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  • 1.
    Backman, Max
    et al.
    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.
    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.
    Kurppa, Pinja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Elfving, Hedvig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnström, Hans
    Division of Pathology, Lund University Skåne University Hospital Lund Sweden.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindberg, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pontén, Victor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Eltahir, Mohamed
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mangsbo, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Gulyas, Miklos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Isaksson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Department of Respiratory Medicine Gävle Hospital Gävle Sweden.
    Jirström, Karin
    Division of Oncology and Therapeutic Pathology Department of Clinical Sciences Lund, Lund, Sweden.
    Kärre, Klas
    Department of Microbiology, Cell and Tumor Biology Karolinska Institutet, Stockholm, Sweden.
    Leandersson, Karin
    Cancer Immunology, Department of Translational Medicine, Lund University Skånes University Hospital, Malmö, Sweden.
    Mezheyeuski, Artur
    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.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Strell, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Infiltration of NK and plasma cells is associated with a distinct immune subset in non‐small cell lung cancer2021Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 255, nr 3, s. 243-256Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Immune cells of the tumor microenvironment are central but erratic targets for immunotherapy. The aim of this study was to characterize novel patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to its molecular and clinicopathologic characteristics. Lymphocytes (CD3+, CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+), PD1+, and PD-L1+ were annotated on a tissue microarray including 357 NSCLC cases. Somatic mutations were analyzed by targeted sequencing for 82 genes and a tumor mutational load score was estimated. Transcriptomic immune patterns were established in 197 patients based on RNA sequencing data. The immune cell infiltration was variable and showed only poor association with specific mutations. The previously defined immune phenotypic patterns, desert, inflamed, and immune excluded, comprised 30, 13, and 57% of cases, respectively. Notably, mRNA immune activation and high estimated tumor mutational load were unique only for the inflamed pattern. However, in the unsupervised cluster analysis, including all immune cell markers, these conceptual patterns were only weakly reproduced. Instead, four immune classes were identified: (1) high immune cell infiltration, (2) high immune cell infiltration with abundance of CD20+ B cells, (3) low immune cell infiltration, and (4) a phenotype with an imprint of plasma cells and NK cells. This latter class was linked to better survival despite exhibiting low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, CTLA4). This compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC reveals two previously unrecognized immune classes. A refined immune classification, including traits of the humoral and innate immune response, is important to define the immunogenic potency of NSCLC in the era of immunotherapy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

    Fulltekst (pdf)
    fulltext
  • 2.
    Backman, Max
    et al.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    La Fleur, Linnea
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Kurppa, Pinja
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Djureinovic, Dijana
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Elfving, Hedvig
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Brunnström, Hans
    Division of Pathology, Lund University, Skåne University Hospital, Lund, Sweden.
    Mattsson, Johanna Sofia Margareta
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Pontén, Victor
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Eltahir, Mohamed
    Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden.
    Mangsbo, Sara
    Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden.
    Isaksson, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Dept. of Respiratory Medicine, Gävle Hospital, Gävle, Sweden..
    Jirström, Karin
    Division of Pathology, Lund University, Skåne University Hospital, Lund, Sweden.
    Kärre, Klas
    Department of Microbiology, Cell and Tumor Biology (MTC), Karolinska Institutet, Stockholm, Sweden..
    Carbone, Ennio
    Department of Microbiology, Cell and Tumor Biology (MTC), Karolinska Institutet, Stockholm, Sweden; Tumor Immunology and Immunopathology Laboratory, Dept. of Experimental and Clinical Medicine, University Magna Graecia of Catanzaro, Catanzaro, Italy..
    Leandersson, Karin
    Cancer Immunology, Dept. of Translational Medicine, Lund University, Skånes University Hospital, Malmö, Sweden.
    Mezheyeuski, Artur
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Lindskog, Cecilia
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Extending the immune phenotypes of lung cancer: Oasis in the desertManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. 

    Methods: Lymphocytes (CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. 

    Results: We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated “oasis”. Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. 

    Conclusion: We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class “oasis”. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy. 

  • 3.
    Backman, Max
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Strell, Carina
    Lindberg, Amanda
    Mattsson, Johanna S. M.
    Elfving, Hedvig
    Brunnström, Hans
    O'Reilly, Aine
    Bosic, Martina
    Gulyas, Miklos
    Isaksson, Johan
    Botling, Johan
    Kärre, Klas
    Jirström, Karin
    Lamberg, Kristina
    Pontén, Fredrik
    Leandersson, Karin
    Mezheyeuski, Artur
    Micke, Patrick
    Spatial immunophenotyping of the tumor microenvironment in non-small cell lung cancerManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Introduction: Immune cells in the tumor microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterize the spatial immune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC).

    Methods: We established a multiplexed fluorescence multispectral imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4 Eff), CD4 regulatory cells (CD4 Treg), CD8 effector cells (CD8 Eff), CD8 regulatory cells (CD8 Treg), B-cells, NK-cells, NKT-cells, M1 macrophages (M1), CD163+ myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs).  

    Results: CD4 Eff cells, CD8 Eff cells, and M1 macrophages were the most abundant immune cells invading the tumor cell compartment and indicated a patient group with a favorable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4 Eff, CD4 Treg, CD8 Treg, and B-cells), as well as pDCs, were independently associated with longer survival. However, when these immune cells were located close to CD8 Treg cells, the favorable impact was attenuated. In the multivariate Cox regression model including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8 Treg–B-cells, CD8 Eff–cancer cells, and B-cells–CD4 Treg) demonstrated positive prognostic impact, while short M2–M1 distances were prognostically unfavorable.

    Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is also crucial for diagnostic use.

  • 4.
    Backman, Max
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Strell, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi. Univ Bergen, Dept Clin Med, Ctr Canc Biomarkers CCBIO, Bergen, Norway.
    Lindberg, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Mattsson, Johanna S. M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Elfving, Hedvig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Pathol, Lund, Sweden..
    O'Reilly, Aine
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Bosic, Martina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin. Univ Belgrade, Fac Med, Belgrade, Serbia.
    Gulyas, Miklos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Isaksson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin. Gävle Cent Hosp, Dept Resp Med, Gävle, Sweden.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Kärre, Klas
    Karolinska Inst, Dept Microbiol Cell & Tumor Biol, Stockholm, Sweden..
    Jirström, Karin
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, Lund, Sweden..
    Lamberg, Kristina
    Akadem Sjukhuset, Dept Resp Med, Uppsala, Sweden.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Leandersson, Karin
    Lund Univ, Skanes Univ Hosp, Dept Translat Med, Malmö, Sweden..
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin. Vall Hebron Inst Oncol, Mol Oncol Grp, Barcelona, Spain.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer2023Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 185, s. 40-52Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Immune cells in the tumour microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterise the spatial im-mune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC).

    Methods: We established a multiplexed fluorescence imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4-Eff), CD4 regulatory cells (CD4-Treg), CD8 effector cells (CD8-Eff), CD8 regulatory cells (CD8-Treg), B-cells, natural killer cells, natural killer T-cells, M1 macrophages (M1), CD163 thorn myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs).

    Results: CD4-Eff cells, CD8-Eff cells and M1 macrophages were the most abundant immune cells invading the tumour cell compartment and indicated a patient group with a favourable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4-Eff, CD4-Treg, CD8-Treg, B-cells and pDCs) were independently associated with longer survival. However, when these immune cells were located close to CD8-Treg cells, the favourable impact was attenuated. In the multivariable Cox regression model, including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8-Treg-B-cells, CD8-Eff-cancer cells and B-cells-CD4-Treg) demonstrated positive prognostic impact, whereas short M2-M1 distances were prognostically unfavourable.

    Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is crucial for diagnostic use.

    Fulltekst (pdf)
    fulltext
  • 5.
    Bogatyrova, Olga
    et al.
    Merck KGaA, Translat Innovat Platform Oncol & Immunooncol, Darmstadt, Germany.
    Mattsson, Johanna S M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ross, Edith M.
    Merck KGaA, Translat Med, Darmstadt, Germany.
    Sanderson, Michael P.
    Merck KGaA, Translat Innovat Platform Oncol & Immunooncol, Darmstadt, Germany.
    Backman, Max
    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.
    Brunnström, Hans
    Lund Univ, Skåne Univ Hosp, Div Pathol, Lund, Sweden.
    Kurppa, Pinja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Strell, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Wilm, Claudia
    Merck KGaA, Translat Innovat Platform Oncol & Immunooncol, Darmstadt, Germany.
    Zimmermann, Astrid
    Merck KGaA, Translat Innovat Platform Oncol & Immunooncol, Darmstadt, Germany.
    Esdar, Christina
    Merck KGaA, Translat Innovat Platform Oncol & Immunooncol, Darmstadt, Germany.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    FGFR1 overexpression in non-small cell lung cancer is mediated by genetic and epigenetic mechanisms and is a determinant of FGFR1 inhibitor response2021Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 151, s. 136-149Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Amplification of fibroblast growth factor receptor 1 (FGFR1) in non-small cell lung cancer (NSCLC) has been considered as an actionable drug target. However, pan-FGFR tyrosine kinase inhibitors did not demonstrate convincing clinical efficacy in FGFR1-amplified NSCLC patients. This study aimed to characterise the molecular context of FGFR1 expression and to define biomarkers predictive of FGFR1 inhibitor response.

    In this study, 635 NSCLC samples were characterised for FGFR1 protein expression by immunohistochemistry and copy number gain (CNG) by in situ hybridisation (n = 298) or DNA microarray (n = 189). FGFR1 gene expression (n = 369) and immune cell profiles (n = 309) were also examined. Furthermore, gene expression, methylation and microRNA data from The Cancer Genome Atlas (TCGA) were compared. A panel of FGFR1-amplified NSCLC patient-derived xenograft (PDX) models were tested for response to the selective FGFR1 antagonist M6123.

    A minority of patients demonstrated FGFR1 CNG (10.5%) or increased FGFR1 mRNA (8.7%) and protein expression (4.4%). FGFR1 CNG correlated weakly with FGFR1 gene and protein expression. Tumours overexpressing FGFR1 protein were typically devoid of driver alterations (e.g. EGFR, KRAS) and showed reduced infiltration of T-lymphocytes and lower PD-L1 expression. Promoter methylation and microRNA were identified as regulators of FGFR1 expression in NSCLC and other cancers. Finally, NSCLC PDX models demonstrating FGFR1 amplification and FGFR1 protein overexpression were sensitive to M6123.

    The unique molecular and immune features of tumours with high FGFR1 expression provide a rationale to stratify patients in future clinical trials of FGFR1 pathway-targeting agents.

    Fulltekst (pdf)
    FULLTEXT01
  • 6.
    Djureinovic, Dijana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Dodig-Crnkovic, Tea
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH - Royal Institute of Technology, Solna, Sweden.
    Hellström, Cecilia
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH - Royal Institute of Technology, Solna, Sweden.
    Holgersson, Georg
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Bergqvist, Michael
    Department of Oncology, Gavle Hospital, Gavle, Sweden..
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    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).
    Schwenk, Jochen M.
    Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH - Royal Institute of Technology, Solna, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Detection of autoantibodies against cancer-testis antigens in non-small cell lung cancer2018Inngår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 125, s. 157-163Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cancer testis antigens (CTAs) are defined as proteins that are specifically expressed in testis or placenta and their expression is frequently activated in cancer. Due to their ability to induce an immune response, CTAs may serve as suitable targets for immunotherapy. The aim of this study was to evaluate if there is reactivity against CTAs in the plasma of non-small cell lung cancer (NSCLC) patients through the detection of circulating antibodies. 

