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  • 1.
    Adolfsson, Emma
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Friberg, Örjan
    Department of Cardiothoracic Surgery, Faculty of Health, Örebro University, Örebro, Sweden.
    Samano, Ninos
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Cardiothoracic Surgery.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Department of Cardiology.
    Johansson, Karin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Bone marrow- and adipose tissue-derived mesenchymal stem cells from donors with coronary artery disease: growth, yield, gene expression and the effect of oxygen concentration2020In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 80, no 4, p. 318-326Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stem cells (MSCs) for cardiovascular cell therapy are procured from different sources including bone marrow and adipose tissue. Differently located MSCs differ in growth potential, differentiation ability and gene expression when cultured in vitro, and studies show different healing abilities for different MSC subgroups. In this study, bone marrow derived MSCs (BMSCs) and adipose tissue derived MSCs (ADSCs) from six human donors with coronary artery disease were compared for growth potential and expression of target genes (Angpt1, LIF, HGF, TGF-β1 and VEGF-A) in response to exposure to 1% and 5% O2, for up to 48 h. We found greater growth of ADSCs compared to BMSCs. ADSCs expressed higher levels of Angpt1, LIF and TGF-β1 and equal levels of VEGF-A and HGF as BMSCs. In BMSCs, exposure to low oxygen resulted in upregulation of TGF-β1, whereas other target genes were unaffected. Upregulation was only present at 1% O2. In ADSCs, LIF was upregulated in both oxygen concentrations, whereas Angpt1 was upregulated only at 1% O2. Different response to reduced oxygen culture conditions is of relevance when expanding cells in vitro prior to administration. These findings indicate ADSCs as better suited for cardiovascular cell therapy compared to BMSCs.

  • 2.
    Berg von Linde, Maria
    et al.
    Department of Cardiology, Faculty of Health, Örebro University, Örebro, Sweden.
    Johansson, Karin
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Kruse, Robert
    Örebro University, School of Medical Sciences. Department of Cardiothoracic and Vascular Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; University Health Care Research Center, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Samano, Ninos
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Cardiothoracic and Vascular Surgery.
    Friberg, Örjan
    Department of Cardiothoracic and Vascular Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Frøbert, Anne Mette
    Department of Chemistry and Bioscience, Faculty of Engineering and Science, Aalborg University, Aalborg, Denmar.
    Fröbert, Ole
    Örebro University, School of Medical Sciences. Department of Cardiology.
    Expression of Paracrine Effectors in Human Adipose-Derived Mesenchymal Stem Cells Treated With Plasma From Brown Bears (Ursus arctos)2021In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 14, no 1, p. 317-325Article in journal (Refereed)
    Abstract [en]

    Adipose-derived mesenchymal stem cells (ADSCs) are promising candidates for novel cell therapeutic applications. Hibernating brown bears sustain tissue integrity and function via unknown mechanisms, which might be plasma borne. We hypothesized that plasma from hibernating bears may increase the expression of favorable factors from human ADSCs. In an experimental study, ADSCs from patients with ischemic heart disease were treated with interventional media containing plasma from hibernating and active bears, respectively, and with control medium. Extracted RNA from the ADSCs was sequenced using next generation sequencing. Statistical analyses of differentially expressed genes were performed using fold change analysis, pathway analysis, and gene ontology. As a result, we found that genes associated with inflammation, such as IGF1, PGF, IL11, and TGFA, were downregulated by > 10-fold in ADSCs treated with winter plasma compared with control. Genes important for cardiovascular development, ADM, ANGPTL4, and APOL3, were upregulated in ADSCs when treated with winter plasma compared with summer plasma. ADSCs treated with bear plasma, regardless if it was from hibernating or active bears, showed downregulation of IGF1, PGF, IL11, INHBA, IER3, and HMOX1 compared with control, suggesting reduced cell growth and differentiation. This can be summarized in the conclusion that plasma from hibernating bears suppresses inflammatory genes and activates genes associated with cardiovascular development in human ADSCs. Identifying the involved regulator(s) holds therapeutic potential.

  • 3.
    Bergengren, Lovisa
    et al.
    Örebro University, School of Health Sciences. Department of Women’s Health.
    Kaliff, Malin
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department of Laboratory Medicine.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    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.

  • 4.
    Bergengren, Lovisa
    et al.
    Örebro University, School of Health Sciences. Deparment of Women's Health.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Deparment of Laboratory Medicine.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Deparment of Laboratory Medicine.
    Prevalence of HPV and pathological changes among women 70 years of age, 10 years after exclusion from the Swedish cervical cancer screening program2020In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 31, no 4, p. 377-381Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Örebro County introduced an updated screening program 2016 with primary HPV test for women over 30 years and prolonged screening, increasing the cut-off age from 56-60 to 64-70. The aim of this study was to investigate the prevalence of HPV genotypes and their correlation to histological changes in women, 10 years after exclusion from the screening program, due to an eventual implementation of a catch-up program including all women aged 60-70.

    METHODS: All women in Örebro County, born 1,946 (n = 1,968), were invited to a liquid-based cell sample with primary HPV screening. Samples were analyzed for hrHPV mRNA and positive samples were genotyped. hrHPV positive women were offered to do a conization.

    RESULTS: Out of 809 participants, 31 (3.8%) were hrHPV positive, of these 22 did a conization. Histologically, 5/22 (23%) had LSIL and 5/22 (23%) had HSIL. Normal histology was found in 12/22 (55%). The most prevalent genotypes were HPV 16, 33, 52, 56, and 68. Of the women with HSIL, one case of cervical cancer was confirmed in a recone biopsy after 4 months.

    CONCLUSION: The study showed considerable prevalence of hrHPV and histologically confirmed LSIL/HSIL. These data led to catch-up screening for women between 60 and 70 years when overlapping two screening strategies.

  • 5.
    Bergengren, Lovisa
    et al.
    Örebro University, School of Health Sciences. Dept. of Women's Health.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Dept. of Laboratory Medicine.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Dept. of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Dept. of Laboratory Medicine.
    HPV-based screening for cervical cancer among women 55-59 years of age2019In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 6, article id e0217108Article in journal (Refereed)
    Abstract [en]

    AIM: Many cervical cancers occurs among women over 65 and prevalence of HPV genotypes in this age cohort is sparingly studied. One aim of this study was to study the prevalence and distribution of HPV genotypes in women 55-59 years, with normal cytology when exiting the screening program. Secondly, HPV clearance as well as the value of HPV genotyping and/or liquid based cytology as triage tests for identifying histological dysplasia among women with persistent HPV was studied.

