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  • 1.
    Bjarnholt, Christel
    et al.
    Karolinska Inst, Huddinge, Sweden.
    Yngve, Agneta
    Karolinska Inst, Huddinge, Sweden.
    Krawinkel, Michael
    Univ Giessen, Giessen, Germany.
    Kristjansdottir, Asa G.
    Univ Iceland, Reykjavik, Iceland.
    Hlastan Ribic, Cirila
    Ctr Community Hlth, Ljubljana, Slovenia.
    Vaz de Almeida, Maria Daniel
    Univ Porto, Fac Ciencias Nutr & Alimentacao, P-4100 Oporto, Portugal.
    Francini, Bela
    Univ Porto, Fac Ciencias Nutr & Alimentacao, Oporto, Portugal.
    Papadaki, Alina
    Univ Crete, Iraklion, Greece.
    Karlsson, Christina
    ICA AB, Solna, Sweden.
    Brug, Johannes
    EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.
    Maucec-Zakotnik, Jozica
    Ctr Community Hlth, Ljubljana, Slovenia.
    Ehrenblad, Bettina
    Karolinska Inst, Huddinge, Sweden.
    Duleva, Vesselka
    Natl Ctr Publ Hlth Protect, Sofia, Bulgaria.
    Lien, Nanna
    Univ Oslo, Oslo, Norway.
    te Velde, Saskia
    EMGO Inst Hlth & Care Res, Amsterdam, Netherlands.
    Izquierdo de Santiago, Raquel
    Freshfel Europe, Brussels, Belgium.
    Roos, Eva
    Folkhalsan, Helsinki, Finland.
    Klepp, Knut-Inge
    Univ Oslo, Oslo, Norway.
    Binard, Philippe
    Freshfel Europe, Brussels, Belgium.
    Petrova, Stefka
    Natl Ctr Publ Hlth Protect, Sofia, Bulgaria.
    Thorsdottir, Inga
    Univ Iceland, Reykjavik, Iceland.
    Progreens: promotion of fruit and vegetable intake in school children across Europe2009In: Annals of Nutrition and Metabolism, ISSN 0250-6807, E-ISSN 1421-9697, Vol. 55, p. 504-504Article in journal (Other academic)
  • 2.
    Botling, Johan
    et al.
    Departments of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Edlund, Karolina
    Departments of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Lohr, Miriam
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Hellwig, Birte
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Holmberg, Lars
    Dept. Surgical Sciences, Uppsala University, Uppsala, Sweden; Regional Cancer Center Uppsala Örebro, Akademiska sjukhuset, Uppsala, Sweden; Division of Cancer Studies, King's College Medical School, London, United Kingdom.
    Lambe, Mats G.
    Regional Cancer Center Uppsala Örebro, Akademiska sjukhuset, Uppsala, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Berglund, Anders
    Regional Cancer Center Uppsala Örebro, Akademiska sjukhuset, Uppsala, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ekman, Simon
    Radiology, Oncology and Radiation Sciences, Section of Oncology, Uppsala University, Uppsala, Sweden.
    Bergqvist, Michael
    Radiology, Oncology and Radiation Sciences, Section of Oncology, Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Departments of 1Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    König, André
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Fernandes, Oswaldo
    Cardiothoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats
    Örebro University Hospital. Laboratory Medicine.
    Helenius, Gisela
    Örebro University Hospital. Laboratory Medicine.
    Karlsson, Christina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rahnenfuehrer, Jörg
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Hengstler, Jan G.
    Leibniz Research Centre for Working Environment and Human Factors (IfADo), Dortmund, Germany.
    Micke, Patrick
    Departments of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Biomarker Discovery in Non-Small Cell Lung Cancer: Integrating Gene Expression Profiling, Meta-analysis, and Tissue Microarray Validation2013In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, no 1, p. 194-204Article in journal (Refereed)
    Abstract [en]

    Purpose: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap.

    Experimental Design: Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860).

    Results: The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate < 1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.

    Conclusions: Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics. Clin Cancer Res; 19(1); 194-204. (c) 2012 AACR.

  • 3.
    Hadgu, Endale
    et al.
    Department of Biochemistry, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
    Seifu, Daniel
    Department of Biochemistry, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
    Tigneh, Wondemagegnhu
    Department of Oncology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
    Bokretsion, Yonas
    Department of Pathology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
    Bekele, Abebe
    Department of Surgery, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia.
    Abebe, Markos
    Armauer Hansen research Institute (AHRI), Addis Ababa, Ethiopia.
    Sollie, Thomas
    Dept of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Merajver, Sofia D.
    University of Michigan Comprehensive Cancer Center, Ann Arbor MI, USA.
    Karlsson, Christina
    Örebro University, School of Health Sciences.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Breast cancer in Ethiopia: evidence for geographic difference in the distribution of molecular subtypes in Africa2018In: BMC Women's Health, ISSN 1472-6874, E-ISSN 1472-6874, Vol. 18, no 1, article id 40Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Breast cancer is a heterogeneous disease with several morphological and molecular subtypes. Widely accepted molecular classification system uses assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker Ki67. Few studies have been conducted on the incidence and molecular types of breast cancer in Sub-Saharan Africa. Previous studies mainly from Western and Central Africa, showed breast cancer to occur at younger ages and to present with aggressive features, such as high-grade, advanced stage and triple-negative phenotype (negative for ER, PR and HER2). Limited data from East Africa including Ethiopia however shows hormone receptor negative tumors to account for a lower proportion of all breast cancers than has been reported from elsewhere in Africa.

