and Western blot analysis, and gsp status determined. An acute octreotide test was performed, and the change in IGF-1 level after 6 months preoperative octreotide treatment was recorded.

    RESULTS: The acute octreotide response in non-pretreated patients and the preoperative long-term octreotide response were significantly better in patients with adenomas containing a large proportion of cells that stained positively for SSTR2a by immunohistochemistry. However, the SSTR2a protein level assessed by Western blot did not correlate with the octreotide response. The preoperatively treated group had lower SSTR2a protein levels and fewer adenomas with a large percentage of positively stained cells. The gsp oncogene was detected in 43% of the adenomas but did not correlate to the octreotide response.

    CONCLUSION: The clinical effect of octreotide correlates with the proportion of cells positive for SSTR2a in immunohistochemical staining, rather than the adenoma SSTR2a protein level. There may be a down-regulation of SSTR2a during octreotide treatment.

  • 111. Fougner, Stine Lyngvi
    et al.
    Casar-Borota, Olivera
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Heck, Ansgar
    Berg, Jens Petter
    Bollerslev, Jens
    Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly2012Inngår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 76, nr 1, s. 96-102Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT:

    Somatotroph adenomas have been classified into densely granulated (DG) and sparsely granulated (SG) tumours with a transitional, intermediate group. Gsp oncogenes are activating mutations in the Gsα subunit gene, found in approximately 40% of somatotroph adenomas.

    OBJECTIVES:

    To explore granulation pattern and presence of gsp oncogene in acromegaly with correlations to clinical and biochemical variables and to the effect of treatment with somatostatin analogues (SA), as well as to describe granulation pattern in adenomas with and without SA pretreatment.

    DESIGN/SETTINGS/PATIENTS:

    Seventy-eight patients with active acromegaly were included. Long-term SA efficacy was evaluated in 29 patients treated preoperatively and in ten treated postoperatively. Granulation pattern was examined, as were immunohistochemical analyses for E-cadherin and SSTR2a. Protein levels of E-cadherin and SSTR2a were measured (Western blot). Gsp mutation analysis was available for 74 adenomas.

    RESULTS:

    DG adenomas and the transitional group had higher serum levels of IGF-1 per tumour volume than SG (P = 0·009; P = 0·005). Acute and long-term SA responses were lower in SG (P = 0·001; P = 0·043). No correlation between gsp mutation and granulation was found, and no difference in granulation pattern according to preoperative SA treatment was demonstrated. A significant correlation between granulation and E-cadherin was found, where SG had lowest immunohistochemical expression, substantiated by protein levels, and a highly significant gradient was observed from DG, through the transitional group, to SG.

    CONCLUSIONS:

    Densely granulated adenomas were highly responsive to somatostatin analogues in contrast to SG adenomas. The transitional group behaved clinically more like DG adenomas. However, based on E-cadherin, a marker of dedifferentiation, the transitional group seemed to be a true intermediate.

  • 112. Fougner, Stine Lyngvi
    et al.
    Lekva, Tove
    Casar Borota, Olivera
    Olivera Casar-Borotas publikationer.
    Hald, John K
    Bollerslev, Jens
    Berg, Jens Petter
    The expression of E-cadherin in somatotroph pituitary adenomas is related to tumor size, invasiveness, and somatostatin analog response2010Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, nr 5, s. 2334-2342Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CONTEXT: Appropriate cell-to-cell adhesion is fundamental for the epithelial phenotype of pituitary cells. Loss of the adhesion protein E-cadherin has been associated with invasiveness, metastasis, and poor prognosis in cancers of epithelial origin. In somatotroph adenomas, a variable and reduced expression of E-cadherin has been demonstrated. In addition, nuclear translocation of E-cadherin was found to correlate with pituitary tumor invasion.

    OBJECTIVE: The objective was to examine the protein expression of E-cadherin in somatotroph pituitary adenomas in relation to adenoma size, invasiveness, and somatostatin analog (SMS) efficacy.

    PATIENTS AND METHODS: Eighty-three patients were included, and 29 were treated preoperatively with SMS. Adenoma E-cadherin protein expression was analyzed by Western blot (61 patients) and immunohistochemistry (IHC) (80 patients) with antibodies directed against both extracellular and intracellular domains (IHC). The acute (direct surgery group) and long-term (preoperatively treated group) SMS responses were evaluated. Baseline tumor volume and invasiveness were measured on magnetic resonance imaging scans.

    RESULTS: Membranous E-cadherin was lost in several adenomas. Nine of these were nuclear E-cadherin positive. The E-cadherin protein expression correlated negatively to tumor size and positively to acute SMS response. Low E-cadherin levels (preoperatively treated group only) and loss of membranous E-cadherin correlated to tumor invasiveness. The E-cadherin level correlated positively to tumor reduction after SMS treatment, and adenomas with nuclear E-cadherin staining had lower IGF-I reduction and tumor shrinkage. Preoperatively treated adenomas had reduced E-cadherin protein levels, but the IHC expression was unaltered.

    CONCLUSION: Reduced E-cadherin expression may correlate to a dedifferentiated phenotype in the somatotroph pituitary adenomas.

  • 113. Fraenkel, Carl-Johan
    et al.
    Melhus, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin, Klinisk bakteriologi.
    Enterococcus faecium coisolated with Lactobacillus species can mimic vancomycin-resistant enterococci2011Inngår i: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 1, s. 7335-Artikkel i tidsskrift (Fagfellevurdert)
  • 114.
    Frisk, Sofia
    et al.
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Dept Clin Genet, Stockholm, Sweden.
    Taylan, Fulya
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden.
    Blaszczyk, Izabela
    Umea Univ Hosp, Dept Surg & Perioperat Sci, Hand & Plast Surg, Umea, Sweden.
    Nennesmo, Inger
    Karolinska Univ Hosp, Dept Pathol, Stockholm, Sweden.
    Annerén, Göran
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Herm, Bettina
    Ostersunds Hosp, Child & Adolescent Habilitat Ctr, Ostersund, Sweden.
    Stattin, Evalena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Zachariadis, Vasilios
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden.
    Lindstrand, Anna
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Dept Clin Genet, Stockholm, Sweden.
    Tesi, Bianca
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Dept Clin Genet, Stockholm, Sweden.
    Laurell, Tobias
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden.
    Nordgren, Ann
    Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden;Karolinska Univ Hosp, Karolinska Univ Lab, Dept Clin Genet, Stockholm, Sweden.
    Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth2019Inngår i: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 96, nr 2, s. 118-125Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles.

  • 115.
    Galant, Natalie J.
    et al.
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Bugyei-Twum, Antoinette
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Rakhit, Rishi
    Stanford Univ, Dept Chem & Syst Biol, Stanford, CA 94305 USA..
    Walsh, Patrick
    Univ Toronto, Dept Biochem, Hosp Sick Children, Mol Struct & Funct Program, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada..
    Sharpe, Simon
    Univ Toronto, Dept Biochem, Hosp Sick Children, Mol Struct & Funct Program, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada..
    Arslan, Pharhad Eli
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Higaki, Jeffrey N.
    Prothena Biosci Inc, Dept Biochem, San Francisco, CA 94080 USA.;Prothena Biosci Inc, Dept Histopathol, San Francisco, CA 94080 USA..
    Torres, Ronald
    Prothena Biosci Inc, Dept Biochem, San Francisco, CA 94080 USA.;Prothena Biosci Inc, Dept Histopathol, San Francisco, CA 94080 USA..
    Tapia, Jose
    Prothena Biosci Inc, Dept Biochem, San Francisco, CA 94080 USA.;Prothena Biosci Inc, Dept Histopathol, San Francisco, CA 94080 USA..
    Chakrabartty, Avijit
    Univ Toronto, Dept Med Biophys, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada.;Univ Toronto, Dept Biochem, Univ Hlth Network, Princess Margaret Canc Ctr, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 25080Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Wild-type and mutant transthyretin (TTR) can misfold and deposit in the heart, peripheral nerves, and other sites causing amyloid disease. Pharmacological chaperones, Tafamidis (R) and diflunisal, inhibit TTR misfolding by stabilizing native tetrameric TTR; however, their minimal effective concentration is in the micromolar range. By immune-targeting sparsely populated TTR misfolding intermediates (i.e. monomers), we achieved fibril inhibition at substoichiometric concentrations. We developed an antibody (misTTR) that targets TTR residues 89-97, an epitope buried in the tetramer but exposed in the monomer. Nanomolar misTTR inhibits fibrillogenesis of misfolded TTR under micromolar concentrations. Pan-specific TTR antibodies do not possess such fibril inhibiting properties. We show that selective targeting of misfolding intermediates is an alternative to native state stabilization and requires substoichiometric concentrations. MisTTR or its derivative may have both diagnostic and therapeutic potential.