    METHODS: Women that exited the screening program with normal cytology, between the years 2012-2014, in Örebro County, Sweden, were invited to this study. A total of 2946 samples were analyzed with a broad-spectrum assay to detect both hrHPV and lrHPV in order to investigate the distribution of genotypes. In the consent group, women with a positive hrHPV test were offered a follow-up test and a cone biopsy for histological confirmation, and a follow up sample 6 months post cone.

    RESULTS: The overall prevalence of hrHPV was 7.4% and 59% of them remained hrHPV positive in a follow-up test after 12 months. A total of 99 women had a cone biopsy done, where 19% showed histological dysplasia. HPV 53 was the most common genotype, and among women with histology confirmed LSIL or HSIL, HPV 31 was most common. A positive hrHPV result showed a PPV of 25% for LSIL+ and 12.5%for HSIL+. Using detection of HPV 16/18 genotypes as a triage test for hrHPV positive tests, indicated FNR for histological LSIL+ and HSIL+ of 94% and 87.5% respectively, whilst triage based on cervical cytology had a FNR of 69% for LSIL+ and 37.5% for HSIL+.

    CONCLUSION: The most common hrHPV genotypes among women 55-59 years of age were non HPV16/18 genotypes, and in this population, these genotypes represented most of the histological verified HSIL lesions. This result does not support the proposition of a HPV 16/18 triaging test after a positive hrHPV test as a marker of histological HSIL+ cervical lesions in women over 55 years of age. Similarly, cytological triage after a positive hrHPV showed no additional benefit in this population. Specific triaging tests should be validated to follow post-menopausal women with a positive hrHPV test.

  • 6.
    Bergengren, Lovisa
    et al.
    Örebro University, School of Medical Sciences. Department of Women’s health.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department Laboratory Medicine.
    Kaliff, Malin
    Örebro University, School of Medical Sciences. Department Laboratory Medicine.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department Laboratory Medicine.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department Laboratory Medicine.
    Concordance between self sampling and professionally taken cervical hpv test-result from population based cohort study2016Conference paper (Refereed)
  • 7.
    Bergengren, Lovisa
    et al.
    Örebro University, School of Medical Sciences. Department of Obstetrics and Gynaecology.
    Ryen, Linda
    University Health Care Research Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Flodström, Clelia
    Department of Women´s health, Örebro University Hospital, Örebro, Sweden.
    Fadl, Helena
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Obstetrics and Gynaecology.
    Udumyan, Ruzan
    Örebro University, School of Medical Sciences.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Effectiveness and costs of implemented primary HPV cervical screening: a populationbased cohort studyManuscript (preprint) (Other academic)
  • 8.
    Bergengren, Lovisa
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Obstetrics and Gynaecology.
    Ryen, Linda
    Örebro University, School of Health Sciences. Örebro University Hospital. University Health Care Research Centre.
    Flodström, Clelia
    Department of Women's Health, Örebro University Hospital, Örebro, Sweden.
    Fadl, Helena
    Department of Obstetrics and Gynaecology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Udumyen, Ruzan
    Örebro University, School of Medical Sciences. Örebro University Hospital. Clinical Epidemiology and Biostatistics.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Effectiveness and costs of an implemented primary HPV cervical screening programme in Sweden: A population based cohort study2022In: Preventive Medicine Reports, E-ISSN 2211-3355, Vol. 25, article id 101675Article in journal (Refereed)
    Abstract [en]

    Swedish guidelines recommend cervical screening with primary HPV for women ≥ 30 years of age. The aim of this study was to compare an implemented HPV cervical screening programme in the Region of Örebro County from September 1, 2016, with the former cytology-based screening programme.

    The clinical effectiveness by means of number of high-grade squamous intraepithelial lesions (HSILs) and cervical cancer cases detected in histology within 12 months after the screening test, together with cost implications were the main outcomes. Data were retrieved from the Swedish National Cervical Screening Registry between the years 2014-2015 (cytology based screening) and 2017-2018(HPV based screening), including screening information such as invitations and cytology and histology diagnoses.

    The detection rate of HSIL + among women ≥ 30 years of age was 1.2 times higher with HPV screening, but data revealed an increase in direct colposcopy referral rate by 54% and a higher percentage of irrelevant findings (≤LSIL). Screening based on HPV for women ≥ 30 has increased yearly cost from 1 to 1.3 million EUR, while increasing the number of HSIL + identified. Two thirds of the total costs are from visits for screening samples in the programme.

    HPV screening detected more cases of HSIL + compared to cytology screening among women ≥ 30 although high colposcopy rate, high rate of clinical irrelevant findings and higher costs were shown in the HPV-based screening programme, which implies that alterations in the screening programme in the future are important to consider.

  • 9.
    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.

  • 10.
    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, 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.

  • 11.
    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.

  • 12.
    Carlsson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences. Univ Skövde, Skövde, Sweden.
    Helenius, Gisela
    Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats
    Örebro University Hospital, Örebro, Sweden.
    Lubovac, Zelmina
    Syst Biol Res Ctr Bioinfomat, Univ Skövde, Skövde, Sweden.
    Andrén, Ove
    Örebro University Hospital, Örebro, Sweden.
    Olsson, Björn
    Syst Biol Res Ctr Bioinfomat, Univ Skövde, Skövde, Sweden.
    Klinga-Levan, Karin
    Syst Biol Res Ctr Tumor Biol, Dept Life Sci, Univ Skövde, Skövde, Sweden.
    Validation of suitable endogenous control genes for expression studies of miRNA in prostate cancer tissues2010In: Cancer Genetics and Cytogenetics, ISSN 0165-4608, E-ISSN 1873-4456, Vol. 202, no 2, p. 71-75Article in journal (Refereed)
    Abstract [en]

    When performing quantitative polymerase chain reaction analysis, there is a need for correction of technical variation between experiments. This correction is most commonly performed by using endogenous control genes, which are stably expressed across samples, as reference genes for normal expression in a specific tissue. In microRNA (miRNA) studies, two types of control genes are commonly used: small nuclear RNAs and small nucleolar RNAs. In this study, six different endogenous control genes for miRNA studies were investigated in prostate tissue material from the Swedish Watchful Waiting cohort. The stability of the controls was investigated using two different software applications, NormFinder and BestKeeper. RNU24 was the most suitable endogenous control gene for miRNA studies in prostate tissue materials. (C) 2010 Elsevier Inc. All rights reserved.

