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  • 1.
    Domanski, A M.
    et al.
    Skåne University Hospital, Sweden .
    Monsef, Nastaran
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Domanski, H A.
    Skåne University Hospital, Sweden .
    Grabau, D
    Skåne University Hospital, Sweden .
    Ferno, M
    Lund University, Sweden .
    Comparison of the oestrogen and progesterone receptor status in primary breast carcinomas as evaluated by immunohistochemistry and immunocytochemistry: a consecutive series of 267 patients2013In: Cytopathology, ISSN 0956-5507, E-ISSN 1365-2303, Vol. 24, no 1, p. 21-25Article in journal (Refereed)
    Abstract [en]

    A.M. Domanski, N. Monsef, H.A. Domanski, D. Grabau and M. Ferno Comparison of the oestrogen and progesterone receptor status in primary breast carcinomas as evaluated by immunohistochemistry and immunocytochemistry: a consecutive series of 267 patients Objective: The use of cytological specimens to evaluate tumour biomarkers in metastatic breast cancer lesions has attracted increased interest because of the considerable number of reports that have shown discordance between the primary tumour and metastatic lesion. Oestrogen receptor (ER) and progesterone receptor (PgR) assays are crucial for the management of patients with breast cancer, in both adjuvant and palliative settings. The aim of this study was to compare the ER and PgR immunocytochemical analysis of fine needle aspiration (FNA) samples with the immunohistochemistry (IHC) of surgical specimens and core biopsies from primary breast cancers. Methods: The FNA specimens were prepared as cell blocks (n = 25) or ThinPreps (n = 258) for the immunocytochemistry (IC) ER and PgR analyses. Sixteen patients were excluded because of lack of follow-up (n = 1), neoadjuvant therapy (n = 3) or cell counts in their fine needle aspirates that were too low (n = 12). The results of IC on 25 cell blocks and 242 ThinPreps were compared with IHC on the corresponding core needle biopsies (n = 16) or excised tumours (n = 251). The ER and PgR status was defined as negative (when less than 10% of the nuclei were stained) or positive (when equal or more than 10% of the nuclei were stained). Kappa statistics were used to evaluate the concordance. Results: The ER concordance was 98% with ThinPrep (kappa = 0.93) and 92% with cell block (kappa = 0.82). The corresponding values for PgR were 96% (kappa = 0.91) and 96% (kappa = 0.92). Conclusions: Our results confirm that, in cases in which biopsies or surgical specimens are not available, IC (with either cell block or ThinPrep techniques) is a reliable method for the determination of the ER and PgR status performed under strict conditions using primary breast carcinomas, and is therefore potentially useful in metastatic settings.

  • 2.
    Forsberg, Daniel
    et al.
    Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, The Institute of Technology. Linköping University, Center for Medical Image Science and Visualization (CMIV). Sectra, Linköping, Sweden.
    Monsef, Nastaran
    Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Evaluating Cell Nuclei Segmentation for Use on Whole-Slide Images in Lung Cytology2014In: 2014 22nd International Conference on Pattern Recognition (ICPR), IEEE Computer Society, 2014, p. 3380-3385Conference paper (Refereed)
    Abstract [en]

    This paper presents results from an evaluation of three previously presented methods for segmentation of cell nuclei in lung cytology samples scanned by whole-slide scanners. Whole-slide images from seven cases of endobronchial ultrasound-guided transbronchial needle aspiration samples were used for extracting a number of regions of interest, in which approximately 2700 cell nuclei were manually segmented to form the ground truth. The segmented cells included benign bronchial epithelium, lymphocytes, granulocytes, histiocytes and malignant epithelial cells. The best results were obtained with a method based upon adaptive thresholding and an added step of clustering for distinguishing between cytoplasm and cell nuclei. This method achieved a mean DICE-score of 0.81 and a sensitivity and specificity of 0.88 and 0.81 respectively. In addition, this method was by far the fastest method, with a mean processing time of 7.8 s per image (2048 x 2048 pixels per image). By further improvements, such as lowering the false positive rate and using parallel computing hardware, this method has the potential to form the first building block in a system for computerized screening of whole-slide images in lung cytology.