    METHODS: In this study from Tikur Anbessa Specialized Hospital, 114 breast cancer patients diagnosed between 2012 and 2015 were enrolled. ER, PR, Ki67 and HER2 receptor status were assessed using immunohistochemistry from tissue microarrays. FISH was used for assessment of gene amplification in all equivocal tumor samples and for confirmation in HER2-enriched cases.

    RESULTS: The distribution of molecular subtypes was: Luminal A: 40%; Luminal B: 26%; HER2-enriched: 10%; TNBC: 23%. ER were positive in 65% of all tumors and 43% the cases were positive for PR. There was statistically significant difference in median age at diagnosis between the molecular subtypes (P < 0.05). There was a bimodal distribution of molecular subtypes in different age ranges with Luminal B subtype being more common at younger ages (median = 36) and Luminal A subtype more prevalent at older ages (median = 42). There were no statistically significant differences in tumor grade, histology, and stage between the molecular subtypes of breast cancer.

    CONCLUSION: The present study detected Luminal A breast cancer to be the most common subtype and reveals a relatively low rate of hormone receptor negative and TNBC. Our findings and results from other East African studies suggest geographic variability in the distribution of the molecular subtypes of breast cancer in Africa and hence have important clinical and policy implications for breast cancer control and treatment in Ethiopia.

  • 4.
    Hellquist, H. B.
    et al.
    Department of Pathology II, University Hospital, Linköping, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Medical Center Hospital, Örebro, Sweden.
    Karlsson, Christina
    Department of Pathology, Medical Center Hospital, Örebro, Sweden.
    Viale, G.
    Department of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan School of Medicine, Milan, Italy.
    Dell'Orto, P.
    Department of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan School of Medicine, Milan, Italy.
    Davidsson, Åke
    Department of Otorhinolaryngology, Medical Center Hospital, Örebro, Sweden.
    Olofsson, J.
    Department of Otolaryngology, Head and Neck Surgery, Haukeland University Hospital, Bergen, Norway .
    Bcl-2 immunoreactivity in salivary gland neoplasms is unrelated to the expression of mRNA for natural killer cell stimulatory cytokines interleukin (IL)-2 and IL-121996In: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 429, no 2-3, p. 149-158Article in journal (Refereed)
    Abstract [en]

    Certain cytokines are involved in the generation of natural killer (NK) cells and participate in the regulation of the proto-oncogene bcl-2. We aimed to study the mRNA expression of interleukin (IL)-2, IL-4 and IL-5, the composition of the tumour infiltrating lymphocytes (TIL), and the expression of bcl-2 in 14 benign and malignant human parotid tumours. T IL were predominantly composed of T lymphocytes and NK cells. We found evidence for the homing of T cells, and for generation of NK cells in the vicinity of the tumours. mRNA for IL-2 and IL-12, were identified but IL-4 mRNA was not found. The cytokine profiles and the composition of TIL of the two tumour categories were indistinguishable, suggesting that these host-response variables do not explain the differences in biological behaviour of these particular tumours. The results support a shift towards Th 1 (T helper 1) cells and interferon-gamma production, and that IL-12 also in vivo may play an important role in the regulatory interaction between innate resistance and adaptive immunity in tumour diseases. Most infiltrating lymphocytes showed strong expression of bcl-2; an interesting observation with regard to lymphocytic apoptosis in neoplastic diseases. The immunoreactivity for the bcl-2 protein varied considerably between and within tumours, and almost all benign tumours showed strong bcl-2 positively whereas several of the malignant tumours showed weak or absent staining. The variable expression of bcl-2 protein suggests a different susceptibility of tumour cells to apoptosis. The results also indicate that bcl-2 cannot pla a major role as protective agent in the specific apoptotic pathway induced by NK cells.

  • 5.
    Karlsson, Christina
    Örebro University, School of Health and Medical Sciences.
    Biomarkers in non-small cell lung carcinoma: methodological aspects and influence of gender, histology and smoking habits on estrogen receptor and epidermal growth factor family receptor signalling2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Non-small cell lung carcinoma is a leading cause of cancer mortality worldwide. There are gender and smoking associated differences both in tumour types and clinical outcome. Squamous cell carcinomas (SCC) are more frequent among smoking men while females develop adenocarcinomas (ADCA). NSCLC among never smokers are mainly ADCA, and occurs mostly in females. The present thesis elucidates the role of estrogen receptor (ER) and epidermal growth factor receptor family (EGFR/HER2-4) in NSCLC in the perspective of gender and histology as well as the influence of smoking on those biomarkers.

    A recently developed technique, tissue micro array (TMA), was employed.The question of how much of a tumour tissue that needed to be included in a TMA for biomarker analysis was analyzed by a statistical approach. Data indicates a sample size of three cylinders of tumour tissue with a diameter of 0.6 mm each as being appropriate and cost-effective. In order to optimally use the up to thousands of different tumour samples within a TMA, it would be optimal to serially cut and store slides before performing in situ detection of proteins and nucleic acids. Applying up to date methodology, and by evaluation with image analysis, data are presented that shows that such handling of TMA slides would be possible without any loss of biomarker information.