    Download full text (pdf)
    Manuscript before referee
  • 13.
    Edsjö, Anders
    et al.
    Region Skåne, Malmö; Lunds universitet, Lund.
    Palmqvist, Richard
    Region Västerbotten, Umeå; Umeå universitet, Umeå.
    Haglund, Felix
    Karolinska universitetssjukhuset, Stockholm; Karolinska institutet, Stockholm.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Universitetssjukhuset Örebro, Region Örebro län, Örebro.
    Lindqvist, Oscar
    Universitetssjukhuset i Linköping, Linköping.
    Fagman, Henrik
    Sahlgrenska universitetssjukhuset, Göteborg; Göteborgs universitet, Göteborg.
    Botling, Johan
    Akademiska sjukhuset, Uppsala; Uppsala universitet, Uppsala.
    Molekylär patologi: nyckeln till målinriktad cancerbehandling [Molecular pathology - the key to precision oncology]2021In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 118, article id 20209Article in journal (Refereed)
    Abstract [sv]

    Rapidly expanding knowledge of the molecular landscape of cancers has resulted in the implementation of an increasing number of specific therapies targeted at tumors with specific molecular aberrations. In response to this development, new tools for predictive testing for molecular targets need to be implemented in routine health care. To achieve robust future molecular diagnostic pathology, and equal opportunity for patients to qualify for targeted therapy, the national working group for Solid Tumors in the initiative Genomic Medicine Sweden (GMS) aims to implement regional and national platforms for comprehensive genomic tumor profiling and linked analysis pipelines. Novel IT-infrastrucutures and recruitment of bioinformaticians and molecular biologists to hospital labotatories are paramount. The infrastructure will allow wider inclusion into clinical trials and supplement the national cancer registries with molecular »real world data« for research and evaluation of implemented cancer therapies and diagnostic procedures.

  • 14.
    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, E-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.

  • 15.
    Fioretos, Thoas
    et al.
    Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden; fioretDepartment of Clinical Genetics, Pathology and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden; Clinical Genomics Lund, Science for Life Laboratory, Lund University, Lund, Sweden.
    Wirta, Valtteri
    Department of Microbiology, Tumor and Cell Biology, Clinical Genomics Stockholm, Science Life Laboratory, Karolinska Institutet, Solna, Sweden; Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden; School of Engineering Sciences in Chemistry, Biotechnology and Health, Clinical Genomics Stockholm, Science Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
    Cavelier, Lucia
    Department of Immunology, Genetics and Pathology, Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics, Karolinska University Hospital, Solna, Sweden.
    Berglund, Eva
    Department of Immunology, Genetics and Pathology, Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Friedman, Mikaela
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Akhras, Michael
    Department of Microbiology, Tumor and Cell Biology, Clinical Genomics Stockholm, Science Life Laboratory, Karolinska Institutet, Solna, Sweden.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Ehrencrona, Hans
    Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden; Department of Clinical Genetics, Pathology and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden.
    Engstrand, Lars
    Department of Microbiology, Tumor and Cell Biology, Centre for Translational Microbiome Research, Karolinska Institutet, Solna, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Fagerqvist, Therese
    Innovation Partnership Office, Uppsala University, Uppsala, Sweden.
    Gisselsson, David
    Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. 11 Department of Clinical Genetics, Pathology and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden.
    Gruvberger-Saal, Sofia
    Department of Clinical Genetics, Pathology and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden.
    Gyllensten, Ulf
    Department of Immunology, Genetics and Pathology, Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Heidenblad, Markus
    Clinical Genomics Lund, Science for Life Laboratory, Lund University, Lund, Sweden.
    Höglund, Kina
    Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Jacobsson, Bo
    Department of Obstetrics and Gynecology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Johansson, Maria
    Lund University Collaboration Office, Lund University, Lund, Sweden.
    Johansson, Åsa
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Soller, Maria Johansson
    Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics, Karolinska University Hospital, Solna, Sweden .
    Landström, Maréne
    Department of Medical Biosciences, Umeå University, Umeå, Sweden.
    Larsson, Pär
    Department of Medical Biosciences, Umeå University, Umeå, Sweden; Clinical Genomics Umeå, Science for Life Laboratory, Umeå University, Umeå, Sweden.
    Levin, Lars-Åke
    Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Lindstrand, Anna
    Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics, Karolinska University Hospital, Solna, Sweden .
    Lovmar, Lovisa
    Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lyander, Anna
    Department of Microbiology, Tumor and Cell Biology, Clinical Genomics Stockholm, Science Life Laboratory, Karolinska Institutet, Solna, Sweden; School of Engineering Sciences in Chemistry, Biotechnology and Health, Clinical Genomics Stockholm, Science Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden .
    Melin, Malin
    Department of Immunology, Genetics and Pathology, Clinical Genomics Uppsala, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Nordgren, Ann
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics, Karolinska University Hospital, Solna, Sweden; Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden; Institute of Biomedicine, Department of Laboratory Medicine, University of Gothenburg, Gothenburg, Sweden .
    Nordmark, Gunnel
    Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala, Sweden.
    Mölling, Paula
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Clinical Pathology and Genetics.
    Palmqvist, Lars
    Institute of Biomedicine, Department of Laboratory Medicine, University of Gothenburg, Gothenburg, Sweden; Clinical Genomics Gothenburg, Science for Life Laboratory, University of Gothenburg, Gothenburg, Sweden; Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden .
    Palmqvist, Richard
    Department of Medical Biosciences, Umeå University, Umeå, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Sikora, Per
    Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden; Clinical Genomics Gothenburg, Science for Life Laboratory, University of Gothenburg, Gothenburg, Sweden; Bioinformatics Data Center, Core Facilities, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden .
    Stenmark, Bianca
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Clinical Pathology and Genetics.
    Söderkvist, Peter
    Division of Medical Genetics, Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Clinical Genomics Linköping, Linköping University, Linköping, Sweden.
    Stranneheim, Henrik
    Department of Microbiology, Tumor and Cell Biology, Clinical Genomics Stockholm, Science Life Laboratory, Karolinska Institutet, Solna, Sweden; Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden .
    Strid, Tobias
    Clinical Genomics Linköping, Linköping University, Linköping, Sweden; Department of Clinical Pathology, Biological and Clinical Sciences, Linköping University, Linköping, Sweden.
    Wheelock, Craig E.
    Unit of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden.
    Wadelius, Mia
    Department of Medical Sciences, Clinical Pharmacogenomics, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Wedell, Anna
    Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden .
    Edsjö, Anders
    Department of Clinical Genetics, Pathology and Molecular Diagnostics, Office for Medical Services, Region Skåne, Lund, Sweden; Division of Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
    Rosenquist, Richard
    Genomic Medicine Center Karolinska, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Clinical Genetics, Karolinska University Hospital, Solna, Sweden.
    Implementing precision medicine in a regionally organized healthcare system in Sweden2022In: Nature Medicine, ISSN 1078-8956, E-ISSN 1546-170X, Vol. 28, no 10, p. 1980-1982Article in journal (Refereed)
  • 16.
    Gunaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Nyhlin, Nils
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Medicine, Div. of Gastroenterol., Örebro University Hospital, Örebro, Sweden.
    Bohr, Johan
    Department of Medicine, Div of Gastroenterol, Örebro Univ Hosp, Örebro, Sweden; Fac of Med and Hlth, Örebro Univ, Örebro, Sweden.
    Hultgren, Olof
    Örebro University, School of Medical Sciences. Department of Microbiology and Immunology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Hultgren Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences. Nutrition-Gut-Brain Interactions Research Centre, Örebro University, Örebro, Sweden.
    Oligoclonal T-cell Receptor Repertoire in Colonic Biopsies of Patients with Microscopic Colitis and Ulcerative Colitis2017In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 23, no 6, p. 932-945Article in journal (Refereed)
    Abstract [en]

