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  • 51.
    Ke, Rongqin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Mignardi, Marco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Pacureanu, Alexandra
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Svedlund, Jessica
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Wählby, Carolina
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för visuell information och interaktion. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Bildanalys och människa-datorinteraktion.
    Nilsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    In situ sequencing for RNA analysis in preserved tissue and cells2013Inngår i: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 10, nr 9, s. 857-860Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tissue gene expression profiling is performed on homogenates or on populations of isolated single cells to resolve molecular states of different cell types. In both approaches, histological context is lost. We have developed an in situ sequencing method for parallel targeted analysis of short RNA fragments in morphologically preserved cells and tissue. We demonstrate in situ sequencing of point mutations and multiplexed gene expression profiling in human breast cancer tissue sections.

  • 52.
    Kerr, K.
    et al.
    Univ Aberdeen, Med Sch, Aberdeen Royal Infirm, Aberdeen, Scotland.
    Tsao, M.
    Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada;Univ Toronto, Toronto, ON, Canada.
    Yatabe, Y.
    Aichi Canc Ctr, Nagoya, Aichi, Japan.
    Thunnissen, E.
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands.
    Nicholson, A.
    Imperial Coll London, Royal Brompton, London, England.
    Moreira, A.
    New York Univ Langone Hlth, New York, NY USA.
    Chou, T.
    Taipei Vet Gen Hosp, Taipei, Taiwan.
    Borczuk, A.
    Weill Cornell Med, New York, NY USA.
    Bubendorf, L.
    Universiteitsspital Basel, Pathol, Basel, Switzerland.
    Mino-Kenudson, M.
    Massachusetts Gen Hosp, Boston, MA 02114 USA;Harvard Med Sch, Boston, MA 02114 USA.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Beasley, M. B.
    Mt Sinai Med Ctr, New York, NY 10029 USA.
    Chirieac, L.
    Harvard Med Sch, Boston, MA 02114 USA;Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA.
    Dacic, S.
    Univ Pittsburgh, Pittsburgh, PA USA.
    Lantuejoul, S.
    Ctr Leon Berard, Lyon, France.
    Pelosi, G.
    Univ Milan, Milan, Italy;IRCCS Multimedia, Interhosp Pathol Div, Milan, Italy.
    Chung, J.
    Seoul Natl Univ, Bundang Hosp, Seoul, South Korea.
    Chen, G.
    Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China.
    Russell, P.
    St Vincents Pathol, Fitzroy, Vic, Australia.
    Poleri, C.
    Consultorio Patol Especializada, Buenos Aires, DF, Argentina.
    Sauter, J.
    Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA.
    Yu, H.
    Univ Colorado, Anschutz Med Campus, Aurora, CO USA.
    Noguchi, M.
    Univ Tsukuba, Fac Med, Tsukuba, Ibaraki, Japan.
    Wistuba, I.
    MD Anderson Canc Ctr, Houston, TX USA.
    Pintilie, M.
    Princess Margaret Canc Ctr, Toronto, ON, Canada.
    Wynes, M.
    lnt Assoc Study Lung Canc, Aurora, CO USA.
    Hirsch, F.
    Univ Colorado, Anschutz Med Campus, Aurora, CO USA.
    Phase 2B of Blueprint PD-L1 Immunohistochemistry Assay Comparability Study2018Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, nr 10, s. S325-S325Artikkel i tidsskrift (Annet vitenskapelig)
  • 53.
    Kerr, Keith M.
    et al.
    Univ Aberdeen, Dept Pathol, Med Sch, Aberdeen AB25 2ZD, Scotland.;Aberdeen Royal Infirm, Aberdeen AB25 2ZD, Scotland..
    Bibeau, Frederic
    Normandy Univ, Caen Univ Hosp, Dept Pathol, Caen, France..
    Thunnissen, Erik
    Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands..
    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.
    Ryska, Ales
    Charles Univ Prague, Dept Pathol, Med Fac Hosp, Hradec Kralove, Czech Republic..
    Wolf, Jurgen
    Univ Hosp Cologne, Dept Internal Med 1, Lung Canc Grp Cologne, Cologne, Germany..
    Ohrling, Katarina
    Amgen Europe GmbH, Rotkreuz, Switzerland..
    Burdon, Peter
    Amgen Europe GmbH, Rotkreuz, Switzerland..
    Malapelle, Umberto
    Univ Naples Federico II, Dept Publ Hlth, I-80131 Naples, Italy..
    Buttner, Reinhard
    Univ Cologne, Cologne Inst Pathol, Cologne, Germany..
    The evolving landscape of biomarker testing for non-small cell lung cancer in Europe2021Inngår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 154, s. 161-175Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The discovery of oncogenic driver mutations rendering non-small cell lung cancer (NSCLC) targetable by small molecule inhibitors, and the development of immunotherapies, have revolutionised NSCLC treatment. Today, instead of non-selective chemotherapies, all patients with advanced NSCLC eligible for treatment (and increasing numbers with earlier, less extensive disease) require fast and comprehensive screening of biomarkers for first-line patient selection for targeted therapy, chemotherapy, or immunotherapy (with or without chemotherapy). To avoid unnecessary re-biopsies, biomarker screening before first-line treatment should also include markers that are actionable from second-line onwards; PD-L1 expression testing is also mandatory before initiating treatment.& nbsp; Population differences exist in the frequency of oncogenic driver mutations: EGFR mutations are more frequent in Asia than Europe, whereas the converse is true for KRAS mutations. In addition to approved first-line therapies, a number of emerging therapies are being investigated in clinical trials. Guidelines for biomarker testing vary by country, with the number of actionable targets and the requirement for extensive molecular screening strategies expected to increase. To meet diagnostic demands, rapid screening technologies for single driver mutations have been implemented. Improvements in DNA-and RNA-based next-generation sequencing & nbsp;technologies enable analysis of a group of genes in one assay; however, turnaround times remain relatively long. Consequently, rapid screening technologies are being implemented alongside next-generation sequencing.& nbsp; Further challenges in the evolving landscape of biomarker testing in NSCLC are actionable primary and secondary resistance mechanisms to targeted therapies. Therefore, comprehensive testing on re-biopsies, collected at the time of disease progression, in combination with testing of circulating tumour DNA may provide important information to guide second-or third-line therapies. Furthermore, longitudinal biomarker testing can provide insights into tumour evolution and heterogeneity during the course of the disease. We summarise best practice strategies for Europe in the changing landscape of biomarker testing at diagnosis and during treatment.

    Fulltekst (pdf)
    FULLTEXT01
  • 54. Kerr, Keith M
    et al.
    Tsao, Ming-Sound
    Nicholson, Andrew G
    Yatabe, Yasushi
    Wistuba, Ignacio I
    Hirsch, Fred R
    Botling, Johan
    IASLC Pathology Committee.
    Programmed Death-Ligand 1 Immunohistochemistry in Lung Cancer: In what state is this art?2015Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, nr 7, s. 985-989Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 55.
    Khadse, Anand
    et al.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.;Univ South Eastern Norway, Fac ofTechnol, Dept Nat Sci & Environm Hlth, Nat Sci & Maritime Sci, Bo, Telemark, Norway..
    Haakensen, Vilde D.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.;Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Silwal-Pandit, Laxmi
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway..
    Hamfjord, Julian
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.;Oslo Univ Hosp, Dept Oncol, Oslo, Norway..
    Micke, Patrick
    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.
    Brustugun, Odd Terje
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.;Vestre Viken Hosp Trust, Drammen Hosp, Sect Oncol, Drammen, Norway..
    Lingjaerde, Ole Christian
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.;Univ Oslo, Ctr Bioinformat, Dept Informat, Oslo, Norway..
    Helland, Aslaug
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.;Oslo Univ Hosp, Dept Oncol, Oslo, Norway.;Univ Oslo, Dept Clin Med, Oslo, Norway..
    Kure, Elin H.
    Oslo Univ Hosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.;Univ South Eastern Norway, Fac ofTechnol, Dept Nat Sci & Environm Hlth, Nat Sci & Maritime Sci, Bo, Telemark, Norway..
    Prognostic Significance of the Loss of Heterozygosity of KRAS in Early-Stage Lung Adenocarcinoma2022Inngår i: Frontiers in Oncology, E-ISSN 2234-943X, Vol. 12, artikkel-id 873532Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lung cancer is a common disease with a poor prognosis. Genomic alterations involving the KRAS gene are common in lung carcinomas, although much is unknown about how different mutations, deletions, and expressions influence the disease course. The first approval of a KRAS-directed inhibitor was recently approved by the FDA. Mutations in the KRAS gene have been associated with poor prognosis for lung adenocarcinomas, but implications of the loss of heterozygosity (LOH) of KRAS have not been investigated. In this study, we have assessed the LOH of KRAS in early-stage lung adenocarcinoma by analyzing DNA copy number profiles and have investigated the effect on patient outcome in association with mRNA expression and somatic hotspot mutations. KRAS mutation was present in 36% of cases and was associated with elevated mRNA expression. LOH in KRAS was associated with a favorable prognosis, more prominently in KRAS mutated than in wild-type patients. The presence of both LOH and mutation in KRAS conferred a better prognosis than KRAS mutation alone. For wild-type tumors, no difference in prognosis was observed between patients with and without LOH in KRAS. Our study indicates that LOH in KRAS is an independent prognostic factor that may refine the existing prognostic groups of lung adenocarcinomas.

    Fulltekst (pdf)
    FULLTEXT01
  • 56.
    Kroeze, Leonie I.
    et al.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Pathol, Nijmegen, Netherlands..
    de Voer, Richarda M.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Human Genet, Nijmegen, Netherlands..
    Kamping, Eveline J.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Human Genet, Nijmegen, Netherlands..
    von Rhein, Daniel
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Human Genet, Nijmegen, Netherlands..
    Jansen, Erik A. M.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Human Genet, Nijmegen, Netherlands..
    Hermsen, Mandy J. W.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Pathol, Nijmegen, Netherlands..
    Barberis, Massimo C. P.
    European Inst Oncol, Div Pathol & Lab Med, Milan, Italy..
    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.
    Garrido-Martin, Eva M.
    Univ Hosp 12 Octubre, Inst Invest I 12, Spanish Natl Ctr Canc Res, Madrid, Spain.;Ctr Invest Biomed Red Canc, Madrid, Spain..
    Haller, Florian
    Univ Hosp Erlangen, Inst Pathol, Erlangen, Germany..
    Lacroix, Ludovic
    Inst Gustave Roussy, Dept Med Biol & Pathol, Villejuif, France..
    Maes, Brigitte
    Jessa Hosp, Lab Mol Diagnost, Dept Biol Clin, Hasselt, Belgium..
    Merkelbach-Bruse, Sabine
    Univ Hosp Cologne, Inst Pathol, Cologne, Germany..
    Pestinger, Valerie
    Univ Birmingham, Inst Canc & Genom Sci, Birmingham, W Midlands, England..
    Pfarr, Nicole
    Tech Univ Munich, Sch Med, Inst Pathol, Munich, Germany..
    Stenzinger, Albrecht
    Heidelberg Univ Hosp, Inst Pathol, Heidelberg, Germany..
    van den Heuvel, Michel M.
    Radboud Univ Nijmegen Med Ctr, Dept Pulmonol, Nijmegen, Netherlands..
    Grunberg, Katrien
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Pathol, Nijmegen, Netherlands..
    Ligtenberg, Marjolijn J. L.
    Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Pathol, Nijmegen, Netherlands.;Radboud Univ Nijmegen Med Ctr, Radboud Inst Mol Life Sci, Dept Human Genet, Nijmegen, Netherlands..
    Evaluation of a Hybrid Capture-Based Pan-Cancer Panel for Analysis of Treatment Stratifying Oncogenic Aberrations and Processes2020Inngår i: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 22, nr 6, s. 757-769Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stratification of patients for targeted and immune-based therapies requires extensive genomic profiling that enables sensitive detection of clinically relevant variants and interrogation of biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI). Detection of single and multiple nucleotide variants, copy number variants, MSI, and TMB was evaluated using a commercially available next-generation sequencing panel containing 523 cancer-related genes (1.94 megabases). Analysis of formalin-fixed, paraffin-embedded tissue sections and cytologic material from 45 tumor samples showed that all previously known MSI-positive samples (n = 7), amplifications (n = 9), and pathogenic variants (n = 59) could be detected. TMB and MSI scores showed high intralaboratory and interlaboratory reproducibility (eight samples tested in 11 laboratories). For reliable TMB analysis, 20 ng DNA was shown to be sufficient, even for relatively poor-quality samples. A minimum of 20% neoplastic cells was required to minimize variations in TMB values induced by chromosomal instability or tumor heterogeneity. Subsequent analysis of 58 consecutive lung cancer samples in a diagnostic setting was successful and revealed sufficient somatic mutations to generate mutational signatures in 14 cases. In conclusion, the 523-gene assay can be applied for evaluation of multiple DNA-based biomarkers relevant for treatment selection.

