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  • 1.
    Andersson, Patiyan
    et al.
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Kolaric, Aleksandra
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Windahl, Torgny
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Kirrander, Peter
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Söderkvist, Peter
    Division of Cell Biology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Karlsson, Mats G
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    PIK3CA, HRAS and KRAS gene mutations in human penile cancer2008In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 179, no 5, p. 2030-2034Article in journal (Refereed)
    Abstract [en]

    Purpose: The knowledge of somatic mutations that arise in penile cancer is limited. We examined the dysregulation of components in the phosphatidylinositol 3-kinase and Ras pathways.

    Materials and Methods: Using single stranded conformational analysis and direct sequencing we performed mutational analysis of the PIK3CA, PTEN, HRAS, KRAS, NRAS and BRAF genes in 28 penile tumors.

    Results: We identified somatic missense mutations in 11 of the 28 penile cancer samples (39%). In the PIK3CA gene 8 mutations (29%) were identified that were E542K or E545K. In the HRAS gene a G12S and a Q61L mutation were found (7%). The KRAS gene contained 1 mutation (3%), that is a G12S change. PIK3CA mutations were found in all grades and stages, whereas HRAS and KRAS mutations were found in larger and more advanced tumors. The mutations were mutually exclusive, suggesting that dysregulation of either pathway is sufficient for the development and progression of penile carcinoma.

    Conclusions: The high frequency of mutations in the PIK3CA, HRAS and KRAS genes leads us to believe that dysregulation of the phosphatidylinositol 3-kinase or Ras pathway is significant for the development and progression of penile carcinoma.

  • 2.
    Bergengren, Lovisa
    et al.
    Örebro University, School of Health Sciences. Department of Women’s Health, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Kaliff, Malin
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Comparison between professional sampling and self-sampling for HPV-based cervical cancer screening among postmenopausal women2018In: International Journal of Gynecology & Obstetrics, ISSN 0020-7292, E-ISSN 1879-3479, Vol. 142, no 3, p. 359-364Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate whether self-sampling is as reliable as professional sampling for HPV testing and genotype detection among postmenopausal women.

    METHODS: In the present prospective cross-sectional study, women in Örebro County, Sweden, who had high-risk HPV (hrHPV) and normal cytology results in exit screening tests conducted in between January 1, 2012, and December 31, 2014, were invited to follow-up screenings between February 24, 2015 and May 15, 2015, that included professional sampling and self-sampling. HPV genotypes were identified by a DNA-based assay that could detect 35 HPV genotypes. Findings between the different sampling methods were compared.

    RESULTS: Of 143 women who participated, 119 returned a self-sample. Completely concordant results were observed in 67 of these samples when both hrHPV and low-risk HPV genotypes were analyzed. Overall, 99 (83.2%) women had the same clinically relevant finding from both sampling methods. Twenty women had discordant hrHPV results (hrHPV detected in 10 self-samples vs 10 professionally collected samples; Cohen κ 0.66, 95% confidence interval 0.53-0.80). There was no significant difference between the two sampling methods for clinically significant infections (P>0.99) or extended genotyping (P=0.827).

    CONCLUSION: Postmenopausal women could be offered self-sampling devices to increase screening-program coverage while maintaining test quality.

  • 3.
    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.

  • 4.
    Carlsson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences.
    Davidsson, Sabina
    Örebro University, School of Health and Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Lubovac, Zelmina
    University of Skövde, Skövde, Sweden.
    Andrén, Ove
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Olsson, Björn
    University of Skövde, Skövde, Sweden.
    Klinga-Levan, Karin
    University of Skövde, Skövde, Sweden.
    A miRNA expression signature that separates between normal and malignant prostate tissues2011In: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, no 11, p. 14-Article in journal (Refereed)
    Abstract [en]

    Background

    MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that post-transcriptionally regulate genes involved in several key biological processes and thus are involved in various diseases, including cancer. In this study we aimed to identify a miRNA expression signature that could be used to separate between normal and malignant prostate tissues.

    Results

    Nine miRNAs were found to be differentially expressed (p <0.00001). With the exception of two samples, this expression signature could be used to separate between the normal and malignant tissues. A cross-validation procedure confirmed the generality of this expression signature. We also identified 16 miRNAs that possibly could be used as a complement to current methods for grading of prostate tumor tissues.

    Conclusions

    We found an expression signature based on nine differentially expressed miRNAs that with high accuracy (85%) could classify the normal and malignant prostate tissues in patients from the Swedish Watchful Waiting cohort. The results show that there are significant differences in miRNA expression between normal and malignant prostate tissue, indicating that these small RNA molecules might be important in the biogenesis of prostate cancer and potentially useful for clinical diagnosis of the disease.

  • 5.
    Carlsson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Klinga-Levan, Karin
    Systems Biology Research Centre, Tumor Biology, School of Life Sciences, University of Skövde, Skövde, Sweden.
    Olsson, Björn
    Systems Biology Research Centre, Bioinformatics, School of Life Sciences, University of Skövde, Skövde, Sweden.
    Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate2013In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, article id 362Article in journal (Refereed)
    Abstract [en]

    Background: The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.

    Methods: Patients with prostate cancer were included in the study if they had a tumor with Gleason grade 3 in the PZ, the TZ, or both (n=16). Normal prostate tissue was collected from men undergoing cystoprostatectomy (n=20). The expression of 667 unique miRNAs was investigated using TaqMan low density arrays for miRNAs. Student's t-test was used in order to identify differentially expressed miRNAs, followed by hierarchical clustering and principal component analysis (PCA) to study the separation of the tissues. The ADtree algorithm was used to identify markers for classification of tissues and a cross-validation procedure was used to test the generality of the identified miRNA-based classifiers.

    Results: The t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentially expressed miRNAs between normal and malignant tissues showed perfect separation between samples, while the corresponding analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmed these results and several potential miRNA markers were identified.

    Conclusions: The results of this study indicate that the major differences in the transcription program are those arising during tumor development, rather than during normal tissue development. In addition, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ. The results also indicate that separate miRNA expression signatures for diagnosis might be needed for tumors arising in the different zones. MicroRNA signatures that are specific for PZ and TZ tumors could also lead to more accurate prognoses, since tumors arising in the PZ tend to be more aggressive than tumors arising in the TZ.

  • 6.
    Dahmoun, Marju
    et al.
    Department of Obstetrics and Gynecology, Mid Sweden Research and Development Center, Sundsvall Hospital, Sundsvall, Sweden; Department of Obstetrics and Gynecology, University of Umeå, Umeå, Sweden.
    Odmark, Inga-Stina
    Department of Obstetrics and Gynecology, University of Umeå, Umeå, Sweden.
    Risberg, Björn
    Department of Pathology, The Norwegian Radium Hospital, Oslo, Norway.
    Karlsson, Mats G
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Pavlenko, Tatjana
    Department of Obstetrics and Gynecology, Mid Sweden Research and Development Center, Sundsvall Hospital, Sundsvall, Sweden.
    Bäckström, Torbjörn
    Department of Obstetrics and Gynecology, University of Umeå, Umeå, Sweden.
    Apoptosis, proliferation, and sex steroid receptors in postmenopausal endometrium before and during HRT2004In: Maturitas, ISSN 0378-5122, E-ISSN 1873-4111, Vol. 49, no 2, p. 114-123Article in journal (Refereed)
    Abstract [en]

    Objectives: Endometrial homeostasis, indicated as the balance between apoptosis and proliferation, was studied with regard to endometrial safety and bleeding disturbances.

    Materials and Methods: The quantitatively sufficient endometrial biopsies of 92 postmenopausal women enrolled in the study were investigated. The participants were divided into two groups, each receiving a continuous combined HRT regimen with either conjugated estrogen (CE) 0.625 mg + 5 mg medroxyprogesterone acetate (MPA) (=CE/MPA) or 17-beta-estradiol (E2) 2 mg + 1 mg norethisterone acetate (NETA) (=E2/NETA). These were evaluated according to apoptotic index (Ai) and proliferation marker Ki-67 index. Estrogen receptor alpha (ER) and progesterone receptor (PR) expression were also monitored, as well as endometrial thickness. Quantitative in situ techniques were used.

    Results: Ai and Ki-67 index were unchanged in epithelial glands of endometrium from baseline to second biopsy obtained after 1 year of combined continuous HRT. In stromal tissue, Ki-67 index was increased, while Ai was on the same level. PR expression in both epithelium and stroma was unchanged. Endometrial thickness was unaffected during therapy, and the histopathological evaluation showed no development of hyperplasia or carcinoma.

    Conclusions: The unaffected homeostasis in endometrial epithelium contributes to endometrial safety and is in accordance with the histopathological findings of no hyperplasia. The homeostasis of stroma was transformed to be more proliferative. Increased stromal proliferation may be of importance for stromal support of the veins and for decreasing breakthrough bleeding during HRT. The increased stromal proliferation, as well as the decreased ER expression both in epithelium and stroma, could be an effect of progesterone.