    Background: Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a type of variation of inflammatory bowel diseases. Local T-cell infiltration in the mucosa plays a major role in MC immunopathology.

    Methods: To understand diversity and clonality of infiltrating T cells, we analyzed the T-cell receptor beta (TCR beta) chains in colonic biopsies of MC, ulcerative colitis (UC), and their remission counterparts (CC/LC-HR [histological remission] or UC-R [remission]) compared with patients with non-inflamed colons using next-generation sequencing.

    Results: Compared with controls and patients with CC, patients with LC had significantly lower diversity with significantly lower evenness and richness in TCRVb-Jb gene segments. Similarly, patients with LC-HR had lower diversity because of significantly lower TCRVb-Jb clone richness. Patients with UC and UC-R showed significantly higher diversity and richness. Univariate and multivariate analyses were performed to identify TCRVb-Jb gene segments differentiating disease types from controls or their remission counterparts. Patients with LC were discriminated from controls by 12 clones and from patients with CC by 8 clones. Neither univariate nor multivariate analyses showed significance for patients with CC or CC-HR compared with controls. Patients with UC and UC-R had 16 and 14 discriminating clones, respectively, compared with controls.

    Conclusions: Altogether, patients with MC and UC showed an oligoclonal TCRb distribution. TCRVb-Jb clone types and their diversity were distinctive between patients with CC and LC, as well as for patients with UC, suggesting different pathophysiological mechanisms according to disease type and stage. This study suggests that CC and LC are different entities because of differences in immunoregulatory responses, as mirrored by their T-cell repertoire.

  • 17.
    Günaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    Nyhlin, Nils
    Örebro University, School of Medical Sciences.
    Bohr, Johan
    Örebro University, School of Health Sciences.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patientsManuscript (preprint) (Other academic)
  • 18.
    Helenius, Gisela
    et al.
    Örebro University, School of Medical Sciences.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences.
    Bergengren, Lovisa
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Women's Health.
    Molecular triage of cervical screening samples in women 55-59 years of age: a pilot study2023In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 18, no 1, article id 31Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: With HPV screening the specificity of screening positives has decreased, even with a cytological triage test. Increases in colposcopies and detection of benign or low-grade dysplasia are reported, not least in older women. These results highlight the necessity to find other triage tests in HPV screening strategies, so that women can be more accurately selected for colposcopy, thus minimizing the clinically irrelevant findings.

    METHODS: The study included 55- to 59-year-old women who exited the screening with normal cytology, but later in a follow-up test were positive for the HPV genotypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68 and had a cervical cone biopsy done. To model a screening situation with hrHPV-positive women, three different triage strategies, namely, cytology, genotyping and methylation, were performed. The study considered the effect of direct referral to colposcopy for HPV genotypes 16, 18, 31, 33, 45, 52 and 58, and methylation for FAM19A4 and hsa-mir124-2 and/or any form of abnormal cytology.

    RESULTS: Seven out of 49 women aged 55-59 years with hrHPV had a cone biopsy with high-grade squamous intraepithelial lesion. No triage method found all cases, and when comparing positive and negative predictive value and false negative rate, cytology showed better results than genotyping and methylation.

    CONCLUSION: This study does not support a switch in triage strategies from cytology to hrHPV genotyping and methylation for women above 55 years of age yet, but demonstrates the need for more evidence on molecular triage strategies.