    Fulltekst (pdf)
    fulltext
  • 57.
    Kvarnbrink, Samuel
    et al.
    Umea Univ, Dept Radiat Sci, Oncol, S-90187 Umea, Sweden..
    Karlsson, Terese
    Umea Univ, Dept Radiat Sci, Oncol, S-90187 Umea, Sweden..
    Edlund, Karolina
    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.
    Lindquist, David
    Umea Univ, Dept Radiat Sci, Oncol, S-90187 Umea, Sweden..
    Jirstrom, Karin
    Lund Univ, Div Pathol, Dept Clin Sci, Lund, Sweden..
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Henriksson, Roger
    Umea Univ, Dept Radiat Sci, Oncol, S-90187 Umea, Sweden..
    Johansson, Mikael
    Umea Univ, Dept Radiat Sci, Oncol, S-90187 Umea, Sweden..
    Hedman, Hakan
    Umea Univ, Dept Radiat Sci, Oncol, S-90187 Umea, Sweden..
    LRIG1 is a prognostic biomarker in non-small cell lung cancer2015Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, nr 8, s. 1113-1119Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. The leucine-rich repeats and immunoglobulin-like domains (LRIG) family of transmembrane proteins are involved in the regulation of cellular signal transduction. LRIG1 is an endogenous inhibitor of receptor tyrosine kinases (RTKs) and an emerging tumor suppressor. In the lung epithelium, the expression of LRIG1 is downregulated by tobacco smoking, and further downregulated in lung squamous cell carcinoma. Material and methods. The expression of LRIG proteins were analyzed in 347 cases of non-small cell lung cancer (NSCLC) by immunohistochemistry, and LRIG1 mRNA expression was evaluated in 807 lung cancer samples in silico in the Oncomine database. Potential associations between the expression data and the clinical parameters, including patient survival, were investigated. Results. Expression of the LRIG1 protein was found to be an independent prognostic factor in NSCLC, whereas expression of LRIG2 or LRIG3 did not correlate with patient survival. The levels of LRIG1 mRNA also correlated with the survival of NSCLC patients. Conclusion. These findings demonstrate that LRIG1 is an independent prognostic factor in patients with NSCLC that could be important in future decision-making algorithms for adjuvant lung cancer treatment.

  • 58.
    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.
    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.
    He, Fei
    Pelicano, Catarina
    Zhou, Chikai
    He, Chenfei
    Palano, Giorgia
    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.
    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.
    Ravetch, Jeffrey V
    Karlsson, Mikael C I
    Sarhan, Dhifaf
    Targeting MARCO and IL-37R on immunosuppressive macrophages in lung cancer blocks regulatory T cells and supports cytotoxic lymphocyte function2021Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 81, nr 4, s. 956-967Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment. In non-small cell lung cancer (NSCLC), accumulation of anti-inflammatory tumor-associated macrophages (TAMs) is associated with worse clinical outcome and resistance to therapy. Here we investigated the immune landscape of NSCLC in the presence of pro-tumoral TAMs expressing the macrophage receptor with collagenous structure (MARCO). MARCO-expressing TAM numbers correlated with increased occurrence of regulatory T cells and effector T cells and decreased Natural Killer (NK) cells in these tumors. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL-37. In vitro studies subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an immune-suppressive phenotype through the release of IL-37. MARCO-expressing TAMs blocked cytotoxic T cell and NK cell activation, inhibiting their proliferation, cytokine production, and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL-10 production and diminished CD8 T cell activities. Targeting MARCO or IL-37 receptor (IL-37R) by antibody or CRISPR knockout of IL-37 in lung cancer cell lines repolarized TAMs, resulting in recovered cytolytic activity and anti-tumoral capacity of NK cells and T cells and down-modulated Treg cell activities. In summary, our data demonstrate a novel immune therapeutic approach targeting human TAMs immune suppression of NK and T cell anti-tumor activities.

  • 59.
    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.

  • 60.
    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)
    fulltext
  • 61.
    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)
  • 62.
    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)
  • 63.
    Lantuejoul, Sylvie
    et al.
    Ctr Leon Berard Unicanc, Lyon, France.;Univ Grenoble Alpes, Grenoble, France..
    Sound-Tsao, Ming
    Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada..
    Cooper, Wendy A.
    Royal Prince Alfred Hosp, Camperdown, NSW, Australia..
    Girard, Nicolas
    Inst Curie, Paris, France.;Univ Claude Bernard, Lyon, France..
    Hirsch, Fred R.
    Tisch Canc Inst, Ctr Thorac Oncol, New York, NY USA.;Mt Sinai Hlth Syst, Ichan Sch Med, New York, NY USA..
    Roden, Anja C.
    Mayo Clin, Rochester, MN USA..
    Lopez-Rios, Fernando
    HM Hosp, Pathol Lab Dianas Terapeut, Madrid, Spain..
    Jain, Deepali
    All India Inst Med Sci, New Delhi, India..
    Chou, Teh-Ying
    Taipei Vet Gen Hosp, Taipei, Taiwan..
    Motoi, Noriko
    Natl Canc Ctr, Tokyo, Japan..
    Kerr, Keith M.
    Aberdeen Royal Infirm, Dept Pathol, Aberdeen, Scotland..
    Yatabe, Yasushi
    Brambilla, Elisabeth
    Univ Grenoble Alpes, Grenoble, France..
    Longshore, John
    Carolinas Pathol Grp, Charlotte, NC USA..
    Papotti, Mauro
    Univ Turin, Turin, Italy..
    Sholl, Lynette M.
    Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA..
    Thunnissen, Erik
    Vrije Univ Amsterdam, Dept Pathol, Med Ctr, Amsterdam, Netherlands..
    Rekhtman, Natasha
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    Borczuk, Alain
    Weill Cornell Med, New York, NY USA..
    Bubendorf, Lukas
    Univ Basel, Inst Pathol, Basel, Switzerland..
    Minami, Yuko
    Ibarakihigashi Natl Hosp, Tokai, Ibaraki, Japan..
    Beasley, Mary Beth
    Mt Sinai Hlth Syst, Ichan Sch Med, New York, NY USA..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala Univ Hosp, Uppsala, Sweden.
    Chen, Gang
    Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China..
    Chung, Jin-Haeng
    Seoul Natl Univ, Bundang Hosp, Seoul, South Korea..
    Dacic, Sanja
    Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA..
    Hwang, David
    Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada..
    Lin, Dongmei
    Peking Univ, Canc Hosp & Inst, Dept Pathol, Beijing, Peoples R China..
    Moreira, Andre
    NYU, Sch Med, New York, NY USA..
    Nicholson, Andrew G.
    Royal Brompton & Harefield NHS Fdn Trust, London, England.;Imperial Coll, Natl Heart & Lung Inst, London, England..
    Noguchi, Masayuki
    Univ Tsukuba, Tsukuba, Ibaraki, Japan..
    Pelosi, Giuseppe
    Univ Milan, Milan, Italy.;IRCCS MultiMed, Milan, Italy..
    Poleri, Claudia
    Off Pathol Consultants, Buenos Aires, DF, Argentina..
    Travis, William
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    Yoshida, Akihiko
    Natl Canc Ctr, Tokyo, Japan..
    Daigneault, Jillian B.
    Int Assoc Study Lung Canc, Aurora, CO USA..
    Wistuba, Ignacio I.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA..
    Mino-Kenudson, Mari
    Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 122, Boston, MA 02114 USA..
    PD-L1 Testing for Lung Cancer in 2019: Perspective From the IASLC Pathology Committee2020Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 15, nr 4, s. 499-519Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The recent development of immune checkpoint inhibitors (ICIs) has led to promising advances in the treatment of patients with NSCLC and SCLC with advanced or metastatic disease. Most ICIs target programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) axis with the aim of restoring antitumor immunity. Multiple clinical trials for ICIs have evaluated a predictive value of PD-L1 protein expression in tumor cells and tumor-infiltrating immune cells (ICs) by immunohistochemistry (IHC), for which different assays with specific IHC platforms were applied. Of those, some PD-L1 IHC assays have been validated for the prescription of the corresponding agent for first- or second-line treatment. However, not all laboratories are equipped with the dedicated platforms, and many laboratories have set up in-house or laboratory-developed tests that are more affordable than the generally expensive clinical trial-validated assays. Although PD-L1 IHC test is now deployed in most pathology laboratories, its appropriate implementation and interpretation are critical as a predictive biomarker and can be challenging owing to the multiple antibody clones and platforms or assays available and given the typically small size of samples provided. Because many articles have been published since the issue of the IASLC Atlas of PD-L1 Immunohistochemistry Testing in Lung Cancer, this review by the IASLC Pathology Committee provides updates on the indications of ICIs for lung cancer in 2019 and discusses important considerations on preanalytical, analytical, and postanalytical aspects of PD-L1 IHC testing, including specimen type, validation of assays, external quality assurance, and training.

  • 64.
    Larsson, Erik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Venables, P.
    Andersson, A-C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Fan, W.
    Rigby, S.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Öberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Cohen, M.
    Nilsson, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Tissue and differentiation specific expression of the endogenous retrovirus ERV3 (HERV-R) in normal human tissues and during induced monocytic differentiation in the U-937 cell line1997Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 11, nr Suppl. 3, s. 142-4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ERV3 (HERV-R) is a complete, single copy human endogenous retrovirus located on the long arm of chromosome 7. The open reading frame in its envelope gene has been conserved during evolution but the gag and pol genes contain in-frame termination codons. To find a suitable experimental model system for analysis of the functions of the ERV3 genome, an extensive screening study of different normal and neoplastic human tissues was performed. Most tissues express low levels of the ERV3 env mRNA although high expression levels are observed in placenta, sebaceous glands, adrenals, testis, bronchial, epithelium and the monocytic cell line U-937. In U-937 cells the ERV3 env expression varied in a manner related to the differentiation status of the cells; being highest in the terminally differentiated non proliferating cells. U-937 cells can be induced to differentiate from the monoblastic to the mature monocyte/macrophage stage upon stimulation by several substances such as phorbolesters (TPA), Vitamin D3, Retinoic Acid (RA) and combinations of some cytokines. We conclude that the ERV3 locus is expressed in a tissue and differentiation specific way and that the U-937 cell line is a suitable model system to further analyze the proposed functions of ERVs such as immunomodulation, cell fusion and protection against exogenous retroviral infections.