  • 7.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden .
    Mölling, Paula
    Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Rider, Jennifer R.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Unemo, Magnus
    Örebro University, School of Health Sciences. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Pathology, Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Elgh, Fredrik
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Söderquist, Bo
    Örebro University, School of Medical Sciences.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Erratum to: Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer2016In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 11, article id 36Article in journal (Refereed)
  • 8.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Rider, Jennifer R.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA.
    Unemo, Magnus
    Örebro University, School of Health Sciences. Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Pathology, Örebro University Hospital, Örebro, Sweden; Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden .
    Andersson, Swen-Olof
    Örebro University, School of Health Sciences. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Elgh, Fredrik
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Söderquist, Bo
    Örebro University, School of Medical Sciences.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer2016In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 11, article id 26Article in journal (Refereed)
    Abstract [en]

    Background: Prostate cancer is the most common cancer among men in Western countries but the exact pathogenic mechanism of the disease is still largely unknown. An infectious etiology and infection-induced inflammation has been suggested to play a role in prostate carcinogenesis and Propionibacterium acnes has been reported as the most prevalent microorganism in prostatic tissue. We investigated the frequency and types of P. acnes isolated from prostate tissue samples from men with prostate cancer and from control patients without the disease.

    Methods: We included 100 cases and 50 controls in this study. Cases were men diagnosed with prostate cancer undergoing radical prostatectomy and controls were men undergoing surgery for bladder cancer without any histological findings of prostate cancer. Six biopsies taken from each patient's prostate gland at the time of surgery were used for cultivation and further characterization of P. acnes.

    Results: The results revealed that P. acnes was more common in men with prostate carcinoma than in controls, with the bacteria cultured in 60 % of the cases vs. 26 % of the controls (p = 0.001). In multivariable analyses, men with P. acnes had a 4-fold increase in odds of a prostate cancer diagnosis after adjustment for age, calendar year of surgery and smoking status (OR: 4.46; 95 % CI: 1.93-11.26). To further support the biologic plausibility for a P. acnes infection as a contributing factor in prostate cancer development, we subsequently conducted cell-based experiments. P. acnes- isolates were co-cultured with the prostate cell line PNT1A. An increased cell proliferation and cytokine/chemokine secretion in infected cells was observed.

    Conclusion: The present study provides further evidence for a role of P. acnes in prostate cancer development.

  • 9.
    Davidsson, Åke
    et al.
    Departments of Otorhinolaryngology, Medical Center Hospital, Örebro, Sweden.
    Danielsen, Arild
    Department of Otorhinolaryngology, Head & Neck Surgery, Haukeland University Hospital, Bergen, Norway.
    Viale, Guiseppe
    Department of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan School of Medicine, Milan, Italy.
    Olofsson, Jan
    Department of Otorhinolaryngology, Head & Neck Surgery, Haukeland University Hospital, Bergen, Norway.
    Dell'Orto, Patrizia
    Department of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan School of Medicine, Milan, Italy.
    Pellegrini, Caterina
    Department of Pathology and Laboratory Medicine, European Institute of Oncology, University of Milan School of Medicine, Milan, Italy.
    Karlsson, Mats G.
    Departments of Pathology, Medical Center Hospital, Örebro, Sweden.
    Hellquist, Henrik B.
    Department of Pathology II, University Hospital, Linköping, Sweden.
    Positive identification in situ of mRNA expression of IL-6, and IL-12, and the chemotactic cytokine RANTES in patients with chronic sinusitis and polypoid disease. Clinical relevance and relation to allergy1996In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 116, no 4, p. 604-610Article in journal (Refereed)
    Abstract [en]

    Interleukins 6 (IL-6) and 12 (IL-12), and the chemoattractant chemokine RANTES were studied in ethmoidal mucosa, using reverse transcriptase polymerase chain reaction. The 49 patients had chronic sinusitis or nasal/paranasal polyposis, and some also allergy. To the best of our knowledge, this is the first study that demonstrates RANTES and IL-12 on mRNA level in human sinonasal mucosa in situ. mRNA for IL-6, IL-12 and RANTES were detected in 2, 8 and 6 patients with chronic sinusitis, respectively, and in mucosa from patients with polyposis a positive expression was observed in 4, 14 and 10 cases. There were no statistically significant differences. Analysing the entire group of 49 patients, disregarding type of mucosal disease, the number of patients with positive RANTES was significantly higher than that for IL-6. Similarly, IL-12 positivity was more frequently expressed than IL-6. mRNA for IL-6 was expressed in only 2 of the allergic patients. The cytokine production studied thus seems to be unrelated to the clinically defined entities. There is thus a local production in human diseased sinonasal mucosa of RANTES, as well as of IL-6 and IL-12. The local production of RANTES is an important prerequisite for recruitment and migration of inflammatory cells into the tissue. IL-12 is a co-stimulator of antigen-specific responses of established T helper 1 (Th1) clones, and regulates the responsiveness of the clones to a number of T cell growth factors. The study supports a shift towards Th1 cells in these disease entities.

  • 10.
    Davidsson, Åke
    et al.
    Örebro Medical Center Hospital, Örebro, Sweden .
    Karlsson, Mats G.
    Örebro Medical Center Hospital, Örebro, Sweden .
    Hellquist, H. B.
    Allergen-induced changes of B-cell phenotypes in patients with allergic rhinitis1994In: Rhinology, ISSN 0300-0729, E-ISSN 1996-8604, Vol. 32, no 4, p. 184-190Article in journal (Refereed)
    Abstract [en]

    We investigated sub-populations of B-lymphocytes in nasal mucosa and peripheral blood of 17 patients with seasonal allergic rhinitis (birch pollen) and 10 controls. The study included provocation with allergen during the non-pollen season, during which no participant used medication. Samples were also taken during the pollen season. Subsets of B-cells as expressed by different CD antigens were investigated by immunohistochemistry on frozen sections and by flow cytometry of peripheral blood. Nasal CD23+ B-cells decreased in allergic patients during provocation, indicating that mature virgin CD23+ B-cells switch into a memory B-cell phenotype with loss of CD23 expression. This indicates differentiation towards cells that can represent a local source for IgE synthesis. No decrease was observed during the pollen season when the patients used medication. Serum IgE was significantly higher in allergic patients on all occasions. The observed up-regulation of CD40 expression on peripheral blood B-cells in allergic patients during the pollen season clearly indicate B-cell activation. Furthermore, a relative increase of CD19+ B-cells was observed in peripheral blood during provocation. Upregulation (by IL-4) of CD40 on B-cells which then may be stimulated by gp39 (CD40 ligand) can constitute an early and important event in the IgE-mediated allergic reaction.

  • 11.
    Dreifaldt, Mats
    et al.
    Departments of Thoracic and Cardiovascular Surgery, Örebro University Hospital, Örebro, Sweden.
    Souza, Domingos S. R.
    Departments of Thoracic and Cardiovascular Surgery, Örebro University Hospital, Örebro, Sweden.
    Loesch, Andrzej
    Departments of Inflammation, UCL Medical School, London, United Kingdom.
    Muddle, John R.
    UCL Medical School, London, United Kingdom.
    Karlsson, Mats G.
    Örebro University Hospital, Örebro, Sweden.
    Filbey, Derek
    Örebro University Hospital, Örebro, Sweden.
    Norgren, Lars
    Örebro University Hospital, Örebro, Sweden.
    Dashwood, Michael R.
    UCL Medical School, London, United Kingdom.
    Bodin, Lennart
    Örebro University Hospital, Örebro, Sweden.
    The ‘‘no-touch’’ harvesting technique for vein grafts in coronary artery bypass surgery preserves an intact vasa vasorum2011In: The Internet Journal of Thoracic and Cardiovascular Surgery, ISSN 1524-0274, Vol. 141, no 1, p. 145-150Article in journal (Refereed)
    Abstract [en]

    Objectives: Our objective was to evaluate the impact of vein graft harvesting technique on structure and function of vasa vasorum.

    Methods: Paired segments of great saphenous veins harvested either with conventional harvesting technique or no-touch technique were obtained from 9 consecutive patients undergoing coronary artery bypass grafting. Quantitative measurements, using immunohistochemistry and morphometry, were performed. Ultrastructural analyses of vasa vasorum were performed with electron microscopy. Video footage of superficial vasa vasorum in an implanted saphenous vein graft harvested with the no-touch technique was captured during a coronary bypass operation and is presented for online viewing.

    Results: The total area of vasa vasorum in vein grafts harvested with the conventional technique was significantly reduced both in the media (P¼.007) and in the adventitia (P¼.014) compared with vein grafts harvested with the no-touch technique. Ultrastructural findings indicated that the no-touch technique preserved an intact vasa vasorum whereas the conventional technique did not. Video footage showed retrograde flow in the vasa vasorum in vein graft harvested with the no-touch technique.