  • 19.
    Helenius, Gisela
    et al.
    Örebro University, School of Medical Sciences.
    Lillsunde-Larsson, Gabriella
    Bergengren, Lovisa
    Örebro University, School of Health Sciences.
    Kaliff, Malin
    Örebro University, School of Medical Sciences.
    Karlsson, Mats
    Örebro University, School of Medical Sciences.
    Preliminary data from a Swedish self-sampling study in postmenopausal women2019Conference paper (Other academic)
    Abstract [en]

    Background: An updated screening algorithm was introduced in Sweden 2015. Primary HPV test for women >30 years old and a prolonged screening with the last test after 64 years of age were some of the changes. In the region of Örebro County, the previous cut-off age was 60 years and with a screening interval of 5 years, women left their last sample when they were 55-59 years old. In the shift between two screening programs, a group of women, 60-64 years old, that left the program 5-10 years ago were now included in the new screening. For re-inclusion, a two year long program was formed to catch-up this group of women and screen them according to the new screening algorithm. At the same time a research project investigating self-sampling was launched. At the same time as the women were invited for a last screening sample they were also asked to participate in a study where they should take a vaginal self-test up to one week after their ordinary screening sample was taken by a midwife.

    Method: Postmenopausal women between 64-70 years was included in the study. HPV status in samples from midwife sampling (MS) was compared to self-sampling (SS) samples. HPV was analyzed using HPV Aptima and all HPV positive samples, independent of sampling method, was triaged with cytology and followed-up according to national guidelines.

    Results: So far, 585 women with paired samples have been included in the study. In the MS, 4% of the women are positive for hrHPV compared to 11% in the SS group. In 486/585 women, the results of the two samples are concordant. Among the non-concordant samples (13%), 62% were positive in SS and negative in MS. The opposite, negative in SS and positive in MS were seen in 4% of the samples. Among the MS negative samples, 32% were invalid in SS. Cytology was used as a triage test for HPV positive women, both for MS and SS. Of 23 hrHPV positive, 18 had normal cytology, 2 ASCUS, 1 LSIL and 1 HSIL. In the samples with abnormal cytology, 4/5 were hrHPV positive in both SS and MS. One sample was positive in SS but negative in MS.

    Discussion: In this age group, more women are hrHPV positive in SS compared to MS. This is in line with what other have seen. Among the very few hrHPV positive samples with abnormal cytology, the majority was hrHPV positive in both MS and SS. But since cytology is a poor triage marker in this age group clinical follow-up is needed before the effectiveness of the both sampling methods can be concluded.

  • 20.
    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)
  • 21.
    Jans, Lina
    et al.
    Department of Women’s Health, Faculty of Medicine and Health, Örebro University, Örebro, Sweden .
    Zetterström, Karin
    Örebro University, School of Medical Sciences. Department of Women’s Health.
    Bergengren, Lovisa
    Örebro University, School of Health Sciences. Örebro University, School of Medical Sciences. Department of Women’s Health.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    The value of adding a single co-test in HPV primary screening2021In: Preventive Medicine, ISSN 0091-7435, E-ISSN 1096-0260, Vol. 149, article id 106617Article in journal (Refereed)
    Abstract [en]

    The screening program for cervical cancer in Sweden, recommends screening with HPV test primarily for women over 30 years, but at the first screening test that is performed after the age of 40, both HPV test and cytology is recommended, so-called co-testing. The aim of this study was to examine how many cases of HPV negative cervical dysplasia that were found in this age-group, to be able to estimate the value of adding a co-test in an HPV screening program. A retrospective study of all abnormal cytological samples found in the cytology based screening program in the age group 41-45 years during the years 2012-2016 in the Region of center dot Orebro County was performed. Out of the 10,511 women included in the study, 468 had an abnormal cytology screening test and 255/468 were HPV negative. The vast majority of the HPV negative cases had a normal cytology test as first follow-up. Of cases with remaining cytological abnormality, only four cases had histologically confirmed highgrade cervical dysplasia (CIN2) and no cases of HPV negative adenocarcinoma in situ or invasive cancer were found. Conclusion: With adding a single co-test to a HPV-based screening program, only a few extra cases of highgrade cervical dysplasia were found and the clinical significance of these cases is unclear.

  • 22.
    Kaliff, Malin
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Bergengren, Lovisa
    Örebro University, School of Health Sciences. Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Women’s Health.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Medical Sciences. Örebro University, School of Health Sciences. Department of Laboratory Medicine.
    DNA methylation analysis in HPV-positive screening samples from women 30-69 years in the cervical cancer-screening program in Örebro, Sweden: a pilot study2019In: EUROGIN 2019 ABSTRACTS: POSTERS, 2019Conference paper (Refereed)
  • 23.
    Kaliff, Malin
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Bohr Mordhorst, Louise
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department of Laboratory Medicine.
    Droplet Digital PCR for type-specific detection and quantification of nine different HPV genotypes in cervical carcinomasManuscript (preprint) (Other academic)
  • 24.
    Kaliff, Malin
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Ekman, Maria
    Department of Research and Development, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Ottestig, Elin
    School of Health Sciences, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Bergengren, Lovisa
    Örebro University, School of Medical Sciences. Department of Women's Health.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Research and Development.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department of Laboratory Medicine.
    Full genotyping and FAM19A4/miR124-2 methylation analysis in high-risk HPV-positive samples from women over 30 years participating in cervical cancer screening in Örebro, SwedenManuscript (preprint) (Other academic)
  • 25.
    Kaliff, Malin
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Karlsson, Mats
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Sorbe, Bengt
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Bohr Mordhorst, Louise
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department of Laboratory Medicine.
    HPV-negative Tumors in a Swedish Cohort of Cervical Cancer2020In: International Journal of Gynecological Pathology, ISSN 0277-1691, E-ISSN 1538-7151, Vol. 39, no 3, p. 279-288Article in journal (Refereed)
    Abstract [en]

    Despite the common perception that the human papilloma virus (HPV) is a requirement for the development of cervical cancer (CC), a considerable number of CCs test HPV negative. Presently, many countries are shifting to HPV primary CC screening, and it is of importance to increase the knowledge about the group of CCs that test HPV negative. The aim of this study was to reinvestigate a proportion of cervical tumors with a primary negative or invalid test result. Reinvestigation with repeated genotyping (targeting L1) was followed by analysis with an alternative target method (targeting E6/E7) on existing or additional tumor material. Consistently negative tumors were histologically evaluated, and cases with low or lacking tumor cell content, consistent invalid test results, or with suspicion of other than cervical origin were excluded. HPV-negative cases were thereafter subjected to immunohistochemistry (Cytokeratin 5, pan cytokeratin, protein 63, P16, and P53). The HPV-negative proportion could after reinvestigation be reduced by one-half (14%-7%). Additional positive samples were often detected in late polymerase chain reaction cycles, with an alternative (E6/E7) or the same (L1) target, or with a method using shorter amplicon lengths. Confirmed HPV negativity was significantly associated with worse prognosis, high patient age, longer storage time, and adenocarcinoma histology. Some of the HPV-negative cases showed strong/diffuse p16 immunoreactivity, indicating some remaining false-negative cases. False HPV negativity in this cohort was mainly linked to methodological limitations in the analysis of stored CC material. The small proportion of presumably true HPV-negative adenocarcinomas is not a reason for hesitation in revision to CC screening with primary HPV testing.