  • 65.
    Larsson, Erik
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Venables, P.J.W.
    Andersson, Ann-Catrin
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Wansheng, F
    Rigby, S
    Botling, J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Oberg, F
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nilsson, K
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Expression of the endogenous retrovirus ERV3 (HERV-R) during induced monocytic differentiation in the U-937 cell line1996Inngår i: Int. J. Cancer, Vol. 67, s. 451-Artikkel i tidsskrift (Fagfellevurdert)
  • 66.
    Lejonklou, Margareta Halin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Bisphenol A increases cortisol production by enhancing phosphorylation of CREB in normal human adrenocortical cells2014Inngår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, s. S243-S243Artikkel i tidsskrift (Annet vitenskapelig)
  • 67.
    Lejonklou, Margareta Halin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Lind, P. Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Björklund, Peyman
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Induction of LINE-1 promoter hypomethylation, a hallmark of tumorigenesis, in normal human adrenocortical cells by Bisphenol A2014Inngår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, s. S149-S149Artikkel i tidsskrift (Annet vitenskapelig)
  • 68.
    Leuchowius, Karl-Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Clausson, Carl-Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Grannas, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Erbilgin, Yücel
    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.
    Zieba, Agata
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Söderberg, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Parallel Visualization of Multiple Protein Complexes in Individual Cells in Tumor Tissue2013Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 12, nr 6, s. 1563-1571Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cellular functions are regulated and executed by complex protein interaction networks. Accordingly, it is essential to understand the interplay between proteins in determining the activity status of signaling cascades. New methods are therefore required to provide information on different protein interaction events at the single cell level in heterogeneous cell populations such as in tissue sections. Here, we describe a multiplex proximity ligation assay for simultaneous visualization of multiple protein complexes in situ. The assay is an enhancement of the original proximity ligation assay, and it is based on using proximity probes labeled with unique tag sequences that can be used to read out which probes, from a pool of probes, have bound a certain protein complex. Using this approach, it is possible to gain information on the constituents of different protein complexes, the subcellular location of the complexes, and how the balance between different complex constituents can change between normal and malignant cells, for example. As a proof of concept, we used the assay to simultaneously visualize multiple protein complexes involving EGFR, HER2, and HER3 homo- and heterodimers on a single-cell level in breast cancer tissue sections. The ability to study several protein complex formations concurrently at single cell resolution could be of great potential for a systems understanding, paving the way for improved disease diagnostics and possibilities for drug development.

  • 69.
    Lohr, Miriam
    et al.
    Department of Statistics, Technical University Dortmund, Germany.
    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.
    Hammad, Seddik
    Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, Dortmund, Germany.
    Hellwig, Birte
    Department of Statistics, Technical University Dortmund, Germany.
    Othman, Amnah
    Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, Dortmund, Germany.
    Berglund, Anders
    Lambe, Mats
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Cadenas, Cristina
    Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, Dortmund, Germany.
    Marchan, Rosemarie
    Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, Dortmund, Germany.
    Hengstler, Jan G.
    Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, Dortmund, Germany.
    Rahnenfuhrer, Jörg
    Department of Statistics, Technical University Dortmund, Germany.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    The prognostic relevance of tumour-infiltrating plasma cells and immunoglobulin kappa C indicates an important role of the humoral immune response in non-small cell lung cancer2013Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 333, nr 2, s. 222-228Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A prognostic impact of immunoglobulin kappa C (IGKC) expression has been described in cancer. We analysed the influence of B-cell and plasma cell markers, as well as IGKC expression, in non-small lung cancer (NSCLC) using immunohistochemistry on a tissue microarray. IGKC protein expression was independently associated with longer survival, with particular impact in the adenocarcinoma subgroup. Moreover, a correlation was seen with CD138+ cells, but not with CD20. CD138 expression revealed a comparable association with survival. In conclusion, IGKC expression in stroma–infiltrating plasma cells is a prognostic marker in NSCLC, supporting emerging treatment concepts that exploit the humoral immune response.

  • 70.
    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
  • 71.
    Mathot, Lucy
    et al.
    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.
    Kundu, Snehangshu
    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.
    Ljungström, Viktor
    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.
    Svedlund, Jessica
    Moens, Lotte
    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.
    Adlerteg, Tom
    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.
    Falk-Sörqvist, Elin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Rendo, Verónica
    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.
    Bellomo, Claudia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mayrhofer, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cortina, Carme
    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.
    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.
    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.
    Isaksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Moustakas, Aristidis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Batlle, Eduard
    Birgisson, Helgi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Glimelius, Bengt
    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.
    Nilsson, Mats
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna.
    Sjöblom, Tobias
    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.
    Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer2017Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, nr 7, s. 1730-1740Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer.

  • 72.
    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)
  • 73.
    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.

  • 74.
    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.

  • 75.
    Mayrhofer, Markus
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Kultima, Hanna Göransson
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Birgisson, Helgi
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Sundström, Magnus
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Mathot, Lucy
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Edlund, Karolina
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Viklund, Björn
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Sjöblom, Tobias
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik.
    Botling, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Micke, Patrick
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Påhlman, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Isaksson, Anders
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II-III colon cancer2014Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, s. 872-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The clinical behaviour of colon cancer is heterogeneous. Five-year overall survival is 50-65% with all stages included. Recurring somatic chromosomal alterations have been identified and some have shown potential as markers for dissemination of the tumour, which is responsible for most colon cancer deaths. We investigated 115 selected stage II-IV primary colon cancers for associations between chromosomal alterations and tumour dissemination. Methods: Follow-up was at least 5 years for stage II-III patients without distant recurrence. Affymetrix SNP 6.0 microarrays and allele-specific copy number analysis were used to identify chromosomal alterations. Fisher's exact test was used to associate alterations with tumour dissemination, detected at diagnosis (stage IV) or later as recurrent disease (stage II-III). Results: Loss of 1p36.11-21 was associated with tumour dissemination in microsatellite stable tumours of stage II-IV (odds ratio = 5.5). It was enriched to a similar extent in tumours with distant recurrence within stage II and stage III subgroups, and may therefore be used as a prognostic marker at diagnosis. Loss of 1p36.11-21 relative to average copy number of the genome showed similar prognostic value compared to absolute loss of copies. Therefore, the use of relative loss as a prognostic marker would benefit more patients by applying also to hyperploid cancer genomes. The association with tumour dissemination was supported by independent data from the The Cancer Genome Atlas. Conclusion: Deletions on 1p36 may be used to guide adjuvant treatment decisions in microsatellite stable colon cancer of stages II and III.

    Fulltekst (pdf)
    fulltext
  • 76.
    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
  • 77.
    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
  • 78.
    Micke, Patrick
    et al.
    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.
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Göransson Kultima, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Mansouri, Larry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Ekman, Simon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Bergqvist, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Scheibenflug, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Lamberg, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Myrdal, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Thoraxkirurgi.
    Berglund, Anders
    Andersson, Annsofie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lambe, Mats
    Nyberg, Fredrik
    Thomas, Andrew
    Isaksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Gene Copy Number Aberrations Are Associated with Survival in Histologic Subgroups of Non-small Cell Lung Cancer2011Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 6, nr 11, s. 1833-1840Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction:

    Non-small cell lung cancer (NSCLC) is characterized by a multitude of genetic aberrations with unknown clinical impact. In this study, we aimed to identify gene copy number changes that correlate with clinical outcome in NSCLC. To maximize the chance to identify clinically relevant events, we applied a strategy involving two prognostically extreme patient groups.

    Methods:

    Short-term (<20 month; n = 53) and long-term survivors (>58 month; n = 47) were selected from a clinically well-characterized NSCLC patient cohort with available fresh frozen tumor specimens. The samples were analyzed using high-resolution single-nucleotide polymorphism array technology to assess gene copy number variations and array-based gene expression profiling. The molecular data were combined with information on clinical parameters.

    Results:

    Genetic aberrations were strongly associated with tumor histology. In adenocarcinoma (n = 50), gene copy number gains on chromosome 8q21-q24.3 (177 genes) were more frequent in long-term than in short-term survivors. In squamous cell carcinoma (n = 28), gains on chromosome 14q23.1-24.3 (133 genes) were associated with shorter survival, whereas losses in a neighboring region, 14q31.1-32.33 (110 genes), correlated with favorable outcome. In accordance with copy number gains and losses, messenger RNA expression levels of corresponding genes were increased or decreased, respectively.

    Conclusion:

    Comprehensive tumor profiling permits the integration of genomic, histologic, and clinical data. We identified gene copy number gains and losses, with corresponding changes in messenger RNA levels that were associated with prognosis in adenocarcinoma and squamous cell carcinoma of the lung.

  • 79.
    Micke, Patrick
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Kappert, Kai
    Ohshima, Mitsuhiro
    Sundquist, Christina
    Scheidl, Stefan
    Lindahl, Per
    Heldin, Carl-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Pontén, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Östman, Arne
    In Situ Identification of Genes Regulated Specifically in Fibroblasts of Human Basal Cell Carcinoma2007Inngår i: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 127, nr 6, s. 1516-1523Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Basal cell carcinoma (BCC) is characterized by slow growth, virtual absence of metastases, and strong stroma-dependency. Cancer-associated fibroblasts (CAFs) in the tumor stroma influence tumor growth, invasion, and metastasis. To comprehensively characterize CAFs of BCC in their in situ cancer environment, laser capture microdissection, linear gene amplification, microarray analysis, and quantitative real-time PCR (qRT-PCR) were combined. Pair-wise comparison of gene expression of microdissected CAFs and corresponding normal perifollicular fibroblasts identified 65 genes that were significantly upregulated in at least two of three different patients. Among the annotated genes, as many as 13 genes encoded secreted proteins, of which six were previously implicated as CAF-associated proteins in various tumor types. Four of the seven novel CAF genes - matrix Gla-protein, secreted frizzled-related protein 2, angiopoietin-related protein-2, and platelet-derived growth factor receptor-like protein - were selected for further analyses by qRT-PCR and were found to be frequently upregulated in CAFs of three independent BCC tissues. Analyses of CAFs from squamous cell cancer, prostate cancer, and colon cancer did not indicate that these genes were upregulated in these cancers. This study thus validates a novel approach for comprehensive characterization CAFs in their in situ environment of BCC. The results suggest a specific expression profile of CAFs in BCC possibly accounting for disease-specific pathological roles.

  • 80.
    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.

  • 81.
    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.

  • 82.
    Micke, Patrick
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ohshima, Mitsuhiro
    Tahmasebpoor, Simin
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ren, Zhi-Ping
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Östman, Arne
    Pontén, Fredrik
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi. Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Botling, Johan
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Biobanking of fresh frozen tissue: RNA is stable in nonfixed surgical specimens.2006Inngår i: Lab Invest, ISSN 0023-6837, Vol. 86, nr 2, s. 202-11Artikkel i tidsskrift (Fagfellevurdert)
  • 83.
    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.

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  • 84. Mignardi, Marco
    et al.
    Mezger, Anja
    Qian, Xiaoyan
    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.
    Larsson, Chatarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Nilsson, Mats
    Oligonucleotide gap-fill ligation for mutation detection and sequencing in situ.2015Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, nr 22, artikkel-id e151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In clinical diagnostics a great need exists for targeted in situ multiplex nucleic acid analysis as the mutational status can offer guidance for effective treatment. One well-established method uses padlock probes for mutation detection and multiplex expression analysis directly in cells and tissues. Here, we use oligonucleotide gap-fill ligation to further increase specificity and to capture molecular substrates for in situ sequencing. Short oligonucleotides are joined at both ends of a padlock gap probe by two ligation events and are then locally amplified by target-primed rolling circle amplification (RCA) preserving spatial information. We demonstrate the specific detection of the A3243G mutation of mitochondrial DNA and we successfully characterize a single nucleotide variant in the ACTB mRNA in cells by in situ sequencing of RCA products generated by padlock gap-fill ligation. To demonstrate the clinical applicability of our assay, we show specific detection of a point mutation in the EGFR gene in fresh frozen and formalin-fixed, paraffin-embedded (FFPE) lung cancer samples and confirm the detected mutation by in situ sequencing. This approach presents several advantages over conventional padlock probes allowing simpler assay design for multiplexed mutation detection to screen for the presence of mutations in clinically relevant mutational hotspots directly in situ.