  • 116.
    Galant, Natalie J.
    et al.
    Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Dept Med Biophys, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Higaki, Jeffrey N.
    Prothena Biosci Inc, San Francisco, CA 94080 USA..
    Chakrabartty, Avijit
    Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Dept Med Biophys, TMDT 4-305,101 Coll St, Toronto, ON M5G 1L7, Canada..
    Transthyretin amyloidosis: an under-recognized neuropathy and cardiomyopathy2017Inngår i: Clinical Science, ISSN 0143-5221, E-ISSN 1470-8736, Vol. 131, nr 5, s. 395-409Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Transthyretin (TTR) amyloidosis (ATTR amyloidosis) is an underdiagnosed and important type of cardiomyopathy and/or polyneuropathy that requires increased awareness within the medical community. Raising awareness among clinicians about this type of neuropathy and lethal form of heart disease is critical for improving earlier diagnosis and the identification of patients for treatment. The following review summarizes current criteria used to diagnose both hereditary and wild-type ATTR (ATTRwt) amyloidosis, tools available to clinicians to improve diagnostic accuracy, available and newly developing therapeutics, as well as a brief biochemical and biophysical background of TTR amyloidogenesis.

  • 117. Gantelius, Stefan
    et al.
    Hedström, Yvette
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Klinisk neurofysiologi.
    Pontén, Eva
    Higher Expression of Myosin Heavy Chain IIx in Wrist Flexors in Cerebral Palsy2012Inngår i: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, Vol. 470, nr 5, s. 1272-1277Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Children with cerebral palsy (CP) use their paretic arm less than normal but have a relative overactivity of wrist flexors, causing an impairing flexed position of the wrist. Voluntary use of a muscle downregulates myosin heavy chain (MyHC) IIx, but it is unclear whether the relative overactivity of wrist flexors and extensors in children with CP affects MyHC expression compared to normal subjects.

    QUESTIONS/PURPOSES:

    We therefore asked whether MyHC expression composition differs in wrist flexors compared to extensors in children with CP and in controls and whether it is related to clinical findings.

    METHODS:

    We took muscle biopsies from wrist flexors and extensors during hand surgery in children with CP (n = 9) and during open reduction of forearm fractures in control children (n = 5). The expression of the MyHC I, IIa, and IIx isoforms were determined on silver-stained 6% SDS-PAGE.

    RESULTS:

    CP flexors showed a higher proportion of MyHC IIx (40%) than control flexors (16%) and CP extensors (20%). MyHC IIa isoform proportion was lower in CP flexors (27%) than in control flexors (46%) and in CP extensors (45%). MyHC I expression was lower in CP (36%) than in controls (46%) for wrist extensors only.

    CONCLUSIONS:

    Both the brain injury in CP and the different demands on flexors and extensors affect the expression of MyHCs. The higher amount of MyHC IIx in CP could be caused by a decreased voluntary use of the hemiplegic arm.

    CLINICAL RELEVANCE:

    More information on the structural difference between flexors and extensors in normal and spastic muscle could improve the understanding of strain of wrist extensors and possibly the development of flexion contractures in CP.

  • 118.
    Garwicz, Daniel
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Farmakogenetisk analys kan avslöja risk för statinbiverkningar: [Pharmacogenetic analysis can predict adverse effects of statins]2013Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 110, nr 19-20, s. 951-952Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [sv]

    Mer än var tionde vuxen i Sverige behandlas med statiner. 

    Muskelsvaghet, -trötthet och -värk är kända biverkningar. I sällsynta fall ses rabdomyolys, som kan leda till akut njursvikt och någon gång dödsfall. 

    Statiners kemiska egenskaper och serumkoncentration påverkar risken för allvarliga biverkningar. Serumkoncentrationen beror på dos och på patientens förmåga att omsätta läkemedlet.

    Akademiska sjukhuset har som första svenska sjukhus infört analys av en genetisk variant (SLCO1B1*5) som kan förutsäga ökad risk för sällsynta, allvarliga muskelbiverkningar vid statinbehandling.

  • 119. Geisler, Christian H.
    et al.
    Kolstad, Arne
    Laurell, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Räty, Riikka
    Jerkeman, Mats
    Eriksson, Mikael
    Nordström, Marie
    Kimby, Eva
    Boesen, Anne Marie
    Nilsson-Ehle, Herman
    Kuittinen, Outi
    Lauritzsen, Grete F.
    Ralfkiaer, Elisabeth
    Ehinger, Mats
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Delabie, Jan
    Karjalainen-Lindsberg, Marja-Liisa
    Brown, Peter
    Elonen, Erkki
    The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT)2010Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, nr 8, s. 1530-1533Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mantle cell lymphoma (MCL) has a heterogeneous clinical course. The recently proposed Mantle Cell Lymphoma International Prognostic Index (MIPI) predicted the survival of MCL better than the International Prognostic Index in MCL patients treated with conventional chemotherapy, but its validity in MCL treated with more intensive immunochemotherapy has been questioned. Applied here to 158 patients of the Nordic MCL2 trial of first-line intensive immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation, the MIPI and the simplified MIPI (s-MIPI) predicted survival significantly better (P < .001) than the International Prognostic Index (P > .004). Both the MIPI and the s-MIPI mainly identified 2 risk groups, low and intermediate versus high risk, with the more easily applied s-MIPI being just as powerful as the MIPI. The MIPI(B) (biological), incorporating Ki-67 expression, identified almost half of the patients as high risk. We suggest that also a simplified MIPI(B) is feasible.

  • 120.
    Gholiha, Alex R.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hedström, Gustaf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Smedby, Karin E
    Karolinska Inst, Dept Med Solna, Div Clin Epidemiol, Stockholm, Sweden.
    Hjalgrim, Henrik
    Karolinska Inst, Dept Med Solna, Div Clin Epidemiol, Stockholm, Sweden.
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    High tumour plasma cell infiltration reflects an important microenvironmental component in classic Hodgkin lymphoma linked to presence of B-symptoms2019Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 184, nr 2, s. 192-201Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Plasma cells are important prognostic actors in different malignancies. The tumour microenvironmental composition in classic Hodgkin lymphoma (cHL) is a major prognostic key element; however, clinicopathological studies regarding plasma cells in cHL are lacking. The aim of this study was to investigate CD138+ (also termed SDC1+) plasma cell and IgG4 producing (IgG4+) plasma cells infiltration in the microenvironment of cHL. Immunohistochemistry with anti-CD138 and IgG4 antibodies was performed on diagnostic tumour biopsies from 124 patients with cHL, on tissue micro array (TMA). In 120 cases, CD138+ plasma cell-infiltration was associated with the presence of B-symptoms (P = 0·028) and advanced stage, IIB-IVB (P = 0·009). In multivariate analysis, CD138+ plasma cells correlated with eosinophil infiltration (P = 0·013). The subgroup of IgG4+ plasma cells was analysed in 122 cases and only correlated to CD138+ plasma cells (P = 0·004). Patients with high proportion of tumour infiltrating CD138+ plasma cells (defined as ≥10%), had a more inferior event-free survival (P = 0·007) and overall survival (P = 0·004) than patients with a low proportion of infiltrating CD138+ plasma cells (<10%), although significance was not maintained in multivariate analysis. In summary, a high proportion of tumour-associated plasma cells in cHL reflect an important component in the microenvironment of cHL.