    Conclusions: These findings showthat the no-touch technique for saphenous vein graft harvesting for coronary bypass grafting preserves an intact vasa vasorum. This could represent one of the mechanisms underlying the improved patency of saphenous vein grafts harvested with this technique.

  • 12.
    Falck, Eva
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Karlsson, Sandra
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Helenius, Gisela
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Klinga-Levan, Karin
    Loss of glutathione peroxidase 3 expression is correlated with epigenetic mechanisms in endometrial adenocarcinoma2010In: Cancer cell international, ISSN 1475-2867, Vol. 10, article id 46Article in journal (Refereed)
    Abstract [en]

    Glutathione peroxidase 3 (GPX3) is one of the key enzymes in the cellular defense against oxidative stress and the hepatocyte growth factor receptor, (MET) has been suggested to be influenced by the GPX3 gene expression. In a previous microarray study performed by our group, Gpx3 was identified as a potential biomarker for rat endometrial adenocarcinoma (EAC), since the expression was highly downregulated in rat EAC tumors. Herein, we have investigated the mRNA expression and Gpx3 and Met in rat EAC by real time quantitative PCR (qPCR), and the methylation status of Gpx3. In addition we have examined the expression of GPX3 and MET in 30 human EACs of different FIGO grades and 20 benign endometrial tissues. We found that the expression of GPX3 was uniformly down regulated in both rat and human EAC, regardless of tumor grade or histopathological subtype, implying that the down-regulation is an early event in EAC. The rate of Gpx3 promoter methylation reaches 91%, where biallelic methylation was present in 90% of the methylated tumors. The expression of the Met oncogene was slightly upregulated in EACs that showed loss of expression of Gpx3, but no tumor suppressor activity of Gpx3/GPX3 was detected. Preliminary results also suggest that the production of H2O2 is higher in rat endometrial tumors with down-regulated Gpx3 expression. A likely consequence of loss of GPX3 protein function would be a higher amount of ROS in the cancer cell environment. Thus, the results suggest important clinical implications of the GPX3 expression in EAC, both as a molecular biomarker for EAC and as a potential target for therapeutic interventions.

  • 13.
    Fergedal, May
    et al.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Åström, Maria
    Department of Internal Medicine, Örebro Medical Center Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Department of Internal Medicine, Örebro Medical Center Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Differences in CD14 and alpha-naphthyl acetate esterase positivity and relation to prognosis in AML1998In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 22, no 1, p. 25-30Article in journal (Refereed)
    Abstract [en]

    Alpha-naphthyl acetate esterase (ANAE) and CD14 expression, used for determination of monocytic cells, were compared and related to prognosis in 65 AML patients. Bone marrow aspiration material from AML patients has been used for the cytochemistry as well as flow cytometry. All non-erythroid cells have been included in the evaluation in both methods. 17/65 cases showed at least 15% difference between the proportion CD14 and ANAE positive cells. Cases with 20% or more CD14 positivity had poorer prognosis. For FAB classes M0-M3, presence of 10% or more CD14 was negative for overall survival (P = 0.01). ANAE did not show significant prognostic influence.

  • 14.
    Fernandes, Oswaldo J. C. B.
    et al.
    Departments of Cardiothoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Almgren, Stig-Olof
    Departments of Cardiothoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Thaning, Lars
    Department of Pulmonary Medicine, Örebro University Hospital, Örebro, Sweden.
    Filbey, Derek
    Department of Transfusion Medicine, Örebro University Hospital, Örebro, Sweden.
    Helsing, Martin
    Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Magnusson, Anders
    Centre for Clinical Research, Örebro University Hospital, Örebro, Sweden.
    Souza, Domingos
    Departments of Cardiothoracic Surgery, Örebro University Hospital, Örebro, Sweden.
    Prognostic factors for the survival of surgically treated patients for non-small cell lung cancer2003In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 42, no 4, p. 338-341Article in journal (Refereed)
    Abstract [en]

    The survival and outcome rates of 284 patients who underwent surgical treatment for non-small cell lung cancer were assessed retrospectively. Resectability rate was 94.1%, hospital mortality 3.9% (n = 11) and the mortality rates in patients who underwent pneumonectomy or lobectomy were 8.9% and 0.6%, respectively. The overall 5-year survival was 43.6%. Female gender, earlier stages of disease and a complete resection were strongly predictive for a long-term survival. Women in stage IA disease had a 5-year survival rate of 92.7%. The 5-year survival rate for patients in stages IIIA and N2 disease who underwent a complete resection was 21.9%, and 9% for those who did not undergo a complete resection. It is concluded that the best surgical results were observed in women who were operated on at an early stage of disease. A complete resection also contributed to a better outcome, even for patients in stage IIIA and N2 disease.

  • 15.
    Graflund, M.
    et al.
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Sigurdardóttir, S.
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    HPV-DNA, vascular space invasion, and their impact on the clinical outcome in early-stage cervical carcinomas2014In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 14, no 5, p. 896-902Article in journal (Refereed)
    Abstract [en]

    The present study was designed to analyze the relationship of human papillomavirus (HPV)-DNA, microvessel density, and their impact on clinical outcome in early cervical carcinoma. HPV-DNA was evaluated in 171 cases of cervical carcinoma treated from 1965 to 1990. In 110 cases, the analyses could be performed. A polymerase chain reaction technique was used on paraffin-embedded specimens obtained before the start of therapy. HPV-DNA of any type was detected in 78% (86/110) of all evaluable tumors. HPV16 was the predominant type and was detected in 56% (62/110), HPV18 in 8% (9/110), and HPV35 in 21% (23/110). Patients with tumors containing HPV16 or HPV18 were significantly (P = 0.011) younger than patients with tumors not containing either of these two subtypes. Vascular space invasion and lymph node metastases were observed more frequently in tumors expressing HPV16 and HPV18 (P = 0.002, P = 0.047) than in tumors negative for these HPV strains. Tumors containing HPV16 and HPV18 were significantly (P = 0.012) larger and more frequently (P = 0.005) associated with higher FIGO stages. The cancer-specific survival rate was lower for patients with HPV16- and HPV18-positive tumors, but the difference was not statistically significant. The microvessel density was a non-significant prognostic factor. The overall 5-year survival rate of the complete series was 91%. It was concluded that HPV-DNA was a prognostic factor in early-stage cervical cancer and was associated with the age of the patient, vascular space invasion, lymph node metastases, tumor size, and FIGO stage.

  • 16.
    Graflund, M.
    et al.
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Sigurdardóttir, S.
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Relation between HPV-DNA and expression of p53, bcl-2, p21WAF-1, MIB-1, HER-2/neu and DNA ploidy in early cervical carcinoma: correlation with clinical outcome2004In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 12, no 1, p. 169-176Article in journal (Refereed)
    Abstract [en]

    The purpose of the present study was to analyze the relation between the expression of p53, bcl-2, p21WAF1, MIB-1, HER-2/neu, DNA ploidy and HPV16 or 18 infections with clinical parameters. HPV-DNA was evaluated in 171 early cervical carcinomas treated from 1965 to 1990 and detected by PCR (polymerase chain reaction) on paraffin specimens obtained before therapy was started. HPV-DNA of any type was detected in 78% (86/110) of all tumors, HPV16 was the predominant type and was seen in 56% (62/110), HPV18 in 8% (9/110) and HPV35 in 21% (23/110). Patients with HPV16 or 18 were significantly (P=0.011) younger than patients with tumors not containing these two HPV subtypes. Lymph node metastases were seen more frequently (P=0.047) in tumors expressing HPV16 or 18. Tumor size was associated with the HPV-type. The frequency of DNA aneuploidy was lower in high-risk HPV tumors than in tumors with other HPV subtypes (P=0.014). MIB-1 expression was highly significantly (P=0.00007) associated with presence of HPV16 or 18. The cancer-specific survival rate was lower for patients with HPV16 and 18 positive tumors, but the difference was not statistically significant. The overall 5-year survival rate of the complete series was 91%. In conclusion, the HPV DNA subtype was a prognostic factor in early stage cervical cancer and it was associated with age, positive lymph nodes, tumor size, DNA ploidy and the proliferation marker MIB-1.

  • 17.
    Graflund, Marianne
    et al.
    Departments of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Departments of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Bryne, M.
    Department of Pathology, Institute of Cancer Research, Norwegian Radium Hospital, Oslo, Norway.
    Karlsson, Mats G.
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    The prognostic value of a histologic grading system, DNA profile, and MIB-1 expression in early stages of cervical squamous cell carcinomas2002In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 12, no 2, p. 149-157Article in journal (Refereed)
    Abstract [en]

    This study evaluated the prognostic importance of a new grading system focusing on the invasive tumor front, DNA profile, and the proliferation marker MIB-1. A complete geographic series of 172 women treated with radical hysterectomy (Wertheim-Meigs) for FIGO stage I-II cervical carcinomas was the target population. The analyses were performed on 141 (82%) squamous cell carcinomas of the complete series. During the period of observation (mean 222 months), 17 recurrences (12.1%) were encountered. Prognostic factors for disease-free survival were lymph node status (P < 0.000001), radical surgical margins (P = 0.00004), and tumor size (P = 0.002). The complete score of the invasive front grading system (IFG), and the individual scores of two variables-pattern of invasion and host response-were all significantly (P = 0.002, P = 0.007, P = 0.0001) associated with pelvic lymph node metastases. Host response was the single most important factor in the IFG system, and it was superior to the complete score in predicting lymph node metastases. The total IFG score was also a significant (P = 0.003) prognostic factor for disease-free survival. DNA ploidy, S-phase fraction, and MIB-1 expression were nonsignificant factors in predicting pelvic lymph node metastases and disease-free survival of the patient. The IFG in the original or modified versions could predict low- and high-risk groups of tumors and therefore be of value in treatment planning for these patients.