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  • 85.
    Mino-Kenudson, Mari
    et al.
    Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,Warren 122, Boston, MA 02114 USA.;Harvard Med Sch, 55 Fruit St,Warren 122, Boston, MA 02114 USA..
    Le Stang, Nolwenn
    Ctr Leon Berard Unicanc, Lyon, France..
    Daigneault, Jillian B.
    Int Assoc Study Lung Canc, Denver, CO USA..
    Nicholson, Andrew G.
    Royal Brompton & Harefield Natl Hlth Serv NHS Fdn, London, England.;Imperial Coll London, Natl Heart & Lung Inst, London, England..
    Cooper, Wendy A.
    Royal Prince Alfred Hosp, New South Wales NSW Hlth Pathol, Camperdown, NSW, Australia.;Univ Sydney, Camperdown, NSW, Australia..
    Roden, Anja C.
    Mayo Clin, Dept Pathol, Rochester, MN USA..
    Moreira, Andre L.
    New York Univ Langone Hlth, Dept Pathol, New York, NY USA..
    Thunnissen, Erik
    Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands..
    Papotti, Mauro
    Univ Turin, Anat Pathol, Turin, Italy..
    Pelosi, Giuseppe
    Univ Milan, Dept Oncol & Hematooncol, Milan, Italy.;Ist Ricovero & Cura Carattere Sci IRCCS MultiMed, Milan, Italy..
    Motoi, Noriko
    Natl Canc Ctr, Diagnost Pathol, Tokyo, Japan..
    Poleri, Claudia
    Off Pathol Consultants, Buenos Aires, DF, Argentina..
    Brambilla, Elisabeth
    Univ Grenoble Alpes, Grenoble, France..
    Redman, Mary
    Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA..
    Jain, Deepali
    All India Inst Med Sci, New Delhi, India..
    Dacic, Sanja
    Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA USA..
    Yatabe, Yasushi
    Natl Canc Ctr, Diagnost Pathol, Tokyo, Japan..
    Tsao, Ming Sound
    Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada..
    Lopez-Rios, Fernando
    HM Hosp, Pathol Lab Dianas Terapeut, Madrid, Spain..
    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.
    Chen, Gang
    Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China..
    Chou, Teh-Ying
    Taipei Vet Gen Hosp, Taipei, Taiwan..
    Hirsch, Fred R.
    Tisch Canc Inst, Ctr Thorac Oncol, New York, NY USA.;Mt Sinai Hlth Syst, Ichan Sch Med, New York, NY USA..
    Beasley, Mary Beth
    Mt Sinai Hlth Syst, Ichan Sch Med, New York, NY USA..
    Borczuk, Alain
    Weill Cornell Med, Dept Pathol, New York, NY USA..
    Bubendorf, Lukas
    Univ Basel, Inst Pathol, Basel, Switzerland..
    Chung, Jin-Haeng
    Seoul Natl Univ, Bundang Hosp, Seoul, South Korea..
    Hwang, David
    Sunnybrook Hlth Sci Ctr, Toronto, ON, Canada..
    Lin, Dongmei
    Peking Univ Canc Hosp & Inst, Dept Pathol, Beijing, Peoples R China..
    Longshore, John
    Carolinas Pathol Grp, Charlotte, NC USA..
    Noguchi, Masayuki
    Univ Tsukuba, Tsukuba, Ibaraki, Japan..
    Rekhtman, Natasha
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    Sholl, Lynette
    Harvard Med Sch, 55 Fruit St,Warren 122, Boston, MA 02114 USA.;Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA..
    Travis, William
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    Yoshida, Akihiko
    Natl Canc Ctr, Diagnost Pathol, Tokyo, Japan..
    Wynes, Murry W.
    Int Assoc Study Lung Canc, Denver, CO USA..
    Wistuba, Ignacio I.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA..
    Kerr, Keith M.
    Aberdeen Royal Infirm, Dept Pathol, Aberdeen, Scotland..
    Lantuejoul, Sylvie
    Ctr Leon Berard Unicanc, Lyon, France..
    The International Association for the Study of Lung Cancer Global Survey on Programmed Death-Ligand 1 Testing for NSCLC2021Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 16, nr 4, s. 686-696Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is required to determine the eligibility for pembrolizumab monotherapy in advanced NSCLC worldwide and for several other indications depending on the country. Four assays have been approved/Communaute Europeene-In vitro Diagnostic (CV-IVD)-marked, but PD-L1 IHC seems diversely implemented across regions and laboratories with the application of laboratory-developed tests (LDTs).

    Method: To assess the practice of PD-L1 IHC and identify issues and disparities, the International Association for the Study of Lung Cancer Pathology Committee conducted a global survey for pathologists from January to May 2019, comprising multiple questions on preanalytical, analytical, and postanalytical conditions.

    Result: A total of 344 pathologists from 64 countries participated with 41% from Europe, 24% from North America, and 18% from Asia. Besides biopsies and resections, cellblocks were used by 75% of the participants and smears by 11%. The clone 22C3 was most often used (69%) followed by SP263 (51%). They were applied as an LDT by 40% and 30% of the users, respectively, and 76% of the participants developed at least one LDT. Half of the participants reported a turnaround time of less than or equal to 2 days, whereas 13% reported that of greater than or equal to 5 days. In addition, quality assurance (QA), formal training for scoring, and standardized reporting were not implemented by 18%, 16%, and 14% of the participants, respectively.

    Conclusions: Heterogeneity in PD-L1 testing is marked across regions and laboratories in terms of antibody clones, IHC assays, samples, turnaround times, and QA measures. The lack of QA, formal training, and standardized reporting stated by a considerable minority identifies a need for additional QA measures and training opportunities.

  • 86.
    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)
  • 87.
    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.

  • 88.
    Mollazadegan, Kazhan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Åkerström, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Eriksson, Barbro
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Welin, Staffan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Crona, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Poor outcome after systemic therapy in secondary high-grade pancreatic neuroendocrine tumors2022Inngår i: Endocrine Connections, E-ISSN 2049-3614, Vol. 11, nr 3, artikkel-id e210604Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Longitudinal changes in pancreatic neuroendocrine tumor (panNET) cell proliferation correlate with fast disease progression and poor prognosis. The optimal treatment strategy for secondary panNET grade (G)3 that has progressed from a previous low- or intermediate-grade to high-grade panNET G3 is currently unknown. This was a single-center retrospective cohort study aimed to characterize treatment patterns and outcomes among patients with secondary panNET-G3. Radiological responses were assessed using the Response Evaluation Criteria in Solid Tumors version 1.1. A total of 22 patients were included and received a median of 2 (range, 1–4) treatment lines in 14 different combinations. Median overall survival (OS) was 9 months (interquartile range (IQR): 4.25–17.5). For the 15 patients who received platinum–etoposide chemotherapy, median OS was 7.5 months (IQR: 3.75–10) and median progression-free survival (PFS) was 4 months (IQR: 2.5–5.5). The 15 patients who received conventional panNET therapies achieved a median OS of 8 months (IQR: 5–16.75) and median PFS was 5.5 months (IQR: 2.75–8.25). We observed one partial response on 177Lu DOTA-TATE therapy. In conclusion, this hypothesis-generating study failed to identify any promising treatment alternatives for patients with secondary panNET-G3. This demonstrates the need for both improved biological understanding of this particular NET entity and for designing prospective studies to further assess its treatment in larger patient cohorts.

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  • 89.
    Moreira, Andre L.
    et al.
    New York Univ Langone Hlth, Dept Pathol, 560 First Ave,TH 4-15B, New York, NY 10016 USA..
    Ocampo, Paolo S. S.
    New York Univ Langone Hlth, Dept Pathol, 560 First Ave,TH 4-15B, New York, NY 10016 USA..
    Xia, Yuhe
    New York Univ Langone Hlth, Dept Biostat, New York, NY 10016 USA..
    Zhong, Hua
    New York Univ Langone Hlth, Dept Biostat, New York, NY 10016 USA..
    Russell, Prudence A.
    St Vincents Hosp, Dept Pathol, Fitzroy, Vic, Australia..
    Minami, Yuko
    Ibarakihigashi Natl Hosp, Dept Pathol, Tokai, Ibaraki, Japan..
    Cooper, Wendy A.
    Royal Prince Alfred Hosp, Dept Pathol, Camperdown, NSW, Australia..
    Yoshida, Akihiko
    Natl Canc Ctr, Dept Diagnost Pathol, Tokyo, Japan..
    Bubendorf, Lukas
    Univ Basel, Univ Hosp Basel, Inst Med Genet & Pathol, Basel, Switzerland..
    Papotti, Mauro
    Univ Turin, Dept Oncol, Turin, Italy..
    Pelosi, Giuseppe
    Univ Milan, Dept Pathol, Milan, Italy.;IRCCS MultiMed, Milan, Italy..
    Lopez-Rios, Fernando
    HM Hosp, Pathol Lab Dianas Terapeut, Madrid, Spain..
    Kunitoki, Keiko
    Harvard TH Chan Sch Publ Hlth, Boston, MA USA..
    Ferrari-Light, Dana
    New York Univ Langone Hlth, Dept Surg, New York, NY 10016 USA..
    Sholl, Lynette M.
    Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA..
    Beasley, Mary Beth
    Mt Sinai Hlth Syst, Icahn Sch Med, Dept Pathol, New York, NY USA..
    Borczuk, Alain
    Weill Cornell Med, Dept Pathol, New York, NY USA..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Brambilla, Elisabeth
    Univ Grenoble Alpes, Dept Anat Pathol & Cytol, Grenoble, France..
    Chen, Gang
    Fudan Univ, Zhongshan Hosp, Dept Pathol, Shanghai, Peoples R China..
    Chou, Teh-Ying
    Taipei Vet Gen Hosp, Dept Pathol, Taipei, Taiwan..
    Chung, Jin-Haeng
    Seoul Natl Univ, Dept Pathol, Bundang Hosp, Seoul, South Korea..
    Dacic, Sanja
    Univ Pittsburgh, Dept Pathol, Med Ctr, Pittsburgh, PA USA..
    Jain, Deepali
    All India Inst Med Sci, Dept Pathol, New Delhi, India..
    Hirsch, Fred R.
    Tisch Canc Inst, Ctr Thorac Oncol, New York, NY USA..
    Hwang, David
    Sunnybrook Hlth Sci Ctr, Dept Lab Med & Mol Diagnost, Toronto, ON, Canada..
    Lantuejoul, Sylvie
    Ctr Leon Berard Unicanc, Dept Pathol, Lyon, France..
    Lin, Dongmei
    Peking Univ, Dept Pathol, Canc Hosp & Inst, Beijing, Peoples R China..
    Longshore, John W.
    Atrium Hlth, Carolinas Pathol Grp, Charlotte, NC USA..
    Motoi, Noriko
    Natl Canc Ctr, Dept Diagnost Pathol, Tokyo, Japan..
    Noguchi, Masayuki
    Univ Tsukuba, Dept Pathol, Tsukuba, Ibaraki, Japan..
    Poleri, Claudia
    Off Pathol Consultants, Buenos Aires, DF, Argentina..
    Rekhtman, Natasha
    Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA..
    Tsao, Ming-Sound
    Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada..
    Thunnissen, Erik
    Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands..
    Travis, William D.
    Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA..
    Yatabe, Yasushi
    Natl Canc Ctr, Dept Diagnost Pathol, Tokyo, Japan..
    Roden, Anja C.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA..
    Daigneault, Jillian B.
    Int Assoc Study Lung Canc, Aurora, CO USA..
    Wistuba, Ignacio I.
    Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA..
    Kerr, Keith M.
    Aberdeen Royal Infirm, Dept Pathol, Aberdeen, Scotland..
    Pass, Harvey
    New York Univ Langone Hlth, Dept Surg, New York, NY 10016 USA..
    Nicholson, Andrew G.
    Royal Brompton & Harefield NHS Fdn Trust, Dept Pathol, London, England.;Imperial Coll, Natl Heart & Lung Inst, London, England..
    Mino-Kenudson, Mari
    Harvard Med Sch, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA..
    A Grading System for Invasive Pulmonary Adenocarcinoma: A Proposal From the International Association for the Study of Lung Cancer Pathology Committee2020Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 15, nr 10, s. 1599-1610Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: A grading system for pulmonary adenocarcinoma has not been established. The International Association for the Study of Lung Cancer pathology panel evaluated a set of histologic criteria associated with prognosis aimed at establishing a grading system for invasive pulmonary adenocarcinoma. Methods: A multi-institutional study involving multiple cohorts of invasive pulmonary adenocarcinomas was conducted. A cohort of 284 stage I pulmonary adenocarcinomas was used as a training set to identify histologic features associated with patient outcomes (recurrence-free survival [RFS] and overall survival [OS]). Receiver operating characteristic curve analysis was used to select the best model, which was validated (n = 212) and tested (n = 300, including stage I-III) in independent cohorts. Reproducibility of the model was assessed using kappa statistics. Results: The best model (area under the receiver operating characteristic curve [AUC] = 0.749 for RFS and 0.787 for OS) was composed of a combination of predominant plus high-grade histologic pattern with a cutoff of 20% for the latter. The model consists of the following: grade 1, lepidic predominant tumor; grade 2, acinar or papillary predominant tumor, both with no or less than 20% of high-grade patterns; and grade 3, any tumor with 20% or more of high-grade patterns (solid, micropapillary, or complex gland). Similar results were seen in the validation (AUC = 0.732 for RFS and 0.787 for OS) and test cohorts (AUC = 0.690 for RFS and 0.743 for OS), confirming the predictive value of the model. Interobserver reproducibility revealed good agreement (k = 0.617). Conclusions: A grading system based on the predominant and high-grade patterns is practical and prognostic for invasive pulmonary adenocarcinoma. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  • 90.
    Moreno-Ruiz, Pablo
    et al.
    Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden.
    Corvigno, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden.
    te Grootenhuis, Nienke C.
    Univ Groningen, Univ Med Ctr Groningen, Dept Obstet & Gynecol, Groningen, Netherlands.
    La Fleur, Linnéa
    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.
    Backman, Max
    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.
    Strell, Carina
    Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, 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. Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden.
    Hoelzlwimmer, Gabriele
    Roche Innovat Ctr Munich Penzberg, Penzberg, Germany.
    Klein, Christian
    Roche Innovat Ctr Zurich, Schlieren, Switzerland.
    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.
    Micke, Patrick
    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.
    Östman, Arne
    Karolinska Inst, Canc Ctr Karolinska, Dept Oncol Pathol, Stockholm, Sweden.
    Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation2021Inngår i: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 155, s. 10-19Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives

    Fibroblasts regulate tumor growth and immune surveillance. Here, we study FAP, PDGFβR and α-SMA fibroblast markers in a well-annotated clinical cohort of non–small-cell lung cancer (NSCLC) for analyses of associations with immune cell infiltration, mutation status and survival.

    Materials and Methods

    A well-annotated NSCLC cohort was subjected to IHC analyses of stromal expression of FAP, PDGFβR and α-SMA and of stromal CD8 density. Fibroblast markers-related measurements were analyzed with regard to potential associations with CD8 density, cancer genetic driver mutations, survival and PD-L1 expression in the whole NSCLC cohort and in subsets of patients.

    Results

    High stromal FAP expression was identified as an independent poor prognostic marker in the whole study population (HR 1.481; 95 % CI, 1.012–2.167, p = 0.023) and in the histological subset of adenocarcinoma (HR 1.720; 95 % CI, 1.126–2.627, p = 0.012). Among patients with adenocarcinoma, a particularly strong association of FAP with poor survival was detected in patients with low stromal CD8 infiltration, and in other subpopulations identified by specific clinical characteristics; elderly patients, females, non-smokers and patients with normal ECOG performance status. α-SMA expression was negatively associated with CD8 infiltration in non-smokers, but none of the fibroblast markers expression was associated with CD8 density in the whole study population. Significant associations were detected between presence of p53 mutations and high α-SMA (p = 0.003) and FAP expression (p < 0.001).

    Conclusion

    The study identifies FAP intensity as a candidate independent NSCLC prognostic biomarker. The study also suggests continued analyses of the relationships between genetic driver mutations and the composition of tumor stroma, as well as continued probing of marker-defined fibroblasts as NSCLC subset-specific modifiers of immune surveillance and outcome.

    Fulltekst (pdf)
    FULLTEXT01
  • 91. Muggerud, Aslaug Aa
    et al.
    Rønneberg, Jo Anders
    Wärnberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Busato, Florence
    Jovanovic, Jovana
    Solvang, Hiroko
    Bukholm, Ida
    Børresen-Dale, Anne-Lise
    Kristensen, Vessela N.
    Sørlie, Therese
    Tost, Jörg
    Frequent aberrant DNA methylation of ABCB1, FOXC1, PPP2R2B and PTEN in ductal carcinoma in situ and early invasive breast cancer2010Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 12, nr 1, s. R3-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-invasive lesion of the breast that is frequently detected by mammography and subsequently removed by surgery. However, it is estimated that about half of the detected lesions would never have progressed into invasive cancer. Identifying DCIS and invasive cancer specific epigenetic lesions and understanding how these epigenetic changes are involved in triggering tumour progression is important for a better understanding of which lesions are at risk of becoming invasive. METHODS: Quantitative DNA methylation analysis of ABCB1, CDKN2A/p16INK4a, ESR1, FOXC1, GSTP1, IGF2, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A was performed by pyrosequencing in a series of 27 pure DCIS, 28 small invasive ductal carcinomas (IDCs), 34 IDCs with a DCIS component and 5 normal breast tissue samples. FOXC1, ABCB1, PPP2R2B and PTEN were analyzed in 23 additional normal breast tissue samples. Real-Time PCR expression analysis was performed for FOXC1. RESULTS: Aberrant DNA methylation was observed in all three diagnosis groups for the following genes: ABCB1, FOXC1, GSTP1, MGMT, MLH1, PPP2R2B, PTEN and RASSF1A. For most of these genes, methylation was already present at the DCIS level with the same frequency as within IDCs. For FOXC1 significant differences in methylation levels were observed between normal breast tissue and invasive tumours (P < 0.001). The average DNA methylation levels were significantly higher in the pure IDCs and IDCs with DCIS compared to pure DCIS (P = 0.007 and P = 0.001, respectively). Real-time PCR analysis of FOXC1 expression from 25 DCIS, 23 IDCs and 28 normal tissue samples showed lower gene expression levels of FOXC1 in both methylated and unmethylated tumours compared to normal tissue (P < 0.001). DNA methylation levels of FOXC1, GSTP1, ABCB1 and RASSF1A were higher in oestrogen receptor (ER) positive vs. ER negative tumours; whereas methylation levels of FOXC1, ABCB1, PPP2R2B and PTEN were lower in tumours with a TP53 mutation. CONCLUSIONS: Quantitative methylation analysis identified ABCB1, FOXC1, PPP2R2B and PTEN as novel genes to be methylated in DCIS. In particular, FOXC1 showed a significant increase in the methylation frequency in invasive tumours. Low FOXC1 gene expression in both methylated and unmethylated DCIS and IDCs indicates that the loss of its expression is an early event during breast cancer progression.

  • 92. Muggerud, Aslaug Aamodt
    et al.
    Hallett, Michael
    Johnsen, Hilde
    Kleivi, Kristine
    Zhou, Wenjing
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Tahmasebpoor, Simin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Amini, Rose-Marie
    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 genetik och patologi.
    Borresen-Dale, Anne-Lise
    Sorlie, Therese
    Wärnberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Molecular diversity in ductal carcinoma in situ (DCIS) and early invasive breast cancer2010Inngår i: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 4, nr 4, s. 357-368Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer where cells restricted to the ducts exhibit an atypical phenotype. Some DCIS lesions are believed to rapidly transit to invasive ductal carcinomas (IDCs), while others remain unchanged. Existing classification systems for DCIS fail to identify those lesions that transit to IDC. We studied gene expression patterns of 31 pure DCIS, 36 pure invasive cancers and 42 cases of mixed diagnosis (invasive cancer with an in situ component) using Agilent Whole Human Genome Oligo Microarrays 44k. Six normal breast tissue samples were also included as controls. qRT-PCR was used for validation. All DCIS and invasive samples could be classified into the "intrinsic" molecular subtypes defined for invasive breast cancer. Hierarchical clustering establishes that samples group by intrinsic subtype, and not by diagnosis. We observed heterogeneity in the transcriptomes among DOS of high histological grade and identified a distinct subgroup containing seven of the 31 DCIS samples with gene expression characteristics more similar to advanced tumours. A set of genes independent of grade, ER-status and HER2-status was identified by logistic regression that univariately classified a sample as belonging to this distinct DCIS subgroup. qRT-PCR of single markers clearly separated this DCIS subgroup from the other DCIS, and contains samples from several histopathological and intrinsic molecular subtypes. The genes that differentiate between these two types of DCIS suggest several processes related to the re-organisation of the microenvironment. This raises interesting possibilities for identification of DCIS lesions both with and without invasive characteristics, which potentially could be used in clinical assessment of a woman's risk of progression, and lead to improved management that would avoid the current over- and under-treatment of patients.