  • 121.
    Glimelius, Bengt
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Melin, Beatrice
    Umeå Univ, Dept Radiat Sci, Umeå.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Beskow, Anna H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Bill-Axelson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Birgisson, Helgi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Gastrointestinalkirurgi.
    Björ, Ove
    Umeå Univ, Dept Radiat Sci, Umeå.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hansson, Tony
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Henriksson, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Hultdin, Magnus
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Häggman, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Jonsson, Håkan
    Umeå Univ, Dept Radiat Sci, Umeå.
    Larsson, Chatarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ljuslinder, Ingrid
    Umeå Univ, Dept Radiat Sci, Umeå.
    Mindus, Stephanie
    Akad Sjukhuset, Lung & Allergy Clin, Uppsala.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Riklund, Katrine
    Umeå Univ, Dept Radiat Sci, Umeå.
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sandin, Fredrik
    Uppsala Univ Hosp, RCC Uppsala Örebro, Uppsala.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Solna.
    Stenling, Roger
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Stålberg, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Sundström, Christer Sundström
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Thellenberg Karlsson, Camilla
    Umeå Univ, Dept Radiat Sci, Umeå.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Bergh, Anders
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Palmqvist, Richard
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.2018Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, nr 2, s. 187-194Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

    Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

    Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

    Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

  • 122. Greiser, Anne
    et al.
    Winter, Theresa
    Mahfoud, Hala
    Kallner, Anders
    Ittermann, Till
    Masuch, Annette
    Lubenow, Norbert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Kohlmann, Thomas
    Greinacher, Andreas
    Nauck, Matthias
    Petersmann, Astrid
    The 99th percentile and imprecision of point-of-care cardiac troponin I in comparison to central laboratory tests in a large reference population2017Inngår i: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 50, nr 18, s. 1198-1202Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Determination of cardiac troponin (cTn) is central in the emergency department (ED) for the diagnosis of myocardial infarction. In view of adverse effects of long waiting time on patient outcome, implementation of point-of-care-testing (POCT) is suggested if the turn-around-time is longer than 60min. The present study aimed to determine the 99th percentile and imprecision of two POCT in a healthy population measuring cTnI and cTnT and compare these analytical characteristics against three central laboratory test (CLT) for cTnI.

    DESIGN & METHODS: CTnI and cTnT were determined in parallel by means of the AQT90 FLEX analyzer in about 2250 plasma samples from individuals with known health status. Results were compared to previously determined performance data of three CLT.

    RESULTS: The 99th percentile of cTnI in the POCT was determined at 19ng/L, the lowest concentration with an imprecision of 10% was reached at 22ng/L while an imprecision of 20% was reached at 13ng/L. Age, sex, or physical activity did not affect the 99th percentile of cTnI. Compared to CLT the AQT90 cTnI POCT the analytical performance was equivalent. The cTnT POCT could not be assessed due a considerable number of high values and an inadequate imprecision profile.

    CONCLUSION: While the cTnI POCT showed analytical performance comparable to CLT, the results of the cTnT assay on the same device did not suffice to determine a reliable 99th percentile. The present evaluation supports the usage of the cTnI POCT, but application of the cTnT POCT needs further evaluation.

  • 123.
    Gremel, Gabriela
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Djureinovic, Dijana
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Niinivirta, Marjut
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Laird, Alexander
    Univ Edinburgh, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Edinburgh Urol Canc Grp, Edinburgh, Midlothian, Scotland..
    Ljungqvist, Oscar
    Atlas Antibodies AB, Stockholm, Sweden..
    Johannesson, Henrik
    Atlas Antibodies AB, Stockholm, Sweden..
    Bergman, Julia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Navani, Sanjay
    Lab Surgpath, Bombay, Maharashtra, India..
    Khan, Naila
    Lab Surgpath, Bombay, Maharashtra, India..
    Patil, Tushar
    Lab Surgpath, Bombay, Maharashtra, India..
    Sivertsson, Asa
    Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Uhlen, Mathias
    Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Harrison, David J.
    Univ St Andrews, Sch Med, St Andrews, Fife, Scotland..
    Ullenhag, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Stewart, Grant D.
    Univ Edinburgh, Inst Genet & Mol Med, Edinburgh Urol Canc Grp, Edinburgh, Midlothian, Scotland.;Univ Cambridge, Addenbrookes Hosp, Acad Urol Grp, Box 43,Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0QQ, England..
    Pontén, Fredrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    A systematic search strategy identifies cubilin as independent prognostic marker for renal cell carcinoma2017Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, artikkel-id 9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There is an unmet clinical need for better prognostic and diagnostic tools for renal cell carcinoma (RCC). Methods: Human Protein Atlas data resources, including the transcriptomes and proteomes of normal and malignant human tissues, were searched for RCC-specific proteins and cubilin (CUBN) identified as a candidate. Patient tissue representing various cancer types was constructed into a tissue microarray (n = 940) and immunohistochemistry used to investigate the specificity of CUBN expression in RCC as compared to other cancers. Two independent RCC cohorts (n = 181; n = 114) were analyzed to further establish the sensitivity of CUBN as RCC-specific marker and to explore if the fraction of RCCs lacking CUBN expression could predict differences in patient survival. Results: CUBN was identified as highly RCC-specific protein with 58% of all primary RCCs staining positive for CUBN using immunohistochemistry. In venous tumor thrombi and metastatic lesions, the frequency of CUBN expression was increasingly lost. Clear cell RCC (ccRCC) patients with CUBN positive tumors had a significantly better prognosis compared to patients with CUBN negative tumors, independent of T-stage, Fuhrman grade and nodal status (HR 0.382, CI 0.203-0.719, P = 0.003). Conclusions: CUBN expression is highly specific to RCC and loss of the protein is significantly and independently associated with poor prognosis. CUBN expression in ccRCC provides a promising positive prognostic indicator for patients with ccRCC. The high specificity of CUBN expression in RCC also suggests a role as a new diagnostic marker in clinical cancer differential diagnostics to confirm or rule out RCC.

  • 124. Grinberg, Marianna
    et al.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnström, Hans R R
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Edlund, Karolina
    Hengstler, Jan G
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Branden, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Ståhle, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Jirström, Karin
    Tracy, Derek K
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Rahnenführer, Jörg
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Reaching the limits of prognostication in non-small cell lung cancer: an optimized biomarker panel fails to outperform clinical parameters.2017Inngår i: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 30, nr 7, s. 964-977Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Numerous protein biomarkers have been analyzed to improve prognostication in non-small cell lung cancer, but have not yet demonstrated sufficient value to be introduced into clinical practice. Here, we aimed to develop and validate a prognostic model for surgically resected non-small cell lung cancer. A biomarker panel was selected based on (1) prognostic association in published literature, (2) prognostic association in gene expression data sets, (3) availability of reliable antibodies, and (4) representation of diverse biological processes. The five selected proteins (MKI67, EZH2, SLC2A1, CADM1, and NKX2-1 alias TTF1) were analyzed by immunohistochemistry on tissue microarrays including tissue from 326 non-small cell lung cancer patients. One score was obtained for each tumor and each protein. The scores were combined, with or without the inclusion of clinical parameters, and the best prognostic model was defined according to the corresponding concordance index (C-index). The best-performing model was subsequently validated in an independent cohort consisting of tissue from 345 non-small cell lung cancer patients. The model based only on protein expression did not perform better compared to clinicopathological parameters, whereas combining protein expression with clinicopathological data resulted in a slightly better prognostic performance (C-index: all non-small cell lung cancer 0.63 vs 0.64; adenocarcinoma: 0.66 vs 0.70, squamous cell carcinoma: 0.57 vs 0.56). However, this modest effect did not translate into a significantly improved accuracy of survival prediction. The combination of a prognostic biomarker panel with clinicopathological parameters did not improve survival prediction in non-small cell lung cancer, questioning the potential of immunohistochemistry-based assessment of protein biomarkers for prognostication in clinical practice.Modern Pathology advance online publication, 10 March 2017; doi:10.1038/modpathol.2017.14.