    To comprehensively analyse auto-antibodies against CTAs the multiplexing capacities of suspension bead array technology was used. Bead arrays were created with 120 protein fragments, representing 112 CTAs. Reactivity profiles were measured in plasma samples from 133 NSCLC patients and 57 cases with benign lung diseases. Altogether reactivity against 69 antigens, representing 81 CTAs, was demonstrated in at least one of the analysed samples. Twenty-nine of the antigens (45 CTAs) demonstrated exclusive reactivity in NSCLC samples. Reactivity against CT47A genes, PAGE3, VCX, MAGEB1, LIN28B and C12orf54 were only found in NSCLC patients at a frequency of 1%-4%. The presence of autoantibodies towards these six antigens was confirmed in an independent group of 34 NSCLC patients.

    In conclusion, we identified autoantibodies against CTAs in the plasma of lung cancer patients. The reactivity pattern of autoantibodies was higher in cancer patients compared to the benign group, stable over time, but low in frequency of occurrence. The findings suggest that some CTAs are immunogenic and that these properties can be utilized as immune targets.

  • 7.
    Djureinovic, Dijana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Grinberg, Marianna
    Tu Dortmund Univ, Dept Stat, Dortmund, Germany..
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Edlund, Karolina
    Tu Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Rahnenfuehrer, Joerg
    Tu Dortmund Univ, Dept Stat, Dortmund, Germany..
    Hengstler, Jan
    Tu Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Brunnström, Hans
    Lund Univ, Div Pathol, Lund, Sweden..
    Koyi, Hirsh
    Gavle Cent Hosp, Dept Pneumol, Gavle, Sweden..
    Branden, Eva
    Gavle Cent Hosp, Dept Pneumol, Gavle, Sweden..
    Lambe, Mats
    Reg Canc Ctr Uppsala Orebro, Uppsala, Sweden..
    Jirström, Karin
    Lund Univ, Div Pathol, Lund, Sweden..
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Micke, Patrick
    The Crux of Molecular Prognostications in NSCLC: An Optimized Biomarker Panel Fails to Outperform Clinical Parameters2015Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, nr 9, s. S712-S713Artikkel i tidsskrift (Annet vitenskapelig)
  • 8.
    Djureinovic, Dijana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hallström, Bjorn M.
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Horie, Masafumi
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan..
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Fagerberg, Linn
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Brunnström, Hans
    Reg Labs Reg Skane, Dept Pathol, Lund, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Madjar, Katrin
    Tech Univ Dortmund, Dept Stat, Dortmund, Germany..
    Rahnenfuehrer, Joerg
    Tech Univ Dortmund, Dept Stat, Dortmund, Germany..
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ståhle, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Edlund, Karolina
    Tech Univ Dortmund, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Hengstler, Jan G.
    Tech Univ Dortmund, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Lambe, Mats
    Univ Uppsala Hosp, Reg Canc Ctr, Uppsala, Sweden..
    Saito, Akira
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Profiling cancer testis antigens in non-small-cell lung cancer2016Inngår i: JCI INSIGHT, ISSN 2379-3708, Vol. 1, nr 10, artikkel-id e86837Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cancer testis antigens (CTAs) are of clinical interest as biomarkers and present valuable targets for immunotherapy. To comprehensively characterize the CTA landscape of non-small-cell lung cancer (NSCLC), we compared RNAseq data from 199 NSCLC tissues to the normal transcriptome of 142 samples from 32 different normal organs. Of 232 CTAs currently annotated in the Caner Testis Database (CTdatabase), 96 were confirmed in NSCLC. To obtain an unbiased CTA profile of NSCLC, we applied stringent criteria on our RNAseq data set and defined 90 genes as CTAs, of which 55 genes were not annotated in the CTdatabase, thus representing potential new CTAs. Cluster analysis revealed that CTA expression is histology dependent and concurrent expression is common. IHC confirmed tissue-specific protein expression of selected new CTAs (TKTL1, TGIF2LX, VCX, and CXORF67). Furthermore, methylation was identified as a regulatory mechanism of CTA expression based on independent data from The Cancer Genome Atlas. The proposed prognostic impact of CTAs in lung cancer was not confirmed, neither in our RNAseq cohort nor in an independent meta-analysis of 1,117 NSCLC cases. In summary, we defined a set of 90 reliable CTAs, including information on protein expression, methylation, and survival association. The detailed RNAseq catalog can guide biomarker studies and efforts to identify targets for immunotherapeutic strategies.

  • 9.
    Djureinovic, Dijana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hallström, Björn
    Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Fagerberg, Linn
    Brunnström, Hans
    Lund Univ, Div Pathol, Lund, Sweden..
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ståhle, Elisabeth
    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 kirurgiska vetenskaper, Thoraxkirurgi.
    Koyi, Hirsh
    Gavle Cent Hosp, Dept Pneumol, S-80187 Gavle, Sweden..
    Lambe, Mats
    Reg Canc Ctr Uppsala Orebro, Uppsala, Sweden..
    Branden, Eva
    Gavle Cent Hosp, Dept Pneumol, S-80187 Gavle, Sweden..
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Uhlen, Mathias
    Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    The Identification of Therapeutic Targets in Lung Cancer Based on Transcriptomic and Proteomic Characterization of Cancer-Testis Antigens2015Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, nr 9, s. S256-S256Artikkel i tidsskrift (Fagfellevurdert)
  • 10. Doffe, Flora
    et al.
    Carbonnier, Vincent
    Tissier, Manon
    Leroy, Bernard
    Martins, Isabelle
    Mattsson, Johanna S. M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pavlova, Sarka
    Pospisilova, Sarka
    Smardova, Jana
    Joerger, Andreas C.
    Wiman, Klas G.
    Kroemer, Guido
    Soussi, Thierry
    Equipe Labellisée par la Ligue Contre le Cancer, Université Paris Descartes, Université Sorbonne Paris Cité, Université Paris Diderot, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France; Department of Oncology–Pathology, Bioclinicum, Karolinska Institutet, Stockholm, Sweden; Department of Life Science, Sorbonne Université, Paris, France.
    Identification and functional characterization of new missense SNPs in the coding region of the TP53 gene2021Inngår i: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 28, nr 5, s. 1477-1492Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Infrequent and rare genetic variants in the human population vastly outnumber common ones. Although they may contribute significantly to the genetic basis of a disease, these seldom-encountered variants may also be miss-identified as pathogenic if no correct references are available. Somatic and germline TP53 variants are associated with multiple neoplastic diseases, and thus have come to serve as a paradigm for genetic analyses in this setting. We searched 14 independent, globally distributed datasets and recovered TP53 SNPs from 202,767 cancer-free individuals. In our analyses, 19 new missense TP53 SNPs, including five novel variants specific to the Asian population, were recurrently identified in multiple datasets. Using a combination of in silico, functional, structural, and genetic approaches, we showed that none of these variants displayed loss of function compared to the normal TP53 gene. In addition, classification using ACMG criteria suggested that they are all benign. Considered together, our data reveal that the TP53 coding region shows far more polymorphism than previously thought and present high ethnic diversity. They furthermore underline the importance of correctly assessing novel variants in all variant-calling pipelines associated with genetic diagnoses for cancer.

    Fulltekst (pdf)
    fulltext
  • 11.
    Edlund, Karolina
    et al.
    TU Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany.
    Madjar, Katrin
    TU Dortmund Univ, Dept Stat, Dortmund, Germany.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnström, Hans
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gävle Cent Hosp, Dept Resp Med, Gävle, Sweden.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gävle Cent Hosp, Dept Resp Med, Gävle, Sweden.
    Jirström, Karin
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Rahnenführer, Jörg
    TU Dortmund Univ, Dept Stat, Dortmund, Germany.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hengstler, Jan G
    TU Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany.
    Prognostic Impact of Tumor Cell Programmed Death Ligand 1 Expression and Immune Cell Infiltration in NSCLC2019Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 14, nr 4, s. 628-640, artikkel-id S1556-0864(19)30009-7Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Infiltration of T and B/plasma cells has been linked to NSCLC prognosis, but this has not been thoroughly investigated in relation to the expression of programmed death ligand 1 (PD-L1). Here, we determine the association of lymphocytes and PD-L1 with overall survival (OS) in two retrospective cohorts of operated NSCLC patients who were not treated with checkpoint inhibitors targeting the programmed death 1/PD-L1 axis. Moreover, we evaluate how PD-L1 positivity and clinicopathologic factors affect the prognostic association of lymphocytes.

    Methods: Cluster of differentiation (CD) 3 (CD3)-, CD8-, CD4-, forkhead box P3 (FOXP3)-, CD20-, CD79A-, and immunoglobulin kappa constant (IGKC)-positive immune cells, and tumor PD-L1 positivity, were determined by immunohistochemistry on tissue microarrays (n = 705). Affymetrix data was analyzed for a patient subset, and supplemented with publicly available transcriptomics data (N = 1724). Associations with OS were assessed by Kaplan-Meier plots and uni- and multivariate Cox regression.

    Results: Higher levels of T and B plasma cells were associated with longer OS (p = 0.004 and p < 0.001, for CD8 and IGKC, respectively). Highly proliferative tumors with few lymphocytes had the worst outcome. No association of PD-L1 positivity with OS was observed in a nonstratified patient population; however, a significant association with shorter OS was observed in never-smokers (p = 0.009 and p = 0.002, 5% and 50% cutoff). Lymphocyte infiltration was not associated with OS in PD-L1–positive tumors (50% cutoff). The prognostic association of lymphocyte infiltration also depended on the patients’ smoking history and histologic subtype.

    Conclusions: Proliferation, PD-L1 status, smoking history, and histology should be considered if lymphocyte infiltration is to be used as a prognostic biomarker.

    Fulltekst (pdf)
    fulltext
  • 12.
    Elfving, Hedvig
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Broström, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Moens, Lotte N.J.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Almlöf, Jonas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Cerjan, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Lauter, Gilbert
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Nord, Helena
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mattsson, Johanna S. M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ullenhag, Gustav J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Strell, Carina
    Backman, Max
    La Fleur, Linnéa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Brunnström, Hans
    Botling, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Micke, Patrick
    Evaluation of NTRK immunohistochemistry as a screening method for NTRK gene fusion detection in non-small cell lung cancer2021Inngår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 151, s. 53-59Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: The small molecule inhibitors larotrectinib and entrectinib have recently been approved as cancer agnostic drugs in patients with tumours harbouring a rearrangement of the neurotrophic tropomyosin receptor kinase (NTRK). These oncogenic fusions are estimated to occur in 0.1-3 % of non-small cell lung cancers (NSCLC). Although molecular techniques are most reliable for fusion detection, immunohistochemical analysis is considered valuable for screening. Therefore, we evaluated the newly introduced diagnostic immunohistochemical assay (clone EPR17341) on a representative NSCLC cohort.

    Methods: Cancer tissue from 688 clinically and molecularly extensively annotated NSCLC patients were comprised on tissue microarrays and stained with the pan-TRK antibody clone EPR17341. Positive cases were further analysed with the TruSight Tumor 170 RNA assay (Illumina). Selected cases were also tested with a NanoString NTRK fusion assay. For 199 cases, NTRK RNA expression data were available from previous RNA sequencing analysis.

