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  • 1.
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Identification of miRNA expression profiles for diagnosis and prognosis of prostate cancer2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cancer of the prostate (CaP) is the most common malignancy diagnosed in men in the Western society. During the last years, prostate specific antigen (PSA) has been used as a biomarker for CaP, although a high PSA value is not specific for CaP. Thus, there is an urgent need for new and improved diagnostic markers for CaP.

    In this thesis, the aim was to find a miRNA signature for diagnosis of CaP and to elucidate if differences in behavior between transition zone and peripheral zone tumors are reflected in miRNA expression. One of the major findings is anexpression signature based on nine miRNAs that with high accuracy (85%) could classify normal and malignant tissues from the transition zone of the prostate. The results furthermore show that the major differences in miRNA expression are found between normal and malignant tissues, rather than between the different zones. In addition, tumors arising in the peripheral zone have fewer changes in miRNA expression compared to tumors in the transition zone, indicating that the peripheral zone is more prone to tumor development compared to the transition zone of the prostate.

    A crucial step in pre-processing of expression data, in order to differentiate true biological changes, is the normalization step. Therefore, an additional aim of this thesis was to compare different normalization methods for qPCR array data in miRNA expression experiments. The results show that data-driven methods based on quantile normalization performs the best. The results also show that in smaller miRNA expression studies, only investigating a few miRNAs, RNU24 is the most suitable endogenous control gene for normalization.

    Taken together, the results in this thesis show the importance of miRNAs and the possibility of their future use as biomarkers in the field of prostate cancer.

    List of papers
    1. Validation of suitable endogenous control genes for expression studies of miRNA in prostate cancer tissues
    Open this publication in new window or tab >>Validation of suitable endogenous control genes for expression studies of miRNA in prostate cancer tissues
    Show others...
    2010 (English)In: Cancer Genetics and Cytogenetics, ISSN 2210-7762, E-ISSN 2210-7770, Vol. 202, no 2, p. 71-75Article in journal (Refereed) Published
    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.

    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-12861 (URN)10.1016/j.cancergencyto.2010.06.009 (DOI)000282862400001 ()
    Available from: 2012-09-17 Created: 2011-01-03 Last updated: 2019-03-26Bibliographically approved
    2. How to choose a normalization strategy for miRNA quantitative real-time (QPCR) arrays
    Open this publication in new window or tab >>How to choose a normalization strategy for miRNA quantitative real-time (QPCR) arrays
    2011 (English)In: Journal of Bioinformatics and Computational Biology, ISSN 0219-7200, E-ISSN 1757-6334, Vol. 9, no 6, p. 795-812Article in journal (Refereed) Published
    Abstract [en]

    Low-density arrays for quantitative real-time PCR (qPCR) are increasingly being used as an experimental technique for miRNA expression profiling. As with gene expression profiling using microarrays, data from such experiments needs effective analysis methods to produce reliable and high-quality results. In the pre-processing of the data, one cruciala nalysis step is normalization, which aims to reduce measurement errors and technical variability among arrays that might have arisen during the execution of the experiments. However, there are currently a number of different approaches to choose among and an unsuitable applied method may induce misleading effects, which could affect the subsequent analysis steps and thereby any conclusions drawn from the results. The hoice of normalization method is hence an important issue to consider. In this study we present the comparison of a number of data-driven normalization methods for TaqManlow-density arrays for qPCR and different descriptive statistical techniques that can facilitate the choice of normalization method. The performance of the normalization methods was assessed and compared against each other as well as against standard normalization using endogenous controls. The results clearly show that the data-driven methods reduce variation and represent robust alternatives to using endogenous controls.

    National Category
    Medical and Health Sciences Natural Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-25827 (URN)10.1142/S0219720011005793 (DOI)000297096300009 ()
    Available from: 2012-09-17 Created: 2012-09-13 Last updated: 2018-05-04Bibliographically approved
    3. A miRNA expression signature that separates between normal and malignant prostate tissues
    Open this publication in new window or tab >>A miRNA expression signature that separates between normal and malignant prostate tissues
    Show others...
    2011 (English)In: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, no 11, p. 14-Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    BioMed Central, 2011
    National Category
    Natural Sciences Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-25828 (URN)10.1186/1475-2867-11-14 (DOI)000292110200001 ()21619623 (PubMedID)
    Available from: 2012-09-17 Created: 2012-09-13 Last updated: 2018-05-04Bibliographically approved
    4. Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate
    Open this publication in new window or tab >>Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostate
    Show others...
    (English)Manuscript (preprint) (Other academic)
    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 to the difference in propensity of tumors in the zones of the prostate.