  • 3.
    Karlsson, Anna
    et al.
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Cirenajwis, Helena
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Ericson-Lindquist, Kajsa
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Department of Pathology, Regional Laboratories Region Skåne, Lund, Sweden.
    Brunnstrom, Hans
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Department of Pathology, Regional Laboratories Region Skåne, Lund, Sweden.
    Reutersward, Christel
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Jönsson, Mats
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    Ortiz-Villalon, Cristian
    Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Hussein, Aziz
    Department of Pathology and cytology, Sahlgrenska university hospital, Gothenburg, Sweden.
    Bergman, Bengt
    Department of Respiratory Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Vikström, Anders
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine.
    Monsef, Nastaran
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Clinical pathology.
    Branden, Eva
    Respiratory Medicine Unit, Department of Medicine Solna and CMM, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Koyi, Hirsh
    Respiratory Medicine Unit, Department of Medicine Solna and CMM, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden; Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    de Petris, Luigi
    Thoracic Oncology Unit, Karolinska University Hospital and Department Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Patthey, Annika
    Department of Pathology, Umeå University Hospital, Umeå, Sweden.
    Behndig, Annelie F.
    Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University, Umeå, Sweden.
    Johansson, Mikael
    Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    Planck, Maria
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden; Department of Respiratory Medicine and Allergology, Skåne University Hospital, Lund, Sweden.
    Staaf, Johan
    Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Medicon Village, Lund, Sweden.
    A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 5207Article in journal (Refereed)
    Abstract [en]

    Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.

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  • 4.
    Munksgaard Persson, Matilda
    et al.
    Lund University.
    Johansson, Martin E
    Lund University.
    Monsef, Nastaran
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Planck, Maria
    Lund University.
    Beckman, Siv
    Lund University.
    Seckl, Michael J
    University of London Imperial Coll Science Technology and Medicine.
    Ronnstrand, Lars
    Lund University.
    Pahlman, Sven
    Lund University.
    Pettersson, Helen M
    Lund University.
    HIF-2 alpha Expression Is Suppressed in SCLC Cells, Which Survive in Moderate and Severe Hypoxia When HIF-1 alpha Is Repressed2012In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 180, no 2, p. 494-504Article in journal (Refereed)
    Abstract [en]

    Small cell lung carcinoma (SCLC) is extremely aggressive and frequently metastasizes widely in its early stage. Because tumor hypoxia is related to aggressive tumor behavior and the hypoxic adaptation of SCLC is poorly documented, we stained SCLC tumors arranged in a tissue microarray for hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha proteins. We found an overall lack of HIF-2 alpha protein expression, which was confirmed in large tumor sections. HIF-1 alpha protein was strongly expressed in most tumors, frequently adjacent to necrotic regions. In concordance, cultured SCLC but not non-small cell lung carcinoma cells showed no or extremely low levels of HIF-2 alpha mRNA and no HIF-2 alpha protein at hypoxia. HIF-1 alpha was stabilized after 4 hours at hypoxia, and its accumulation increased up to 96 hours. SCLC cells survived well and showed net proliferation and low cell death in modest (1% oxygen) and severe (0.1% oxygen) hypoxia. HIF-1 alpha repression virtually did not influence cell death or viability despite reduced levels of hypoxia-inducible genes, such as BNIP3 and BNIP3L. At 1% oxygen no increased autophagy (LC3B-II activation) or NF-kappa B signaling were detected, whereas the unfolded protein response was activated at severe hypoxia. Our data indicate that HIFs are not exclusively required for SCLC cell survival at modest or severe hypoxia and that additional, yet uncharacterized, hypoxia-driven adaptation pathways may become activated.

  • 5.
    Olsson, Hans
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Monsef, Nastaran
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Rosell, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Johanson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Urology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Immunohistochemical Evaluation of Cell Cycle Regulators: Impact on Predicting Prognosis in Stage T1 Urinary Bladder Cancer2012In: ISRN Urology, ISSN 2090-5807, E-ISSN 2090-5815, Vol. 2012, article id 379081Article in journal (Other academic)
    Abstract [en]

    Background and Objective. The cell cycle is regulated by proteins at different checkpoints, and dysregulation of this cycle plays a role in carcinogenesis. Matrix metalloproteinases (MMPs) are enzymes that degrade collagen and promote tumour infiltration. The aim of this study was to evaluate the expression of various cell cycle regulators and MMPs, and to correlate such expression with progression and recurrence in patients with stage T1 urothelial carcinoma of the bladder (UCB).

    Patients and Methods. This population-based cohort study comprised 201 well-characterized patients with primary stage T1 urothelial carcinoma of the bladder. Immunohistochemistry was performed on formalin-fixed material to quantify expression of cell cycle regulators and two MMPs.

    Results. Normal expression of p53 and abnormal expression of MMP9 were associated with greater risk of tumour recurrence. Also, normal p16 expression was related to a lower risk of tumour progression. MMP2, p21, cyclin D1, and pRb showed no significant results that could estimate progression or recurrence.

    Conclusions. Normal p16 expression is associated with a lower risk of tumour progression, but immunohistochemistry on cell cycle regulators and MMPs has little value in predicting the prognosis in stage T1 UCB.

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