  • 125. Gullsby, Karolina
    et al.
    Hallander, Hans O
    Bondeson, Kåre
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin.
    Performance of Bordetella pertussis IS481 real-time PCR in a vaccine trial setting2007Inngår i: Apmis, Vol. 115, nr 12, s. 1370-1375Artikkel i tidsskrift (Fagfellevurdert)
  • 126. Gullsby, Karolina
    et al.
    Storm, Martin
    Bondeson, Kåre
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk mikrobiologi och infektionsmedicin.
    Simultaneous detection of Chlamydophila pneumoniae and Mycoplasma pneumoniae by use of molecular beacons in a duplex real-time PCR2008Inngår i: Journal of clinical microbiology, Vol. 46, nr 2, s. 727-731Artikkel i tidsskrift (Fagfellevurdert)
  • 127.
    Gulyas, Miklos
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindgren, Andrea
    Ek, Lars
    Lamberg, Kristina
    Behndig, Annelie
    Holmberg, Erik
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Bergman, Bengt
    COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.Inngår i: Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyse COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition.

    Methods: In the multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells.

    Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95%CI 0.81-1.27 and HR 1.12; 95%CI 0.78-1.61, respectively). Similarly, in patients with high COX-2 expression in tumor cells (n=71) or stromal cells (n=55), survival did not differ significantly between patients who received celecoxib or placebo (HR 1.07; 95%CI 0.74-1.54 and HR 0.80; 95%CI 0.56-1.15). No significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p=0.48 and 0.25, respectively).

    Conclusion: In this subgroup analysis of patients with advanced NSCLC, we could not detect any significant interaction between COX-2 expression in tumor or stromal cells and outcome of celecoxib treatment in addition to standard chemotherapy.

  • 128.
    Gulyas, Miklos
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindgren, Andrea
    Linköping Univ, Dept Clin & Expt Med, Allergy Ctr, Fac Hlth Sci.
    Ek, Lars
    Skåne Univ Hosp, Pulm Med, Lund.
    Lamberg Lundström, Kristina
    Akad Hosp, Pulm Med, Uppsala.
    Behndig, Annelie
    Norrland Univ Hosp, Pulm Med, Umeå.
    Holmberg, Erik
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Oncol, Gothenburg.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Bergman, Bengt
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Resp Med.
    COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.2018Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, nr 2, s. 244-250Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: Inhibition of cyclooxygenase-2 (COX-2) is proposed as a treatment option in several cancer types. However, in non-small cell lung cancer (NSCLC), phase III trials have failed to demonstrate a benefit of adding COX-2 inhibitors to standard chemotherapy. The aim of this study was to analyze COX-2 expression in tumor and stromal cells as predictive biomarker for COX-2 inhibition.

    Methods: In a multicenter phase III trial, 316 patients with advanced NSCLC were randomized to receive celecoxib (400 mg b.i.d.) or placebo up to one year in addition to a two-drug platinum-based chemotherapy combination. In a subset of 122 patients, archived tumor tissue was available for immunohistochemical analysis of COX-2 expression in tumor and stromal cells. For each compartment, COX-2 expression was graded as high or low, based on a product score of extension and intensity of positively stained cells.

    Results: An updated analysis of all 316 patients included in the original trial, and of the 122 patients with available tumor tissue, showed no survival differences between the celecoxib and placebo arms (HR 1.01; 95% CI 0.81–1.27 and HR 1.12; 95% CI 0.78–1.61, respectively). High COX-2 scores in tumor (n = 71) or stromal cells (n = 55) was not associated with a superior survival outcome with celecoxib vs. placebo (HR =0.96, 95% CI 0.60–1.54; and HR =1.51; 95% CI 0.86–2.66), and no significant interaction effect between COX-2 score in tumor or stromal cells and celecoxib effect on survival was detected (p = .48 and .25, respectively).

    Conclusions: In this subgroup analysis of patients with advanced NSCLC treated within the context of a randomized trial, we could not detect any interaction effect of COX-2 expression in tumor or stromal cells and the outcome of celecoxib treatment in addition to standard chemotherapy.

  • 129.
    Hallberg, Pär
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Collin, Sofie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Preventivt arbete kan minska läkemedelsbiverkningar2017Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, artikkel-id ERYWArtikkel i tidsskrift (Annet vitenskapelig)
  • 130.
    Hamberg, Anna-Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Pharmacogenetics-based warfarin dosing in children2014Inngår i: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 15, nr 3, s. 361-374Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Clinical factors, demographic variables and variations in two genes, CYP2C9 and VKORC1, have been shown to contribute to the variability in warfarin dose requirements among adult patients. Less is known about their relative importance for dose variability in children. A few small studies have been reported, but the results have been conflicting, especially regarding the impact of genotypes. In this article, we critically review published pharmacogenetic-based prediction models for warfarin dosing in children, and present results from a head-to-head comparison of predictive performance in a distinct cohort of warfarin-treated children. Finally we discuss what properties a prediction model should have, and what knowledge gaps need to be filled, to improve warfarin therapy in children of all ages.

  • 131.
    Hamberg, Anna-Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Friberg, Lena E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Biss, Tina T
    Kamali, Farhad
    Jonsson, E Niclas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Characterising variability in warfarin dose requirements in children using modelling and simulation2013Inngår i: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 78, nr 1, s. 158-169Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: Although genetic, clinical and demographic factors have been shown to explain approximately half of the inter-individual variability in warfarin dose requirement in adults, less is known about causes of dose variability in children. This study aimed to identify and quantify major genetic, clinical and demographic sources of warfarin dose variability in children using modelling and simulation.

    METHODS: Clinical, demographic and genetic data from 163 children with a median age of 6.3 years (range 0.06-18.9 years), covering over 183 years of warfarin therapy and 6445 INR observations were used to update and optimise a published adult pharmacometric warfarin model for use in children.

    RESULTS: Genotype effects in children were found to be comparable to what has been reported for adults, with CYP2C9 explaining up to a 4-fold difference in dose (CYP2C9 *1/*1 vs. *3/*3) and VKORC1 explaining up to a 2-fold difference in dose (VKORC1 G/G vs. A/A), respectively. The relationship between bodyweight and warfarin dose was non-linear, with a 3-fold difference in dose for a 4-fold difference in bodyweight. In addition, age, baseline and target INR, and time since initiation of therapy, but not CYP4F2 genotype, had a significant impact on typical warfarin dose requirements in children.

    CONCLUSIONS: The updated model provides quantitative estimates of major clinical, demographic and genetic factors impacting warfarin dose variability in children. With this new knowledge more individualised dosing regimens can be developed and prospectively evaluated in the pursuit of improving both efficacy and safety of warfarin therapy in children.