    Methods:

    The expression of 667 unique miRNAs was investigated in normal and malignant transition zone and peripheral zone prostate tissues using TaqMan low density arrays for miRNAs. Student’s t-test was used in order to identify differentially expressed miRNAs and hierarchical clustering and principal component analyses were used to note the separation of the tissues. A cross-validation test using the ADtree algorithm was used to test the generality of the identified miRNA signatures.

    Results:

    The Student’s t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentiallyexpressed miRNAs between normal and malignant tissues showed a perfect separation between samples while analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmedt hese results and several potential miRNA markers were identified.

    Conclusions:

    The results of this study indicate that the major differences in the transcription programme are those arising during tumor development, rather than during normal tissue development. In conclusion, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ, indicating that the PZ are more prone to tumor development than the TZ. The results also indicate that separate miRNA expression signatures for diagnosis might be needed for tumors arising in the transition- or peripheral zone.

    National Category
    Medical and Health Sciences Natural Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-25829 (URN)
    Available from: 2012-09-17 Created: 2012-09-13 Last updated: 2017-10-17Bibliographically approved
  • 2.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    The Potential Role of miR-126 as a Prognostic Biomarker in Renal Cell Carcinoma2018Conference paper (Refereed)
    Abstract [en]

    Renal cell carcinoma (RCC) is the most common renal tumor, consisting of ~3% of all malignancies worldwide. The prognosis of RCC can vary widely, and detecting patients at risk for recurrence at an early stage could improve the outcome for the patient. The factors used in the clinics today cannot reliably predict the natural history of the disease, thus there is a need for finding new biomarkers that can aid in predicting patient outcome. Several studies indicate that miRNAs are potential candidates as prognostic biomarkers for patients suffering from RCC. The aim of this study was to validate the potential of miR-126 to predict prognosis in a Swedish cohort of RCC patients. Methods: The expression of miR-126 was measured using quantitative PCR (qPCR) in formalin-fixed paraffin-embedded (FFPE) tumor tissue from 116 patients diagnosed with RCC between 1987 and 2010. Results: miR-126 was found to be differentially expressed between malignant and adjacent benign tissue. The expression of miR-126 was also differentially expressed between tumor grades, and stages of RCC. We could furthermore show that in a univariate model, a low expression of miR-126 was associated with shorter time to recurrence of the disease. Conclusion: Our results indicate that miR-126 expression has a potential to be used as a prognostic biomarker for patients suffering from RCC. However, further studies are needed in order to confirm these results.

  • 3.
    Carlsson, Jessica
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Christiansen, Jesper
    Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Davidsson, Sabina
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Giunchi, Francesca
    Department of Pathology, F. Addari Institute of Oncology, S. Orsola Hospital, Bologna, Italy.
    Fiorentino, Michelangelo
    Department of Pathology, F. Addari Institute of Oncology, S. Orsola Hospital, Bologna, Italy.
    Sundqvist, Pernilla
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    The potential role of miR-126, miR-21 and miR-10b as prognostic biomarkers in renal cell carcinoma2019In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 17, no 5, p. 4566-4574Article in journal (Refereed)
    Abstract [en]

    Renal cell carcinoma (RCC) is the most commonly diagnosed renal tumor, consisting of ~3% of all malignancies worldwide. The prognosis of RCC can vary widely, and detecting patients at risk of recurrence at an early stage of disease may improve patient outcome. The factors presently used in a clinical setting cannot reliably predict the natural history of the disease. Therefore, there is a requirement to identify novel biomarkers that can aid in predicting patient outcome. Previous studies have indicated that microRNAs (miRNAs/miRs) are potential candidates as prognostic biomarkers for patients suffering from RCC. Consequently, the aims of the present study were to validate the potential of 3 of these miRNAs to predict the prognosis of patients with RCC, and to investigate the stability of endogenous control genes for miRNA studies in RCC tissues. The expression of 7 endogenous controls was measured using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in formalin-fixed paraffin-embedded tumor and benign tissues from patients suffering from clear cell RCC (ccRCC). The analyses identified RNU48 and U47 as the most stable endogenous controls. The expression of miR-126, miR-21 and miR-10b was analyzed using RT-qPCR in renal tissues from 116 patients diagnosed with ccRCC. All three investigated miRNAs were differentially expressed between malignant and benign tissues. miR-126 and miR-10b were also differentially expressed between grades and stages of ccRCC. In a univariate, but not in a multivariate model, low expression of miR-126 was associated with shorter time to recurrence of the disease. The results of the present study indicate that of the 3 miRNAs investigated, the expression of miR-126 has the strongest potential as a prognostic biomarker for patients suffering from ccRCC.