  • 18.
    Graflund, Marianne
    et al.
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden .
    Sorbe, Bengt
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Hussein, A.
    Department of Pathology, Medical Center Hospital, Örebro, Sweden.
    Bryne, M.
    Department of Pathology, Institute of Cancer Research, the Norwegian Radium Hospital, Oslo, Norway.
    Karlsson, Mats G.
    Department of Pathology, Medical Center Hospital, Örebro, Sweden.
    The prognostic value of histopathologic grading parameters and microvessel density in patients with early squamous cell carcinoma of the uterine cervix2002In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 12, no 1, p. 32-41Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the prognostic importance of clinical and histopathologic factors, including malignancy grading systems (MGS), partial index (PI), invasive front grading (IFG), and microvessel density. A complete geographic series of 172 early stage (FIGO I-II) cervical carcinomas treated by Wertheim-Meigs surgery during the period 1965-1990 was studied. The patients were followed up for at least 10 years. Significant prognostic factors for disease-free survival were lymph node status (P < 0.0000001), radical surgical margins (P = 0.00003), and tumor size (P = 0.008). In a multivariate Cox analysis it was shown that lymph node status was the single most important prognostic factor with regard to disease-free survival. The total MGS and the PI scores were highly significantly (P = 0.0001) associated with pelvic lymph node metastases and disease-free survival rate in squamous cell carcinomas. The MGS and the PI systems were superior to the IFG system in predicting lymph node metastases. The total IFG score was also a statistically highly significant (P = 0.003) prognostic factor with regard to disease-free survival in both univariate and multivariate analyses. Microvessel density was a nonsignificant prognostic factor. There was a highly significant (P = 0.002) association between vascular space invasion of tumor cells and the presence of lymph node metastases. In conclusion, histopathologic malignancy grading systems provide valuable prognostic information in patients with early stage squamous cell carcinomas of the uterine cervix.

  • 19.
    Graflund, Marianne
    et al.
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Department of Gynecological Oncology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G
    Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Immunohistochemical expression of p53, bcl-2, and p21(WAF1/CIP1) in early cervical carcinoma: correlation with clinical outcome2002In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 12, no 3, p. 290-298Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to assess the value of p53, bcl-2, and p21(WAF1/CIP1) immunoreactivity as predictors of pelvic lymph node metastases (LNM), recurrences, and death due to the disease in early stage (FIGO I-II) cervical carcinomas. FIGO stage, type of histopathology, and tumor grade were also evaluated in this series of patients treated by radical hysterectomy (Wertheim-Meigs) between 1965 and 1990. A total of 172 patients were included. A tumor was regarded as positive when more than 30% of the neoplastic cells exhibited immunoreactivity. Positive immunostaining was found in 8.9% for p53, in 43.5% for bcl-2, and in 25.0% for p21(WAF1/CIP1). None of them was able to predict LNM or clinical outcome. Presence of LNM, tumor recurrence, and death from disease were significantly associated with the FIGO stage (P = 0.014, P = 0.009, and P = 0.001, respectively). The 5-year cancer-specific survival rate was 91.6% and the overall survival rate was 90.5%. It was concluded that immunohistochemically detected p53, bcl-2, and p21(WAF1/CIP1) appeared to be of no predictive value with regard to LNM, tumor recurrences, or long-term survival in early cervical carcinomas.

  • 20.
    Graflund, Marianne
    et al.
    Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G
    Örebro University Hospital, Örebro, Sweden.
    MIB-1, p53, bcl-2, and WAF-1 expression in pelvic lymph nodes and primary tumors in early stage cervical carcinomas: correlation with clinical outcome2002In: International Journal of Oncology, ISSN 1019-6439, Vol. 20, no 5, p. 1041-1047Article in journal (Refereed)
    Abstract [en]

    A complete series of 40 cervical carcinomas with pelvic lymph node metastases were analysed immunohistochemically for prognostic markers. The aims of this study were to examine whether the detection of MIB-1, p53, bcl-2, and WAF-1 could be used as a prognostic marker for tumor recurrence and survival rate. During the period of observation (mean 222, range 72-360 months) 22 (55%) recurrences were encountered and 20 patients died of the disease. There were 35 squamous cell carcinomas (87.5%), 2 adenosquamous carcinomas (5.0%), and 3 pure adenocarcinomas (7.5%). One tumor (2.5%) was well differentiated, 12 tumors (30%) were moderately differentiated, and 27 tumors (67.5%) were poorly differentiated. The primary tumor grade (P=0.037) and radicality of the surgical margins (P=0.021) were significant prognostic factors with regard to tumor recurrence. The site and number of lymph nodes with metastases had no prognostic value. P53, bcl-2, and WAF-1 were not predictive factors for recurrences or the cancer-specific survival rate. The concordant expression of WAF-1 in the primary tumor and in lymph node metastases was lower than for p53 and bcl-2. The proliferative activity (MIB-1) seemed to be lower in tumor cells metastasized to the pelvic lymph nodes than in cells of the primary tumor. Expression of MIB-1 in lymph nodes was predictive of disease-free survival in both univariate and multivariate proportional hazard Cox analyses.

  • 21.
    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.

  • 22.
    Helenius, Gisela
    et al.
    Örebro University, School of Medical Sciences.
    Ottestig, Elin
    Kaliff, Malin
    Örebro University, School of Medical Sciences.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences.
    Karlsson, Mats
    Örebro University, School of Medical Sciences.
    Bergengren, Lovisa
    Örebro University, School of Medical Sciences.
    Distribution of HPV-genotypes in a Swedish screening population2018Conference paper (Refereed)
  • 23.
    Hellquist, H. B.
    et al.
    Departments of Pathology, Medical Center Hospital, Örebro, Sweden; Department of Pathology II, University Hospital, Linköping, Sweden.
    Dahl, F.
    Departments of Pathology, Medical Center Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Departments of Pathology, Medical Center Hospital, Örebro, Sweden.
    Nilsson, C.
    Departments of Otorhinolaryngology, Medical Center Hospital, Örebro, Sweden.
    Basaloid squamous cell carcinoma of the palate1994In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 25, no 2, p. 178-180Article in journal (Refereed)
  • 24.
    Hellquist, H. B.
    et al.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Nasal memory T lymphocytes capable of producing IL-4 in the allergic reaction1992In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 47, no 4 Pt 1, p. 334-336Article in journal (Refereed)
    Abstract [en]

    This paper reports the presence of memory T cells in the nasal mucosa of allergic patients. The demonstration of CD4+/CD29+ (CD4+/CD45RO+) T lymphocytes, which are capable of interleukin-4 production, can indicate a complementary cell-mediated regulatory mechanism for mast cell proliferation and IgE synthesis in human nasal allergy. No substantial IgE production can be obtained in the absence of IL-4. Therefore, the existence of IL-4 producing cells on site in the nasal mucosa of allergic subjects probably implies a complementary interaction between cytokines and different immunocompetent nasal cells in the regulation of B cells and IgE synthesis.

  • 25.
    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.

  • 26.
    Hellquist, H. B.
    et al.
    Örebro Medical Center, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro Medical Center, Örebro, Sweden.
    Rudblad, S.
    Ekedahl, C.
    Davidsson, Åke
    Örebro Medical Center, Örebro, Sweden.
    Activated T cells in the nasal mucosa of patients with grass-pollen allergy. A pilot study1992In: Rhinology, ISSN 0300-0729, E-ISSN 1996-8604, Vol. 30, no 1, p. 57-63Article in journal (Refereed)
    Abstract [en]

    Six patients with grass-pollen allergy were provoked with water-soluble grass pollen until a pronounced allergic reaction occurred. This was performed outside the grass-pollen season, and the allergen was administered on the edge of the inferior turbinate. Biopsies were taken both before provocation and during the reaction, 15-30 minutes after provocation. The nasal population of immunohistochemically positive cells for HLA-DR, CD1, interleukin-2-receptor, IgE, CD4 and CD8 were studied. There was a marked increase of IL2-R-positive cells (activated T lymphocytes) in the nasal mucosa after provocation, whilst the other cell populations approximately remained unchanged (apart from a certain increase of IgE). The increase of activated T lymphocytes may imply that certain subsets of T cells play a role in the allergic response, and that the role of helper T cells very likely is much more complex than the regulation of mast cells and eosinophils. The concomitant presence of Langerhans' cells (CD1-positive) and activated T lymphocytes may indicate a possible association on site between an antigen-presenting cell and both effector as well as memory cells in allergic reactions.