  • 93.
    Nesti, Cedric
    et al.
    Univ Hosp Bern, Inselspital, Dept Visceral Surg & Med, CH-3010 Bern, Switzerland..
    Braeutigam, Konstantin
    Univ Bern, Inst Pathol, Bern, Switzerland..
    Benavent, Marta
    Univ Hosp Virgen del Rocio, Dept Med Oncol, Inst Biomed Sevilla, Seville, Spain..
    Bernal, Laura
    Univ Hosp Virgen del Rocio, Dept Med Oncol, Inst Biomed Sevilla, Seville, Spain..
    Boharoon, Hessa
    Royal Free Hosp London, ENETS Ctr Excellence, Neuroendocrine Tumour Unit, London, England..
    Botling, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin. Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Bouroumeau, Antonin
    Univ Hosp Geneva, Div Clin Pathol, Diagnost Dept, Geneva, Switzerland..
    Brcic, Iva
    Med Univ Graz, Diagnost & Res Inst Pathol, Graz, Austria..
    Brunner, Maximilian
    Friedrich Alexander Univ Erlangen Nurnberg, Dept Surg, Univ Hosp, Erlangen, Germany..
    Cadiot, Guillaume
    Univ Reims, CHU Reims, Serv Hepatogastroenterol & Oncol Digest, Reims, France..
    Camara, Maria
    UCM, Imas12, Hosp Univ 12 Octubre, Dept Pathol, Madrid, Spain..
    Christ, Emanuel
    Univ Hosp Basel, ENETS Ctr Excellence, Dept Endocrinol Diabetol & Metab, Basel, Switzerland..
    Clerici, Thomas
    Kantonsspital St Gallen, Klin Allgemein Viszeral Endokrin & Transplantat, St Gallen, Switzerland..
    Clift, Ashley K.
    Imperial Coll London, Dept Surg & Canc, London, England..
    Clouston, Hamish
    Christie NHS Fdn Trust, Colorectal & Peritoneal Oncol Ctr, Manchester, Lancs, England..
    Cobianchi, Lorenzo
    Univ Pavia, Dept Clin Diagnost & Pediat Sci, Pavia, Italy.;IRCCS Policlin San Matteo Fdn, Dept Gen Surg, Pavia, Italy..
    Cwikla, Jaroslaw B.
    Indywidualna Specjalistyczna Praktyka Lekarska, Warsaw, Poland..
    Daskalakis, Kosmas
    Natl & Kapodistrian Univ Athens, ENETS Ctr Excellence, Dept Propaedeut Internal Med 1, Endocrine Unit, Athens, Greece..
    Frilling, Andrea
    Imperial Coll London, Dept Surg & Canc, London, England..
    Garcia-Carbonero, Rocio
    UCM, Imas12, Hosp Univ 12 Octubre, Dept Oncol, Madrid, Spain..
    Grozinsky-Glasberg, Simona
    Hebrew Univ Jerusalem, Hadassah Med Org, Neuroendocrine Tumor Unit, ENETS Ctr Excellence,Dept Endocrinol & Metab, Jerusalem, Israel.;Hebrew Univ Jerusalem, Fac Med, Jerusalem, Israel..
    Hernando, Jorge
    Vall dHebron Inst Oncol, Vall dHebron Univ Hosp, Dept Med Oncol, Barcelona, Spain..
    Hervieu, Valerie
    Hosp Civils Lyon, HEH, Lyon, France..
    Hofland, Johannes
    Erasmus MC, Dept Internal Med, Endocrinol Sect, ENETS Ctr Excellence, Rotterdam, Netherlands.;Erasmus MC, Erasmus Canc Inst, Rotterdam, Netherlands..
    Holmager, Pernille
    Copenhagen Univ Hosp, Rigshosp, ENETS Neuroendocrine Tumor Ctr Excellence, Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Dept Endocrinol, Copenhagen, Denmark..
    Inzani, Frediano
    Fdn Policlin Univ A Gemelli IRCCS, Gen Pathol, Dept Woman & Child Hlth Sci & Publ Hlth, Rome, Italy.;Roma European NeuroEndocrine Tumor Soc, Ctr Excellence, Rome, Italy..
    Jann, Henning
    Charite Univ Med Berlin, Hepatol & Gastroenterol, Berlin, Germany..
    Jimenez-Fonseca, Paula
    Hosp Univ Cent Asturias, ISPA, Dept Med Oncol, Oviedo, Spain..
    Kacmaz, Enes
    Univ Amsterdam, Amsterdam UMC, Dept Surg, Amsterdam, Netherlands..
    Kaemmerer, Daniel
    Zent Klin Bad Berka, Dept Gen & Visceral Surg, Bad Berka, Germany..
    Kaltsas, Gregory
    Natl & Kapodistrian Univ Athens, ENETS Ctr Excellence, Dept Propaedeut Internal Med 1, Endocrine Unit, Athens, Greece..
    Klimàcek, Branislav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Uppsala Univ, Dept Surg, Endocrine Surg Unit, Uppsala, Sweden..
    Knigge, Ulrich
    Copenhagen Univ Hosp, Rigshosp, ENETS Neuroendocrine Tumor Ctr Excellence, Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Dept Endocrinol, Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Dept Surg, Copenhagen, Denmark..
    Kolasinska-Cwikla, Agnieszka
    Maria Sklodowska Curie Natl Res Inst Oncol, Warsaw, Poland..
    Kolb, Walter
    Kantonsspital St Gallen, Klin Allgemein Viszeral Endokrin & Transplantat, St Gallen, Switzerland..
    Kos-Kudla, Beata
    Med Univ Silesia, Dept Endocrinol & Neuroendocrine Neoplasms, Katowice, Poland.;Med Univ Silesia, Dept Endocrinol & Pathophysiol, Katowice, Poland..
    Kunze, Catarina Alisa
    Charite Univ Med Berlin, Inst Pathol, Berlin, Germany.;Free Univ Berlin, Berlin, Germany.;Humboldt Univ, Berlin, Germany..
    Landolfi, Stefania
    Vall dHebron Univ Hosp, Dept Pathol, Barcelona, Spain..
    La Rosa, Stefano
    Univ Lausanne, Inst Pathol, Dept Lab Med & Pathol, Lausanne, Switzerland.;Univ Insubria, Dept Med & Surg, Unit Pathol, Varese, Italy..
    Lopez, Carlos Lopez
    Hosp Univ Marques de Valdecilla, Dept Med Oncol, IDIVAL, Santander, Spain..
    Lorenz, Kerstin
    Martin Luther Univ Halle Wittenberg, Dept Visceral Vascular & Endocrine Surg, Halle, Germany..
    Matter, Maurice
    Univ Lausanne, Dept Visceral Surg, Univ Lausanne Hosp, Lausanne, Switzerland..
    Mazal, Peter
    Med Univ Vienna, Gen Hosp Vienna, Dept Clin Pathol, Vienna, Austria..
    Mestre-Alagarda, Claudia
    Kings Coll Hosp London, Inst Liver Studies, Histopathol, London, England..
    del Burgo, Patricia Morales
    Hosp Univ Cent Asturias, Dept Pathol, Oviedo, Spain..
    van Dijkum, Els J. M. Nieveen
    Univ Amsterdam, Amsterdam UMC, Dept Surg, Amsterdam, Netherlands..
    Oleinikov, Kira
    Hebrew Univ Jerusalem, Hadassah Med Org, Neuroendocrine Tumor Unit, ENETS Ctr Excellence,Dept Endocrinol & Metab, Jerusalem, Israel.;Hebrew Univ Jerusalem, Fac Med, Jerusalem, Israel..
    Orci, Lorenzo A.
    Geneva Univ Hosp, Div Abdominal Surg, Dept Surg, Geneva, Switzerland..
    Panzuto, Francesco
    Sapienza Univ Rome, Dept Med Surg Sci & Translat Med, Rome, Italy.;St Andrea Univ Hosp, ENETS Ctr Excellence, Digest Dis Unit, Rome, Italy..
    Pavel, Marianne
    Friedrich Alexander Univ Erlangen Nurnberg, Dept Med 1, Erlangen, Germany..
    Perrier, Marine
    Univ Reims, CHU Reims, Serv Hepatogastroenterol & Oncol Digest, Reims, France..
    Reims, Henrik Mikael
    Rigshosp, Oslo Univ Hosp, Dept Pathol, Oslo, Norway..
    Rindi, Guido
    Fdn Policlin Univ A Gemelli IRCCS, Unit Head & Neck Lung & Endocrine Pathol, Dept Woman & Child Hlth Sci & Publ Hlth, Rome, Italy.;Roma European NeuroEndocrine Tumor Soc, Ctr Excellence, Rome, Italy.;Univ Cattolica Sacro Cuore, Dept Life Sci & Publ Hlth, Sect Anat Pathol, Rome, Italy..
    Rinke, Anja
    UKGM, Dept Gastroenterol & Endocrinol, Marburg, Germany.;Philipps Univ Marburg, Marburg, Germany..
    Rinzivillo, Maria
    St Andrea Univ Hosp, ENETS Ctr Excellence, Digest Dis Unit, Rome, Italy..
    Sagaert, Xavier
    Katholieke Univ Leuven, Translat Cell & Tissue Res, Leuven, Belgium..
    Satiroglu, Ilker
    Martin Luther Univ Halle Wittenberg, Dept Visceral Vascular & Endocrine Surg, Halle, Germany..
    Selberherr, Andreas
    Med Univ Vienna, Dept Gen Surg, Div Visceral Surg, Vienna, Austria..
    Siebenhuener, Alexander R.
    Univ Spital Zurich, Klin Med Onkol & Hamatol, Zurich, Switzerland.;Univ Zurich, Zurich, Switzerland.;Kantonsspital Schaffhausen, Dept Med Onkol, Schaffhausen, Switzerland..
    Tesselaar, Margot E. T.
    Netherlands Canc Inst, Dept Med Oncol, Amsterdam, Netherlands..
    Thalhammer, Michael J.
    Med Univ Graz, Dept Surg, Div Visceral & Transplant Surg, Graz, Austria..
    Thiis-Evensen, Espen
    Rigshosp, Oslo Univ Hosp, Dept Gastroenterol, Oslo, Norway..
    Toumpanakis, Christos
    Royal Free Hosp London, ENETS Ctr Excellence, Neuroendocrine Tumour Unit, London, England..
    Vandamme, Timon
    Univ Hosp Antwerp, Edegem, Belgium..
    van den Berg, Jose G.
    Netherlands Canc Inst, Dept Pathol, Amsterdam, Netherlands..
    Vanoli, Alessandro
    Univ Pavia, Dept Mol Med, Anat Pathol Unit, Pavia, Italy.;IRCCS Policlin San Matteo Fdn, Anat Pathol Unit, Pavia, Italy..
    van Velthuysen, Marie-Louise F.
    Erasmus MC, Dept Pathol, Rotterdam, Netherlands..
    Verslype, Chris
    Univ Hosp Leuven, Clin Digest Oncol, Leuven, Belgium..
    Vorburger, Stephan A.
    Teaching Hosp Emmental, Dept Surg, Burgdorf, Switzerland..
    Lugli, Alessandro
    Univ Bern, Inst Pathol, Bern, Switzerland..
    Ramage, John
    Univ Winchester, Winchester, Hants, England.;Hampshire Hosp, Basingstoke, Hants, England..
    Zwahlen, Marcel
    Univ Bern, Inst Social & Prevent Med, Bern, Switzerland..
    Perren, Aurel
    Univ Bern, Inst Pathol, Bern, Switzerland..
    Kaderli, Reto M.
    Univ Hosp Bern, Inselspital, Dept Visceral Surg & Med, CH-3010 Bern, Switzerland..
    Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size: a retrospective, Europe-wide, pooled cohort study2023Inngår i: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 24, nr 2, s. 187-194Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy.Methods In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693.Findings 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36 center dot 0 years (SD 18 center dot 2). Median follow-up was 13 center dot 0 years (IQR 11 center dot 0-15 center dot 6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12 center dot 8% (95% CI 6 center dot 5 -21 center dot 1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0 center dot 88 [95% CI 0 center dot 36-2 center dot 17]; p=0 center dot 71).Interpretation This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1-2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort.Funding Swiss Cancer Research foundation.Copyright (c) 2023 Elsevier Ltd. All rights reserved.