  • 4.
    Carlsson, Jessica
    et al.
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Prostate cancer and inflammation: The role of miRNAs2013In: European Medical Journal Oncology, ISSN 2054-619X, p. 56-60Article, review/survey (Refereed)
    Abstract [en]

    Approximately 15-20% of all human cancers are assumed to be a result of infection and chronic inflammation due to a constant supply of cytokines and reactive oxygen species, giving rise to genomic instability and a subsequent tumour development. In recent years, chronic inflammation has also been hypothesised to influence prostate carcinogenesis, since both acute and chronic inflammation is commonly seen in prostatic tissues. The signalling pathways involved in the immune response and tumour development are overlapping with each other, and it has been proposed that miRNAs are a possible link between the two processes. In this review, we are describing some of the miRNAs which could constitute a conceivable link between inflammation and prostate cancer.

  • 5.
    Carlsson, Jessica
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health, University Hospital, Örebro, Sweden.
    Fridfeldt, Jonna
    Department of Urology, Faculty of Medicine and Health, University Hospital Örebro, Örebro, Sweden; Örebro University, Örebro, Sweden.
    Giunchi, Francesca
    Department of Pathology, F. Addari Institute of Oncology S. Orsola Hospital, Bologna, Italy.
    Fiano, Valentina
    Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin and CPO-Piemonte, Turin, Italy.
    Grasso, Chiara
    Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin and CPO-Piemonte, Turin, Italy.
    Zelic, Renata
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Richiardi, Lorenzo
    Cancer Epidemiology Unit-CERMS, Department of Medical Sciences, University of Turin and CPO-Piemonte, Turin, Italy.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health, University Hospital Örebro, Örebro, Sweden.
    Pettersson, Andreas
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
    Fiorentino, Michelangelo
    Department of Pathology, F. Addari Institute of Oncology S. Orsola Hospital, Bologna, Italy.
    Akre, Olof
    Department of Medicine Solna, Karolinska Institute, and Department of Urology, Karolinska University Hospital, Stockholm, Sweden.
    Quantity and quality of nucleic acids extracted from archival formalin fixed paraffin embedded prostate biopsies2018In: BMC Medical Research Methodology, ISSN 1471-2288, E-ISSN 1471-2288, Vol. 18, no 1, article id 161Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In Sweden, human tissue samples obtained from diagnostic and surgical procedures have for decades been routinely stored in a formalin-fixed, paraffin-embedded, form. Through linkage with nationwide registers, these samples are available for molecular studies to identify biomarkers predicting mortality even in slow-progressing prostate cancer. However, tissue fixation causes modifications of nucleic acids, making it challenging to extract high-quality nucleic acids from formalin fixated tissues.

    METHODS: In this study, the efficiency of five commercial nucleic acid extraction kits was compared on 30 prostate biopsies with normal histology, and the quantity and quality of the products were compared using spectrophotometry and Agilent's BioAnalyzer. Student's t-test's and Bland-Altman analyses were performed in order to investigate differences in nucleic acid quantity and quality between the five kits. The best performing extraction kits were subsequently tested on an additional 84 prostate tumor tissues. A Spearman's correlation test and linear regression analyses were performed in order to investigate the impact of tissue age and amount of tissue on nucleic acid quantity and quality.

    RESULTS: Nucleic acids extracted with RNeasy® FFPE and QIAamp® DNA FFPE Tissue kit had the highest quantity and quality, and was used for extraction from 84 tumor tissues. Nucleic acids were successfully extracted from all biopsies, and the amount of tumor (in millimeter) was found to have the strongest association with quantity and quality of nucleic acids.