    Results: Altogether, staining patterns for 617 NSCLC cases were evaluable. Of these, four cases (0.6 %) demonstrated a strong diffuse cytoplasmic and membranous staining, and seven cases a moderate staining (1.1 %). NanoString or TST170-analysis could not confirm an NTRK fusion in any of the IHC positive cases, or any of the cases with high mRNA levels. In the four cases with strong staining intensity in the tissue microarray, whole section staining revealed marked heterogeneity of NTRK protein expression.

    Conclusion: The presence of NTRK fusion genes in non-small cell lung cancer is exceedingly rare. The use of the immunohistochemical NTRK assay will result in a small number of false positive cases. This should be considered when the assay is applied as a screening tool in clinical diagnostics.

  • 13.
    Elfving, Hedvig
    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.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Menzel, Uwe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Programmed Cell Death Ligand 1 Immunohistochemistry: A Concordance Study Between Surgical Specimen, Biopsy, and Tissue Microarray2019Inngår i: Clinical Lung Cancer, ISSN 1525-7304, E-ISSN 1938-0690, Vol. 20, nr 4, s. 258-262.e1Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Programmed cell death ligand 1 (PD-L1) expression within the same lung cancer tissue is variable. In this study we evaluated if the PD-L1 expression on small biopsy specimens represent the PD-L1 status of the corresponding resection specimen. Our results indicate a relative good agreement between biopsy and surgical specimens, with a discordance in approximately 10% of the cases. Background: The immunohistochemical analysis of programmed cell death ligand 1 (PD-L1) expression in tumor tissue of non-small-cell lung cancer patients has now been integrated in the diagnostic workup. Analysis is commonly done on small tissue biopsy samples representing a minimal fraction of the whole tumor. The aim of the study was to evaluate the correlation of PD-L1 expression on biopsy specimens with corresponding resection specimens. Materials and Methods: In total, 58 consecutive cases with preoperative biopsy and resected tumor specimens were selected. From each resection specimen 2 tumor cores were compiled into a tissue microarray (TMA). Immunohistochemical staining with the antibody SP263 was performed on biopsy specimens, resection specimens (whole sections), as well as on the TMA. Results: The proportion of PD-L1-positive stainings were comparable between the resection specimens (48% and 19%), the biopsies (43% and 17%), and the TMAs (47% and 14%), using cutoffs of 1% and 50%, respectively (P > .39 all comparisons). When the resection specimens were considered as reference, PD-L1 status differed in 16%/5% for biopsies and in 9%/9% for TMAs (1%/50% cutoff). The sensitivity of the biopsy analysis was 79%/82% and the specificity was 90%/98% at the 1%/50% cutoff. The Cohens kappa value for the agreement between biopsy and tumor. was 0.70 at the 1% cutoff and 0.83 at the 50% cutoff. Conclusion: The results indicate a moderate concordance between the analysis of biopsy and whole tumor tissue, resulting in misclassification of samples in particular when the lower 1% cutoff was used. Clinicians should be aware of this uncertainty when interpreting PD-L1 reports for treatment decisions.

  • 14.
    Elfving, Hedvig
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Thurfjell, Viktoria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Strell, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Strell is currently with the Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Tumor Heterogeneity Confounds Lymphocyte Metrics in Diagnostic Lung Cancer Biopsies2024Inngår i: Archives of Pathology & Laboratory Medicine, ISSN 0003-9985, E-ISSN 1543-2165, Vol. 148, nr 1, s. e18-e24Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context.—The immune microenvironment is involved in fundamental aspects of tumorigenesis, and immune scores are now being developed for clinical diagnostics. Objective.—To evaluate how well small diagnostic biopsies and tissue microarrays (TMAs) reflect immune cell infiltration compared to the whole tumor slide, in tissue from patients with non–small cell lung cancer. Design.—A TMA was constructed comprising tissue from surgical resection specimens of 58 patients with non–small cell lung cancer, with available preoperative biopsy material. Whole sections, biopsies, and TMA were stained for the pan-T lymphocyte marker CD3 to determine densities of tumor-infiltrating lymphocytes. Immune cell infiltration was assessed semiquantitatively as well as objectively with a microscopic grid count. For 19 of the cases, RNA sequencing data were available. Results.—The semiquantitative comparison of immune cell infiltration between the whole section and the biopsy displayed fair agreement (intraclass correlation coefficient [ICC], 0.29; P ¼ .01; CI, 0.03–0.51). In contrast, the TMA showed substantial agreement compared with the whole slide (ICC, 0.64; P , .001; CI, 0.39–0.79). The grid-based method did not enhance the agreement between the different tissue materials. The comparison of CD3 RNA sequencing data with CD3 cell annotations confirmed the poor representativity of biopsies as well as the stronger correlation for the TMA cores. Conclusions.—Although overall lymphocyte infiltration is relatively well represented on TMAs, the representativity in diagnostic lung cancer biopsies is poor. This finding challenges the concept of using biopsies to establish immune scores as prognostic or predictive biomarkers for diagnostic applications.

    Fulltekst (pdf)
    fulltext
  • 15.
    Eltahir, Mohamed
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Isaksson, Johan
    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 och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Karre, Klas
    Karolinska Inst, Dept Microbiol Cell & Tumor Biol, S-17177 Stockholm, Sweden..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lord, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mangsbo, Sara
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Plasma Proteomic Analysis in Non-Small Cell Lung Cancer Patients Treated with PD-1/PD-L1 Blockade2021Inngår i: Cancers, ISSN 2072-6694, Vol. 13, nr 13, artikkel-id 3116Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Simple Summary Immunotherapy leads to highly variable responses in lung cancer patients. We assessed the value of a blood-based test to predict which patients would benefit from this new treatment modality. We determined that some patients have higher and lower levels of immune markers in their blood samples, and that this is related to better survival without tumor growth. The blood test has the potential to help select the optimal therapy for lung cancer patients. Checkpoint inhibitors have been approved for the treatment of non-small cell lung cancer (NSCLC). However, only a minority of patients demonstrate a durable clinical response. PD-L1 scoring is currently the only biomarker measure routinely used to select patients for immunotherapy, but its predictive accuracy is modest. The aim of our study was to evaluate a proteomic assay for the analysis of patient plasma in the context of immunotherapy. Pretreatment plasma samples from 43 NSCLC patients who received anti-PD-(L)1 therapy were analyzed using a proximity extension assay (PEA) to quantify 92 different immune oncology-related proteins. The plasma protein levels were associated with clinical and histopathological parameters, as well as therapy response and survival. Unsupervised hierarchical cluster analysis revealed two patient groups with distinct protein profiles associated with high and low immune protein levels, designated as "hot" and "cold". Further supervised cluster analysis based on T-cell activation markers showed that higher levels of T-cell activation markers were associated with longer progression-free survival (PFS) (p < 0.01). The analysis of single proteins revealed that high plasma levels of CXCL9 and CXCL10 and low ADA levels were associated with better response and prolonged PFS (p < 0.05). Moreover, in an explorative response prediction model, the combination of protein markers (CXCL9, CXCL10, IL-15, CASP8, and ADA) resulted in higher accuracy in predicting response than tumor PD-L1 expression or each protein assayed individually. Our findings demonstrate a proof of concept for the use of multiplex plasma protein levels as a tool for anti-PD-(L)1 response prediction in NSCLC. Additionally, we identified protein signatures that could predict the response to anti-PD-(L)1 therapy.

    Fulltekst (pdf)
    FULLTEXT01
  • 16.
    Eltahir, Mohamed
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Isaksson, Johan
    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. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Kärre, Klas
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. 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.
    Lord, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mangsbo, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Micke, Patrick
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Plasma proteomic analysis in non-small cell lung cancer patients treated with PD1/PD-L1 blockadeManuskript (preprint) (Annet vitenskapelig)
  • 17.
    Goldmann, Torsten
    et al.
    Leibniz Lung Ctr, Res Ctr Borstel, Div Pathol, Borstel, Germany.;German Ctr Lung Res DZL, Airway Res Ctr North ARCN, Grosshansdorf, Germany..
    Marwitz, Sebastian
    Leibniz Lung Ctr, Res Ctr Borstel, Div Pathol, Borstel, Germany.;German Ctr Lung Res DZL, Airway Res Ctr North ARCN, Grosshansdorf, Germany..
    Nitschkowski, Dorte
    Leibniz Lung Ctr, Res Ctr Borstel, Div Pathol, Borstel, Germany.;German Ctr Lung Res DZL, Airway Res Ctr North ARCN, Grosshansdorf, Germany..
    Krupar, Rosemarie
    Leibniz Lung Ctr, Res Ctr Borstel, Div Pathol, Borstel, Germany.;Univ Hosp Schleswig Holstein, Inst Pathol, Campus Lubeck, Lubeck, Germany..
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Elfving, Hedvig
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Thurfjell, Viktoria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindberg, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnstrom, Hans
    Lund Univ, Dept Clin Sci Lund, Div Pathol, Lund, Sweden.;Reg Skane, Dept Genet & Pathol, Div Lab Med, Lund, Sweden..
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Mattsson, Johanna Sofia Margareta
    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.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Strell, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung2021Inngår i: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 70, nr 9, s. 2577-2587Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gene amplification is considered to be one responsible cause for upregulation of Programmed Death Ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) and to represent a specific molecular subgroup possibly associated with immunotherapy response. Our aim was to analyze the frequency of PD-L1 amplification, its relation to PD-L1 mRNA and protein expression, and to characterize the immune microenvironment of amplified cases. The study was based on two independent NSCLC cohorts, including 354 and 349 cases, respectively. Tissue microarrays were used to evaluate PD-L1 amplification by FISH and PD-L1 protein by immunohistochemistry. Immune infiltrates were characterized immunohistochemically by a panel of immune markers (CD3, CD4, CD8, PD-1, Foxp3, CD20, CD138, CD168, CD45RO, NKp46). Mutational status was determined by targeted sequencing. RNAseq data was available for 197 patients. PD-L1 amplification was detected in 4.5% of all evaluable cases. PD-L1 amplification correlated only weakly with mRNA and protein expression. About 37% of amplified cases were negative for PD-L1 protein. PD-L1 amplification did not show any association with the mutational status. In squamous cell cancer, PD-L1 amplified cases were enriched among patients with high tumoral immune cell infiltration and showed gene expression profiles related to immune exhaustion. In conclusion, PD-L1 amplification correlates with PD-L1 expression in squamous cell cancer and was associated with an immune cell rich tumor phenotype. The correlative findings help to understand the role of PD-L1 amplification as an important immune escape mechanism in NSCLC and suggest the need to further evaluate PD-L1 amplification as predictive biomarker for checkpoint inhibitor therapy.

    Fulltekst (pdf)
    FULLTEXT01
  • 18. 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.

  • 19.
    Gulyas, Miklos
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mattsson, Johanna S. M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Lindgren, Andrea
    Linkoping Univ, Inst Med & Hlth, Linkoping, Sweden..
    Sederholm, Christer
    Linkoping Univ Hosp, Pulm Med, S-58185 Linkoping, Sweden..
    Ek, Lars
    Skane Univ Hosp, Pulm Med, Lund, Sweden..
    Lamberg, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Behndig, Annelie
    Norrland Univ Hosp, Pulm Med, Umea, Sweden..
    Holmberg, Erik
    Univ Gothenburg, Inst Clin Sci, Sahlgrensk Acad, Dept Oncol, Gothenburg, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Bergman, Bengt
    Sahlgrens Univ Hosp, Dept Pulm Med, Gothenburg, Sweden..
    COX-2 Expression Does Not Predict Outcome of Celecoxib in Addition to Standard Chemotherapy in Advanced Non-Small Cell Lung Cancer2015Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, nr 9, s. S541-S542Artikkel i tidsskrift (Annet vitenskapelig)
  • 20.
    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.