    ERα is more frequently observed in ADCA and in females and a local estradiol synthesis is supported by the presence of aromatase. ERβ is identified as a positive prognostic marker in ADCA. Smoking is associated to increased levels of ERβ mRNA. EGFR over expression is associated with a ligand. Independent phosporylation of ERα. HER-4 intracellular domain may also act as a co-activator to ERα in ADCA, especially among neversmokers. The question of ER and EGFR family signalling crosstalk as a potential target for combined targeted therapy is raised.

    List of papers
    1. Tissue microarray validation: a methodologic study with special reference to lung cancer
    Open this publication in new window or tab >>Tissue microarray validation: a methodologic study with special reference to lung cancer
    2009 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 7, p. 2014-2021Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Although tissue microarray (TMA) studies of histopathologic material have been frequently reported in studies of malignant diseases, the question of sample size (i.e., the diameter and the number of tissue cylinders investigated) has been rarely discussed. This study addresses the methodologic question of sample size in a variety of tumor types.

    MATERIAL AND METHODS: Material from 29 cases of lung carcinoma (small cell, squamous cell, and adenocarcinomas) was examined immunohistochemically for Ki-67 and p53 expression in virtually constructed cylinders of different diameters. The influence of tissue sample size (i.e., different numbers of virtual cylinders) was also investigated. Results from Ki-67 evaluation were analyzed as a continuous variable, whereas p53 expression was scored. p53 evaluations based on scoring in cylinders versus scoring of whole sections were also compared. Furthermore, 10 cases of endometrial and breast carcinomas were evaluated for estrogen receptor, Ki-67, and HER2 by scoring up to five cylinders.

    RESULTS AND CONCLUSIONS: Tissue cylinders of 0.6 and 1.0 mm diameters were compared and found equally informative about Ki-67 expression (intraclass correlation, 0.96). A statistical approach considering intraindividual and interindividual variation data is presented, indicating that in this specific setting three cylinders per case is an adequate sample size for TMA studies. Further sampling yields only a small gain in accuracy as determined by Ki-67 quantification and p53 scoring (kappa-coefficient, 0.9). For endometrial and breast tissues, TMA scoring of three cylinders yielded excellent agreement (kappa, >0.75) compared with whole-section scoring.

    Place, publisher, year, edition, pages
    American Association for Cancer Research, 2009
    National Category
    Medical and Health Sciences Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:oru:diva-12067 (URN)10.1158/1055-9965.EPI-08-0743 (DOI)000268059700010 ()19531681 (PubMedID)2-s2.0-67650462275 (Scopus ID)
    Available from: 2010-10-05 Created: 2010-10-05 Last updated: 2017-12-12Bibliographically approved
    2. Effects of long-term storage on the detection of proteins, DNA, and mRNA in tissue microarray slides
    Open this publication in new window or tab >>Effects of long-term storage on the detection of proteins, DNA, and mRNA in tissue microarray slides
    2011 (English)In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 59, no 12, p. 1113-1121Article in journal (Refereed) Published
    Abstract [en]

    Storage of tissue slides has been claimed to induce dramatically reduced antigen detection particularly for immunohistochemistry (IHC). With tissue microarrays, the necessity to serially cut blocks in order to obtain as much material as possible is obvious. The presumed adverse effect of storage might hamper such an approach. The authors designed an experimental setting consisting of four different storage conditions with storage time of tissue slides of up to 1 year. Detection of proteins, DNA, and mRNA was performed using IHC and in situ hybridization techniques. Slight but significant changes in IHC occurred over time. The most important factor is the primary antibody used: four showed no significant changes, whereas limited decreases in 8 antibodies could be detected by image analysis. Whether the antigen was nuclear or cytoplasmic/membranous did not matter. No major differences between different storage conditions could be shown, but storage at 4C was overall the best procedure. Furthermore, gene copy number aberrations, chromosomal translocations, and the presence of mRNA could be detected on slides stored up to 1 year. In conclusion, in tissues optimally formalin fixed and using modern histological techniques, only minute changes in tissue antigenicity are induced by long-term storage.

    Place, publisher, year, edition, pages
    Sage Publications, 2011
    Keywords
    immunohistochemistry, heat-induced antigen retrieval, antigenicity, formalin-fixed paraffin-embedded, FISH, CISH, tissue microarray
    National Category
    Medical Biotechnology
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-20595 (URN)10.1369/0022155411423779 (DOI)000297649800006 ()22147608 (PubMedID)2-s2.0-84856012999 (Scopus ID)
    Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2018-05-03Bibliographically approved
    3. Estrogen receptor β in NSCLC: prevalence, proliferative influence, prognostic impact and smoking
    Open this publication in new window or tab >>Estrogen receptor β in NSCLC: prevalence, proliferative influence, prognostic impact and smoking
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In non-small cell lung carcinoma (NSCLC) there are gender differences. The female gender is associated with more adenocarcinomas (ADCA), among both smokers and non-smokers compared to men. Women with NSCLC have a better prognosis compared to men, regardless of other factors. A possible role for estrogen receptor (ER) signalling has been proposed and experimental as well as epidemiological data supports this view. In a material of NSCLC (n=262), ERβ and cyclins A and A2 were studied by immunohistochemistry on formalin-fixed paraffin embedded tissue. In 137 of those cases, frozen material was available, on which expression analysis of ESR2 (ERβ) and cyclin A1 were performed. Data was correlated to histology, gender, smoking habits, stage and clinical outcome.