  • 27.
    Hellquist, Henrik B.
    et al.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden .
    Karlsson, Mats G.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Nilsson, Christer
    Department of Otorhinolaryngology, Örebro Medical Center Hospital, Örebro, Sweden.
    Salivary duct carcinoma: a highly aggressive salivary gland tumour with overexpression of c-erbB-21994In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 172, no 1, p. 35-44Article in journal (Refereed)
    Abstract [en]

    The clinicopathological and immunocytochemical features of nine cases of salivary duct carcinoma are described. This relatively rare tumour, which only recently has been widely recognized as a separate entity, is highly malignant and caused the death in eight of the patients. The tumour cells are arranged in cribriform and solid growth patterns, where the solid tumour nests frequently have comedo necrosis, and a fibrous, often sclerotic, stroma is present. The infiltrating desmoplasmic component and the diffuse invasive growth into adjacent adipose parotid tissue have similarities to ductal breast carcinoma. Immunocytochemical investigation of salivary duct carcinoma showed constant overexpression of c-erbB-2 as detected by membrane accentuation, and high proliferative activity as detected by nuclear positivity for MIB 1 (Ki-67). Changes in the expression of p53 and retinoblastoma gene product do not constitute a constant event in salivary duct carcinoma. A few of the tumours showed scattered cells with distinct nuclear positivity for both progesterone and oestrogen receptors. We emphasize that this highly malignant salivary gland tumour has a characteristic morphology, may not be as rare as previously considered, and that prompt and aggressive therapy is needed.

  • 28.
    Jahnson, S.
    et al.
    Örebro Medical Centre, Örebro, Sweden.
    Risberg, B.
    Karlsson, Mats G.
    Örebro Medical Centre, Örebro, Sweden.
    Westman, G.
    Bergström, R.
    Pedersen, J.
    p53 and Rb immunostaining in locally advanced bladder cancer: relation to prognostic variables and predictive value for the local response to radical radiotherapy1995In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 28, no 2, p. 135-142Article in journal (Refereed)
    Abstract [en]

    The association between known prognostic variables and altered immunostaining for the nuclear proteins retinoblastoma (Rb) and p53 was studied in a homogeneous series of locally advanced bladder cancer. The predictive value of this immunostaining for the local response to intended radical radiotherapy was investigated. Among 262 patients treated with intended radical radiotherapy between 1967 and 1986, a total of 154 patients were evaluable with respect to local response to treatment. The paraffin-embedded specimen from the tumour prior to irradiation was immunostained with the monoclonal antibodies PMG3-245 for Rb and 1801 for p53 nuclear proteins after heating in a microwave oven for 40 min at 650 W. An altered expression of Rb and p53 was observed in 18 and 42% of the tumours, respectively. p53 overexpression was associated with higher tumour grade. However, the results of the p53 and Rb immunostaining procedures had no predictive value for tumor response to radiation treatment, local control or cancer-specific mortality.

  • 29.
    Jahnson, Staffan
    et al.
    Department of Urology, Örebro Medical Centre, Örebro, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Örebro Medical Centre, Örebro, Sweden.
    Predictive value of p53 and pRb immunostaining in locally advanced bladder cancer treated with cystectomy1998In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 160, no 4, p. 1291-1296Article in journal (Refereed)
    Abstract [en]

    Purpose: We elucidate the association between altered immunostaining for retinoblastoma gene protein (pRb) and p53 nuclear proteins, and cancer specific death in patients treated with cystectomy for locally advanced bladder cancer.

    Materials and Methods: The hospital records of 173 patients treated with cystectomy for advanced urothelial bladder cancer between 1967 and 1992 were retrospectively reviewed. Representative biopsies obtained before treatment were sectioned and stained using the standard immunohistochemical technique with antibody DO-7 (p53) and antibody PMG3-245 (pRb). A tumor was considered to have an altered p53 expression if 20% or more of tumor cells exhibited nuclear staining. Similarly, if no tumor cell had nuclear immunostaining the tumor was considered to have an altered pRb expression.

    Results: An altered expression was observed for p53 in 98 tumors (57%) and for pRb in 60 (35%). In a proportional hazards analysis no association was found between an altered expression of pRb or p53 and cancer specific death. This finding was also true in another analysis when the results of immunostaining for pRb and p53 were combined.

    Conclusions: An altered expression for pRb and/or p53 was not correlated to cancer specific death. Thus, these parameters could not be used as predictors of treatment outcome after cystectomy for locally advanced bladder cancer.

  • 30.
    Jahnson, Staffan
    et al.
    Department of Urology, Örebro Medical Centre, Örebro, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Örebro Medical Centre, Örebro, Sweden.
    Tumor mapping of regional immunostaining for p21, p53, and mdm2 in locally advanced bladder carcinoma2000In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 89, no 3, p. 619-629Article in journal (Refereed)
    Abstract [en]

    Background: The aim of this study was to elucidate the associations among immunostaining for p53, p21, and mdm2; their respective expression within each tumor; and the value of these variables for predicting treatment outcome after cystectomy for patients with locally advanced bladder carcinoma.

    Methods: The hospital records from all 173 patients treated with cystectomy for locally advanced urothelial bladder carcinoma between 1967 and 1992 were retrospectively reviewed. Three consecutive sections from biopsies taken before any treatment were stained using the standard immunohistochemical technique for p53, p21, and mdm2, respectively. The cutoff limit was 20% or more for positive p53 expression and 10% or more for positive p21 and mdm2 expression.

    Results: Positive immunostaining was observed for p53 in 98 tumors (57%), for p21 in 89 tumors (51%), and for mdm2 in only 16 tumors (9%). The only association found between immunostaining for the three antibodies was that most mdm2-positive tumors had positive p21 expression. Tumor mapping of regional immunostaining showed no association between immunostaining for p53 and p21. In a proportional hazards analysis, no association was found between the results of immunostaining for the three antibodies and treatment outcome.

    Conclusions: Positive or negative expression of p53, p21, or mdm2, or combinations of these, was not associated with cancer specific mortality after cystectomy for bladder carcinoma. There was no association between immunostaining for p21 and p53, whereas positive immunostaining for mdm2 was observed in a minority of the tumors. These results indicate that, in addition to p21, p53, and mdm2, there are other oncoproteins and tumor suppressor proteins along the p53 pathway that are involved in tumor development and progression.

  • 31.
    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.

  • 32.
    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.

  • 33.
    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.

  • 34.
    Karlsson, Mats G.
    et al.
    Department of Otorhinolaryngology, Örebro Medical Center Hospital, Örebro, Sweden; Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Davidsson, Åke
    Department of Otorhinolaryngology, Örebro Medical Center Hospital, Örebro, Sweden; Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Hellquist, H. B.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Quantitative computerized image analysis of immunostained lymphocytes: A methodological approach1994In: Pathology, Research and Practice, ISSN 0344-0338, E-ISSN 1618-0631, Vol. 190, no 8, p. 799-807Article in journal (Refereed)
    Abstract [en]

    A methodological approach by computerized image analysis to quantify immunostained objects in histological sections is described. We have investigated antibodies against CD4, CD8, CD20, CD23 and CD25 in frozen sections of human nasal mucosa; however, the methodology of standardization is of general validity. The study was designed particularly to investigate the following points: 1) light intensity, 2) the grey level for counter staining intensity, 3) the grey level threshold value for positive objects, 4) the minimal acceptable size of a positive object, 5) the influence of the brightness of the light on both the number and the area of objects. Furthermore, random sampling and determination of 6) the area per section, and 7) the number of histological sections to be measured per biopsy. Finally, a study of reproducibility of immunostaining intensity was performed. The influence of the different parameters mentioned above was studied and the values (eg. threshold value) for our particular setting of microscope, image analysis equipment, computer software etc, were defined. The method was then tested for intra- and interindividual variation which was found to be less than 5%. Correlation analysis of the reproducibility gave coefficients of correlation of 0.99, both concerning number of immunopositive objects and immunopositive area. We emphasize the importance of a highly standardized methodology if the numeric data obtained from computer assisted image analysis are to be more accurate than semiquantitative assessments by experienced observers. With a thorough standardization as described in this method it is possible to obtain numeric values, and data with low deviations, which are two obvious and important advantages.