    CONCLUSIONS: To conclude, this study shows that the choice of nucleic acid extraction kit affects the quantity and quality of extracted products. Furthermore, we show that extraction of nucleic acids from archival formalin-fixed prostate biopsies is possible, allowing molecular studies to be performed on this valuable sample collection.

  • 6.
    Carlsson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences.
    Davidsson, Sabina
    Örebro University, School of Health and Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Lubovac, Zelmina
    University of Skövde, Skövde, Sweden.
    Andrén, Ove
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Olsson, Björn
    University of Skövde, Skövde, Sweden.
    Klinga-Levan, Karin
    University of Skövde, Skövde, Sweden.
    A miRNA expression signature that separates between normal and malignant prostate tissues2011In: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, no 11, p. 14-Article in journal (Refereed)
    Abstract [en]

    Background

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

    Results

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

    Conclusions

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

  • 7.
    Carlsson, Jessica
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Helenius, Gisela
    Universitetssjukhuset Örebro.
    Karlsson, Mats
    Universitetssjukhuset Örebro.
    Andrén, Ove
    Universitetssjukhuset Örebro.
    Klinga-Levan, Karin
    Högskolan i Skövde.
    Olsson, Björn
    Högskolan i Skövde.
    Differences in microRNA expression during tumor development in the transition and peripheral zones of the prostateManuscript (preprint) (Other academic)
    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 to the difference in propensity of tumors in the zones of the prostate.

    Methods:

    The expression of 667 unique miRNAs was investigated in normal and malignant transition zone and peripheral zone prostate tissues using TaqMan low density arrays for miRNAs. Student’s t-test was used in order to identify differentially expressed miRNAs and hierarchical clustering and principal component analyses were used to note the separation of the tissues. A cross-validation test using the ADtree algorithm was used to test the generality of the identified miRNA signatures.

    Results:

    The Student’s t-tests revealed that the major differences in miRNA expression are found between normal and malignant tissues. Hierarchical clustering and PCA based on differentiallyexpressed miRNAs between normal and malignant tissues showed a perfect separation between samples while analyses based on differentially expressed miRNAs between the two zones showed several misplaced samples. A classification and cross-validation procedure confirmedt hese results and several potential miRNA markers were identified.

    Conclusions:

    The results of this study indicate that the major differences in the transcription programme are those arising during tumor development, rather than during normal tissue development. In conclusion, tumors arising in the TZ have more unique differentially expressed miRNAs compared to the PZ, indicating that the PZ are more prone to tumor development than the TZ. The results also indicate that separate miRNA expression signatures for diagnosis might be needed for tumors arising in the transition- or peripheral zone.

  • 8.
    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.

  • 9.
    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 2210-7762, E-ISSN 2210-7770, 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.

  • 10.
    Carlsson, Jessica
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Sundqvist, Pernilla
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Kosuta, Vezira
    Department of Urology, Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Fält, Anna
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Giunchi, Francesca
    Molecular Pathology Laboratory, Department of Hematology-Oncology, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    Fiorentino, Michelangelo
    Molecular Pathology Laboratory, Department of Hematology-Oncology, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    Davidsson, Sabina
    Department of Urology, Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    PD-L1 Expression is Associated With Poor Prognosis in Renal Cell Carcinoma2019In: Applied immunohistochemistry & molecular morphology (Print), ISSN 1541-2016, E-ISSN 1533-4058Article in journal (Refereed)
    Abstract [en]

    Programmed death ligand 1 (PD-L1) is a protein which, when interacting with its receptor programmed death 1, acts as a negative regulator of the antitumor T-cell-mediated immune response. The prognostic value of PD-L1 expression in renal cell carcinoma (RCC) has been controversial. In this study, the prognostic value of PD-L1 expression in RCC was evaluated by analyzing PD-L1 immunoreactivity in tumor cells and tumor-infiltrating immune cells (TIICs) in 346 RCC patients with long-term follow-up. PD-L1 positivity in tumor cells was associated with higher World Health Organization nucleolar grade (P<0.001), recurrence (P=0.011), and death due to RCC (P=0.031). PD-L1 positivity in TIICs was associated with higher nucleolar grade (P<0.001), higher T-stage (P=0.031), higher N-stage (P=0.01), recurrence (P=0.007), and death due to RCC (P=0.001). A significant positive association of time to cancer-specific death with both PD-L1-positive tumor cells and TIICs were also found. The data indicate that RCC patients with PD-L1-positive tumor cells and TIICs are at significant risk for cancer progression and the expression may be used as a complementary prognostic factor in the management of RCC patients.