  • 132.
    Hansson, Lars-Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Flodin, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Althaus, Harald
    Blirup-Jensen, Sören
    Grubb, Anders
    The first harmonization step on cystatin C, with the aim to introduce the first ERM-DA471/IFCC cystatin C calibrator and one worldwide company-independent EGFR equation2011Inngår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 49, nr s1, s. s557-s557Artikkel i tidsskrift (Fagfellevurdert)
  • 133. Hansson Petersen, Camilla A
    et al.
    Alikhani, Nyosha
    Behbahani, Homira
    Wiehager, Birgitta
    Pavlov, Pavel F
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Leinonen, Ville
    Ito, Akira
    Winblad, Bengt
    Glaser, Elzbieta
    Ankarcrona, Maria
    The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae.2008Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 35, s. 13145-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The amyloid beta-peptide (Abeta) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by Abeta and accumulation of Abeta has been detected in mitochondria. Because Abeta is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial Abeta uptake. Our results from rat mitochondria show that Abeta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed Abeta association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Abeta to mitochondrial cristae. A similar distribution pattern of Abeta in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for Abeta in mitochondria and demonstrate both in vitro and in vivo that Abeta is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied Abeta can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of Abeta, a peptide considered to be of major significance in Alzheimer's disease.

  • 134.
    Hasni, Muhammad Sharif
    et al.
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Berglund, Mattias
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Yakimchuk, Konstantin
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Guan, Jiyu
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Linderoth, Johan
    Lund Univ, Skane Univ Hosp, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Okret, Sam
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Estrogen receptor beta 1 in diffuse large B-cell lymphoma growth and as a prognostic biomarker2017Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, nr 2, s. 418-427Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diffuse large B-cell lymphoma (DLBCL) shows a higher incidence in males versus females. Epidemiological studies have shown that female gender is a favorable prognostic factor, which may be explained by estrogens. Here we show that when grafting human DLBCL cells to immunocompromised mice, tumor growth in males is faster. When treating mice grafted with either germinal center or activated B-cell like DLBCL cells with the selective estrogen receptor beta (ER beta) agonist diarylpropionitrile, tumor growth was significantly inhibited. Furthermore, nuclear ER beta 1 expression analysis in primary DLBCL's by immunohistochemistry revealed expression in 89% of the cases. Nuclear ERb1 expression was in a univariate and multivariate analysis, an independent prognostic factor for adverse progression-free survival in Rituximab-chemotherapy treated DLBCL (p = 0.02 and p = 0.04, respectively). These results suggest that estrogen signaling through ERb1 is an interesting future therapeutic target for treatment of DLBCL, and that ERb1 expression can be used as a prognostic marker.

  • 135.
    Hellström, Jussi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Romanos Zapata, Romina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Libard, Sylwia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ortiz-Nieto, Francisco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Evaluation of the INTERPRET decision-support system: can it improve the diagnostic value of magnetic resonance spectroscopy of the brain?2019Inngår i: Neuroradiology, ISSN 0028-3940, E-ISSN 1432-1920, Vol. 61, nr 1, s. 43-53Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: We evaluated in a clinical setting the INTERPRET decision-support system (DSS), a software generated to aid in MRS analysis to achieve a specific diagnosis for brain lesions.

    Methods: The material consisted of 100 examinations of focal intracranial lesions with confirmed diagnoses. MRS was obtained at 1.5 T using TE 20–30 ms. Data were processed with the LCModel for conventional analysis. The INTERPRET DSS 3.1. was used to obtain specific diagnoses. MRI and MRS were reviewed by one interpreter. DSS analysis was made by another interpreter, in 80 cases by two interpreters. The diagnoses were compared with the definitive diagnoses. For comparisons between DSS, conventional MRS analysis, and MRI, the diagnoses were categorised: high-grade tumour, low-grade tumour, non-neoplastic lesion.

    Results: Interobserver agreement in choosing the diagnosis from the INTERPRET database was 75%. The diagnosis was correct in 38/100 cases, incorrect in 57 cases. No good match was found in 5/100 cases. The diagnostic category was correct with DSS/conventional MRS/MRI in 67/58/52 cases, indeterminate in 5/8/20 cases, incorrect in 28/34/28 cases. Results with DSS were not significantly better than with conventional MRS analysis. All definitive diagnoses did not exist in the INTERPRET database. In the 61 adult patients with the diagnosis included in the database, DSS/conventional MRS/MRI yielded a correct diagnosis category in 48/32/29 cases (DSS vs conventional MRS: p = 0.002, DSS vs MRI: p = 0.0004).

    Conclusion: Use of the INTERPRET DSS did not improve MRS categorisation of the lesions in the unselected clinical cases. In adult patients with lesions existing in the INTERPRET database, DSS improved the results, which indicates the potential of this software with an extended database.

  • 136.
    Hellström, Jussi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Romanos Zapata, Romina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Libard, Sylwia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ortiz-Nieto, Francisco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    The value of magnetic resonance spectroscopy as a supplement to MRI of the brain in a clinical setting2018Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 11, artikkel-id e0207336Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: There are different opinions of the clinical value of MRS of the brain. In selected materials MRS has demonstrated good results for characterisation of both neoplastic and non-neoplastic lesions. The aim of this study was to evaluate the supplemental value of MR spectroscopy (MRS) in a clinical setting.

    MATERIAL AND METHODS: MRI and MRS were re-evaluated in 208 cases with a clinically indicated MRS (cases with uncertain or insufficient information on MRI) and a confirmed diagnosis. Both single voxel spectroscopy (SVS) and chemical shift imaging (CSI) were performed in 105 cases, only SVS or CSI in 54 and 49 cases, respectively. Diagnoses were grouped into categories: non-neoplastic disease, low-grade tumour, and high-grade tumour. The clinical value of MRS was considered very beneficial if it provided the correct category or location when MRI did not, beneficial if it ruled out suspected diseases or was more specific than MRI, inconsequential if it provided the same level of information, or misleading if it provided less or incorrect information.

    RESULTS: There were 70 non-neoplastic lesions, 43 low-grade tumours, and 95 high-grade tumours. For MRI, the category was correct in 130 cases (62%), indeterminate in 39 cases (19%), and incorrect in 39 cases (19%). Supplemented with MRS, 134 cases (64%) were correct, 23 cases (11%) indeterminate, and 51 (25%) incorrect. Additional information from MRS was beneficial or very beneficial in 31 cases (15%) and misleading in 36 cases (17%).

    CONCLUSION: In most cases MRS did not add to the diagnostic value of MRI. In selected cases, MRS may be a valuable supplement to MRI.

  • 137.
    Helmersson, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Ridefelt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Boija, Elisabet Eriksson
    External Qual Assessment Clin Lab Investigat Equa, Uppsala, Sweden.
    Nordin, Gunnar
    External Qual Assessment Clin Lab Investigat Equa, Uppsala, Sweden.
    Lower creatinine concentration values and lower inter-laboratory variation among Swedish hospital laboratories in 2014 compared to 1996: results from the Equalis external quality assessment program2019Inngår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 57, nr 6, s. 838-844Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background:

    Creatinine measurement for estimation of glomerular filtration rate (GFR) is a frequently used laboratory test. Differences in analytic creatinine methods have caused large inter-laboratory variation. International and national standardization efforts have been made in the last decade.

    Methods:

    This study describes the results of the standardization efforts in Sweden by summarizing data for creatinine concentration in blood plasma in the Equalis quality assessment program during 1996-2014.

    Results:

    Non-compensated Jaffe methods dominated in 1996-2001 (91 of 103 laboratories; 90%) and were then gradually replaced by either compensated Jaffe methods or enzymatic creatinine methods. In 2014 a majority of Swedish hospital laboratories (139 of 159; 87%) used enzymatic methods. The reported mean creatinine value by the Swedish laboratories was about 10 mu mol/L higher than the isotope dilution mass spectrometry (IDMS) assured reference value in 2003, but consistent with the reference value from 2009 to 2014. The inter-laboratory CV was 7%-9% for creatinine values until 2007, and thereafter gradually decreased to about 4%-5% in 2014.