    ERβ was expressed in 86% of the cases. ERβ was most frequently expressed in Stage I ADCAs, especially in male subjects. A correlation between ERβ expression and cyclins was observed in ADCA, also with a male predominance. ERβ transcripts had a positive prognostic impact in ADCA. ERβ transcripts were also increased in NSCLC among smokers compared to non-smokers.

    In conclusion, we report data supporting a role for ERβ in lung ADCAs where ERβ could be a biomarker for future targeted therapies.

    Keywords
    NSCLC, ERβ, immunohistochemistry, gene expression, gender, prognosis, smoking habits
    National Category
    Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:oru:diva-20596 (URN)
    Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-10-17Bibliographically approved
    4. Nuclear HER-4 (4ICD) and Estrogen Receptor α in non-small-cell lung carcinoma
    Open this publication in new window or tab >>Nuclear HER-4 (4ICD) and Estrogen Receptor α in non-small-cell lung carcinoma
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    In non-small cell lung carcinoma (NSCLC) squamous cell carcinomas (SCC) occurs more frequently among men and adenocarcinomas (ADCA) in females. The presence of estrogen receptors (ERs) in NSCLC have been proposed as a factor contributing to the gender associated differences. HER-4, a member of the epidermal growth factor receptor family, has recently been identified as a co-activator to ER by action of the shredded intracellular domain, 4ICD.

    Our study was performed on tissue material from 262 NSCLC. In 137 cases, frozen material was available. HER-4/4ICD, ERα, PgR and aromatase was determined by immunohistochemistry. HER-4 gene copy number and HER-4 and ERα transcripts was also studied. Data was correlated to proliferation, histology, gender, smoking habits and clinical outcome.

    We report the presence of n4ICD, significantly more frequently occurring in ADCA than in SCC. Furthermore, n4ICD and ERα expression was associated with the concomitant expression of aromatase. n4ICD was negatively correlated to proliferation in ADCA. Interestingly, a strong correlation between never smoking and n4ICD positivity was found among females and in the ADCA group.

    In breast carcinomas, n4ICD is a biomarker for anti-ER treatment. A number of observations including our finding of n4ICD can constitute support for anti-ER treatment strategies in NSCLC.

    Keywords
    NSCLC, HER-4, ERα, gender, smoking habits
    National Category
    Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:oru:diva-20597 (URN)
    Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-10-17Bibliographically approved
    5. Estrogen receptor α phosphorylation and EGFR in non-small cell lung carcinoma
    Open this publication in new window or tab >>Estrogen receptor α phosphorylation and EGFR in non-small cell lung carcinoma
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Non small cell lung carcinoma (NSCLC) occurs in two major histological types, squamous cell carcinoma (SCC) and adenocarcinoma (ADCA). There are well characterized differences in the carcinogenesis between these types. For example, epidermal growth factor receptor (EGFR) is frequently amplified and over expressed in SCC whilst mutations occur in ADCA. There are also gender associated differences in the relative incidence of SCC and ADCA. Estrogen receptor (ER) driven signalling have been proposed to play a role in this context. ER occurs in two different forms, α and β. The presence of ERα in NSCLC has been a matter of discussion. Immunohistochemical (IHC) analysis has reported divergent results, but the presence of ERα transcripts has been established to be widespread in NSCLC. ERα could be activated/phosphorylated in several ways, either ligand (estradiol) dependent or ligand independent. A potential crosstalk between EGFR and ERα has been proposed by a mechanism where EGFR signalling induces phosphorylation at specific sites within the ERα receptor.

    We investigated in the present study, in a material of 262 NSCLC, by IHC the presence of a phosphorylated form of ERα, pERαS118, and correlated these findings to EGFR over expression as well as an ERα co-activator, CREB, which has been associated to ligand independent phosphorylation of ERα at that specific site.

    We describe a widespread occurrence of pERαS118 in both SCC and ADCA. Furthermore, pERαS118is correlated to EGFR over expression in SCC. We propose a combined targeting of ERα and EGFR crosstalk as a possibility in the targeted therapy of SCC.

    Keywords
    NSCLC, ERα, ERβ, Immunohistochemistry, gene expression, gender, prognosis, smoking habits
    National Category
    Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:oru:diva-20600 (URN)
    Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-10-17Bibliographically approved
  • 6.
    Karlsson, Christina
    et al.
    Örebro University, School of Health and Medical Sciences.
    Bodin, Lennart
    Piehl-Aulin, Karin
    Örebro University, School of Health and Medical Sciences.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences.
    Tissue microarray validation: a methodologic study with special reference to lung cancer2009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 7, p. 2014-2021Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although tissue microarray (TMA) studies of histopathologic material have been frequently reported in studies of malignant diseases, the question of sample size (i.e., the diameter and the number of tissue cylinders investigated) has been rarely discussed. This study addresses the methodologic question of sample size in a variety of tumor types.

    MATERIAL AND METHODS: Material from 29 cases of lung carcinoma (small cell, squamous cell, and adenocarcinomas) was examined immunohistochemically for Ki-67 and p53 expression in virtually constructed cylinders of different diameters. The influence of tissue sample size (i.e., different numbers of virtual cylinders) was also investigated. Results from Ki-67 evaluation were analyzed as a continuous variable, whereas p53 expression was scored. p53 evaluations based on scoring in cylinders versus scoring of whole sections were also compared. Furthermore, 10 cases of endometrial and breast carcinomas were evaluated for estrogen receptor, Ki-67, and HER2 by scoring up to five cylinders.