  • 11.
    Carlsson, Jessica
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Vikerfors, Anders
    Örebro University, School of Medical Sciences.
    Frey, Janusz
    Jerlström, Tomas
    Örebro University, School of Medical Sciences.
    Davidsson, Sabina
    Is soluble PD-L1 a potential biomarker for urothelial bladder cancer?2019Conference paper (Refereed)
  • 12.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Ohlson, Anna-Lena
    Department of Laboratory Medicine, Pathology, University Hospital Örebro, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Giunchi, Francesca
    Department of Hematology-Oncology, Molecular Pathology Laboratory, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    Rider, Jennifer R.
    Department of Epidemiology, Boston University School of Public Health, Boston MA, USA.
    Fiorentino, Michelangelo
    Department of Hematology-Oncology, Molecular Pathology Laboratory, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    FOXP3+ regulatory T cells in normal prostate tissue, postatrophic hyperplasia, prostatic intraepithelial neoplasia, and tumor histological lesions in men with and without prostate cancer2018In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 78, no 1, p. 40-47Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The tumor promoting or counteracting effects of the immune response to cancer development are thought to be mediated to some extent by the infiltration of regulatory T cells (Tregs ). In the present study we evaluated the prevalence of Treg populations in stromal and epithelial compartments of normal, post atrophic hyperplasia (PAH), prostatic intraepithelial neoplasia (PIN), and tumor lesions in men with and without prostate cancer.

    METHODS: Study subjects were 102 men consecutively diagnosed with localized prostate cancer undergoing radical prostatectomy and 38 men diagnosed with bladder cancer undergoing cystoprostatectomy without prostate cancer at the pathological examination. Whole mount sections from all patients were evaluated for the epithelial and stromal expression of CD4+ Tregs and CD8+ Tregs in normal, PAH, PIN, and tumor lesions. A Friedmańs test was used to investigate differences in the mean number of Tregs across histological lesions. Logistic regression was used to estimate crude and adjusted odds ratios (OR) for prostate cancer for each histological area.

    RESULTS: In men with prostate cancer, similarly high numbers of stromal CD4+ Tregs were identified in PAH and tumor, but CD4+ Tregs were less common in PIN. Greater numbers of epithelial CD4+ Tregs in normal prostatic tissue were positively associated with both Gleason score and pT-stage. We observed a fourfold increased risk of prostate cancer in men with epithelial CD4+ Tregs in the normal prostatic tissue counterpart.

    CONCLUSIONS: Our results may suggest a possible pathway through which PAH develops directly into prostate cancer in the presence of CD4+ Tregs and indicate that transformation of the anti-tumor immune response may be initiated even before the primary tumor is established.

  • 13.
    Davidsson, Sabina
    et al.
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Giunchi, Francesca
    Molecular Pathology Laboratory, Addarii Institute of Oncology, Department of Specialist Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy.
    Harlow, Alyssa
    Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
    Kirrander, Peter
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Rider, Jennifer
    Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
    Fiorentino, Michelangelo
    Molecular Pathology Laboratory, Addarii Institute of Oncology, Department of Specialist Diagnostic and Experimental Medicine, University of Bologna, Bologna, Italy.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    PD-L1 Expression in Men with Penile Cancer and its Association with Clinical Outcomes2019In: European Urology Oncology, E-ISSN 2588-9311, Vol. 2, no 2, p. 214-221Article in journal (Refereed)
    Abstract [en]

    Background: It has been hypothesized that PD-L1 expression in tumor cells and tumor-infiltrating immune (TII) cells may contribute to tumor progression by inhibiting antitumor immunity.

    Objective: To investigate the association between PD-L1 expression in tumor cells and TII cells and clinical outcomes in penile cancer.

    Design, setting, and participants: A cohort of 222 men treated for penile squamous cell carcinoma (SqCC) at Örebro University Hospital between 1984 and 2008 with long-term follow-up (median 34 mo) was evaluated for PD-L1 expression in tumor cells and TII cells via immunohistochemistry.