  • 21.
    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.

  • 22.
    Haraldsson, Erik
    et al.
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden.;Karolinska Inst, CLINTEC, Div Surg, Stockholm, Sweden.;Skaraborg Hosp, Skovde, Sweden..
    Swahn, Fredrik
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden.;Karolinska Inst, CLINTEC, Div Surg, Stockholm, Sweden..
    Verbeke, Caroline
    Karolinska Inst, Dept Lab Med, Div Pathol, Stockholm, Sweden..
    Mattsson, Johanna S. M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Enochsson, Lars
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden.;Karolinska Inst, CLINTEC, Div Surg, Stockholm, Sweden..
    Ung, Kjell-Arne
    Skaraborg Hosp, Skovde, Sweden..
    Lundell, Lars
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden.;Karolinska Inst, CLINTEC, Div Surg, Stockholm, Sweden..
    Heuchel, Rainer
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden.;Karolinska Inst, CLINTEC, Div Surg, Stockholm, Sweden..
    Lohr, J. -Matthias
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden.;Karolinska Inst, CLINTEC, Div Surg, Stockholm, Sweden..
    Arnelo, Urban
    Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden.;Karolinska Inst, CLINTEC, Div Surg, Stockholm, Sweden..
    Endoscopic papillectomy and KRAS expression in the treatment of adenoma in the major duodenal papilla2015Inngår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 50, nr 11, s. 1419-1427Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. The use of endoscopic papillectomy for resecting adenomas in the major duodenal papilla is increasing. This study focuses on the following three issues: Can endoscopic papillectomy be performed as a safe diagnostic and/or therapeutic procedure in biopsy-verified or suspected ampullary adenoma? Does expression of mutated KRAS in resected adenomatous tissue predict long-term outcome? What other factors may affect long-term outcome and should, therefore, be considered in decision making prior to endoscopic papillectomy? Material and methods. Thirty-six prospectively collected patients who underwent endoscopic papillectomy at Karolinska University Hospital between 2005 and 2014 were analyzed. Results. The rate of exact agreement between the histomorphological grading of the endoscopic biopsies and the papillectomy specimens was low (48%). Obstructive jaundice at presentation increased the risk of undetected adenocarcinoma (RR = 3.98; 95% CI = 1.46-10.85, p = 0.007). Lesions with malignancies were significantly larger (mean 30.6 mm) than those where only adenomas were found (mean 14.4 mm, p = 0.001). Mutated KRAS was detected in 9 of the 36 post-papillectomy specimens, including 4 of the 5 cases of ampullary adenocarcinoma. Eighteen cases were endoscopically cured after a mean follow-up period of 47 months (range 16-92 months). Conclusions. Endoscopic papillectomy is a valuable staging tool because of the limitations of endoscopic biopsy. Endoscopic papillectomy concomitantly offers a curative treatment for most patients with adenoma in the major duodenal papilla. Jaundice at presentation and large adenomas may indicate the presence of more advanced disease. Determination of mutated KRAS seems to be of limited value in predicting long-term outcome.

  • 23.
    Hikmet Noraddin, Feria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Rassy, Marc
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Méar, Loren
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Yale Univ, Sch Med, Dept Med Med Oncol, New Haven, CT USA..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Pathol, Lund, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Expression of cancer-testis antigens in the immune microenvironment of non-small cell lung cancer2023Inngår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 17, nr 12, s. 2603-2617Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The antigenic repertoire of tumors is critical for successful anti-cancer immune response and the efficacy of immunotherapy. Cancer-testis antigens (CTAs) are targets of humoral and cellular immune reactions. We aimed to characterize CTA expression in non-small cell lung cancer (NSCLC) in the context of the immune microenvironment. Of 90 CTAs validated by RNA sequencing, eight CTAs (DPEP3, EZHIP, MAGEA4, MAGEB2, MAGEC2, PAGE1, PRAME, and TKTL1) were selected for immunohistochemical profiling in cancer tissues from 328 NSCLC patients. CTA expression was compared with immune cell densities in the tumor environment and with genomic, transcriptomic, and clinical data. Most NSCLC cases (79%) expressed at least one of the analyzed CTAs, and CTA protein expression correlated generally with RNA expression. CTA profiles were associated with immune profiles: high MAGEA4 expression was related to M2 macrophages (CD163) and regulatory T cells (FOXP3), low MAGEA4 was associated with T cells (CD3), and high EZHIP was associated with plasma cell infiltration (adj. P-value < 0.05). None of the CTAs correlated with clinical outcomes. The current study provides a comprehensive evaluation of CTAs and suggests that their association with immune cells may indicate in situ immunogenic effects. The findings support the rationale to harness CTAs as targets for immunotherapy.

    Fulltekst (pdf)
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  • 24.
    Horie, Masafumi
    et al.
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan;Univ Tokyo, Div Hlth Serv Promot, Bunkyo Ku, 7-3-1 Hongo, Tokyo, Japan;RIKEN, Ctr Life Sci Technol, DGT, Tsurumi Ku, 1-7-22 Suehiro Cho, Yokohama, Kanagawa, Japan.
    Miyashita, Naoya
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Mikami, Yu
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Sandelin, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Brunnstrom, Hans
    Lund Univ, Dept Clin Sci Lund, Lab Med Reg Skane, Pathol, Lund, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Nagase, Takahide
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan.
    Saito, Akira
    Univ Tokyo, Grad Sch Med, Dept Resp Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan;Univ Tokyo, Div Hlth Serv Promot, Bunkyo Ku, 7-3-1 Hongo, Tokyo, Japan.
    An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer2018Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 246, nr 2, s. 154-165Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Small cell lung cancer (SCLC) is a neuroendocrine tumour that exhibits rapid growth and metastatic spread. Although SCLC represents a prototypically undifferentiated cancer type, thyroid transcription factor-1 (TTF-1, gene symbol NKX2-1), a master regulator for pulmonary epithelial cell differentiation and lung morphogenesis, is strongly upregulated in this aggressive cancer type. The aim of this study was to evaluate a functional role for TTF-1 in SCLC. We demonstrated that achaete-scute complex homolog 1 (ASCL1), an essential transcription factor for neuroendocrine differentiation, positively regulated TTF-1 in SCLC cell lines. Subsequently, we described genes and microRNAs (miRNAs) that were possibly controlled by TTF-1 and identified nuclear factor IB (NFIB), a recently characterised driver of SCLC progression, as a transcriptional target of TTF-1. Our findings shine light on a regulatory axis in SCLC consisting of ASCL1/TTF-1/NFIB that potentially contributes to the tumourigenesis of SCLC.

  • 25.
    Isaksson, Johan
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin. Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden.
    Wennström, Leo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden;Department of Oncology–Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.
    Berglund, Anders
    EpiStat, Uppsala, Sweden.
    Micke, Patrick
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Willén, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Department of Radiation Sciences and Oncology, Umeå University Hospital, Umeå, Sweden;Department of Oncology, Gävle Hospital, Gävle, Sweden.
    Botling, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Highly elevated systemic inflammation is a strong independent predictor of early mortality in advanced non-small cell lung cancer2022Inngår i: Cancer Treatment and Research Communications, E-ISSN 2468-2942, Vol. 31, artikkel-id 100556Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Ample evidence support inflammation as a marker of outcome in non-small cell lung cancer (NSCLC). Here we explore the outcome for a subgroup of patients with advanced disease and substantially elevated systemic inflammatory activity.

    Methods

    The source cohort included consecutive patients diagnosed with NSCLC between January 2016 – May 2017 (n = 155). Patients with active infection were excluded. Blood parameters were examined individually, and cut-offs (ESR > 60 mm, CRP > 20 mg/L, WBC > 10 × 109, PLT > 400 × 109) were set to define the group of hyperinflamed patients. A score was developed by assigning one point for each parameter above cut-off (0–4 points).

    Results

    High systemic inflammation was associated with advanced stage and was seldom present in limited NSCLC. However, the one year survival of patients in stage IIIB-IV (n = 93) with an inflammation score of ≥2 was 0% compared to 33% and 50% among patients with a score of 1 and 0 respectively. The effect of a high inflammation score on overall survival remained significant in multi-variate analysis adjusted for confounding factors. The independent hazard ratio of an inflammation score ≥ 2 in multi-variate analysis (HR 3.43, CI 1.76–6.71) was comparable to a change in ECOG PS from 0 to 2 (HR 2.42, CI 1.13–5.18).

    Conclusion

    Our results show that high level systemic inflammation is a strong independent predictor of poor survival in advanced stage NSCLC. This observation may indicate a need to use hyperinflammation as an additional clinical parameter for stratification of patients in clinical studies and warrants further research on underlying mechanisms linked to tumor progression.

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  • 26.
    Karlsson, Anna
    et al.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.;Reg Labs Reg Skane, Dept Pathol, Lund, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Veerla, Srinivas
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    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.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Jönsson, Mats
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Reuterswärd, Christel
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Planck, Maria
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden.;Skane Univ Hosp, Dept Resp Med & Allergol, Lund, Sweden..
    Staaf, Johan
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22381 Lund, Sweden..
    Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification2017Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, nr 8, s. 1257-1267Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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

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  • 27.
    La Fleur, Linnea
    et al.
    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.
    Boura, Vanessa F.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Alexeyenko, Andrey
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden;Natl Bioinformat Infrastruct Sweden, Sci Life Lab, Solna, Sweden.
    Berglund, Anders
    Epistat, Uppsala, Sweden.
    Ponten, Victor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Persson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Brunnström, Hans
    Lund Univ, Skane Univ Hosp, Div Pathol, Lund, Sweden.
    Isaksson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Micke, Patrick
    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.
    Karlsson, Mikael C. I.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
    Botling, Johan
    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.
    Expression of scavenger receptor MARCO defines a targetable tumor-associated macrophage subset in non-small cell lung cancer2018Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, nr 7, s. 1741-1752Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 28.
    La Fleur, Linnea
    et al.
    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.
    Falk-Sörqvist, Elin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Smeds, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Berglund, Anders
    Sundström, Magnus
    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.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Dept. of Respiratory Medicine, Gävle Hospital, Gävle.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Dept. of Respiratory Medicine, Gävle Hospital, Gävle.
    Isaksson, Johan
    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. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Dept. of Respiratory Medicine, Gävle Hospital, Gävle.
    Brunnström, Hans
    Nilsson, Mats
    Micke, Patrick
    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.
    Moens, Lotte
    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.
    Botling, Johan
    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.
    Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK112019Inngår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 130, s. 50-58Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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