  • 94.
    Nesti, Cedric
    et al.
    Univ Hosp Bern, Inselspital, Dept Visceral Surg & Med, CH-3010 Bern, Switzerland..
    Bräutigam, Konstantin
    Univ Bern, Inst Pathol, Bern, Switzerland..
    Benavent, Marta
    Univ Hosp Virgen del Rocio, Dept Med Oncol, Inst Biomed Sevilla, Seville, Spain..
    Bernal, Laura
    Univ Hosp Virgen del Rocio, Dept Med Oncol, Inst Biomed Sevilla, Seville, Spain..
    Boharoon, Hessa
    Royal Free Hosp London, ENETS Ctr Excellence, Neuroendocrine Tumour Unit, London, England..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerprecisionsmedicin.
    Bouroumeau, Antonin
    Univ Hosp Geneva, Div Clin Pathol, Diagnost Dept, Geneva, Switzerland..
    Brcic, Iva
    Med Univ Graz, Diagnost & Res Inst Pathol, Graz, Austria..
    Brunner, Maximilian
    Friedrich Alexander Univ Erlangen Nurnberg, Dept Surg, Univ Hosp, Erlangen, Germany..
    Cadiot, Guillaume
    Univ Reims, CHU Reims, Serv Hepatogastroenterol & Oncol Digest, Reims, France..
    Camara, Maria
    UCM, Imas12, Hosp Univ 12 Octubre, Dept Pathol, Madrid, Spain..
    Christ, Emanuel
    Univ Hosp Basel, ENETS Ctr Excellence, Dept Endocrinol Diabetol & Metab, Basel, Switzerland..
    Clerici, Thomas
    Kantonsspital St Gallen, Klin Allgemein Viszeral Endokrin & Transplantat, St Gallen, Switzerland..
    Clift, Ashley K.
    Imperial Coll London, Dept Surg & Canc, London, England..
    Clouston, Hamish
    Christie NHS Fdn Trust, Colorectal & Peritoneal Oncol Ctr, Manchester, Lancs, England..
    Cobianchi, Lorenzo
    Univ Pavia, Dept Clin Diagnost & Pediat Sci, Pavia, Italy.;IRCCS Policlin San Matteo Fdn, Dept Gen Surg, Pavia, Italy..
    Cwikla, Jaroslaw B.
    Indywidualna Specjalistyczna Praktyka Lekarska, Warsaw, Poland..
    Daskalakis, Kosmas
    Natl & Kapodistrian Univ Athens, ENETS Ctr Excellence, Dept Propaedeut Internal Med 1, Endocrine Unit, Athens, Greece..
    Frilling, Andrea
    Imperial Coll London, Dept Surg & Canc, London, England..
    Garcia-Carbonero, Rocio
    UCM, Imas12, Hosp Univ 12 Octubre, Dept Oncol, Madrid, Spain..
    Grozinsky-Glasberg, Simona
    Hebrew Univ Jerusalem, Hadassah Med Org, Neuroendocrine Tumor Unit, ENETS Ctr Excellence,Dept Endocrinol & Metab, Jerusalem, Israel.;Hebrew Univ Jerusalem, Fac Med, Jerusalem, Israel..
    Hernando, Jorge
    Vall dHebron Inst Oncol, Vall dHebron Univ Hosp, Dept Med Oncol, Barcelona, Spain..
    Hervieu, Valerie
    Hosp Civils Lyon, HEH, Lyon, France..
    Hofland, Johannes
    Erasmus MC, Dept Internal Med, Endocrinol Sect, ENETS Ctr Excellence, Rotterdam, Netherlands.;Erasmus MC, Erasmus Canc Inst, Rotterdam, Netherlands..
    Holmager, Pernille
    Copenhagen Univ Hosp, Rigshosp, ENETS Neuroendocrine Tumor Ctr Excellence, Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Dept Endocrinol, Copenhagen, Denmark..
    Inzani, Frediano
    Fdn Policlin Univ A Gemelli IRCCS, Gen Pathol, Dept Woman & Child Hlth Sci & Publ Hlth, Rome, Italy.;Roma European NeuroEndocrine Tumor Soc, Ctr Excellence, Rome, Italy..
    Jann, Henning
    Charite Univ Med Berlin, Hepatol & Gastroenterol, Berlin, Germany..
    Jimenez-Fonseca, Paula
    Hosp Univ Cent Asturias, ISPA, Dept Med Oncol, Oviedo, Spain..
    Kacmaz, Enes
    Univ Amsterdam, Amsterdam UMC, Dept Surg, Amsterdam, Netherlands..
    Kaemmerer, Daniel
    Zent Klin Bad Berka, Dept Gen & Visceral Surg, Bad Berka, Germany..
    Kaltsas, Gregory
    Natl & Kapodistrian Univ Athens, ENETS Ctr Excellence, Dept Propaedeut Internal Med 1, Endocrine Unit, Athens, Greece..
    Klimàcek, Branislav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Knigge, Ulrich
    Copenhagen Univ Hosp, Rigshosp, ENETS Neuroendocrine Tumor Ctr Excellence, Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Dept Endocrinol, Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Dept Surg, Copenhagen, Denmark..
    Kolasinska-Cwikla, Agnieszka
    Maria Sklodowska Curie Natl Res Inst Oncol, Warsaw, Poland..
    Kolb, Walter
    Kantonsspital St Gallen, Klin Allgemein Viszeral Endokrin & Transplantat, St Gallen, Switzerland..
    Kos-Kudla, Beata
    Med Univ Silesia, Dept Endocrinol & Neuroendocrine Neoplasms, Katowice, Poland.;Med Univ Silesia, Dept Endocrinol & Pathophysiol, Katowice, Poland..
    Kunze, Catarina Alisa
    Charite Univ Med Berlin, Inst Pathol, Berlin, Germany.;Free Univ Berlin, Berlin, Germany.;Humboldt Univ, Berlin, Germany..
    Landolfi, Stefania
    Vall dHebron Univ Hosp, Dept Pathol, Barcelona, Spain..
    La Rosa, Stefano
    Univ Lausanne, Inst Pathol, Dept Lab Med & Pathol, Lausanne, Switzerland.;Univ Insubria, Dept Med & Surg, Unit Pathol, Varese, Italy..
    Lopez, Carlos Lopez
    Hosp Univ Marques de Valdecilla, Dept Med Oncol, IDIVAL, Santander, Spain..
    Lorenz, Kerstin
    Martin Luther Univ Halle Wittenberg, Dept Visceral Vascular & Endocrine Surg, Halle, Germany..
    Matter, Maurice
    Univ Lausanne, Dept Visceral Surg, Univ Lausanne Hosp, Lausanne, Switzerland..
    Mazal, Peter
    Med Univ Vienna, Gen Hosp Vienna, Dept Clin Pathol, Vienna, Austria..
    Mestre-Alagarda, Claudia
    Kings Coll Hosp London, Inst Liver Studies, Histopathol, London, England..
    del Burgo, Patricia Morales
    Hosp Univ Cent Asturias, Dept Pathol, Oviedo, Spain..
    van Dijkum, Els J. M. Nieveen
    Univ Amsterdam, Amsterdam UMC, Dept Surg, Amsterdam, Netherlands..
    Oleinikov, Kira
    Hebrew Univ Jerusalem, Hadassah Med Org, Neuroendocrine Tumor Unit, ENETS Ctr Excellence,Dept Endocrinol & Metab, Jerusalem, Israel.;Hebrew Univ Jerusalem, Fac Med, Jerusalem, Israel..
    Orci, Lorenzo A.
    Geneva Univ Hosp, Div Abdominal Surg, Dept Surg, Geneva, Switzerland..
    Panzuto, Francesco
    Sapienza Univ Rome, Dept Med Surg Sci & Translat Med, Rome, Italy.;St Andrea Univ Hosp, ENETS Ctr Excellence, Digest Dis Unit, Rome, Italy..
    Pavel, Marianne
    Friedrich Alexander Univ Erlangen Nurnberg, Dept Med 1, Erlangen, Germany..
    Perrier, Marine
    Univ Reims, CHU Reims, Serv Hepatogastroenterol & Oncol Digest, Reims, France..
    Reims, Henrik Mikael
    Rigshosp, Oslo Univ Hosp, Dept Pathol, Oslo, Norway..
    Rindi, Guido
    Fdn Policlin Univ A Gemelli IRCCS, Unit Head & Neck Lung & Endocrine Pathol, Dept Woman & Child Hlth Sci & Publ Hlth, Rome, Italy.;Roma European NeuroEndocrine Tumor Soc, Ctr Excellence, Rome, Italy.;Univ Cattolica Sacro Cuore, Dept Life Sci & Publ Hlth, Sect Anat Pathol, Rome, Italy..
    Rinke, Anja
    UKGM, Dept Gastroenterol & Endocrinol, Marburg, Germany.;Philipps Univ Marburg, Marburg, Germany..
    Rinzivillo, Maria
    St Andrea Univ Hosp, ENETS Ctr Excellence, Digest Dis Unit, Rome, Italy..
    Sagaert, Xavier
    Katholieke Univ Leuven, Translat Cell & Tissue Res, Leuven, Belgium..
    Satiroglu, Ilker
    Martin Luther Univ Halle Wittenberg, Dept Visceral Vascular & Endocrine Surg, Halle, Germany..
    Selberherr, Andreas
    Med Univ Vienna, Dept Gen Surg, Div Visceral Surg, Vienna, Austria..
    Siebenhuener, Alexander R.
    Univ Spital Zurich, Klin Med Onkol & Hamatol, Zurich, Switzerland.;Univ Zurich, Zurich, Switzerland.;Kantonsspital Schaffhausen, Dept Med Onkol, Schaffhausen, Switzerland..
    Tesselaar, Margot E. T.
    Netherlands Canc Inst, Dept Med Oncol, Amsterdam, Netherlands..
    Thalhammer, Michael J.
    Med Univ Graz, Dept Surg, Div Visceral & Transplant Surg, Graz, Austria..
    Thiis-Evensen, Espen
    Rigshosp, Oslo Univ Hosp, Dept Gastroenterol, Oslo, Norway..
    Toumpanakis, Christos
    Royal Free Hosp London, ENETS Ctr Excellence, Neuroendocrine Tumour Unit, London, England..
    Vandamme, Timon
    Univ Hosp Antwerp, Edegem, Belgium..
    van den Berg, José G.
    Netherlands Canc Inst, Dept Pathol, Amsterdam, Netherlands..
    Vanoli, Alessandro
    Univ Pavia, Dept Mol Med, Anat Pathol Unit, Pavia, Italy.;IRCCS Policlin San Matteo Fdn, Anat Pathol Unit, Pavia, Italy..
    van Velthuysen, Marie-Louise F.
    Erasmus MC, Dept Pathol, Rotterdam, Netherlands..
    Verslype, Chris
    Univ Hosp Leuven, Clin Digest Oncol, Leuven, Belgium..
    Vorburger, Stephan A.
    Teaching Hosp Emmental, Dept Surg, Burgdorf, Switzerland..
    Lugli, Alessandro
    Univ Bern, Inst Pathol, Bern, Switzerland..
    Ramage, John
    Univ Winchester, Winchester, Hants, England.;Hampshire Hosp, Basingstoke, Hants, England..
    Zwahlen, Marcel
    Univ Bern, Inst Social & Prevent Med, Bern, Switzerland..
    Perren, Aurel
    Univ Bern, Inst Pathol, Bern, Switzerland..
    Kaderli, Reto M.
    Univ Hosp Bern, Inselspital, Dept Visceral Surg & Med, CH-3010 Bern, Switzerland..
    Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size: a retrospective, Europe-wide, pooled cohort study2023Inngår i: The Lancet Oncology, ISSN 1470-2045, E-ISSN 1474-5488, Vol. 24, nr 2, s. 187-194Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1–2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1–2 cm in size in patients with or without right-sided hemicolectomy.

    Methods

    In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1–2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693.

    Findings

    282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1–2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0–15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 –21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36–2·17]; p=0·71).

    Interpretation

    This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1–2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort.

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  • 95.
    Nicholson, Andrew G.
    et al.
    Royal Brompton & Harefield Natl Hlth Serv Fdn Tru, London, England.;Imperial Coll, Natl Heart & Lung Inst, London, England..
    Torkko, Kathleen
    Univ Colorado, Anschutz Med Campus, Aurora, CO USA..
    Viola, Patrizia
    Royal Brompton & Harefield Natl Hlth Serv Fdn Tru, London, England.;Imperial Coll, Natl Heart & Lung Inst, London, England..
    Duhig, Edwina
    Sullivan Nicolaides Pathol, Taringa, Qld, Australia..
    Geisinger, Kim
    Univ Mississippi, Med Ctr, Jackson, MS 39216 USA..
    Borczuk, Alain C.
    Weill Cornell Med, New York, NY USA..
    Hiroshima, Kenzo
    Tokyo Womens Med Univ, Yachiyo, Japan..
    Tsao, Ming S.
    Princess Margaret Canc Ctr, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada..
    Warth, Arne
    Heidelberg Univ Hosp, Heidelberg, Germany..
    Lantuejoul, Sylvie
    Canc Inst Leon Berard, Lyon, France..
    Russell, Prudence A.
    St Vincents Pathol, Fitzroy, Vic, Australia..
    Thunnissen, Erik
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Marchevsky, Alberto
    Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA..
    Mino-Kenudson, Mari
    Massachusetts Gen Hosp, Boston, MA 02114 USA..
    Beasley, Mary Beth
    Mt Sinai Med Ctr, New York, NY 10029 USA..
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Dacic, Sanja
    Univ Pittsburgh, Pittsburgh, PA USA..
    Yatabe, Yasushi
    Aichi Canc Ctr, Nagoya, Aichi, Japan..
    Noguchi, Masayuki
    Univ Tsukuba, Tsukuba, Ibaraki, Japan..
    Travis, William D.
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    Kerr, Keith
    Aberdeen Royal Infirm, Aberdeen, Scotland..
    Hirsch, Fred R.
    Univ Colorado, Anschutz Med Campus, Aurora, CO USA..
    Chirieac, Lucian R.
    Harvard Med Sch, Boston, MA USA..
    Wistuba, Ignacio I.
    MD Anderson, Houston, TX USA..
    Moreira, Andre
    NYU, Langone Med Ctr, New York, NY USA..
    Chung, Jin-Haeng
    Seoul Natl Univ, Bundang Hosp, Seoul, South Korea..
    Chou, Teh Ying
    Taipei Vet Gen Hosp, Taipei, Taiwan..
    Bubendorf, Lukas
    Univ Hosp Basel, Basel, Switzerland..
    Chen, Gang
    Fudan Univ, Zhongshan Hosp, Shanghai, Peoples R China..
    Pelosi, Giuseppe
    Univ Milan, Dept Oncol & Hematooncol, Milan, Italy..
    Poleri, Claudia
    Detterbeck, Frank C.
    Yale Univ, Dept Thorac Surg, New Haven, CT USA..
    Franklin, Wilbur A.
    Univ Colorado, Anschutz Med Campus, Aurora, CO USA..
    Interobserver Variation among Pathologists and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung2018Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, nr 2, s. 205-217Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Multiple tumor nodules are seen with increasing frequency in clinical practice. On the basis of the 2015 WHO classification of lung tumors, we assessed the reproducibility of the comprehensive histologic assessment to distinguish second primary lung cancers (SPLCs) from intrapulmonary metastases (IPMs), looking for the most distinctive histologic features. An international panel of lung pathologists reviewed a scanned sequential cohort of 126 tumors from 48 patients and recorded an agreed set of histologic features, including tumor typing and predominant pattern of adenocarcinoma, thereby opining whether the case was SPLC, IPM, or a combination thereof. Cohen kappa statistics of 0.60 on overall assessment of SPLC or IPM indicated a good agreement. Likewise, there was good agreement (kappa score 0.64, p < 0.0001) between WHO histologic pattern in individual cases and SPLC or IPM status, but the proportions diversified for histologic pattern and SPLC or IPM status (McNemar test, p < 0.0001). The strongest associations for distinguishing between SPLC and IPM were observed for nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intraalveolar clusters, and necrosis. Conversely, the associations for lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization, and emperipolesis did not reach significance with tumor extent. Comprehensive histologic assessment is recommended for distinguishing SPLC from IPM with good reproducibility among lung pathologists. In addition to main histologic type and predominant patterns of histologic subtypes, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate strongly correlate with pathologic staging status.