    Conclusions:

    The introduction of enzymatic methods in Swedish laboratories has contributed to achieving a low inter-laboratory variation. Also, the reported values are lower for enzymatic methods compared to Jaffe methods, and the values obtained with enzymatic methods were consistent with IDMS certified values established at reference laboratories. Thus, many Swedish hospital laboratories reported 10 mu mol/L lower, and more true, creatinine concentrations in 2012 than in 2003, which may cause bias in longitudinal studies.

  • 138.
    Helmersson, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Ridefelt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Reference values for 34 frequently used laboratory tests in 80-year-old men and women2016Inngår i: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 92, s. 97-101Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Reference values are usually based on blood samples from healthy individuals in the age range 20-50 years. Most patients seeking health care are older than this reference population. Many reference intervals are age dependent and there is thus a need to have appropriate reference intervals also for elderly individuals.

    METHODS: We analyzed a group of frequently used laboratory tests in an 80-year-old population (n=531, 266 females and 265 males). The 2.5th and 97.5th percentiles for these markers were calculated according to the International Federation of Clinical Chemistry guidelines on the statistical treatment of reference values.

    RESULTS: Reference values are reported for serum alanine transaminase (ALT), albumin, alkaline phosphatase, pancreatic amylase, apolipoprotein A1, apolipoprotein B, apolipoprotein B/apolipoprotein A1 ratio, aspartate aminotransferase (AST), AST/ALT ratio, bilirubin, calcium, calprotectin, cholesterol, HDL-cholesterol, creatinine kinase (CK), creatinine, creatinine estimated GFR, C-reactive protein, cystatin C, cystatin C estimated GFR, gamma-glutamyltransferase (GGT), iron, iron saturation, lactate dehydrogenase (LDH), magnesium, phosphate, transferrin, triglycerides, urate, urea, zinc, hemoglobin, platelet count and white blood cell count. The upper reference limit for creatinine and urea was significantly increased while the lower limit for iron and albumin was decreased in this elderly population in comparison with the population in the Nordic Reference Interval Project (NORIP).

    CONCLUSIONS: Reference values calculated from the whole population and a subpopulation without cardiovascular disease showed strong concordance. Several of the reference interval limits were outside the 90% confidence interval of NORIP.

  • 139.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Flodin, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Hansson, Lars-Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    The age related association is more pronounced for cystatin C estimated GFR than for creatinine estimated GFR in primary care patients2013Inngår i: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 46, nr 16-17, s. 1761-1763Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives

    There is an age associated change in GFR but this association may be influenced by the method used. The aims of the present study were to assess the association between age and cystatin C and creatinine based glomerular filtration rate estimates in primary care patients, and to determine the proportion of patients with clinically important renal impairment.

    Materials and methods

    1552 samples with simultaneous requests for creatinine and cystatin C from 1552 primary care patients in the county of Uppsala, Sweden were analysed. MDRD, CKD-EPI and cystatin C equations were used to calculate glomerular filtration rate (GFR) and the associations between GFR and age were explored.

    Results

    The yearly change in cystatin C estimated GFR was 1.24 mL/min/1.73 m2 while the corresponding decline for creatinine estimated GFR was 0.76 mL/min/1.73 m2 for MDRD and 0.99 mL/min/1.73 m2 for CKD-EPI.

    Conclusions

    The age related association with GFR estimates is smaller for creatinine estimates than for cystatin C estimates. This leads to differences in the number of patients with reduced eGFR detected with the three estimates and the patient treatment will depend on the estimate used. This is not coherent with a good patient care and we thus need to develop new eGFR equations with better agreement between the estimates.

  • 140.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Flodin, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Havelka, Aleksandra Mandic
    Karolinska Univ Hosp, Dept Clin Chem, Stockholm, Sweden.
    Xu, Xiao Yan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    The Roche Immunoturbidimetric Albumin Method on Cobas c 501 Gives Higher Values Than the Abbott and Roche BCP Methods When Analyzing Patient Plasma Samples2016Inngår i: Journal of clinical laboratory analysis (Print), ISSN 0887-8013, E-ISSN 1098-2825, Vol. 30, nr 5, s. 677-681Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Serum/plasma albumin is an important and widely used laboratory marker and it is important that we measure albumin correctly without bias. We had indications that the immunoturbidimetric method on Cobas c 501 and the bromocresol purple (BCP) method on Architect 16000 differed, so we decided to study these methods more closely.

    METHOD: A total of 1,951 patient requests with albumin measured with both the Architect BCP and Cobas immunoturbidimetric methods were extracted from the laboratory system. A comparison with fresh plasma samples was also performed that included immunoturbidimetric and BCP methods on Cobas c 501 and analysis of the international protein calibrator ERM-DA470k/IFCC.

    RESULTS: The median difference between the Abbott BCP and Roche immunoturbidimetric methods was 3.3 g/l and the Roche method overestimated ERM-DA470k/IFCC by 2.2 g/l. The Roche immunoturbidimetric method gave higher values than the Roche BCP method: y = 1.111x - 0.739, R² = 0.971.

    CONCLUSION: The Roche immunoturbidimetric albumin method gives clearly higher values than the Abbott and Roche BCP methods when analyzing fresh patient samples. The differences between the two methods were similar at normal and low albumin levels.

  • 141.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Karlsson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Fredricsson, Annika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Gastroenterologi/hepatologi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Evaluation of the Alere D-dimer test for point of care testing2014Inngår i: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 38, nr 2, s. 250-252Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The primary care regularly sees patients that have symptoms that could be due to thromboembolic diseases. It would be valuable to be able to rule out deep venous thrombosis or pulmonary embolism using Wells score and a negative D-dimer testing already at the primary care unit. This requires a validated D-dimer assay suitable for primary care use. We compared D-dimer results obtained with the new point of care analyzer Alere Triage(®) and the central hospital laboratory STA-R Evolution analyzer from the same patient samples (n = 102). We also calculated the total coefficient of variation (CV) for the Alere method. The two methods showed a good linear correlation (R(2) = 0.977) and a slope of 0.975. CV for the Alere D-dimer method was well below 10 %. The study shows that the Alere D-dimer assay and the central laboratory standard assay show similar results. We suggest that the Alere D-dimer assay could be used in primary care in combination with Wells score to reduce referrals to the emergency unit.

  • 142.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden.
    Carlsson, Axel C.
    Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden; Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Family Med, Huddinge, Sweden.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Urinary KIM-1, but not urinary cystatin C, should be corrected for urinary creatinine2016Inngår i: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 49, nr 15, s. 1164-1166Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: The interest for tubular damage markers such as urinary cystatin C (U-CystC) and kidney injury molecule-1 (U-KIM-1) grows, especially for the diagnosis of acute kidney injury. The trend to measure proteins in spot urine samples instead of 24-h urine collections calls for adjustment of urine dilution with urinary creatinine (UCr). However, it is not known whether UCr adjustment provides a more true value of basal U-CystC and U-KIM-1 levels than absolute values.

    DESIGN & METHODS: This study examines the rationale for UCr correction for U-CystC and U-KIM-1 by exploring the linear relations between U-CystC and U-KIM-1 and UCr, respectively, and the biological day to day variation of absolute concentrations and UCr adjusted values of the two biomarkers.