    Fulltekst (pdf)
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  • 29.
    La Fleur, Linnea
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Falk-Sörqvist, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Smeds, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sundström, Magnus
    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.
    Brandén, Eva
    Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Koyi, Hirsh
    Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Isaksson, Johan
    Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Brunnström, Hans
    Reg Labs Reg Skane, Pathol, Lund, Sweden.
    Sandelin, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Lamberg, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Landelius, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi.
    Nilsson, Mats
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Moens, Lotte
    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.
    Mutation Profiling by Targeted Next Generation Sequencing of an Unselected NSCLC Cohort2017Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, nr 1, s. S526-S527Artikkel i tidsskrift (Annet vitenskapelig)
  • 30.
    La Fleur, Linnea
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Moens, Lotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Falk-Sörqvist, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mattsson, Johanna S. M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Koyi, Hirsh
    Gavle Cent Hosp, Dept Resp Med, S-80187 Gavle, Sweden..
    Branden, Eva
    Gavle Cent Hosp, Dept Resp Med, S-80187 Gavle, Sweden..
    Brunnström, Hans
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden..
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sandelin, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Isaksson, Johan
    Gavle Cent Hosp, Dept Resp Med, S-80187 Gavle, Sweden..
    Jirström, Karin
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Nilsson, Mats
    Stockholm Univ, Dept Biochem & Biophys, S-10691 Stockholm, Sweden..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mutation Profiling by Targeted Next-Generation Sequencing for Diagnostics and Patient Cohort Screening in FFPE NSCLC Samples2015Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, nr 9, s. S697-S697Artikkel i tidsskrift (Annet vitenskapelig)
  • 31.
    Lindskog, Cecilia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Edlund, Karolina
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Immunohistochemistry-based prognostic biomarkers in NSCLC: novel findings on the road to clinical use?2015Inngår i: Expert Review of Molecular Diagnostics, ISSN 1473-7159, E-ISSN 1744-8352, Vol. 15, nr 4, s. 471-490Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Prognostication of non-small cell lung cancer is principally based on stage, age and performance status. This review provides an overview of 342 potential prognostic biomarkers in non-small cell lung cancer described between January 2008 and June 2013, evaluating the association between immunohistochemical protein expression and survival endpoint. Numerous studies proposed prognostic biomarkers, but many were only evaluated in a single patient cohort, and a large number of biomarkers revealed inconclusive findings when analyzed in more than one study. Only 26 proteins first described after 2008 (ALDH1A1, ANXA1, BCAR1, CLDN1, EIF4E, EZH2, FOLR1, FOXM1, IL7R, IL12RB2, KIAA1524, CRMP1, LOX, MCM7, MTA1, MTDH, NCOA3, NDRG2, NEDD9, NES, PBK, PPM1D, SIRT1, SLC7A5, SQSTM1 and WNT1) demonstrated a consistent prognostic association in two or more independent patient cohorts, thus qualifying as promising candidates for diagnostic use. Raised quality standards for study design and antibody validation, and integration of preclinical findings with clinical needs are clearly warranted.

  • 32.
    Lohr, Miriam
    et al.
    TU Dortmund Univ, Dept Stat, D-44227 Dortmund, Germany..
    Hellwig, Birte
    TU Dortmund Univ, Dept Stat, D-44227 Dortmund, Germany..
    Edlund, Karolina
    Dortmund TU, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Mattsson, Johanna S. M.
    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.
    Schmidt, Marcus
    Univ Hosp, Dept Obstet & Gynecol, Mainz, Germany..
    Hengstler, Jan G.
    Dortmund TU, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Rahnenfuehrer, Joerg
    TU Dortmund Univ, Dept Stat, D-44227 Dortmund, Germany..
    Identification of sample annotation errors in gene expression datasets2015Inngår i: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 89, nr 12, s. 2265-2272Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The comprehensive transcriptomic analysis of clinically annotated human tissue has found widespread use in oncology, cell biology, immunology, and toxicology. In cancer research, microarray-based gene expression profiling has successfully been applied to subclassify disease entities, predict therapy response, and identify cellular mechanisms. Public accessibility of raw data, together with corresponding information on clinicopathological parameters, offers the opportunity to reuse previously analyzed data and to gain statistical power by combining multiple datasets. However, results and conclusions obviously depend on the reliability of the available information. Here, we propose gene expression-based methods for identifying sample misannotations in public transcriptomic datasets. Sample mix-up can be detected by a classifier that differentiates between samples from male and female patients. Correlation analysis identifies multiple measurements of material from the same sample. The analysis of 45 datasets (including 4913 patients) revealed that erroneous sample annotation, affecting 40 % of the analyzed datasets, may be a more widespread phenomenon than previously thought. Removal of erroneously labelled samples may influence the results of the statistical evaluation in some datasets. Our methods may help to identify individual datasets that contain numerous discrepancies and could be routinely included into the statistical analysis of clinical gene expression data.

    Fulltekst (pdf)
    fulltext
  • 33.
    Mattsson, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    An integrative strategy for targeted evaluation of biomarker expression in non-small cell lung cancer2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Despite improvements in therapy, the prognosis for non-small cell lung cancer (NSCLC) patients remains poor, and cure is only possible in localized tumors after surgical resection. A new generation of targeted cancer drugs has led to the expectation that lung cancer therapy can be significantly improved, but these drugs are today only an option in a small subset of NSCLC patients, and their effect is temporary. Therefore, the aim of this thesis was to characterize NSCLC in order to find new treatment targets and to evaluate biomarkers that further optimize therapy selection.

    In Paper I, the expression of the potential treatment targets claudin 6 and claudin 18.2 were evaluated based on immunohistochemical- and gene expression analysis. High ectopic protein and gene expression were demonstrated for both claudins in small subgroups of NSCLC. Clinical trials using humanized monoclonal antibodies against both proteins are ongoing in other cancer forms and may be extended to NSCLC.

    In Paper II, the prognostic impact of the inflammatory mediator cyclooxygenase 2 (COX-2) was evaluated. No prognostic significance was found in a meta-analysis incorporating gene expression data of 1337 NSCLC patients. Likewise, COX-2 protein expression in tumor cells was not associated with survival in two independent NSCLC cohorts. However, in one of the analyzed cohorts, higher COX-2 expression in the tumor stroma was associated with longer survival and may therefore be a subject for further investigation.

    In Paper III, tumor and stromal COX-2 protein expression was examined in patients treated with the COX-2 inhibitor celecoxib in order to evaluate if COX-2 expression is a predictive biomarker for benefit of celecoxib therapy. Celecoxib did not prolong overall survival neither in the whole cohort nor in patients stratified according to COX-2 expression in tumor or stromal cells. Noteworthy, a tendency towards longer survival was again demonstrated in patients with high COX-2 stromal expression.

    In Paper IV, the diagnostic methods for identification of ALK rearrangements were assessed in a large representative Swedish NSCLC population. Fluorescence in situ hybridization (FISH), as the diagnostic standard, was compared to two immunohistochemical assays. ALK gene expression levels were incorporated to supplement the molecular data. The frequency of ALK rearrangements was lower than previously reported. The different methods to detect the ALK fusion demonstrated overlapping results. However, the overlap was poor, so the methods cannot be regarded as interchangeable and should thereby be interpreted with caution when used in clinical diagnostics.

    In summary, this thesis applied an integrative translational approach to characterize potential new treatment targets and to evaluate the detection of existing predictive biomarkers in NSCLC.

    Delarbeid
    1. Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer
    Vise andre…
    2014 (engelsk)Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, nr 9, s. 2206-2214Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Claudins (CLDNs) are central components of tight junctions that regulate epithelial-cell barrier function and polarity. Altered CLDN expression patterns have been demonstrated in numerous cancer types and lineage-specific CLDNs have been proposed as therapy targets. The objective of this study was to assess which fraction of patients with non-small-cell lung cancer (NSCLC) express CLDN6 and CLDN18 isoform 2 (CLDN18.2). Protein expression of CLDN6 and CLDN18.2 was examined by immunohistochemistry on a tissue microarray (n=355) and transcript levels were supportively determined based on gene expression microarray data from fresh-frozen NSCLC tissues (n=196). Both were analyzed with regard to frequency, distribution and association with clinical parameters. Immunohistochemical analysis of tissue sections revealed distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) proteins in virtually non-overlapping subgroups of adenocarcinomas and large-cell carcinomas. Pneumocytes and bronchial epithelial cells were consistently negative. Corresponding to the protein expression, in subsets of non-squamous lung carcinoma high mRNA levels of CLDN6 (7-16%) and total CLDN18 (5-12%) were observed. Protein expression correlated well with total mRNA expression of the corresponding gene (rho=0.4-0.8). CLDN18.2 positive tumors were enriched among slowly proliferating, thyroid transcription factor 1 (TTF-1)-negative adenocarcinomas, suggesting that isoform-specific CLDN expression may delineate a specific subtype. Noteworthy, high CLDN6 protein expression was associated with worse prognosis in lung adenocarcinoma in the univariate [hazard ratio (HR): 1.8; p=0.03] and multivariate COX regression model (HR: 1.9; p=0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC.

    Emneord
    non-small-cell lung cancer, targeted therapy, gene expression profiling, claudin, tissue microarray
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-235148 (URN)10.1002/ijc.28857 (DOI)000341983700026 ()24710653 (PubMedID)
    Merknad

    De 2 första författarna delar förstförfattarskapet. (The 2 first authors contributed equally to the study)

    Tilgjengelig fra: 2014-11-06 Laget: 2014-10-29 Sist oppdatert: 2022-01-28
    2. Prognostic impact of COX-2 in non-small cell lung cancer: A comprehensive compartment-specific evaluation of tumor and stromal cell expression
    Åpne denne publikasjonen i ny fane eller vindu >>Prognostic impact of COX-2 in non-small cell lung cancer: A comprehensive compartment-specific evaluation of tumor and stromal cell expression
    Vise andre…
    2015 (engelsk)Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 356, nr 2, s. 837-845Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n=1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n=616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC.

    HSV kategori
    Forskningsprogram
    Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-239073 (URN)10.1016/j.canlet.2014.10.032 (DOI)000348005500057 ()25449785 (PubMedID)
    Forskningsfinansiär
    Swedish Cancer Society
    Merknad

    De 2 sista författarna delar sistaförfattarskapet. (The 2 last authors contributed equally to the study)

    Tilgjengelig fra: 2015-01-06 Laget: 2014-12-18 Sist oppdatert: 2020-02-05bibliografisk kontrollert
    3. COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.
    Åpne denne publikasjonen i ny fane eller vindu >>COX-2 expression and effects of celecoxib in addition to standard chemotherapy in advanced non-small cell lung cancer.
    Vise andre…
    (engelsk)Inngår i: Artikkel i tidsskrift (Fagfellevurdert) Submitted
    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.

    Emneord
    cyclooxygenase 2, lung cancer, celecoxib, prognosis, inflammation, cancer immunity
    HSV kategori
    Forskningsprogram
    Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-284590 (URN)
    Tilgjengelig fra: 2016-04-19 Laget: 2016-04-18 Sist oppdatert: 2019-04-02
    4. Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer
    Vise andre…
    2016 (engelsk)Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, artikkel-id 603Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data.

    Methods: ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients.

    Results: ALK rearrangements were detected in 1.7% in the complete cohort and 2.0% in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.9% and 1.5% when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (>99%), while the sensitivity was between 69% (Ventana) and 62% (in house Dako protocol). Furthermore, only 67% of the ALK IHC positive cases were positive in both IHC assays. Gene expression analysis revealed that 6/194 (3%) tumors showed high ALK gene expression (≥6AU) and of them only three were positive by either FISH or IHC.

    Conclusion: The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC.