  • 35.
    Karlsson, Mats G.
    et al.
    Departments of Pathology and Otorhionolaryngology, Medical Center Hospital, Örebro, Sweden.
    Davidsson, Åke
    Departments of Pathology and Otorhionolaryngology, Medical Center Hospital, Örebro, Sweden.
    Hellquist, Henrik B.
    Department of Pathology II, University Hospital, Linköping, Sweden.
    Increase in CD4+ and CD45RO+ memory T cells in the nasal mucosa of allergic patients1994In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 102, no 10, p. 753-758Article in journal (Refereed)
    Abstract [en]

    By means of immunocytochemistry we have investigated subsets of T lymphocytes in frozen sections of nasal mucosa from patients with seasonal allergic rhinitis and healthy control persons. All participants were subjected to time-course provocation during the non-pollen season, and samples were taken during provocation as well as during the natural pollen season. Computerized image analysis was applied for evaluation of the immunostained lymphocytes. CD45RO+ memory T cells outnumbered the remaining leukocyte populations in the mucosa of both allergic patients and controls on all occasions. During the repeat provocation there was no difference in numerical values, with respect to any of the five leukocyte subpopulations studied (CD4, CD8, CD25, CD45RA and CD45RO), between patients and controls. However, during continuous exposure in the pollen season a significant increase in CD4+ cells was observed in allergic patients compared to before provocation (p < 0.05). No changes were observed with respect to CD8+ and CD25+ cells. Similarly, an increase in CD45RO+ memory was found in allergic patients during the pollen season compared to the non-pollen season (p < 0.02). This latter finding was, however, only evident in the patients who did not use nasal corticosteroids. Hence the present investigation has demonstrated an allergen-induced increase in CD4+ and CD45RO+ memory T cells in the mucosa of allergic patients during the pollen season. These events may constitute a cellular basis for local continuous production of certain cytokines, particularly interleukin-4, which is essential for IgE synthesis.

  • 36.
    Karlsson, Mats G.
    et al.
    Departments of Pathology, Medical Center Hospital, Örebro, Sweden.
    Davidsson, Åke
    Departments of Otorhinolaryngology, Medical Center Hospital, Örebro, Sweden.
    Viale, Guiseppe
    Universitá degli Studi di Milano, Ospedale S. Paolo, Milan, Italy .
    Graziani, Daniela
    Universitá degli Studi di Milano, Ospedale S. Paolo, Milan, Italy .
    Hellquist, Henrik B.
    Departments of Pathology, Medical Center Hospital, Örebro, Sweden; Departments of Otorhinolaryngology, Medical Center Hospital, Örebro, Sweden.
    Nasal messenger RNA expression of interleukins 2, 4, and 5 in patients with allergic rhinitis1995In: Diagnostic molecular pathology (Print), ISSN 1052-9551, E-ISSN 1533-4066, Vol. 4, no 2, p. 85-92Article in journal (Refereed)
    Abstract [en]

    In nasal biopsies from 17 adult patients with seasonal allergic rhinitis and from 10 healthy controls, cytokines were analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR). The time-course study during winter included repeated local allergen provocation with subsequent nasal biopsies as well as biopsies taken during pollen season. The RT-PCR for CD44 yielded positive bands in 65 of 71 cases, in which cases mRNA for interleukins 2, 4, and 5 (IL-2, IL-4, and IL-5) were thus investigated by means of seminested PCR. IL-4 mRNA was found almost exclusively in the allergic patients. During provocation a significant increase in IL-4 was noticed compared with controls (p = 0.043). Equally, during the natural pollen season, IL-4 mRNA expression was significantly higher in patients not using nasal corticosteroids compared with those who did (p = 0.011). No differences in IL-2 or IL-5 were observed between the groups. These findings also indicate, together with earlier observations of T-cell activation, a phenotype switch toward T-helper 2 (Th2) cells, and the accumulation (homing) of these T cells in the nasal mucosa, that T cells constitute the main source for IL-4 in the nasal mucosa. Therefore, allergic patients have an increased synthesis of IL-4 when provoked with the allergen, and during natural pollen season this synthesis can be downregulated by corticosteroids. Furthermore, this study exemplifies the versatility of molecular biology in surgical pathology and that even low-copy-number cytokine mRNA can be examined in routinely snap-frozen surgical specimens.

  • 37.
    Karlsson, Mats G.
    et al.
    Department of Pathology, Örebro Medical Center, Örebro, Sweden.
    Hardell, Lennart
    Department of Oncology, Örebro Medical Center, Örebro, Sweden.
    Hallquist, Arne
    Stockholms Sjukhem, Stockholm, Sweden.
    No association between immunohistochemical expression of p53, c-erbB-2, Ki-67, estrogen and progesterone receptors in female papillary thyroid cancer and ionizing radiation1997In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 120, no 2, p. 173-177Article in journal (Refereed)
    Abstract [en]

    An association has previously been reported between exposure to medical diagnostic ionizing radiation and papillary thyroid cancer in women. To further evaluate potential mechanisms in carcinogenesis, the expression of p53, c-erbB-2, as well as Ki-67, estrogen and progesterone receptors were analyzed by immunohistochemistry in 19 women exposed to X-rays and for comparison in nine women without such reported exposure. They all had papillary thyroid cancer. No difference was found between these groups. The results of this study showed that p53, c-erbB-2, Ki-67, estrogen and progesterone receptors are not involved in papillary thyroid cancer associated with exposure to medical diagnostic ionizing radiation.

  • 38.
    Karlsson, Mats G.
    et al.
    Department of Pathology, Medical Center Hospital, Örebro, Sweden .
    Hellquist, H. B.
    Department of Pathology II, University Hospital, Linköping, Sweden.
    Endothelial adhesion molecules for nasal-homing T cells in allergy1996In: Virchows Archiv, ISSN 0945-6317, E-ISSN 1432-2307, Vol. 429, no 1, p. 49-54Article in journal (Refereed)
    Abstract [en]

    During the allergic reaction mucosal T cells are activated and a local increase in numbers occurs. In peripheral blood, a concomitant T cell activation and switch towards memory phenotype appears. E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 were studied in nasal mucosal biopsies taken during a time-course provocation study, including patients with seasonal allergic rhinitis and healthy controls. Allergic patients were also studied during the natural pollen season with particular attention to the influence of local corticosteroid treatment. Before provocation allergic patients and controls did not differ concerning the expression of endothelial adhesion molecules. However, the epithelial ICAM-1 expression was increased among allergics (P < 0.05). Repetitive allergen provocation induces an increased endothelial expression of VCAM-1 in allergic patients (P < 0.01). Similarly, VCAM-1 expression was increased during the natural pollen season (P < 0.05). Interestingly, the increased VCAM-1 expression was inhibited by the use of local corticosteroids. The present data demonstrate a putative integrin-VCAM-1 mechanism for selective homing of T memory cells to the allergic nasal mucosa and new in vivo effects of local corticosteroid treatment are demonstrated.

  • 39.
    Karlsson, Mats G.
    et al.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Hellquist, H. B.
    Phenotype switch and activation of T lymphocytes in patients with allergic rhinitis1994In: Journal for Oto-Rhino-Laryngology, ISSN 0301-1569, E-ISSN 1423-0275, Vol. 56, no 3, p. 166-172Article in journal (Refereed)
    Abstract [en]

    The peripheral blood of 17 patients with seasonal allergic rhinitis (birch pollen) and of 10 healthy subjects were analysed before and during a provocation study in the non-pollen season as well as during the pollen season. Analytical flow cytometry comprised a panel of monoclonal antibodies investigating helper/suppressor T cells, activated T cells, and naive/memory T helper cells. Allergic patients showed no increase in the amount of T lymphocytes but an increased proportion of CD4+ helper T cells early during pronounced exposure (provocation) but not during natural antigen exposure (pollen season). Allergic patients showed a significant increase in activated T cells during the non-pollen season compared with healthy subjects, and furthermore, the nasal allergen provocation induced an additional increase in activated T cells among allergics. The T cell activation mainly affected helper T cells (85%) rather than suppressor T cells. Furthermore, allergic patients showed a significant increase in naive T helper cells during the pollen season. The presence of a double-positive subpopulation indicates an activated T helper subpopulation that switches its phenotype from naive (CD45RA) to memory (CD29). The results indicate at least two important differences between patients with allergic rhinitis and healthy controls. In allergic patients T helper cells become activated upon allergen exposure, and circulate in the blood and switch their phenotype. These T cells have a potential homing tendency to the nasal mucosa. These two events do not occur in non-allergic individuals and may thus constitute new insights into the basic mechanisms of allergic rhinitis.

  • 40.
    Kirrander, Peter
    et al.
    Örebro University Hospital, Örebro, Sweden.
    Kolaric, Aleksandra
    Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University Hospital, Örebro, Sweden.
    Windahl, Torgny
    Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University Hospital, Örebro, Sweden.
    Stark, Jennifer Rider
    Örebro University Hospital, Örebro, Sweden; Brigham & Women’s Hospital, Boston MA, USA; Harvard Medical School, Boston MA, USA.
    Lillsunde-Larsson, Gabriella
    Örebro University Hospital, Örebro, Sweden.
    Elgh, Fredrik
    Örebro University, School of Health and Medical Sciences. Umeå University, Umeå, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden.
    Human papillomavirus prevalence, distribution and correlation to histopathological parameters in a large Swedish cohort of men with penile carcinoma2011In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 108, no 3, p. 355-359Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE To analyse the overall and type-specific human papillomavirus (HPV) prevalence and distribution in penile carcinoma and determine the correlation to histopathological parameters.