    RESULTS AND CONCLUSIONS: Tissue cylinders of 0.6 and 1.0 mm diameters were compared and found equally informative about Ki-67 expression (intraclass correlation, 0.96). A statistical approach considering intraindividual and interindividual variation data is presented, indicating that in this specific setting three cylinders per case is an adequate sample size for TMA studies. Further sampling yields only a small gain in accuracy as determined by Ki-67 quantification and p53 scoring (kappa-coefficient, 0.9). For endometrial and breast tissues, TMA scoring of three cylinders yielded excellent agreement (kappa, >0.75) compared with whole-section scoring.

  • 7.
    Karlsson, Christina
    et al.
    Örebro University, School of Health and Medical Sciences.
    Helenius, Gisela
    Dept of Laboratory Medicine Örebro University Hospital, SE70185 Örebro, Sweden.
    Fernandes, Oswaldo
    Dept of Thoracic Surgery Örebro University Hospital, SE70185 Örebro, Sweden.
    Karlsson, Mats G.
    School of Health and Medical Sciences, Örebro University, SE70182 Örebro, Sweden, and Dept of Laboratory Medicine, Örebro University Hospital, SE70185 Örebro, Sweden.
    Estrogen receptor β in NSCLC: prevalence, proliferative influence, prognostic impact and smokingManuscript (preprint) (Other academic)
    Abstract [en]

    In non-small cell lung carcinoma (NSCLC) there are gender differences. The female gender is associated with more adenocarcinomas (ADCA), among both smokers and non-smokers compared to men. Women with NSCLC have a better prognosis compared to men, regardless of other factors. A possible role for estrogen receptor (ER) signalling has been proposed and experimental as well as epidemiological data supports this view. In a material of NSCLC (n=262), ERβ and cyclins A and A2 were studied by immunohistochemistry on formalin-fixed paraffin embedded tissue. In 137 of those cases, frozen material was available, on which expression analysis of ESR2 (ERβ) and cyclin A1 were performed. Data was correlated to histology, gender, smoking habits, stage and clinical outcome.

    ERβ was expressed in 86% of the cases. ERβ was most frequently expressed in Stage I ADCAs, especially in male subjects. A correlation between ERβ expression and cyclins was observed in ADCA, also with a male predominance. ERβ transcripts had a positive prognostic impact in ADCA. ERβ transcripts were also increased in NSCLC among smokers compared to non-smokers.

    In conclusion, we report data supporting a role for ERβ in lung ADCAs where ERβ could be a biomarker for future targeted therapies.

  • 8.
    Karlsson, Christina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Helenius, Gisela
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Fernandes, Oswaldo
    Department of Thoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Thoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Oestrogen receptor ss in NSCLC: prevalence, proliferative influence, prognostic impact and smoking2012In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 120, no 6, p. 451-458Article in journal (Refereed)
    Abstract [en]

    In non-small-cell lung carcinoma (NSCLC) there are gender differences. The female gender is associated with more adenocarcinomas (ADCA), among both smokers and non-smokers compared to men. Women with NSCLC have a better prognosis compared to men, regardless of other factors. A possible role for oestrogen receptor (ER) signalling has been proposed. The role for ER beta in NSCLC is still not clear, especially concerning the impact of smoking. In a material of NSCLC (n = 262), ER beta and cyclins A1 and A2 were studied by immunohistochemistry on formalin-fixed paraffin embedded tissue. In 137 of those cases, frozen material was available, on which expression analysis of ESR2 (ER beta) and cyclin A1 were performed. Data were correlated to histology, gender, smoking habits, stage and clinical outcome. ER beta was expressed in 86% of the cases. ER beta was most frequently expressed in Stage I ADCAs, especially in male subjects. A correlation between ER beta expression and cyclins was observed in ADCA, also with a male predominance. ER beta transcripts had a positive prognostic impact in ADCA. ER beta transcripts were increased in NSCLC among smokers compared to non-smokers. In conclusion, our data support a role for ER beta in lung ADCAs, proposing a role for ER beta in lungcarcinogenesis, especially among smokers.

  • 9.
    Karlsson, Christina
    et al.
    Örebro University, School of Health and Medical Sciences.
    Helenius, Gisela
    Laboratory Medicine, Örebro University Hospital, SE70185 Örebro, Sweden.
    Karlsson, Mats G.
    School of Health and Medical Sciences, Örebro University, SE70182 Örebro, Sweden, Dept of Laboratory Medicine, Örebro University Hospital, SE70185 Örebro, Sweden.
    Estrogen receptor α phosphorylation and EGFR in non-small cell lung carcinomaManuscript (preprint) (Other academic)
    Abstract [en]

    Non small cell lung carcinoma (NSCLC) occurs in two major histological types, squamous cell carcinoma (SCC) and adenocarcinoma (ADCA). There are well characterized differences in the carcinogenesis between these types. For example, epidermal growth factor receptor (EGFR) is frequently amplified and over expressed in SCC whilst mutations occur in ADCA. There are also gender associated differences in the relative incidence of SCC and ADCA. Estrogen receptor (ER) driven signalling have been proposed to play a role in this context. ER occurs in two different forms, α and β. The presence of ERα in NSCLC has been a matter of discussion. Immunohistochemical (IHC) analysis has reported divergent results, but the presence of ERα transcripts has been established to be widespread in NSCLC. ERα could be activated/phosphorylated in several ways, either ligand (estradiol) dependent or ligand independent. A potential crosstalk between EGFR and ERα has been proposed by a mechanism where EGFR signalling induces phosphorylation at specific sites within the ERα receptor.