    Emneord
    Anaplastic lymphoma kinase, non-small cell lung cancer, immunohistochemistry, fluorescence in situ hybridization
    HSV kategori
    Forskningsprogram
    Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-284591 (URN)10.1186/s12885-016-2646-x (DOI)000381219600002 ()27495736 (PubMedID)
    Forskningsfinansiär
    Swedish Cancer Society
    Tilgjengelig fra: 2016-04-19 Laget: 2016-04-18 Sist oppdatert: 2019-03-29bibliografisk kontrollert
    Fulltekst (pdf)
    fulltext
    Download (jpg)
    preview image
  • 34.
    Mattsson, Johanna S. M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Svensson, Maria A.
    Univ Orebro, Fac Med & Hlth, Dept Pathol, SE-70182 Orebro, Sweden..
    Hallström, Björn
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Koyi, Hirsh
    Gavle Cent Hosp, Dept Resp Med, S-80187 Gavle, Sweden..
    Branden, Eva
    Gavle Cent Hosp, Dept Resp Med, S-80187 Gavle, Sweden..
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden..
    Edlund, Karolina
    Dortmund TU, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany..
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Grinberg, Marianna
    Dortmund TU, Dept Stat, Dortmund, Germany..
    Rahnenfuehrer, Joerg
    Dortmund TU, Dept Stat, Dortmund, Germany..
    Jirström, Karin
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden..
    Pontén, Fredrik
    Karlsson, Mats G.
    Univ Orebro, Fac Med & Hlth, Dept Pathol, SE-70182 Orebro, Sweden..
    Karlsson, Christina
    Univ Orebro, Fac Med & Hlth, Dept Pathol, SE-70182 Orebro, Sweden..
    Helenius, Gisela
    Univ Orebro, Fac Med & Hlth, Dept Pathol, SE-70182 Orebro, Sweden..
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    ALK Rearrangements in Non-Small Cell Lung Cancer: Comprehensive Integration of Genomic, Gene Expression and Protein Analysis2015Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, nr 9, s. S298-S298Artikkel i tidsskrift (Annet vitenskapelig)
  • 35.
    Mattsson, Johanna Sofia Margareta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Bergman, Bengt
    Grinberg, Marianna
    Edlund, Karolina
    Marincevic, Millaray
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Jirstrom, Karin
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hengstler, Jan G
    Rahnenfuhrer, Jorg
    Karlsson, Mats G
    Karlsson, Christina
    Helenius, Gisela
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Gulyas, Miklos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Prognostic impact of COX-2 in non-small cell lung cancer: A comprehensive compartment-specific evaluation of tumor and stromal cell expression2015Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 356, nr 2, s. 837-845Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n=1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n=616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC.

  • 36.
    Mattsson, Johanna Sofia Margareta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnström, Hans
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden; Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden.
    Jabs, Verena
    TU Dortmund Univ, Dept Stat, Dortmund, Germany.
    Edlund, Karolina
    Dortmund TU, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany.
    Jirström, Karin
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci Lund, Lund, Sweden.
    Mindus, Stephanie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    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.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Karlsson, Mats
    Univ Orebro, Fac Med & Hlth, Dept Res & Educ, Orebro, Sweden.
    Karlsson, Christina
    Univ Orebro, Sch Hlth Sci, Orebro, Sweden.
    Koyi, Hirsh
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Brandén, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Gävleborg. Gavle Cent Hosp, Dept Resp Med, Gavle, Sweden.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Helenius, Gisela
    Univ Orebro, Fac Med & Hlth, Dept Lab Med, Orebro, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Svensson, Maria
    Univ Orebro, Fac Med & Hlth, Clin Res Ctr, Orebro, Sweden.
    Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer2016Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, artikkel-id 603Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data.

    Methods: ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients.

    Results: ALK rearrangements were detected in 1.7% in the complete cohort and 2.0% in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.9% and 1.5% when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (>99%), while the sensitivity was between 69% (Ventana) and 62% (in house Dako protocol). Furthermore, only 67% of the ALK IHC positive cases were positive in both IHC assays. Gene expression analysis revealed that 6/194 (3%) tumors showed high ALK gene expression (≥6AU) and of them only three were positive by either FISH or IHC.

    Conclusion: The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC.

    Fulltekst (pdf)
    fulltext
  • 37.
    Mattsson, Johanna Sofia Margareta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Imgenberg-Kreuz, Juliana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Molekylär och morfologisk patologi.
    Edlund, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Consistent mutation status within histologically heterogeneous lung cancer lesions2012Inngår i: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 61, nr 4, s. 744-748Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: Activating epidermal growth factor receptor (EGFR) and KRAS mutations characterize molecular subgroups of non-small-cell lung cancer (NSCLC) with a strong predictive value for response to EGFR inhibitor therapy. However, the temporal occurrence and clonal stability of these mutations during the course of cancer progression are debated. The aim of this study was to characterize the presence of EGFR and KRAS mutations in histologically different areas of primary NSCLC lesions. Methods and results: Formalin-fixed paraffin-embedded cancer specimens from six cases with EGFR mutations and five cases with KRAS mutations were selected from a pool of primary resected NSCLC patients. From each tumour, three morphologically distinct areas were manually microdissected and analysed for the presence of mutations. The results demonstrated consistent EGFR and KRAS mutation status in the different histological areas of all primary tumours. Conclusions: The results support the concept that activating EGFR and KRAS mutations are oncogenic events that are consistently present throughout the primary tumour independently of histological heterogeneity. Thus, for molecular diagnostics, any part of the tumour is likely to be representative for EGFR and KRAS mutation testing.

  • 38.
    Mezheyeuski, Artur
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mattsson, Johanna
    Martín-Bernabé, Alfonso
    Larsson, Chatarina
    Hrynchyk, Ina
    Hammarström, Klara
    Ström, Simon
    Ekström, Joakim
    Mauchanski, Siarhei
    Khelashvili, Salome
    Agnarsdóttir, Margrét
    Edqvist, Per-Henrik
    Huvila, Jutta
    Segersten, Ulrika
    Malmström, Per-Uno
    Botling, Johan
    Nodin, Björn
    Hedner, Charlotta
    Borg, David
    Brändstedt, Jenny
    Sartor, Hanna
    Leandersson, Karin
    Glimelius, Bengt
    Portyanko, Anna
    Pontén, Fredrik
    Jirström, Karin
    Micke, Patrick
    Sjöblom, Tobias
    The ratio of CD8+ lymphocytes to CD68+CD163+ macrophages is prognostic in immunogenic tumors and predicts immunotherapy responseManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Immune cells in the microenvironment shape tumor development and progression. Through in situ analyses we assessed 15 immune cell classes in 352 colorectal cancers and identified a simpleprognostic signature based on the ratio of anti-tumoral CD8+ lymphocytes to tumor-supportiveCD68+CD163+ macrophages in the tumor microenvironment. The prognostic ability of this signature was superior to the state-of-art immune score and was also demonstrated in four other tumor types. Single-cell analyses identified these CD68+CD163+ macrophages as the source of complement C1q, and the ratio of CD8A to C1QA gene expression levels in bulk RNA predicted survival in five tumor types. In single cell analyses, RNA-based versions of the signature also predicted response to checkpoint inhibitor therapy. This supports broad clinical applicability of immune scores considering CD68+CD163+ macrophages as prognostic and predictive biomarkers in common cancers.

  • 39.
    Mezheyeuski, Artur
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Martin-Bernabe, Alfonso
    Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Karolinska Vagen A2 07, S-17164 Solna, Sweden..
    Larsson, Chatarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Hrynchyk, Ina
    City Clin Pathologoanat Bur, Minsk 220116, BELARUS..
    Hammarström, Klara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Ström, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ekström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Mauchanski, Siarhei
    NN Alexandrov Natl Canc Ctr Belarus, Minsk 223040, BELARUS..
    Khelashvili, Salome
    NN Alexandrov Natl Canc Ctr Belarus, Minsk 223040, BELARUS..
    Lindberg, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Agnarsdóttir, Margrét
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Huvila, Jutta
    Univ Turku, Dept Pathol, Turku 20500, Finland..
    Segersten, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Malmström, Per-Uno
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Nodin, Bjoern
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, Barngatan 4, S-22185 Lund, Sweden..
    Hedner, Charlotta
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, Barngatan 4, S-22185 Lund, Sweden..
    Borg, David
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, Barngatan 4, S-22185 Lund, Sweden..
    Brandstedt, Jenny
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, Barngatan 4, S-22185 Lund, Sweden..
    Sartor, Hanna
    Lund Univ, Skane Univ Hosp, Dept Translat Med, Diagnost Radiol, Carl Bertil Laurells Gata 9, S-20502 Malmö, Sweden..
    Leandersson, Karin
    Lund Univ, Dept Translat Med, Canc Immunol, J Waldenstroms Gata 35, S-21428 Malmö, Sweden..
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Portyanko, Anna
    NN Alexandrov Natl Canc Ctr Belarus, Minsk 223040, BELARUS..
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Jirstrom, Karin
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, Barngatan 4, S-22185 Lund, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers2023Inngår i: EBioMedicine, E-ISSN 2352-3964, Vol. 88, artikkel-id 104452Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression.

    Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations.

    Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy.

    Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types.

    Fulltekst (pdf)
    fulltext
  • 40.
    Micke, Patrick
    et al.
    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.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Planck, Maria
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Skane Univ Hosp, Dept Resp Med & Allergol, SE-22185 Lund, Sweden.
    Tran, Lena
    Region Skane, Div Lab Med, Dept Genet & Pathol, SE-22185 Lund, Sweden.
    Vidarsdottir, Halla
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Helsingborg Hosp, Dept Surg, SE-25187 Helsingborg, Sweden.
    Nodin, Bjorn
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden.
    Jirstrom, Karin
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Region Skane, Div Lab Med, Dept Genet & Pathol, SE-22185 Lund, Sweden.
    Brunnstrom, Hans
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, SE-22100 Lund, Sweden;Region Skane, Div Lab Med, Dept Genet & Pathol, SE-22185 Lund, Sweden.
    Mucin staining is of limited value in addition to basic immunohistochemical analyses in the diagnostics of non-small cell lung cancer2019Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 9, artikkel-id 1319Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Accurate diagnosis of histological type is important for therapy selection in lung cancer. Immunohistochemical (IHC) and histochemical stains are often used to complement morphology for definite diagnosis and are incorporated in the WHO classification. Our main aim was to compare different mucin stains and assess their value in relation to common IHC analyses in lung cancer diagnostics. Using tissue microarrays from 657 surgically treated primary lung cancers, we evaluated the mucin stains periodic acid-Schiff with diastase (PASD), alcian blue-periodic acid-Schiff (ABPAS) and mucicarmine, and compared with the IHC markers p40, p63, cytokeratin 5, thyroid transcription factor 1 (TTF-1), napsin A and cytokeratin 7. Ten or more cytoplasmic mucin inclusions in a tissue microarray core were seen in 51%, 48% and 31% of the 416 adenocarcinomas and 3%, 4% and 0.5% of the 194 squamous cell carcinomas with PASD, ABPAS and mucicarmine, respectively. Diagnostic pitfalls, such as entrapped benign epithelium, apoptotic/necrotic cells and glycogen, partly differed for the mucin stains. TTF-1 and napsin A IHC stainings had similar specificity but better sensitivity for adenocarcinoma than the mucin stains, but addition of PASD or ABPAS identified more tumors as adenocarcinomas (n = 8 and n = 10, respectively) than napsin A (n = 1) in cases with solid growth that were negative for TTF-1 and p40. We conclude that PASD and ABPAS have similar diagnostic performance and that these markers are of value in poorly differentiated cases. However, morphology and TTF-1 and p40 IHC staining is sufficient for correct diagnosis in most non-small cell lung cancers.