    PATIENTS AND METHODS In this retrospective study, we analysed HPV status in 241 patients with penile carcinoma, treated at Orebro University Hospital, Orebro, Sweden, between 1984 and 2008. Age and date at diagnosis was recorded. The tumour specimens were categorized according to the UICC 2002 TNM classification. A subset of patients was operatively staged with regard to lymph node status. A commercially available Real Time PCR was used to detect 13 different types of HPV (6,11,16,18,31,33,35,45,51,52,56,58 and 59).

    RESULTS We excluded 25 patients due to low DNA quality. Of the remaining 216, 179 (82.9%) tumour specimens were HPV infected. The majority of cases positive for HPV (70.4%) were infected by a single-type. The most frequent type was HPV 16 followed by HPV 18. No significant association between HPV status and pathological tumour stage, grade or lymph node status was found.

    CONCLUSION The HPV prevalence found is higher than in most other studies, further strengthening HPV as an etiological agent in penile carcinoma. Furthermore, the high prevalence of HPV 16 and 18 raises the question of what potential impact current HPV vaccines that target these specific HPV types might have on penile carcinoma. No significant association between HPV status and histopathological parameters was found in the present study. Additional investigations are needed to draw final conclusions on the prognostic value of HPV status in penile carcinoma.

  • 41.
    Kumakech, Edward
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Makerere University College of Health Sciences, Kampala, Uganda.
    Berggren, Vanja
    Medical Faculty, Lund University, Lund; Global Health, Karolinska Institute, Stockholm.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro.
    Kaliff, Malin
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University.
    Karlsson, Mats
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro.
    Musubika, Carol
    Makerere University College of Health Sciences, Kampala, Uganda.
    Kirimunda, Samuel
    Makerere University College of Health Sciences, Kampala, Uganda.
    Wabinga, Henry
    Makerere University College of Health Sciences, Kampala, Uganda.
    Andersson, Sören
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University.
    Prevalence, genotypes and risk factors for vaccine and non-vaccine types of Human Papillomavirus (HPV) infections among Bivalent HPV-16/18 vaccinated and non-vaccinated young women in Ibanda district Uganda: 5 year follow up studyManuscript (preprint) (Other academic)
  • 42.
    Kumakech, Edward
    et al.
    Örebro University, School of Health Sciences. Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Berggren, Vanja
    Faculty of Medicine, Lund University, Lund, Sweden; Department of Public Health (Global Health/IHCAR), Karolinska Institute, Stockholm, Sweden.
    Wabinga, Henry
    Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Kaliff, Malin
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital and Örebro University, Örebro, Sweden.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Kirimunda, Samuel
    Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Musubika, Caroline
    Department of Pathology, School of Biomedical Sciences, Makerere University College of Health Sciences, Kampala, Uganda.
    Andersson, Sören
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Significantly Reduced Genoprevalence of Vaccine-Type HPV-16/18 Infections among Vaccinated Compared to Non-Vaccinated Young Women 5.5 Years after a Bivalent HPV-16/18 Vaccine (Cervarix®) Pilot Project in Uganda2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0160099Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to determine the prevalence and some predictors for vaccine and non-vaccine types of HPV infections among bivalent HPV vaccinated and non-vaccinated young women in Uganda. This was a comparative cross sectional study 5.5 years after a bivalent HPV 16/18 vaccination (Cervarix®, GlaxoSmithKline, Belgium) pilot project in western Uganda. Cervical swabs were collected between July 2014-August 2014 and analyzed with a HPV genotyping test, CLART® HPV2 assay (Genomica, Madrid Spain) which is based on PCR followed by microarray for determination of genotype. Blood samples were also tested for HIV and syphilis infections as well as CD4 and CD8 lymphocyte levels. The age range of the participants was 15-24 years and mean age was 18.6(SD 1.4). Vaccine-type HPV-16/18 strains were significantly less prevalent among vaccinated women compared to non-vaccinated women (0.5% vs 5.6%, p 0.006, OR 95% CI 0.08(0.01-0.64). At type-specific level, significant difference was observed for HPV16 only. Other STIs (HIV/syphilis) were important risk factors for HPV infections including both vaccine types and non-vaccine types. In addition, for non-vaccine HPV types, living in an urban area, having a low BMI, low CD4 count and having had a high number of life time sexual partners were also significant risk factors. Our data concurs with the existing literature from other parts of the world regarding the effectiveness of bivalent HPV-16/18 vaccine in reducing the prevalence of HPV infections particularly vaccine HPV- 16/18 strains among vaccinated women. This study reinforces the recommendation to vaccinate young girls before sexual debut and integrate other STI particularly HIV and syphilis interventions into HPV vaccination packages.

  • 43.
    Larsson, Gabriella Lillsunde
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    HPV testing of biobanked liquid-based cytology: a validation study2016In: International Journal of Biological Markers, ISSN 0393-6155, E-ISSN 1724-6008, Vol. 31, no 2, p. E218-E223Article in journal (Refereed)
    Abstract [en]

    Introduction: The aim of the study was to investigate whether biobanked liquid-based cytology (LBC) vaginal samples could be reanalyzed for the biomarkers HPV DNA and mRNA without loss of sensitivity.

    Methods: One hundred LBC samples with ASCUS or CIN1 were tested for HPV DNA and mRNA before and after biobanking. DNA analysis targeted the viral genes E6 and E7, 12 high-risk and 2 low-risk HPV types together with the human control gene HBB, using real-time PCR. The Aptima HPV assay was used for mRNA analysis of 14 high-risk HPV types.

    Results: With Aptima there was 84% agreement between results before and after biobanking. The sensitivity and specificity were 0.79 (95% CI, 0.68-0.88) and 0.94 (95% CI, 0.80-0.99), respectively. With the DNA-based method, the agreement between results was 87%, the sensitivity 0.85 (95% CI, 0.75-0.92) and the specificity 0.95 (95% CI, 0.77-1.00). Both methods presented a significant difference between positive results before and after biobanking; McNemar test: p = 0.004, p = 0.003, Cohen's kappa: 0.67 (95% CI, 0.53-0.81), 0.68 (95% CI, 0.52-0.84). Cycle threshold values for the DNA method were higher for all genotypes after biobanking, except for HPV-59. Some loss of sensitivity was seen after biobanking but the concordance between HPV detection before and after biobanking was good for both evaluated methods.

    Conclusions: Biobanking of LBC vaginal samples offers a good platform for HPV testing and could be extended to further molecular analyses. However, in order to ensure a valid test result a larger portion needs to be analyzed from the biobanked sample.

  • 44. Li, Hui-xiang
    et al.
    Zh, Suo
    Zhang, Yun-han
    Risberg, Bjørn
    Karlsson, Mats G
    Örebro University Hospital, Örebro, Sweden.
    Nesland, Jahn M.
    [Expressions of thymidine phosphorylase, thymidylate synthase and dihydropyrimidine dehydrogenase in breast cancer and their correlations with prognosis]2004In: Zhonghua zhong liu za zhi [Chinese journal of oncology], ISSN 0253-3766, Vol. 26, no 11, p. 669-672Article in journal (Refereed)
    Abstract [en]

    Objective: To study the expression of thymidine phosphorylase (TP), thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) mRNA in breast cancer and its correlation with prognosis.

    Methods: Expression levels of TP, TS and DPD mRNA in 86 micro-selected breast cancer tissues and 9 normal breast tissues were detected by real-time quantitative PCR.

    Results: The median expression levels of TP, TS and DPD mRNA in tumor tissue and in normal tissues were 16.54, 0.38, 2.47 and 11.75, 0.25, 8.33, respectively, there were no significant differences (P >0.05). The expression levels of TP, TS and DPD mRNA showed no association with tumor size, lymph node metastasis, pathological grade and clinical stage, except that of DPD showed a negative association with patients' ages. There was no significant difference in disease-free survival or overall survival between the patients with high and low TP or DPD mRNA levels. Disease-free survival tends to be better in the patients with low TS mRNA level than those with high TS mRNA, but the difference was not significant (P=0.069), while the overall survival showed a statistically difference (59.00 month and 70.30 month) (P=0.0496).

    Conclusion: The expression level of TS mRNA may serve as a prognostic marker for breast cancer patients.