    We investigated in the present study, in a material of 262 NSCLC, by IHC the presence of a phosphorylated form of ERα, pERαS118, and correlated these findings to EGFR over expression as well as an ERα co-activator, CREB, which has been associated to ligand independent phosphorylation of ERα at that specific site.

    We describe a widespread occurrence of pERαS118 in both SCC and ADCA. Furthermore, pERαS118is correlated to EGFR over expression in SCC. We propose a combined targeting of ERα and EGFR crosstalk as a possibility in the targeted therapy of SCC.

  • 10.
    Karlsson, Christina
    et al.
    Örebro University, School of Health and Medical Sciences.
    Helenius, Gisela
    Dept of Laboratory Medicine, Örebro University Hospital, SE70185 Örebro, Sweden.
    Karlsson, Mats G.
    Nuclear HER-4 (4ICD) and Estrogen Receptor α in non-small-cell lung carcinomaManuscript (preprint) (Other academic)
    Abstract [en]

    In non-small cell lung carcinoma (NSCLC) squamous cell carcinomas (SCC) occurs more frequently among men and adenocarcinomas (ADCA) in females. The presence of estrogen receptors (ERs) in NSCLC have been proposed as a factor contributing to the gender associated differences. HER-4, a member of the epidermal growth factor receptor family, has recently been identified as a co-activator to ER by action of the shredded intracellular domain, 4ICD.

    Our study was performed on tissue material from 262 NSCLC. In 137 cases, frozen material was available. HER-4/4ICD, ERα, PgR and aromatase was determined by immunohistochemistry. HER-4 gene copy number and HER-4 and ERα transcripts was also studied. Data was correlated to proliferation, histology, gender, smoking habits and clinical outcome.

    We report the presence of n4ICD, significantly more frequently occurring in ADCA than in SCC. Furthermore, n4ICD and ERα expression was associated with the concomitant expression of aromatase. n4ICD was negatively correlated to proliferation in ADCA. Interestingly, a strong correlation between never smoking and n4ICD positivity was found among females and in the ADCA group.

    In breast carcinomas, n4ICD is a biomarker for anti-ER treatment. A number of observations including our finding of n4ICD can constitute support for anti-ER treatment strategies in NSCLC.

  • 11.
    Karlsson, Christina
    et al.
    Örebro University, School of Health and Medical Sciences.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Effects of long-term storage on the detection of proteins, DNA, and mRNA in tissue microarray slides2011In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 59, no 12, p. 1113-1121Article in journal (Refereed)
    Abstract [en]

    Storage of tissue slides has been claimed to induce dramatically reduced antigen detection particularly for immunohistochemistry (IHC). With tissue microarrays, the necessity to serially cut blocks in order to obtain as much material as possible is obvious. The presumed adverse effect of storage might hamper such an approach. The authors designed an experimental setting consisting of four different storage conditions with storage time of tissue slides of up to 1 year. Detection of proteins, DNA, and mRNA was performed using IHC and in situ hybridization techniques. Slight but significant changes in IHC occurred over time. The most important factor is the primary antibody used: four showed no significant changes, whereas limited decreases in 8 antibodies could be detected by image analysis. Whether the antigen was nuclear or cytoplasmic/membranous did not matter. No major differences between different storage conditions could be shown, but storage at 4C was overall the best procedure. Furthermore, gene copy number aberrations, chromosomal translocations, and the presence of mRNA could be detected on slides stored up to 1 year. In conclusion, in tissues optimally formalin fixed and using modern histological techniques, only minute changes in tissue antigenicity are induced by long-term storage.

  • 12. Karlsson, Christina
    et al.
    Tisell, Anna
    Engström, Åsa
    Andershed, Birgitta
    Örebro University, School of Health and Medical Sciences.
    Family members' satisfaction with critical care: a pilot study2011In: Nursing in Critical Care, ISSN 1362-1017, E-ISSN 1478-5153, Vol. 16, no 1, p. 11-18Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of this pilot study was to describe family members' satisfaction with the care provided in a Swedish intensive care unit (ICU) based on the following needs: assurance, information, proximity, support, and comfort, which are all included in the Critical Care Family Satisfaction Survey (CCFSS). Background: Knowledge concerning satisfaction with care among family members with a critically ill relative in an ICU is important if the family is to be met professionally. Design: The study design was descriptive and retrospective, with a consecutive selection of family members of critically ill people cared for in an ICU. In total 35 family members participated. Method: Quantitative analyses based on 20 questions, and a qualitative analysis, based on two open questions was used. The median, average value and percent were computed for every question. The open questions were analyzed using qualitative content analysis. Results: The family members had a high level of satisfaction regarding all groups of needs. They were especially satisfied with flexible visiting hours and the high quality of treatment that the ill person received. The shortcomings that emerged were that family members wanted the physician to be more available for regular talks, the room for relatives was felt to be uncomfortable; and it was felt there were deficiencies in the preparations before the patient's transferral to a ward. Relevance to clinical practice: The results highlight the family members' need for regular information and the need to improve the environment in the waiting rooms for family members. The ICU staff's competence and their way of encountering the ill person and their family seem to be important for family members' satisfaction with the care.