    RESULTS: Both U-CystC and U-KIM-1 concentrations correlated positively with UCr (R=0.37, P<0.001 and R=0.62, P<0.001, respectively) in 378 participants in a community cohort, which indicated a rationale for adjustment with UCr. However, U-CystC/Cr ratio associated negatively with UCr (R=- 0.31, P<0.001), which could indicate a certain amount of 'over-adjustment'. Morning urine collected for 10 consecutive days from 13 healthy volunteers showed a biological day to day variation of 82% for U-CystC, 75% for U-cystC/Cr ratio, 70% for U-KIM-1 and 46% for U-KIM-1/Cr ratio.

    CONCLUSIONS: This study supports the use of U-KIM-1/Cr ratio in clinical population studies. Data supporting the use of U-CysC/U-Cr ratio were less convincing and the possible confounding of UCr has to be acknowledged in clinical settings.

  • 143.
    Henein, Michael Y.
    et al.
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Suhr, Ole B.
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Arvidsson, Sandra
    Umea Univ, Ctr Heart, Clin Physiol, Umea, Sweden.
    Pilebro, Björn
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Westermark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hörnsten, Rolf
    Umea Univ, Ctr Heart, Clin Physiol, Umea, Sweden.
    Lindqvist, Per
    Umea Univ, Publ Hlth & Clin Med, Umea, Sweden.
    Reduced left atrial myocardial deformation irrespective of cavity size: a potential cause for atrial arrhythmia in hereditary transthyretin amyloidosis2018Inngår i: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 25, nr 1, s. 46-53Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Cardiac amyloidosis (CA) is a myocardial disease and commonly under-diagnosed condition. In CA patients, atrial fibrillation might occur in the absence of left atrial (LA) enlargement.

    Objectives: The aim of this study is to assess LA size and function, and its relationship with atrial arrhythmia in patients with hereditary transthyretin amyloidosis (ATTR).

    Methods: Forty-six patients with confirmed ATTR amyloidosis on abdominal biopsy were studied. Assessment with 2D echocardiography and 2D strain showed 31 patients had increased LV wall thickness (LVWT) (septal thickness >12mm), and 15 had normal LVWT. In addition to conventional measurements, LV and LA global longitudinal strain (GLS%) and strain rate (SR) were obtained. Western blot analysis was done to assess fibril type. ATTR patients with increased LVWT were compared with 23 patients with hypertrophic cardiomyopathy (HCM) and 31 healthy controls. ATTR amyloidosis patients also underwent 24hour Holter monitoring to determine the presence of atrial arrhythmia.

    Results: Atrial deformation during atrial systole was reduced in ATTR amyloidosis patients with increased LVWT independent of LA size and in contrast to HCM. Twenty of the ATTR amyloidosis patients (54%) had ECG evidence of significant atrial arrhythmic events. LA strain rate, during atrial systole, was the only independent predictor of atrial arrhythmia (=3.28, p=.012).

    Conclusion: In ATTR cardiomyopathy with increased LVWT, LA myocardial function is abnormal, irrespective of atrial cavity size. Reduced LA myocardial SR during atrial systole, irrespective of cavity volume, E/e and LV deformation, is also a strong predictor for atrial arrhythmic events.

  • 144. Hesstvedt, Liv
    et al.
    Arendrup, Maiken C
    Poikonen, Eira
    Klingpor, Lena
    Friman, Vanda
    Nordøy, Ingvild
    Differences in epidemiology of candidaemia in the Nordic countries - what is to blame?2017Inngår i: Mycoses (Berlin), ISSN 0933-7407, E-ISSN 1439-0507, Vol. 60, nr 1, s. 11-19Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    National data from Denmark, Finland, Norway and Sweden demonstrate remarkable differences in candidaemia epidemiology. Only Denmark has reported a high incidence of 10 per 100 000 inhabitants and a species shift towards increased C. glabrata candidaemias. The reasons for this development remain unclear. The aim of this study was to explore possible contributing factors for the differences in Candida epidemiology in the Nordic countries. We used public data from 2011 from Denmark, Finland, Norway and Sweden on epidemiology, demographics, health facilities, predisposing risk factors, consumption of antimicrobial drugs and fungicides in agricultural industry. Only the prevalence of haematological malignancies (P < 0.001) was significantly higher in Denmark compared to the other Nordic countries. The antibacterial drug use of metronidazole, piperacillin-tazobactam, ciprofloxacin, colistin and carbapenems, and antifungal use of fluconazole in humans (P < 0.001), were significantly higher in Denmark compared to the other Nordic countries (all P < 0.001). Our findings suggest haematological malignancy, the use of certain antibacterial drugs and azoles in humans as possible contributing factors for the differences in Candida epidemiology. However, our results should be interpreted with caution due to the lack of long-term, case-specific data. Further studies are needed.

  • 145. Hjalgrim, Henrik
    et al.
    Rostgaard, Klaus
    Johnson, Paul C. D.
    Lake, Annette
    Shield, Lesley
    Little, Ann-Margaret
    Ekström-Smedby, Karin
    Adami, Hans-Olov
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Hamilton-Dutoit, Stephen
    Kane, Eleanor
    Taylor, G. Malcolm
    McConnachie, Alex
    Ryder, Lars P.
    Andersen, Paal Skytt
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Chang, Ellen T.
    Alexander, Freda E.
    Melbye, Mads
    Jarrett, Ruth F.
    HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma2010Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, nr 14, s. 6400-6405Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60-2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51-0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBV-related HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74-6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL.

  • 146.
    Hjort, Marcus
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Eggers, Kai M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lindhagen, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Agewall, Stefan
    Univ Oslo, Inst Clin Sci, Oslo Univ Hosp, Oslo, Norway.
    Brolin, Elin B.
    Soder Sjukhuset, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    Collste, Olov
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Daniel, Maria
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Ekenbäck, Christina
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Frick, Mats
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Henareh, Loghman
    Karolinska Univ Hosp, Dept Med, Heart & Vasc Theme, Stockholm, Sweden.
    Hofman-Bang, Claes
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Malmqvist, Karin
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Spaak, Jonas
    Danderyd Hosp, Dept Clin Sci, Div Cardiovasc Med, Stockholm, Sweden.
    Sörensson, Peder
    Karolinska Univ Hosp, Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Y-Hassan, Shams
    Karolinska Univ Hosp, Dept Med, Heart & Vasc Theme, Stockholm, Sweden.
    Tornvall, Per
    Soder Sjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Lindahl, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Increased Inflammatory Activity in Patients 3 Months after Myocardial Infarction with Nonobstructive Coronary Arteries2019Inngår i: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 65, nr 8, s. 1023-1030Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Around 5%-10% of patients with myocardial infarction (MI) present with nonobstructive coronary arteries (MINOCA). We aimed to assess pathophysiological mechanisms in MINOCA by extensively evaluating cardiovascular biomarkers in the stable phase after an event, comparing MINOCA patients with cardiovascular healthy controls and MI patients with obstructive coronary artery disease (MI-CAD).

    METHODS: Ninety-one biomarkers were measured with a proximity extension assay 3 months after MI in 97 MINOCA patients, 97 age-and sex-matched MI-CAD patients, and 98 controls. Lasso analyses (penalized logistic regression models) and adjusted multiple linear regression models were used for statistical analyses.

    RESULTS: In the Lasso analysis (MINOCA vs MI-CAD), 8 biomarkers provided discriminatory value: P-selectin glycoprotein ligand 1, C-X-C motif chemokine 1, TNF-related activation-induced cytokine, and pappalysin-1 (PAPPA) with increasing probabilities of MINOCA, and tissue-type plasminogen activator, B-type natriuretic peptide, myeloperoxidase, and interleukin-1 receptor antagonist protein with increasing probabilities of MI-CAD. Comparing MINOCA vs controls, 7 biomarkers provided discriminatory value: N-terminal pro-B-type natriuretic peptide, renin, NF-kappa-B essential modulator, PAPPA, interleukin-6, and soluble urokinase plasminogen activator surface receptor with increasing probabilities of MINOCA, and agouti-related protein with increasing probabilities of controls. Adjusted multiple linear regression analyses showed that group affiliation was associated with the concentrations of 7 of the 8 biomarkers in the comparison MINOCA vs MI-CAD and 5 of the 7 biomarkers in MINOCA vs controls.