    Fulltekst (pdf)
    FULLTEXT01
  • 41.
    Micke, Patrick
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Djureinovic, Dijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Nodin, Björn
    Jirström, Karin
    Tran, Lena
    Jönsson, Per
    Planck, Maria
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Brunnström, Hans
    The Impact of the Fourth Edition of the WHO Classification of Lung Tumours on Histological Classification of Resected Pulmonary NSCCs2016Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 11, nr 6, s. 862-872Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: Histopathological classification of lung cancer is of central importance in the diagnostic routine and guides therapy in the majority of patients. The 4(th) edition of the WHO classification was recently published and includes changes to the diagnostic procedure of non-small cell carcinomas (NSCC) with more emphasis on immunohistochemical (IHC) staining.

    METHODS: 656 unselective cases of resected pulmonary NSCC were diagnosed according to the 2004 WHO classification. After IHC staining with cytokeratin 5, p40, p63, thyroid transcription factor 1 (clones 8G7G3/1 and SPT24) and napsin A the diagnoses were revised in accordance with the new 4(th) edition of the WHO classification.

    RESULTS: Reclassification led to a new histological annotation in 36 (5%) of the 656 cases. Most notable was the decrease of cases previously classified as large cell carcinomas (56 vs. 12 cases). This was partially due to the exclusion of 21 neuroendocrine tumors from this group, while 20 cases were ascribed to the group of adenocarcinoma based on IHC markers. Only 7 cases of adenocarcinoma or squamous cell carcinoma were reclassified after the addition of IHC staining. There was a substantial overlap in staining properties between different markers of squamous and adenocarcinomatous differentiation, respectively, but in 17-31 cases (3-5%) the diagnosis depended on the choice of markers.

    CONCLUSIONS: The 4(th) edition of the WHO classification of lung tumours leads to changes of histological type in 5% of resected NSCC cases. The incorporation of IHC staining in NSCC diagnostics demands awareness that the choice of ancillary stains has an effect on diagnosis.

  • 42.
    Micke, Patrick
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Edlund, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Lohr, Miriam
    Jirstrom, Karin
    Berglund, Anders
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Rahnenfuehrer, Joerg
    Marincevic, Millaray
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Hengstler, Jan
    Woell, Stefan
    Sahin, Ugur
    Tuereci, Oezlem
    Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer2014Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, nr 9, s. 2206-2214Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Claudins (CLDNs) are central components of tight junctions that regulate epithelial-cell barrier function and polarity. Altered CLDN expression patterns have been demonstrated in numerous cancer types and lineage-specific CLDNs have been proposed as therapy targets. The objective of this study was to assess which fraction of patients with non-small-cell lung cancer (NSCLC) express CLDN6 and CLDN18 isoform 2 (CLDN18.2). Protein expression of CLDN6 and CLDN18.2 was examined by immunohistochemistry on a tissue microarray (n=355) and transcript levels were supportively determined based on gene expression microarray data from fresh-frozen NSCLC tissues (n=196). Both were analyzed with regard to frequency, distribution and association with clinical parameters. Immunohistochemical analysis of tissue sections revealed distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) proteins in virtually non-overlapping subgroups of adenocarcinomas and large-cell carcinomas. Pneumocytes and bronchial epithelial cells were consistently negative. Corresponding to the protein expression, in subsets of non-squamous lung carcinoma high mRNA levels of CLDN6 (7-16%) and total CLDN18 (5-12%) were observed. Protein expression correlated well with total mRNA expression of the corresponding gene (rho=0.4-0.8). CLDN18.2 positive tumors were enriched among slowly proliferating, thyroid transcription factor 1 (TTF-1)-negative adenocarcinomas, suggesting that isoform-specific CLDN expression may delineate a specific subtype. Noteworthy, high CLDN6 protein expression was associated with worse prognosis in lung adenocarcinoma in the univariate [hazard ratio (HR): 1.8; p=0.03] and multivariate COX regression model (HR: 1.9; p=0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC.

  • 43.
    Micke, Patrick
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Strell, Carina
    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.
    Martin-Bernabe, Alfonso
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Pathol, Lund, Sweden.;Dept Genet & Pathol, Div Lab Med, Lund, Sweden..
    Huvila, Jutta
    Univ British Columbia, Dept Pathol, Vancouver, BC, Canada.;Univ Turku, Dept Pathol, Turku, Finland..
    Sund, Malin
    Umeå Univ, Dept Surg & Perioperat Sci Surg, Umeå, Sweden..
    Wärnberg, Fredrik
    Sahlgrenska Univ Hosp Göteborg, Inst Clin Sci, Dept Surg, Gothenburg, Sweden..
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hrynchyk, Ina
    City Clin Pathologoanat Bur, Minsk, BELARUS..
    Mauchanski, Siarhei
    NN Alexandrov Natl Canc Ctr Belarus, Minsk 223040, BELARUS..
    Khelashvili, Salome
    NN Alexandrov Natl Canc Ctr Belarus, Minsk 223040, BELARUS..
    Garcia-Vicien, Gemma
    Catalan Inst Oncol, Program Canc Therapeut Resistance, IDIBELL,ProCURE, Mol Mech & Expt Therapy Oncol Program ONCOBELL, Barcelona, Spain..
    Mollevi, David G.
    Catalan Inst Oncol, Program Canc Therapeut Resistance, IDIBELL,ProCURE, Mol Mech & Expt Therapy Oncol Program ONCOBELL, Barcelona, Spain..
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Reilly, Aine O.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Corvigno, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Dahlstrand, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Segersten, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Krzyzanowska, Agnieszka
    Lund Univ, Dept Translat Med, Div Urol Canc, Lund, Sweden..
    Bjartell, Anders
    Lund Univ, Dept Translat Med, Div Urol Canc, Lund, Sweden..
    Elebro, Jacob
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, SE-22100 Lund, Sweden..
    Heby, Margareta
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, SE-22100 Lund, Sweden..
    Lundgren, Sebastian
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, SE-22100 Lund, Sweden..
    Hedner, Charlotta
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, SE-22100 Lund, Sweden..
    Borg, David
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, SE-22100 Lund, Sweden..
    Brändstedt, Jenny
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, SE-22100 Lund, Sweden..
    Sartor, Hanna
    Lund Univ, Skane Univ Hosp, Dept Translat Med, Diagnost Radiol, Lund, Sweden..
    Malmström, Per-Uno
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Johansson, Martin
    Sahlgrenska Univ Hosp Göteborg, Inst Biomed, Dept Lab Med, Gothenburg, Sweden..
    Nodin, Björn
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, SE-22100 Lund, Sweden..
    Backman, Max
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Lindskog, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Jirström, Karin
    Dept Genet & Pathol, Div Lab Med, Lund, Sweden.;Lund Univ, Dept Clin Sci Lund, Div Oncol & Therapeut Pathol, SE-22100 Lund, Sweden..
    Mezheyeuski, Artur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala Univ, Dept Immunol Genet & Pathol, S-75185 Uppsala, Sweden..
    The prognostic impact of the tumour stroma fraction: A machine learning-based analysis in 16 human solid tumour types2021Inngår i: EBioMedicine, E-ISSN 2352-3964, Vol. 65, artikkel-id 103269Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed.

    Methods: Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns.

    Findings: The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR (95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59 (1.49-8.62)) associations of the tumour stroma fraction with survival.

    Interpretation: Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance.

    Fulltekst (pdf)
    fulltext
  • 44.
    Moens, Lotte. N.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Falk-Sörqvist, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mattsson, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Bergfors, M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Sundström, M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Nilsson, M.
    Stockholm Univ, S-10691 Stockholm, Sweden..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Clinical Validation of HaloPlex Targeted Resequencing in Formalin-Fixed, Paraffin-Embedded (FFPE) Cancer Biopsies2015Inngår i: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, nr 6, s. 822-822Artikkel i tidsskrift (Annet vitenskapelig)
  • 45.
    Moens, Lotte N. J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Falk-Sörqvist, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Ljungström, Viktor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Mattsson, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sundström, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Mathot, Lucy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Nilsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Stockholm Univ, Sci Life Lab, Dept Biochem & Biophys, S-10691 Stockholm, Sweden..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    HaloPlex Targeted Resequencing for Mutation Detection in Clinical Formalin-Fixed, Paraffin-Embedded Tumor Samples2015Inngår i: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, nr 6, s. 729-739Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In recent years, the advent of massively parallel next-generation sequencing technologies has enabled substantial advances in the study of human diseases. Combined with targeted DNA enrichment methods, high sequence coverage can be obtained for different genes simultaneously at a reduced cost per sample, creating unique opportunities for clinical cancer diagnostics. However, the formalin-fixed, paraffin-embedded (FFPE) process of tissue samples, routinely used in pathology departments, results in DNA fragmentation and nucleotide modifications that introduce a number of technical challenges for downstream biomotecular analyses. We evaluated the HaloPlex target enrichment system for somatic mutation detection in 80 tissue fractions derived from 20 clinical cancer cases with paired tumor and normal tissue available in both FFPE and fresh-frozen format. Several modifications to the standard method were introduced, including a reduced target fragment Length and two strand capturing. We found that FFPE material can be used for HaloPlex-based target enrichment and next-generation sequencing, even when starting from small amounts of DNA. By specifically capturing both strands for each target fragment, we were able to reduce the number of false-positive errors caused by FFPE-induced artifacts and Lower the detection limit for somatic mutations. We believe that the HaloPlex method presented here will be broadly applicable as a tool for somatic mutation detection in clinical cancer settings.

  • 46. Noguchi, Satoshi
    et al.
    Saito, Akira
    Horie, Masafumi
    Mikami, Yu
    Suzuki, Hiroshi I.
    Morishita, Yasuyuki
    Ohshima, Mitsuhiro
    Abiko, Yoshimitsu
    Mattsson, Johanna S. M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Koenig, Helena
    Lohr, Miriam
    Edlund, Karolina
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Nagase, Takahide
    An Integrative Analysis of the Tumorigenic Role of TAZ in Human Non-Small Cell Lung Cancer2014Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, nr 17, s. 4660-4672Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: TAZ, also known as WWTR1, has recently been suggested as an oncogene in non-small cell lung cancer (n =SCLC). We investigated the clinical relevance of TAZ expression and its functional role in NSCLC tumorigenesis. Experimental Design: We characterized TAZ at the DNA (n = 192), mRNA (n = 196), and protein levels (n = 345) in an NSCLC patient cohort. Gene expression analysis was complemented by a meta-analysis of public datasets (n = 1,382). The effects of TAZ on cell proliferation and cell cycle were analyzed in cell cultures and on tumor growth in mice. TAZ-dependent microarray-based expression profiles in NSCLC cells were combined with molecular profiles in human NSCLC tissues for in silico analysis. Results: Higher TAZmRNA and protein levels were associated with shorter patient survival. Transduction of TAZ enhanced cell proliferation and tumorigenesis in bronchial epithelial cells, whereas TAZ silencing suppressed cell proliferation and induced cell cycle arrest in NSCLC cells. Microarray and cell culture experiments showed that ErbB ligands (amphiregulin, epiregulin, and neuregulin 1) are downstream targets of TAZ. Our in silico analysis revealed a TAZ signature that substantiated the clinical impact of TAZ and confirmed its relationship to the epidermal growth factor receptor signaling pathway. Conclusion: TAZ expression defines a clinically distinct subgroup of patients with NSCLC. ErbB ligands are suggested to mediate the effects of TAZ on lung cancer progression. Our findings emphasize the tumorigenic role of TAZ and may serve as the basis for new treatment strategies.