  • 13.
    Mattsson, Johanna S. M.
    et al.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Bergman, Bengt
    Department of Respiratory Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Grinberg, Marianna
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Edlund, Karolina
    Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Dortmund, Germany.
    Marincevic, Millaray
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Jirström, Karin
    Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
    Pontén, Fredrik
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Hengstler, Jan G.
    Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Dortmund, Germany.
    Rahnenführer, Joerg
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Christina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Gulyas, Miklos
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Prognostic impact of COX-2 in non-small cell lung cancer: a comprehensive compartment-specific evaluation of tumor and stromal cell expression2015In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 356, no 2, p. 837-845Article in journal (Refereed)
    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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

  • 14.
    Mattsson, Johanna S. M.
    et al.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Brunnström, Hans
    Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden; Department of Pathology, Regional Laboratories Region Skåne, Lund, Sweden.
    Jabs, Verena
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Edlund, Karolina
    Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, Dortmund, Germany.
    Jirström, Karin
    Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
    Mindus, Stephanie
    Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.
    la Fleur, Linnéa
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Research and Education.
    Karlsson, Christina
    Örebro University, School of Health Sciences.
    Koyi, Hirsh
    Department of Respiratory Medicine, Gävle hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University, Uppsala, Sweden; County Council of Gävleborg, Gävle, Sweden.
    Brandén, Eva
    Department of Respiratory Medicine, Gävle hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University/County Council of Gävleborg, Gävle, Sweden.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Svensson, Maria A
    Clinical Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer2016In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, no 1, article id 603Article in journal (Refereed)
    Abstract [en]

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

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

    Results: ALK rearrangements were detected in 1.7 % in the complete cohort and 2.0 % in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.8 and 1.4 % when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (> 98 %), while the sensitivity was between 69 % (Ventana) and 62 % (in house Dako protocol). Furthermore, only 67 % of the ALK IHC positive cases were positive with both IHC assays. Gene expression analysis revealed that 6/194 (3 %) tumors showed high ALK gene expression (≥ 6 AU) and of them only three were positive by either FISH or IHC.

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

  • 15.
    Mattsson, Johanna S. M.
    et al.
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Svensson, Maria A.
    Institutionen för hälsovetenskap och medicin, Department of Pathology, Örebro universitet, Örebro, Sweden.
    Hallström, Bjorn
    Sci Life Lab, KTH Royal Inst Technol, Stockholm, Sweden.
    Koyi, Hirsh
    Dept Resp Med, Gävle Cent Hosp, Gävle, Sweden.
    Branden, Eva
    Dept Resp Med, Gävle Cent Hosp, Gävle, Sweden.
    Brunnström, Hans
    Dept Clin Sci Lund, Div Oncol & Pathol, Lund Univ, Lund, Sweden.
    Edlund, Karolina
    Leibniz Res Ctr Working Environm & Human Factors, Dortmund TU, Dortmund, Germany.
    Ekman, Simon
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    La Fleur, Linnea
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Grinberg, Marianna
    Dept Stat, Dortmund TU, Dortmund, Germany.
    Rahnenfuehrer, Joerg
    Dept Stat, Dortmund TU, Dortmund, Germany.
    Jirström, Karin
    Dept Clin Sci Lund, Div Oncol & Pathol, Lund Univ, Lund, Sweden.
    Ponten, Fredrik
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Christina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Uhlen, Mathias
    Sci Life Lab, KTH Royal Inst Technol, Stockholm, Sweden.
    Botling, Johan
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Micke, Patrick
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    ALK Rearrangements in Non-Small Cell Lung Cancer: Comprehensive Integration of Genomic, Gene Expression and Protein Analysis2015In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, no 9, p. S298-S298Article in journal (Other academic)
  • 16.
    Sadeghi, Mitra
    et al.
    Örebro University, School of Medical Sciences. Department of Cardiothoracic and Vascular Surgery.
    Dogan, Emanuel M.
    Örebro University, School of Medical Sciences. Department of Anesthesiology and Intensive Care.
    Karlsson, Christina
    Örebro University, School of Health Sciences.
    Jansson, Kjell
    Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Seilitz, Jenny
    Örebro University, School of Medical Sciences. Department of Cardiothoracic and Vascular Surgery.
    Skoog, Per
    Department of Vascular Surgery and Institute of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital and Academy, Gothenburg, Sweden.
    Hörer, Tal M.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Cardiothoracic and Vascular Surgery.
    Nilsson, Kristofer F.
    Örebro University, School of Medical Sciences. Department of Cardiothoracic and Vascular Surgery.
    Total resuscitative endovascular balloon occlusion of the aorta causes inflammatory activation and organ damage within 30 minutes of occlusion in normovolemic pigsManuscript (preprint) (Other academic)
  • 17.
    Santti, Kirsi
    et al.
    Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
    Ihalainen, Hanna
    Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Department of Plastic Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
    Rönty, Mikko
    Department of Pathology, HUSLAB and University of Helsinki, Helsinki, Finland.
    Böhling, Tom
    Department of Pathology, HUSLAB and University of Helsinki, Helsinki, Finland.
    Karlsson, Christina
    Örebro University, School of Health Sciences. Department of Medical Diagnostics.
    Haglund, Caj
    Department of Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Reseach Program Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland.
    Tarkkanen, Maija
    Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
    Blomqvist, Carl
    Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    High cyclin A expression, but not Ki67, is associated with early recurrence in desmoid tumors2018In: Journal of Surgical Oncology, ISSN 0022-4790, E-ISSN 1096-9098, Vol. 118, no 1, p. 192-198Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Desmoid tumors are soft-tissue tumors originating from myofibroblasts with a tendency to recur after surgery. High expression of proliferation markers is associated with shortened progression-free and/or overall survival in many neoplasms, including soft-tissue sarcomas. We investigated the prognostic role of cyclin A and Ki67 in desmoid tumors by immunohistochemistry.