    CONCLUSIONS: Three months after the MI, the biomarker concentrations indicated greater inflammatory activity in MINOCA patients than in both MI-CAD patients and healthy controls, and a varying degree of myocardial dysfunction among the 3 cohorts. 

  • 147.
    Hollander, Peter
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ginman, Beatrice
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Expression of PD-1 and PD-L1 increase in consecutive biopsies in patients with classical Hodgkin lymphoma2018Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 9, artikkel-id e0204870Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High expression of programmed death receptor 1 (PD-1) and its ligand (PD-L1) by leukocytes in primary classical Hodgkin lymphoma (cHL) is associated with inferior outcome. However, it is unclear how expression varies during disease progression, and in the event of relapse. Our aim was to study PD-1 and PD-L1 in consecutive biopsies from untreated and treated cHL patients. We screened pathology registries from 3500 cHL patients. Eleven patients had a diagnostic cHL biopsy and a previous benign lymph node biopsy reclassified as cHL when reviewed and designated as the untreated. Thirty patients had a primary and a relapse biopsy, designated as the treated. Biopsies were immunostained to detect PD-1+ and PD-L1+ leukocytes, and PD-L1+ tumor cells. In the untreated, none of the markers were statistically significantly different when biopsies 1 and 2 were compared. In the treated, 19, 22, and 18 of 30 cases had increased proportions of PD-1+ leukocytes, PD-L1+ leukocytes and PD-L1+ tumor cells, respectively, and were all statistically significantly increased when primary and relapse biopsies were compared. PD-1 and PD-L1 most likely increase due to primary treatment with chemotherapy and radiotherapy, which could have implications regarding treatment with PD-1 inhibitors.

  • 148.
    Hollander, Peter
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Kamper, Peter
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Smedby, Karin Ekstrom
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ludvigsen, Maja
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Mortensen, Julie
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hamilton-Dutoit, Stephen
    Aarhus Univ Hosp, Inst Pathol, Aarhus, Denmark..
    d'Amore, Francesco
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    High proportions of PD-1+ and PD-L1+ leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome2017Inngår i: Blood Advances, ISSN 2473-9529, Vol. 1, nr 18, s. 1427-1439Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Immune checkpoint inhibition targeting the programmed death receptor (PD)-1 pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). Identifying patients with a high risk of treatment failure could support the use of PD-1 inhibitors as front-line treatment. Our aim was to investigate the prognostic impact of PD-1, programmed death-ligand 1 (PD-L1), and PD-L2 in the tumor microenvironment in diagnostic biopsies of patients with cHL. Patients from Denmark and Sweden, diagnosed between 1990 and 2007 and ages 15 to 86 years, were included. Tissue microarray samples were available from 387 patients. Immunohistochemistry was used to detect PD-1, PD-L1, and PD-L2, and the proportions of positive cells were calculated. Event-free survival (EFS; time to treatment failure) and overall survival (OS) were analyzed using Cox proportional hazards regression. High proportions of both PD-1(+) (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.10-2.86) and PD-L1(+) (HR 5 1.89; 95% CI, 1.08-3.30) leukocytes in the microenvironment were associated with inferior EFS in a multivariate analysis (adjusted for white blood cell count >15 x 10(9)/L, hemoglobin <105 g/L, albumin <40 g/L, B symptoms, extranodal involvement, stage, bulky tumor, nodular sclerosis subtype, Epstein-Barr virus status, lymphocyte count <0.6 x 10(9)/L, sex, and country). A high proportion of PD-L1(+) leukocytes was also associated with inferior OS in a multivariate analysis (HR, 3.46; 95% CI, 1.15-10.37). This is the first study to show a correlation after multivariate analysis between inferior outcome in cHL and a high proportion of both PD-1(+) and PD-L1(+) leukocytes in the tumor microenvironment.

  • 149.
    Hollander, Peter
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Rostgaard, Klaus
    Ekström-Smedby, Karin
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Loskog, Angelica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    de Nully Brown, Peter
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hjalgrim, Henrik
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome2018Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, nr 1, s. 88-97Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: The classical Hodgkin lymphoma (cHL) tumor microenvironment shows anongoing inflammatory response consisting of varying degrees of infiltrating eosinophils,mast cells, macrophages, regulatory T lymphocytes (Tregs), and activated lymphocytes surrounding the malignant cells. Herein, different immune signatures are characterized and correlated with treatment outcome.

    Methods: Tumor-infiltrating leukocytes were phenotyped in biopsies from 459 patients with cHL. Time to progression (TTP) (primary progression, relapse, or death from cHL) and overall survival were analyzed using Cox proportional hazards regression.

    Results: The leukocyte infiltration in the microenvironment was highly diverse between patients and was categorized in 4 immune signatures (active, anergic, innate, or mixed). A high proportion of Tregs (anergic) resulted in shorter TTP (median 12.9-year follow-up) in age-adjusted analyses (hazard ratio = 1.82; 95% confidence interval 1.05-3-15). Epstein-Barrvirus (EBV)-positive cases had higher proportions of macrophages and activated lymphocytes than EBV negative, but neither of those leukocytes predicted prognosis.

    Conclusions: Abundant Tregs (anergic signature) indicate a shorter TTP, particularly in younger patients. This is probably due to a reduced ability of the immune system to attack the tumor cells. Our data warrant further investigation if these suggested immune signatures could predict outcome of immunotherapy such as immune checkpoint inhibitors.

  • 150.
    Hollander, Peter
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Rostgaard, Klaus
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark..
    Smedby, Karin E.
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Chang, Ellen T.
    Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA.;Exponent Inc, Hlth Sci, Menlo Pk, CA USA..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brown, Peter de Nully
    Rigshosp, Dept Haematol, DK-2100 Copenhagen, Denmark..
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Adami, Hans-Olov
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Melbye, Mads
    Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hjalgrim, Henrik
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark..
    Autoimmune and Atopic Disorders and Risk of Classical Hodgkin Lymphoma2015Inngår i: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 182, nr 7, s. 624-632Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Results from previous investigations have shown associations between the risk of Hodgkin lymphoma (HL) and a history of autoimmune and atopic diseases, but it remains unknown whether these associations apply to all types of HL or only to specific subtypes. We investigated immune diseases and the risk of classical HL in a population-based case-control study that included 585 patients and 3,187 controls recruited from October 1999 through August 2002. We collected information on immune diseases through telephone interviews and performed serological analyses of specific immunoglobulin E reactivity. Tumor Epstein-Barr virus (EBV) status was determined for 498 patients. Odds ratios with 95% confidence intervals were calculated using logistic regression analysis. Rheumatoid arthritis was associated with a higher risk of HL (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.47, 4.70), especially EBV-positive HL (OR = 3.18; 95% CI: 1.23, 8.17), and with mixed-cellularity HL (OR = 4.25; 95% CI: 1.66, 10.90). HL risk was higher when we used proxies of severe rheumatoid arthritis, such as ever having received daily rheumatoid arthritis medication (OR = 3.98; 95% CI: 2.08, 7.62), rheumatoid arthritis duration of 6-20 years (OR = 3.80; 95% CI: 1.72, 8.41), or ever having been hospitalized for rheumatoid arthritis (OR = 7.36; 95% CI: 2.95, 18.38). Atopic diseases were not associated with the risk of HL. EBV replication induced by chronic inflammation in patients with autoimmune diseases might explain the higher risk of EBV-positive HL.

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