  • 26.
    Kaliff, Malin
    et al.
    Department of Laboratory Medicine, Örebro University, Örebro, Sweden.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department of Laboratory Medicine.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department of Research and Development.
    Bergengren, Lovisa
    Örebro University, School of Medical Sciences. Department of Women's Health.
    Full genotyping and FAM19A4/miR124-2 methylation analysis in high-risk human papillomavirus-positive samples from women over 30 years participating in cervical cancer screening in Örebro, Sweden2022In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 9, article id e0274825Article in journal (Refereed)
    Abstract [en]

    Currently, cervical cancer prevention is undergoing comprehensive development regarding human papillomavirus (HPV) vaccination and cervical cancer screening. In Sweden and many other countries, high coverage vaccinated cohorts are entering screening within the next few years. This entails demands for baseline HPV genotype data across the screening age range for surveillance and a basis for screening program adjustment. In 2016, Örebro County, Sweden, changed to primary HPV screening using HPV mRNA testing followed by cytology triage. An alternative triage method to cytology could allow for a fully molecular screening algorithm and be implemented in a screening program where self-sampling is included. Hypermethylation analysis of the human genes FAM19A4/miR124-2 has been suggested as a promising triage method. HPV mRNA-positive screening samples (n = 529) were included and subjected to genotyping targeting a broad range of both low-risk and high-risk genotypes in addition to hypermethylation analysis of the two human genes FAM19A4/miR124-2. Data were connected to cytological and histological status and age. The most commonly detected genotypes were HPV31, 16, and 52. In addition, HPV18 was one of the most common genotypes in high-grade squamous intraepithelial lesions (HSILs) samples. In relation to available vaccines, 26% of the women with histological HSIL or cancer (≥HSIL) tested positive for only hrHPV included in the quadrivalent vaccine and 77% of the genotypes in the nonavalent vaccine. According to these figures, a relatively large proportion of the HSILs will probably remain, even after age cohorts vaccinated with the quadrivalent vaccine enter the screening program. Hypermethylation positivity was associated with increasing age, but no HPV-related independently predictive factors were found. Accordingly, age needs to be considered in development of future screening algorithms including triage with hypermethylation methodology.

  • 27.
    Kaliff, Malin
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Louise, Bohr Mordhorst
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Optimization of droplet digital PCR assays for the type specific detection and quantification of five HPV genotypes, also including additional data on viral load of nine different HPV genotypes in cervical carcinomas2021In: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 294, article id 114193Article in journal (Refereed)
    Abstract [en]

    The droplet digital PCR (ddPCR) system enables high-sensitivity detection of nucleic acids and direct absolute quantification of the targets. The aim of this research was to evaluate this system for viral load (VL) analysis of the human papillomavirus (HPV) genotypes HPV31, 35, 39, 51 and 56 measured in number of viral particles per cell. The sample types used for the optimization of the ddPCR assay were formalin-fixed paraffin-embedded (FFPE) tissues and cervical liquid cytology samples. The presently optimized ddPCR assays, together with assays optimized previously for HPV16, 18, 33 and 45, with the same ddPCR method, were used for the VL analysis of cervical tumor samples. Results published previously on the present study cohort showed that women with a cervical tumor containing multiple high-risk HPV genotypes had a worse prognosis compared to women with single-genotype-infected tumors. The VL was therefore analyzed in this study for the same cohort, as a possible explanatory factor to the prognostic differences. The results of the optimization part of the study, with analysis of VL using ddPCR in DNA from varying sample types (FFPE and liquid cytology samples), showed that each of the five assays demonstrated good inter- and intra-assay means with a coefficient of variation (CV) under 8% and 6% respectably. The cohort results showed no difference in VL between tumors with multiple and single HPV infections, and therefore did most likely not constitute a contributing factor for prognostic differences observed previously. However, tumors from women aged 60 years or older or containing certain HPV genotypes and genotype genera were associated with a higher VL.

  • 28.
    Kaliff, Malin
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Sorbe, Bengt
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Mordhorst, Louise Bohr
    Department of Oncology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Lillsunde-Larsson, Gabriella
    Örebro University, School of Health Sciences. Department of Laboratory Medicine.
    Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy2018In: Oncotarget, E-ISSN 1949-2553, Vol. 9, no 27, p. 18786-18796Article in journal (Refereed)
    Abstract [en]

    Cervical cancer (CC) is one of the most common cancers in women and virtually all cases of CC are a result of a persistent infection of human papillomavirus (HPV). For disease detected in early stages there is curing treatment but when diagnosed late with recurring disease and metastasis there are limited possibilities. Here we evaluate HPV impact on treatment resistance and metastatic disease progression. Prevalence and distribution of HPV genotypes and HPV16 variants in a Swedish CC patient cohort (n=209) was evaluated, as well as HPV influence on patient prognosis. Tumor samples suitable for analysis (n=204) were genotyped using two different real-time PCR methods. HPV16 variant analysis was made using pyrosequencing. Results showed that HPV prevalence in the total series was 93%. Of the HPV-positive samples, 13% contained multiple infections, typically with two high-risk HPV together. Primary cure rate for the complete series was 95%. Recurrence rate of the complete series was 28% and distant recurrences were most frequent (20%). Patients with tumors containing multiple HPV-strains and particularly HPV genotypes belonging to the alpha 7 and 9 species together had a significantly higher rate of distant tumor recurrences and worse cancer-specific survival rate.

  • 29.
    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.

  • 30.
    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.