  • 96. 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.

  • 97.
    Pellinen, Teijo
    et al.
    Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki , Helsinki, Finland.
    Paavolainen, Lassi
    Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki , Helsinki, Finland.
    Martín-Bernabé, Alfonso
    Department of Oncology-Pathology, Karolinska Institutet , Stockholm, Sweden.
    Papatella Araujo, Renata
    Department of Oncology-Pathology, Karolinska Institutet , Stockholm, Sweden.
    Strell, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Mezheyeuski, Artur
    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.
    La Fleur, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Brück, Oscar
    Hematology Research Unit Helsinki, University of Helsinki and Comprehensive Cancer Center, Helsinki University Hospital , Helsinki, Finland.
    Sjölund, Jonas
    Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University Cancer Centre, Lund University , Sweden.
    Holmberg, Erik
    Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital , Gothenburg, Sweden.
    Välimäki, Katja
    Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki , Helsinki, Finland.
    Brunnström, Hans
    Division of Pathology, Lund University, Skåne University Hospital , Lund, Sweden.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Moreno-Ruiz, Pablo
    Department of Oncology-Pathology, Karolinska Institutet , Stockholm, Sweden.
    Kallioniemi, Olli
    Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki , Helsinki, Finland;Department of Oncology-Pathology, Karolinska Institutet , Stockholm, Sweden;Science for Life Laboratory (SciLifeLab), Department of Oncology-Pathology, Karolinska Institutet , Stockholm, Sweden.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancerimmunterapi.
    Östman, Arne
    Department of Oncology-Pathology, Karolinska Institutet , Stockholm, Sweden.
    Fibroblast subsets in non-small cell lung cancer: Associations with survival, mutations, and immune features2023Inngår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 115, nr 1, s. 71-82Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Cancer-associated fibroblasts (CAFs) are molecularly heterogeneous mesenchymal cells that interact with malignant cells and immune cells and confer anti- and protumorigenic functions. Prior in situ profiling studies of human CAFs have largely relied on scoring single markers, thus presenting a limited view of their molecular complexity. Our objective was to study the complex spatial tumor microenvironment of non-small cell lung cancer (NSCLC) with multiple CAF biomarkers, identify novel CAF subsets, and explore their associations with patient outcome.

    Methods

    Multiplex fluorescence immunohistochemistry was employed to spatially profile the CAF landscape in 2 population-based NSCLC cohorts (n = 636) using antibodies against 4 fibroblast markers: platelet-derived growth factor receptor-alpha (PDGFRA) and -beta (PDGFRB), fibroblast activation protein (FAP), and alpha-smooth muscle actin (αSMA). The CAF subsets were analyzed for their correlations with mutations, immune characteristics, and clinical variables as well as overall survival.

    Results

    Two CAF subsets, CAF7 (PDGFRA-/PDGFRB+/FAP+/αSMA+) and CAF13 (PDGFRA+/PDGFRB+/FAP-/αSMA+), showed statistically significant but opposite associations with tumor histology, driver mutations (tumor protein p53 [TP53] and epidermal growth factor receptor [EGFR]), immune features (programmed death-ligand 1 and CD163), and prognosis. In patients with early stage tumors (pathological tumor-node-metastasis IA-IB), CAF7 and CAF13 acted as independent prognostic factors.

    Conclusions

    Multimarker-defined CAF subsets were identified through high-content spatial profiling. The robust associations of CAFs with driver mutations, immune features, and outcome suggest CAFs as essential factors in NSCLC progression and warrant further studies to explore their potential as biomarkers or therapeutic targets. This study also highlights multiplex fluorescence immunohistochemistry–based CAF profiling as a powerful tool for the discovery of clinically relevant CAF subsets.

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  • 98. Planck, Maria
    et al.
    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.
    Isaksson, Sofi
    Staaf, Johan
    Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to EGFR and KRAS Mutation Status2013Inngår i: PLOS ONE, E-ISSN 1932-6203, Vol. 8, nr 10, s. e78614-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: In lung adenocarcinoma, the mutational spectrum is dominated by EGFR and KRAS mutations. Improved knowledge about genomic and transcriptional alterations in and between mutation-defined subgroups may identify genes involved in disease development or progression. Methods: Genomic profiles from 457 adenocarcinomas, including 113 EGFR-mutated, 134 KRAS-mutated and 210 EGFR and KRAS-wild type tumors (EGFRwt/KRASwt), and gene expression profiles from 914 adenocarcinomas, including 309 EGFR-mutated, 192 KRAS-mutated, and 413 EGFRwt/KRASwt tumors, were assembled from different repositories. Genomic and transcriptional differences between the three mutational groups were analyzed by both supervised and unsupervised methods. Results: EGFR-mutated adenocarcinomas displayed a larger number of copy number alterations and recurrent amplifications, a higher fraction of total loss-of-heterozygosity, higher genomic complexity, and a more distinct expression pattern than EGFR-wild type adenocarcinomas. Several of these differences were also consistent when the three mutational groups were stratified by stage, gender and smoking status. Specific copy number alterations were associated with mutation status, predominantly including regions of gain with the highest frequency in EGFR-mutated tumors. Differential regions included both large and small regions of gain on 1p, 5q34-q35.3, 7p, 7q11.21, 12p12.1, 16p, and 21q, and losses on 6q16.3-q21, 8p, and 9p, with 20-40% frequency differences between the mutational groups. Supervised gene expression analyses identified 96 consistently differentially expressed genes between the mutational groups, and together with unsupervised analyses these analyses highlighted the difficulty in broadly resolving the three mutational groups into distinct transcriptional entities. Conclusions: We provide a comprehensive overview of the genomic and transcriptional landscape in lung adenocarcinoma stratified by EGFR and KRAS mutations. Our analyses suggest that the overall genomic and transcriptional landscape of lung adenocarcinoma is affected, but only to a minor extent, by EGFR and KRAS mutation status.

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  • 99.
    Raja, Erna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Tzavlaki, Kalliopi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Molekylär cellbiologi.
    Vuilleumier, Robin
    Edlund, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Kahata, Kaoru
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Zieba, Agata
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Morén, Anita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Watanabe, Yukihide
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Voytyuk, Iryna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Söderberg, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Pyrowolakis, George
    Heldin, Carl-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Moustakas, Aristidis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    The protein kinase LKB1 negatively regulates bone morphogenetic protein receptor signaling2016Inngår i: Oncotarget, E-ISSN 1949-2553, Vol. 7, nr 2, s. 1120-1143Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The protein kinase LKB1 regulates cell metabolism and growth and is implicated in intestinal and lung cancer. Bone morphogenetic protein (BMP) signaling regulates cell differentiation during development and tissue homeostasis. We demonstrate that LKB1 physically interacts with BMP type I receptors and requires Smad7 to promote downregulation of the receptor. Accordingly, LKB1 suppresses BMP-induced osteoblast differentiation and affects BMP signaling in Drosophila wing longitudinal vein morphogenesis. LKB1 protein expression and Smad1 phosphorylation analysis in a cohort of non-small cell lung cancer patients demonstrated a negative correlation predominantly in a subset enriched in adenocarcinomas. Lung cancer patient data analysis indicated strong correlation between LKB1 loss-of-function mutations and high BMP2 expression, and these two events further correlated with expression of a gene subset functionally linked to apoptosis and migration. This new mechanism of BMP receptor regulation by LKB1 has ramifications in physiological organogenesis and disease.

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  • 100.
    Rao, Shuan
    et al.
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Sigl, Verena
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Wimmer, Reiner Alois
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Novatchkova, Maria
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Jais, Alexander
    Med Univ Vienna, Dept Lab Med, A-1090 Vienna, Austria.;Max Planck Inst Metab Res, Dept Neuronal Control Metab, D-50931 Cologne, Germany..
    Wagner, Gabriel
    Med Univ Vienna, Dept Lab Med, A-1090 Vienna, Austria..
    Handschuh, Stephan
    Univ Vet Med, VetCore Facil Res, A-1220 Vienna, Austria..
    Uribesalgo, Iris
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Hagelkruys, Astrid
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Kozieradzki, Ivona
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Tortola, Luigi
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Nitsch, Roberto
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Cronin, Shane J.
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Orthofer, Michael
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    Branstetter, Daniel
    Amgen Inc, Dept Pathol, Seattle, WA 98119 USA..
    Canon, Jude
    Amgen Inc, Dept Oncol Res, Seattle, WA 98119 USA..
    Rossi, John
    Amgen Inc, Dept Mol Sci, Seattle, WA 98119 USA..
    D'Arcangelo, Manolo
    Univ Colorado, Ctr Canc, Aurora, CO 80045 USA..
    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.
    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.
    Edlund, Karolina
    Leibniz Res Ctr Working Environm & Human Factors, D-44139 Dortmund, Germany..
    Bergqvist, Michael
    Gavle Cent Hosp, Dept Oncol, S-80187 Gavle, Sweden..
    Ekman, Simon
    Karolinska Inst, Dept Oncol Pathol, S-17177 Stockholm, Sweden..
    Lendl, Thomas
    Gregor Mendel Inst Mol Plant Biol GMI, A-1030 Vienna, Austria..
    Popper, Helmut
    Med Univ Graz, Inst Pathol, Res Unit Mol Lung & Pleura Pathol, A-8036 Graz, Austria..
    Takayanagi, Hiroshi
    Univ Tokyo, Dept Immunol, Tokyo 1088639, Japan..
    Kenner, Lukas
    Med Univ Vienna, Dept Clin Pathol, A-1090 Vienna, Austria.;Ludwig Boltzmann Inst Canc Res, A-1090 Vienna, Austria.;Univ Vet Med Vienna, Unit Pathol Lab Anim, A-1220 Vienna, Austria..
    Hirsch, Fred R.
    Univ Colorado, Ctr Canc, Aurora, CO 80045 USA..
    Dougall, William
    Amgen Inc, Dept Oncol Res, Seattle, WA 98119 USA.;QIMR, Berghofer Med Res Inst, Dept Immunol Canc & Infect, Brisbane, Qld 4006, Australia..
    Penninger, Josef
    Austrian Acad Sci IMBA, Inst Mol Biotechnol, A-1030 Vienna, Austria..
    RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer2017Inngår i: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 31, nr 20, s. 2099-2112Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas(G12D) in mouse lung epithelial cells markedly impairs the progression of KRas(G12D)-driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas(G12D)-driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer.

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