  • 45.
    Lillsunde Larsson, Gabriella
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Kaliff, M.
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Bergengren, Lovisa
    Department of Women's health, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    HPV Genotyping from the high risk mRNA Aptima assay: a direct approach using DNA from Aptima sample tubes2016In: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 235, p. 80-84Article in journal (Refereed)
    Abstract [en]

    The underlying cause of cervical cancer is infection with the human papilloma virus (HPV) and HPV testing can be used for cervical cancer screening. The Aptima HPV assay from Hologic is an mRNA HPV test used to identify clinically relevant infections but the method does not discriminate between the different high risk genotypes. The aim of the current study was to evaluate if analyzed Aptima sample transfer tubes could be used as a source for HPV genotyping, using sample DNA. Study samples (n=108); were HPV-tested with mRNA Aptima assay and in parallel DNA was extracted and genotyped with Anyplex II HPV28. Analyzed mRNA Aptima tubes were thereafter used as source for a second DNA extraction and genotyping. Using mRNA Aptima result as reference, 90% of the samples (35/39) were high risk positive with the Anyplex II HPV28. Cohen's kappa 0.78 (95% CI: 0.66-0.90), sensitivity 0.90 (95% CI: 0.76-0.97) and specificity 0.90 (95% CI: 0.80-0.96). Two discordant samples carried low-risk genotypes (HPV 82 and HPV 44) and two were negative. DNA-genotyping results, in parallel to and after mRNA testing, were compared and differed significantly (McNemar test: P=0.021) possibly due to sample extraction volume difference. Cohen's kappa 0.81 (95% CI: 0.70-0.92), sensitivity 0.85 (95% CI: 0.74-0.93) and specificity 0.98 (95% CI: 0.88-1.00). In conclusion, analyzed mRNA Aptima sample tubes could be used as a source for DNA HPV genotyping. The sample volume used for extraction needs to be further explored.

  • 46.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Evaluation of HPV Genotyping Assays for Archival Clinical Samples2015In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 3, p. 293-301Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) testing and genotyping of FFPE tissue samples is important in epidemiological investigations. Here, we compare four different HPV genotyping methods for use in FFPE clinical samples. Comparative testing was performed on 99 samples with a clinical suspicion of HPV. Specimens were analyzed with Anyplex II HPV28 detecting 28 genotypes using real-time PCR and melting curve analysis, CLART HPV2 detecting 35 genotypes using PCR and microarray detection, and MGP5+/6+ consensus primer system together with pyrosequencing. Results were compared to a real-time PCR reference protocol detecting 14 genotypes. In total, 68% of the samples were positive for an HPV genotype using the reference protocol and MGP5+/6+ primer system. Anyplex II HPV28 analysis and CLART HPV2 had 82% and 72% positive samples, respectively. All four methods showed good agreement when comparing the 14 genotypes included in the reference protocol. When evaluating all genotypes, the Anyplex II HPV28 assay and the CLART assay changed the status of the sample (individually or together) from negative with respect to the reference protocol to positive for either a Group 1 (n = 4) or Group 2 (n = 6) genotype. We conclude from this study that for an extended genotyping approach with a high sensitivity for FFPE specimens, both the Anyplex II HPV28 and CLART HPV2 assays are suitable alternatives despite minor intra-assay differences.

  • 47.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Carlsson, Jessica
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital.
    HPV genotyping assays for archival clinical samples: an evaluation studyManuscript (preprint) (Other academic)
  • 48.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Andersson, Sören
    Örebro University Hospital, Örebro, Sweden.
    Elgh, Fredrik
    Umeå University Hospital, Umeå, Sweden.
    Sorbe, Bengt
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital, Örebro, Sweden.
    Human Papillomavirus (HPV) and HPV 16-Variant Distribution in Vulvar Squamous Cell Carcinoma in Sweden2012In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 22, no 8, p. 1413-1419Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the human papillomavirus (HPV) and HPV type 16-variant distribution in a series of vulvar squamous cell carcinomas (VSCC) and to evaluate the impact of HPV and HPV 16-variant on prognosis.

    Methods: A series of 133 patients who had a diagnosis of VSCC (1983-2008) was selected for the study. Detection of 11 high-risk HPV types (16, 18, 31, 33, 39, 45, 51, 52, 56, 58, and 59) and 2 low-risk HPV types (6 and 11) was performed with real-time polymerase chain reaction. Samples positive for HPV 16 were further analyzed for variant determination of 7 positions in the E6 gene with polymerase chain reaction and pyrosequencing.

    Results: Forty (30.8%) of 130 tumors were found to be HPV positive. Human papillomavirus type 16 was found in 31 cases, HPV 18 was found in 2 cases, HPV 33 was found in 5 cases, and HPV 56 and HPV 59 were found in one case each. All but one tumor harboring HPV 16 were of European linage, and the 3 most common variants were E-p (n = 13), E-G350 (n = 7), and E-G131 (n = 5). HPV positivity was associated with the basaloid tumor type and occurred in significantly younger patients. Overall and recurrence-free survival rates were better in HPV-positive cases, but after correction for age and tumor size, HPV status was no longer an independent and significant prognostic factor. The survival rates of the various HPV 16 variants were not significantly different, but there was a trend of worse outcome for the E-G131-variant group.

    Conclusions: Human papillomavirus positivity of 30.8% is similar to other reports on VSCC. To our knowledge, this first variant determination of HPV 16 in vulvar carcinoma in a Swedish cohort indicated that the variant E-G131 may have an increased oncogenic potential in patients with VSCC.

  • 49.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Andersson, Sören
    Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Sorbe, Bengt
    Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital. Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Prognostic impact of human papilloma virus (HPV) genotyping and HPV-16 subtyping in vaginal carcinoma2013In: Gynecologic Oncology, ISSN 0090-8258, E-ISSN 1095-6859, Vol. 129, no 2, p. 406-411Article in journal (Refereed)
    Abstract [en]

    Objective

    The objectives of this study are to investigate the human papilloma virus (HPV) distribution in vaginal cancer and to evaluate HPV-genotype as well as HPV16-variant impact on prognosis.

    Methods

    Sixty-nine patients diagnosed with primary vaginal carcinoma (1975-2002) were included in the study. Detection of twelve high-risk HPV (hr HPV) and two low-risk HPV (lr HPV) was performed with realtime-PCR. Samples positive for HPV-16 were analyzed for variants in the E6-gene with PCR and pyrosequencing.

    Results

    53.6% (37/69) of the tumors were found to be HPV-positive, mostly for HPV-16 (N=26). Other HPV-types were HPV-18 (N=2), HPV-31 (N=2), HPV-33 (N=2), HPV-45 (N=1), HPV-52 (N=2), HPV-56 (N=1) and HPV-58 (N=1). Only European subtypes of HPV-16 were represented and the two most common HPV-16-variants were E-p (N=13) and E-G350 (N=11). Patients with HPV-positive tumors (N=37) had a significantly (log-rank test=3341; p = 0.0008) superior 5-year overall survival rate as well as cancer-specific survival rate and progression-free survival rate (p = 0.0002; p = 0.0004), compared with patients with HPV-negative tumors (N=32). Interestingly, patients with HPV-16-positive tumors had a superior overall survival compared with patients with tumors containing other HPV-genotypes. In a Cox proportional multivariate analysis age, tumor size, and HPV-status were independent and significant prognostic factors with regard to overall survival rate.

    Conclusions

    HPV-status is of prognostic importance in vaginal carcinoma and varies with viral genotype. In this era of HPV-vaccination, genotypes other than those included in the vaccination program could still lead to vaginal carcinoma with unfavorable prognosis.

  • 50.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Sorbe, Bengt
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Viral Load, Integration and Methylation of E2BS3 and 4 in Human Papilloma Virus (HPV) 16-Positive Vaginal and Vulvar Carcinomas2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, article id e112839Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate if viral load, integration and methylation of E2BS3 and 4 represent different ways of tumor transformation in vaginal and vulvar carcinoma and to elucidate its clinical impact.

    Methods: Fifty-seven samples, positive for HPV16, were selected for the study. Detection of viral load was made with realtime-PCR using copy numbers of E6 and integration was calculated from comparing E2 to E6-copies. Methylation of E2BS3 and 4 was analysed using bisulphite treatment of tumor DNA, followed by PCR and pyrosequencing.

    Results: Vaginal tumors were found to have a higher viral load (p=0.024) compared to vulvar tumors but a high copy number (> median value, 15 000) as well as high methylation (> 50%) was significantly (p=0.010 and p=0.045) associated with a worse cancer-specific survival rate in vulvar carcinoma, but not in vaginal carcinoma. Four groups could be defined for the complete series using a Cluster Two step analysis; (1) tumors holding episomal viral DNA, viral load below 150 000 copies not highly methylated (n=25, 46.3%); (2) tumors harboring episomal viral DNA and being highly methylated (>50%; n=6, 11.1%); (3) tumors with viral DNA fully integrated (n=11, 20.4%), and (4) tumors harboring episomal viral DNA and being medium-or unmethylated (< 50%) and having a high viral load (> total mean value 150 000; n=12, 22.2%). The completely integrated tumors were found to be distinct group, whilst some overlap between the groups with high methylation and high viral load was observed.

    Conclusion: HPV16-related integration, methylation in E2BS3 and 4 and viral load may represent different viral characteristics driving vaginal and vulvar carcinogenesis. HPV16-related parameters were found to be of clinical importance in the vulvar series only.

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