  • 47.
    Staaf, Johan
    et al.
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden.
    Tran, Lena
    Reg Skåne, Div Lab Med, Dept Genet & Pathol, Lund, Sweden.
    Söderlund, Linnea
    Reg Skåne, Div Lab Med, Dept Genet & Pathol, Lund, Sweden.
    Nodin, Björn
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden.
    Jirström, Karin
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden; Reg Skåne, Div Lab Med, Dept Genet & Pathol, Lund, Sweden.
    Vidarsdottir, Halla
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden; Helsingborg Hosp, Dept Surg, Helsingborg, Sweden.
    Planck, Maria
    Skåne Univ Hosp, Dept Resp Med & Allergol, Lund, Sweden.
    Mattsson, Johanna S. M.
    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.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnström, Hans
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, Lund, Sweden; Reg Skåne, Div Lab Med, Dept Genet & Pathol, Lund, Sweden.
    Diagnostic Value of Insulinoma-Associated Protein 1 (INSM1) and Comparison With Established Neuroendocrine Markers in Pulmonary Cancers: A Comprehensive Study and Review of the Literature2020Inngår i: Archives of Pathology & Laboratory Medicine, ISSN 0003-9985, E-ISSN 1543-2165, Vol. 144, nr 9, s. 1075-1085Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Context.—

    The diagnostic distinction of pulmonary neuroendocrine (NE) tumors from non–small cell lung carcinomas (NSCLCs) is clinically relevant for prognostication and treatment. Diagnosis is based on morphology and immunohistochemical staining.

    Objective.—

    To determine the diagnostic value of insulinoma-associated protein 1 (INSM1), in comparison with established NE markers, in pulmonary tumors.

    Design.—

    Fifty-four pulmonary NE tumors and 632 NSCLCs were stained for INSM1, CD56, chromogranin A, and synaptophysin. In a subset, gene expression data were available for analysis. Also, 419 metastases to the lungs were stained for INSM1. A literature search identified 39 additional studies with data on NE markers in lung cancers from the last 15 years. Seven of these included data on INSM1.

    Results.—

    A positive INSM1 staining was seen in 39 of 54 NE tumors (72%) and 6 of 623 NSCLCs (1%). The corresponding numbers were 47 of 54 (87%) and 14 of 626 (2%) for CD56, 30 of 54 (56%) and 6 of 629 (1%) for chromogranin A, and 46 of 54 (85%) and 49 of 630 (8%) for synaptophysin, respectively. Analysis of literature data revealed that CD56 and INSM1 were the best markers for identification of high-grade NE pulmonary tumors when considering both sensitivity and specificity, while synaptophysin also showed good sensitivity. INSM1 gene expression was clearly associated with NE histology.

    Conclusions.—

    The solid data of both our and previous studies confirm the diagnostic value of INSM1 as a NE marker in pulmonary pathology. The combination of CD56 with INSM1 and/or synaptophysin should be the first-hand choice to confirm pulmonary high-grade NE tumors. INSM1 gene expression could be used to predict NE tumor histology.

  • 48.
    Thurfjell, Viktoria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Yu, Hui
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Krupar, Rosemarie
    Svensson, Maria A
    Brunnström, Hans
    Lamberg, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lung- allergi- och sömnforskning.
    Moens, Lotte
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Strell, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Gulyas, Miklos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Helenius, Gisela
    Yoshida, Akihiko
    Goldmann, Torsten
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Comparison of ROS1-rearrangement detection methods in a cohort of surgically resected non-small cell lung carcinomas.2022Inngår i: Translational lung cancer research, ISSN 2218-6751, Vol. 11, nr 12, s. 2477-2494Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Patients with non-small cell lung cancer (NSCLC) harboring a ROS proto-oncogene 1 (ROS1)-rearrangement respond to treatment with ROS1 inhibitors. To distinguish these rare cases, screening with immunohistochemistry (IHC) for ROS1 protein expression has been suggested. However, the reliability of such an assay and the comparability of the antibody clones has been debated. Therefore we evaluated the diagnostic performance of current detection strategies for ROS1-rearrangement in two NSCLC-patient cohorts.

    METHODS: Resected tissue samples, retrospectively collected from consecutive NSCLC-patients surgically treated at Uppsala University Hospital were incorporated into tissue microarrays [all n=676, adenocarcinomas (AC) n=401, squamous cell carcinomas (SCC) n=213, other NSCLC n=62]. ROS1-rearrangements were detected using fluorescence in situ hybridization (FISH) (Abbott Molecular; ZytoVision). In parallel, ROS1 protein expression was detected using IHC with three antibody clones (D4D6, SP384, EPMGHR2) and accuracy, sensitivity, and specificity were determined. Gene expression microarray data (Affymetrix) and RNA-sequencing data were available for a subset of patients. NanoString analyses were performed for samples with positive or ambiguous results (n=21).

    RESULTS: Using FISH, 2/630 (0.3% all NSCLC; 0.5% non-squamous NSCLC) cases were positive for ROS1 fusion. Additionally, nine cases demonstrated ambiguous FISH results. Using IHC, ROS1 protein expression was detected in 24/665 (3.6% all NSCLC; 5.1% non-squamous NSCLC) cases with clone D4D6, in 18/639 (2.8% all NSCLC; 3.9% non-squamous NSCLC) cases with clone SP384, and in 1/593 (0.2% all NSCLC; 0.3% non-squamous NSCLC) case with clone EPMGHR2. Elevated RNA-levels were seen in 19/369 (5.1%) cases (Affymetrix and RNA-sequencing combined). The overlap of positive results between the assays was poor. Only one of the FISH-positive cases was positive with all antibodies and demonstrated high RNA-expression. This rearrangement was confirmed in the NanoString-assay and also in the RNA-sequencing data. Other cases with high protein/RNA-expression or ambiguous FISH were negative in the NanoString-assay.

    CONCLUSIONS: The occurrence of ROS1 fusions is low in our cohorts. The IHC assays detected the fusions, but the accuracy varied depending on the clone. The presumably false-positive and uncertain FISH results questions this method for detection of ROS1-rearrangements. Thus, when IHC is used for screening, transcript-based assays are preferable for validation in clinical diagnostics.

  • 49.
    Tran, Lena
    et al.
    Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden.
    Mattsson, Johanna Sofia Margareta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Nodin, Björn
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Jönsson, Per
    Lund Univ, Dept Thorac Surg, Lund, Sweden; Skane Univ Hosp, Lund, Sweden.
    Planck, Maria
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden; Skane Univ Hosp, Dept Oncol, Lund, Sweden.
    Jirström, Karin
    Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden; Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brunnström, Hans
    Reg Labs Reg Skane, Dept Pathol, SE-22185 Lund, Sweden; Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Various Antibody Clones of Napsin A, Thyroid Transcription Factor 1, and p40 and Comparisons With Cytokeratin 5 and p63 in Histopathologic Diagnostics of Non-Small Cell Lung Carcinoma2016Inngår i: Applied immunohistochemistry & molecular morphology (Print), ISSN 1541-2016, E-ISSN 1533-4058, Vol. 24, nr 9, s. 648-659Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Histopathologic classification of cancer in the lung is important for choice of treatment. Cytokeratin 5 (CK5), p63, and p40 are commonly used immunohistochemical markers for squamous cell carcinoma, and napsin A (NAPA) and thyroid transcription factor 1 (TTF-1) are markers for adenocarcinoma of the lung. The aim of the present study was to evaluate these 5 markers and to compare different commercially available antibody clones in lung cancer. Tissue microarrays including 557 cases of surgically treated primary tumors and 73 matched metastases of non-small cell lung carcinoma were stained with CK5, p63, p40 (monoclonal and polyclonal), NAPA (5 different clones/protocols), and TTF-1 (2 different clones). The sensitivity and specificity to separate squamous cell carcinomas from non-small cell carcinomas of nonsquamous type were 95% and 97%, respectively, for CK5, 95% and 87% for p63, 94% and 96% for p40, 75% to 79% and 96% to 98% for the NAPA clones/protocols and 80% to 85% and 95% to 97% for the TTF-1 clones. A combination of NAPA and TTF-1 resulted in a higher sensitivity (85% to 88%), whereas combining CK5 and p40 did not increase the diagnostic performance. The sensitivity was generally lower in evaluation of lung cancer metastases. The κ-values for comparison of staining results between monoclonal and polyclonal p40 and between the 5 NAPA clones/protocols were 0.97 to 1.0, whereas the corresponding figure for the 2 TTF-1 clones was 0.91 to 0.93. Conclusively, CK5 and p40 are good diagnostic markers for squamous cell carcinoma and superior to p63. In addition, it may be useful to combine NAPA and TTF-1 for increased sensitivity in lung cancer diagnostics. There is no substantial difference between monoclonal and polyclonal p40 and between different NAPA clones, whereas there is a difference between the TTF-1 clones 8G7G3/1 and SPT24.

  • 50.
    Tsakonas, Georgios
    et al.
    Karolinska Inst, Dept Oncol Pathol, Karolinska Univ Hosp, Thorac Oncol Ctr,Theme Canc, Stockholm, Sweden.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Rivard, Chris
    Univ Colorado, Div Med Oncol, Anschutz Med Campus, Aurora, CO USA.
    La Fleur, Linnea
    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.
    Boyle, Teresa
    Univ Colorado, Div Med Oncol, Anschutz Med Campus, Aurora, CO USA.
    Hirsch, Fred R.
    Univ Colorado, Div Med Oncol, Anschutz Med Campus, Aurora, CO USA.
    Ekman, Simon
    Karolinska Inst, Dept Oncol Pathol, Karolinska Univ Hosp, Thorac Oncol Ctr,Theme Canc, Stockholm, Sweden.
    c-MET as a biomarker in patients with surgically resected non-small cell lung cancer2019Inngår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 133, s. 69-74Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: c-MET protein overexpression has been proposed as a biomarker in non-small cell lung cancer (NSCLC), albeit its role in the clinical setting has not been firmly established yet. Patients and methods: We designed a retrospective cohort study, consisting of 725 patients with surgically removed NSCLC. Immunohistochemistry (IHC) was conducted in tissue microarrays (TMA) from lung tumors and healthy tissue. IHC staining was quantified using H-scores (range 0-300). Association between c-MET H-score and overall survival (OS) as well as progression-free survival (PFS) was explored. Results: c-MET H-score >= 20 had a significant positive impact on OS in the multivariate analysis in the whole study population, HR = 0.79 (95%CI: 0.64 - 0.97). The prognostic effect of c-MET H-score >= 20 was even stronger in patients who received adjuvant treatment with a HR = 0.61 (95% CI: 0.40 - 0.93). In the subgroup of adenocarcinoma and squamous cell carcinoma patients with stage IIA-IIIB disease, the prognostic impact of c-MET was significant in the univariate analysis (HR = 0.60, 95% CI: 0.43 - 0.83). Conclusion: c-MET H-score >= 20 is a positive prognostic biomarker for OS in early stage NSCLC. This benefit seems to be strongly correlated to adjuvant chemotherapy, therefore rendering c-MET H-score >= 20 a possible predictive biomarker for platinum-based adjuvant chemotherapy in early stage NSCLC.

12 1 - 50 of 54
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