  • 31.
    Koskela, Anita
    et al.
    University Hospital Örebro, Örebro, Sweden.
    Qvick, Alvida
    University Hospital Örebro, Örebro, Sweden.
    Jakobsen, Ingrid
    University Hospital Örebro, Örebro, Sweden.
    Lindqvist, Carl Mårten
    University Hospital Örebro, Örebro, Sweden.
    Farkas, Sanja A.
    Örebro University Hospital.
    Green, Anna
    Örebro University Hospital.
    Isaksson, Helena S.
    Örebro University Hospital.
    Holmgren, Benjamin
    Halland Hospital, Halmstad, Sweden.
    Levéen, Per
    Region Skåne and Lund University, Lund, Sweden.
    Thankaswamy, Subazini
    University Hospital Örebro, Örebro, Sweden.
    Fredriksson, Johan
    Örebro University, Örebro Sweden.
    Andersson, Lina
    University Hospital Örebro, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    Evaluation of Microsatellite instability score from GMS560 DNA panel2022Conference paper (Other academic)
    Abstract [en]

    Microsatellite instability is characterised by gains or losses of nucleotides in short tandem repeat sequences, microsatellites, dispersed throughout the human genome. Microsatellite instability status is a molecular fingerprint for DNA mismatch repair deficiency. Clinical detection of microsatellite instability status is important for identifying inherited disease in patients with colorectal and endometrial cancer but has also a prognostic value for survival and prediction of treatment response. Lately, microsatellite instability has been used as a tumor agnostic biomarker that predicts response to immune checkpoint inhibitors. To identify microsatellite instability status clinically, PCR and immunohistochemistry have been the gold standard. On the contrary, next generation sequencing provide simultaneous accession of large number of microsatellite loci and can be combined with detection of several other biomarkers. 

    The national collaboration Genome Medicine Sweden have developed a solid tumour gene panel composed of 560 cancer associated genes with integrated microsatellite instability score. Our aim was to validate the microsatellite instability status based on microsatellite instability score from GMS560 DNA panel against the clinically used methods. Extracted DNA (100 ng) from formalin fixed paraffin embedded tissue sections with various tumour cell content >10% were analysed. During target enrichment sequencing analysis, allelic distribution from 5000 microsatellite markers were calculated by MSIsensor Pro to generate an instability score. 

    The cohort consisted of microsatellite instable verified colorectal cancer samples (n=20), microsatellite stable solid tumour material (n=60). Preliminary results generated a microsatellite instability score for the colorectal cancer samples with a mean of 26.5 % (CI: 23.4-29.6, range: 16.9-32.3). Microsatellite stable tumour samples had a mean microsatellite instability score of 1.5 % (CI: 0.93-2.07, range: 1-4.45). 

    In conclusion, we found the microsatellite instability score from GMS560 DNA panel to be both diagnostically sensitive and specific for determining MSI status due to obvious separation in instability. 

    Download full text (pdf)
    Poster
  • 32.
    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)
  • 33.
    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, 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.

  • 34.
    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.

  • 35.
    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.

  • 36.
    Lillsunde Larsson, Gabriella
    et al.
    Örebro University, School of Health Sciences. Department of Laboratory Medicine.
    Kaliff, Malin
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Sorbe, Bengt
    Örebro University, School of Health Sciences. Department of Oncology.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    HPV16 viral characteristics in primary, recurrent and metastatic vulvar carcinoma2018In: Papillomavirus research, ISSN 2405-8521, Vol. 6, p. 63-69Article in journal (Refereed)
    Abstract [en]

    Vulvar carcinoma is the fourth most common gynecological malignancy. Two separate carcinogenic pathways are suggested, where one is associated with the human papillomavirus (HPV) and HPV16 the most common genotype.

    The aim of this study was to evaluate HPV-markers in a set of primary tumors, metastases and recurrent lesions of vulvar squamous cell carcinomas (VSCC). Ten HPV16-positive VSCC with metastatic regional lymph nodes, distant lymphoid/hematogenous metastases or local recurrent lesions were investigated for HPV genotype, HPV16 variant, HPV16 viral load, HPV16 integration and HPV16 E2BS3 and 4 methylation.

    In all 10 analyzed case series, the same HPV genotype (HPV16), HPV16 variant and level of viral load were detected in all lesions within a patient case. Primary tumors with a high E2/E6 ratio were found to have fewer vulvar recurrences and/or metastases after diagnosis and treatment. Also, a significantly lower viral load was evident in regional lymph nodes compared to primary tumors.

    The data presented strengthens the evidence for a clonal HPV-induced pathway for vulvar carcinoma.

  • 37.
    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.

  • 38.
    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)
  • 39.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Digital droplet PCR (ddPCR) for the detection and quantification of HPV 16, 18, 33 and 45: a short report2017In: Cellular Oncology, ISSN 2211-3428, E-ISSN 2211-3436, Vol. 40, no 5, p. 521-527Article in journal (Refereed)
    Abstract [en]

    Human papilloma virus (HPV) infection is associated with several anogenital malignancies. Here, we set out to evaluate digital droplet PCR (ddPCR) as a tool for HPV 16, 18, 33 and 45 viral load quantification and, in addition, to compare the efficacy of the ddPCR assay for HPV 16 detection with that of quantitative real-time PCR (qPCR).

    Clinical samples, positive for HPV genotypes 16, 18, 33 and 45 were analyzed for viral load using ddPCR. Sample DNA was cleaved before droplet generation and PCR. Droplets positive for VIC and FAM fluorescence were read in a QX200 Droplet reader (TM) (BIO-RAD) after which the viral load was calculated using Quantasoft software.

    We found that DNAs extracted from formalin fixed paraffin embedded (FFPE) tissue samples yielded lower amplification signals compared to those obtained from liquid based cytology (LBC) samples, but they were clearly distinguishable from negative background signals. The viral limit of detection was 1.6 copies of HPV 16, 2.8 copies of HPV 18, 4.6 copies of HPV 33 and 1.6 copies of HPV 45. The mean inter-assay coefficients of variability (CV) for the assays ranged from 3.4 to 7.0%, and the mean intra-assay CV from 2.6 to 8.2%. The viral load in the different cohorts of tumor samples ranged from 154 to 340,200 copies for HPV 16, 244 to 31,300 copies for HPV 18 and 738 to 69,100 copies for HPV 33. One sample positive for HPV 45 contained 1331 viral copies. When comparing qPCR data with ddPCR copy number data, the qPCR values were found to be 1 to 31 times higher.