    METHODS: The study included 76 patients with desmoid tumor operated at Helsinki University Hospital between 1987 and 2011. A tissue micro array (TMA) was constructed and the TMA sections were immunostained with cyclin A and Ki67 antibodies. A computer-assisted image analysis was performed.

    RESULTS: Cyclin A expression was evaluable in 74 and Ki67 in 70 patients. Cyclin A immunopositivity varied from 0% to 9.9%, with a mean of 1.9%. Cyclin A expression correlated significantly with Ki67. Cyclin A expression was associated with recurrence-free survival (HR 1.9, 95% CI = 1.1-3.2, P = .02), as were positive margin (HR 6.0, 95% CI = 1.6-22.5, P = .008) and extremity location (HR 5.3, 95% CI = 1.7-16.8, P = 0.005). Ki67 immunopositivity varied from 0.33% to 13.8%, with a mean of 4.6%, but had no significant prognostic impact (HR 1.1, P = .2).

    CONCLUSIONS: Our study indicates that cyclin A may be a new prognostic biomarker in surgically treated desmoid tumors.

  • 18.
    Santti, Kirsi
    et al.
    Department of Oncology, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
    Ihalainen, Hanna
    Department of Oncology, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Department of Plastic Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
    Rönty, Mikko
    Department of Pathology, HUSLAB and University of Helsinki, Helsinki, Finland.
    Karlsson, Christina
    Örebro University, School of Health Sciences. Department of Medical Diagnostics.
    Haglund, Caj
    Department of Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Translational Cancer Biology, Reseach Programs Unit, University of Helsinki, Helsinki, Finland.
    Sampo, Mika
    Department of Pathology, HUSLAB and University of Helsinki, Helsinki, Finland.
    Tarkkanen, Maija
    Department of Oncology, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
    Blomqvist, Carl
    Department of Oncology, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Estrogen receptor beta expression correlates with proliferation in desmoid tumors2019In: Journal of Surgical Oncology, ISSN 0022-4790, E-ISSN 1096-9098, Vol. 119, no 7, p. 873-879Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES: Estrogen receptor signaling and cyclin D1 have a major role in tumor cell proliferation in breast cancer. Desmoid tumors are rare neoplasms that may respond to endocrine treatment. The present study aimed to investigate the expression levels and the clinical relevance of estrogen receptor beta (ERβ) and cyclin D1 in desmoid tumors.

    METHODS: This study consists of 83 patients with a surgically treated desmoid tumor. ERβ and cyclin D1 expression was examined by immunohistochemistry in tissue microarrays. Cyclin A and Ki67 were studied in our previous work.

    RESULTS:  = 0.34, P = 0.004). ERβ immunoexpression showed a trend towards predictive impact for recurrence as a continuous variable. Further explorative analysis indicated that very high ERβ expression was related to high risk of relapse (hazard ratio [HR] 2.6; P = 0.02). Median cyclin D1 expression was 15.6%. High cyclin D1 expression was associated with high Ki67 and cyclin A expression. Cyclin D1 was not associated with time to recurrence.

    CONCLUSIONS: ERβ and cyclin D1 immunopositivity correlated with high proliferation in desmoid tumors. High ERβ expression might be predictive for postoperative recurrence.

  • 19.
    Stjernström, Annika
    et al.
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Karlsson, Christina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fernandez, Oswaldo J.
    Department of Vascular and Thoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Söderkvist, Peter
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Thunell, Lena K.
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
    Alterations of INPP4B, PIK3CA and pAkt of the PI3K pathway are associated with squamous cell carcinoma of the lung2014In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 3, no 2, p. 337-348Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to investigate how alterations in the PI3K pathway correlate with non-small cell lung cancer subtypes squamous cell carcinoma (SSC) and adenocarcinoma (ADCA). We analyzed copy number variation and protein expression of INPP4B, protein expression of pAkt, PDPK1, and PTEN and mutational status of PIK3CA and PTEN in 180 cases. Nineteen% displayed loss of INPP4B copy, whereas 47% lacked expression, both showing correlation with SCC. Elevated pAkt expression was seen in 63% of all cases, also correlating to SCC. PDPK1 was expressed in 70%, more in male than female patients. Regarding PTEN, 50% displayed loss of expression, of which seven were identified with mutations in the phosphatase domain. We detected nine cases (5%) of PIK3CA mutations, all identified as the E545K hot spot mutation in the helical domain, all except one in SCC. When analyzing all PI3K pathway components together, we show that patients with at least one alteration in the PI3K pathway are twice as likely to have SCC, than ADCA. Interestingly, we also found a strong correlation between high pAkt expression and PTEN expression. As comparison, we also analyzed mitogen-activated protein kinase (MAPK) pathway genes, where we identified fifteen KRAS mutations (8%) and one BRAF mutation (1%), significantly associated to ADCA. No association was found to the Gly972Arg polymorphism of IRS-1, involved in activation of both PI3K and MAPK pathways. In conclusion, we show here that several components of the PI3K pathway, alone and in combination, are correlated to development of SCC of the lung.

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