    Separation of fragments in nanodroplets may facilitate the amplification of fragmented human and viral DNA. The method of digital droplet PCR may, thus, provide a new and promising tool for evaluating the HPV viral load in clinical samples.

  • 40.
    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.

  • 41.
    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.

  • 42.
    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, 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.

  • 43.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health Sciences. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Kaliff, Malin
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Hansen, Marit
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Comparison of mRNA and DNA HPV levels in HRHPV-positive primary screening samples using digital droplet PCR2017Conference paper (Refereed)
  • 44.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Medical Sciences. Örebro University, School of Health Sciences.
    Kaliff, Malin
    Örebro University, School of Medical Sciences.
    Ottestig, Elin
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    HPV genotyping of HPV primary screening positive samples in Örebro, Sweden2019Conference paper (Refereed)
  • 45.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health Sciences.
    Kaliff, Malin
    Örebro University, School of Medical Sciences.
    Ottestig, Elin
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    HPV genotyping of HPV primary screening positive samples in Örebro, Sweden2018Conference paper (Other academic)
  • 46.
    Lillsunde-Larsson, Gabriella
    et al.
    Örebro University, School of Health Sciences. Dep. of Laboratory Medicine.
    Kaliff, Malin
    Örebro University, School of Medical Sciences. Dep. of Laboratory Medicine.
    Sorbe, Bengt
    2Faculty of Medicine and Health- Örebro University, Dep. Of Oncology, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Dep. of Laboratory Medicine.
    Karlsson, Mats
    Örebro University, School of Medical Sciences. Dep. of Laboratory Medicine.
    HPV16 VIRAL CHARACTERISTICS IN PRIMARY AND RECURRENT VULVAR CARCINOMA2018Conference paper (Other academic)
  • 47.
    Mattsson, Johanna S. M.
    et al.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Bergman, Bengt
    Department of Respiratory Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Grinberg, Marianna
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Edlund, Karolina
    Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Dortmund, Germany.
    Marincevic, Millaray
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Jirström, Karin
    Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
    Pontén, Fredrik
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Hengstler, Jan G.
    Leibniz Research Centre for Working Environment and Human Factors (IfADo), TU Dortmund University, Dortmund, Germany.
    Rahnenführer, Joerg
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Christina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro University, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Gulyas, Miklos
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Prognostic impact of COX-2 in non-small cell lung cancer: a comprehensive compartment-specific evaluation of tumor and stromal cell expression2015In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 356, no 2, p. 837-845Article in journal (Refereed)
    Abstract [en]

    Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n = 1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n = 616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

  • 48.
    Mattsson, Johanna S. M.
    et al.
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Brunnström, Hans
    Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden; Department of Pathology, Regional Laboratories Region Skåne, Lund, Sweden.
    Jabs, Verena
    Department of Statistics, TU Dortmund University, Dortmund, Germany.
    Edlund, Karolina
    Leibniz Research Centre for Working Environment and Human Factors (IfADo) at Dortmund TU, Dortmund, Germany.
    Jirström, Karin
    Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden.
    Mindus, Stephanie
    Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden.
    la Fleur, Linnéa
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Pontén, Fredrik
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Research and Education.
    Karlsson, Christina
    Örebro University, School of Health Sciences.
    Koyi, Hirsh
    Department of Respiratory Medicine, Gävle hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University, Uppsala, Sweden; County Council of Gävleborg, Gävle, Sweden.
    Brandén, Eva
    Department of Respiratory Medicine, Gävle hospital, Gävle, Sweden; Centre for Research and Development, Uppsala University/County Council of Gävleborg, Gävle, Sweden.
    Botling, Johan
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Helenius, Gisela
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Micke, Patrick
    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Svensson, Maria A
    Clinical Research Center, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer2016In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, no 1, article id 603Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 49.
    Mattsson, Johanna S. M.
    et al.
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Svensson, Maria A.
    Institutionen för hälsovetenskap och medicin, Department of Pathology, Örebro universitet, Örebro, Sweden.
    Hallström, Bjorn
    Sci Life Lab, KTH Royal Inst Technol, Stockholm, Sweden.
    Koyi, Hirsh
    Dept Resp Med, Gävle Cent Hosp, Gävle, Sweden.
    Branden, Eva
    Dept Resp Med, Gävle Cent Hosp, Gävle, Sweden.
    Brunnström, Hans
    Dept Clin Sci Lund, Div Oncol & Pathol, Lund Univ, Lund, Sweden.
    Edlund, Karolina
    Leibniz Res Ctr Working Environm & Human Factors, Dortmund TU, Dortmund, Germany.
    Ekman, Simon
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    La Fleur, Linnea
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Grinberg, Marianna
    Dept Stat, Dortmund TU, Dortmund, Germany.
    Rahnenfuehrer, Joerg
    Dept Stat, Dortmund TU, Dortmund, Germany.
    Jirström, Karin
    Dept Clin Sci Lund, Div Oncol & Pathol, Lund Univ, Lund, Sweden.
    Ponten, Fredrik
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Christina
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Uhlen, Mathias
    Sci Life Lab, KTH Royal Inst Technol, Stockholm, Sweden.
    Botling, Johan
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    Micke, Patrick
    Dept Immunol Genet & Pathol, Uppsala Univ, Uppsala, Sweden.
    ALK Rearrangements in Non-Small Cell Lung Cancer: Comprehensive Integration of Genomic, Gene Expression and Protein Analysis2015In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, no 9, p. S298-S298Article in journal (Other academic)
  • 50.
    Nyberg, Jan
    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.
    Dahlin, Christer
    Sahlgrenska Academy University of Gothenburg; NU-hospital organization, Trollhättan, Sweden.
    Johansson, Carina B.
    Sahlgrenska Academy University of Gothenburg.
    Omar, Omar
    Sahlgrenska Academy University of Gothenburg.
    Effect of radiotherapy on osseointegration: in vivo gene expression and implant stability after single high-dose irradiationManuscript (preprint) (Other academic)
12 1 - 50 of 60
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