    Outcome measurements and statistical analysis: Association between clinicopathological features and PD-L1 expression was estimated using χ2 and Fisher's exact tests. For survival analyses, Kaplan-Meier curves with log-rank tests and multivariate Cox proportional hazards regression models were used.

    Results and limitations: We found that 32.1% of the tumors and 64.2% of the TII cells expressed PD-L1. Our data demonstrate that penile SqCC patients with PD-L1–positive tumor cells or TII cells are at significant risk of lower cancer-specific survival and that the prognostic value of PD-L1 expression was strongest for tumor cell positivity. The use of tissue microarrays rather than whole sections may be viewed as a limitation.

    Conclusions: Tumor PD-L1 expression independently identifies penile SqCC patients at risk of poor clinical outcomes.

    Patient summary: We investigated how many patients with penile cancer had tumors that manufactured PD-L1, a protein that decreases the ability of the immune system to fight cancer. We found that up to one-third of penile tumors make this protein. Patients whose tumors make PD-L1 have more aggressive penile cancer and worse clinical outcomes.

  • 14.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Gashi, Natyra
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Brzuszkiewicz, Elzbieta
    Department of Genomic and Applied Microbiology, Institute of Microbiology and Genetics, University of Göttingen, Göttingen, Germany.
    Poehlein, Anja
    Department of Genomic and Applied Microbiology, Institute of Microbiology and Genetics, University of Göttingen, Göttingen, Germany.
    Al-Zeer, Munir A.
    Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
    Brinkmann, Volker
    Microscopy Core Facility, Max Planck Institute for Infection Biology, Berlin, Germany.
    Scavenius, Carsten
    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
    Nazipi, Seven
    Department of Biomedicine, Aarhus University, Aarhus, Denmark.
    Söderquist, Bo
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Clinical Microbiology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Brüggemann, Holger
    Department of Biomedicine, Aarhus University, Aarhus, Denmark.
    Prevalence of Flp Pili-Encoding Plasmids in Cutibacterium acnes Isolates Obtained from Prostatic Tissue2017In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 8, article id 2241Article in journal (Refereed)
    Abstract [en]

    Inflammation is one of the hallmarks of prostate cancer. The origin of inflammation is unknown, but microbial infections are suspected to play a role. In previous studies, the Gram-positive, low virulent bacterium Cutibacterium (formerly Propionibacterium) acnes was frequently isolated from prostatic tissue. It is unclear if the presence of the bacterium represents a true infection or a contamination. Here we investigated Cutibacterium acnes type II, also called subspecies defendens, which is the most prevalent type among prostatic C. acnes isolates. Genome sequencing of type II isolates identified large plasmids in several genomes. The plasmids are highly similar to previously identified linear plasmids of type I C. acnes strains associated with acne vulgaris. A PCR-based analysis revealed that 28.4% (21 out of 74) of all type II strains isolated from cancerous prostates carry a plasmid. The plasmid shows signatures for conjugative transfer. In addition, it contains a gene locus for tight adherence (tad) that is predicted to encode adhesive Flp (fimbrial low-molecular weight protein) pili. In subsequent experiments a tad locus-encoded putative pilin subunit was identified in the surface-exposed protein fraction of plasmid-positive C. acnes type II strains by mass spectrometry, indicating that the tad locus is functional. Additional plasmid-encoded proteins were detected in the secreted protein fraction, including two signal peptide-harboring proteins; the corresponding genes are specific for type II C. acnes, thus lacking from plasmid-positive type I C. acnes strains. Further support for the presence of Flp pili in C. acnes type II was provided by electron microscopy, revealing cell appendages in tad locus-positive strains. Our study provides new insight in the most prevalent prostatic subspecies of C. acnes, subsp. defendens, and indicates the existence of Flp pili in plasmid-positive strains. Such pili may support colonization and persistent infection of human prostates by C. acnes.

  • 15.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Fiorentino, Michelangelo
    Molecular Pathology Laboratory, Addarii Institute of Oncology, Department of Hematology-Oncology, University of University of Bologna, Bologna, Italy.
    Giunchi, Francesca
    Molecular Pathology Laboratory, Addarii Institute of Oncology, Department of Hematology-Oncology, University of Bologna, Bologna, Italy .
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    The presence of PD-L1 in men with localized prostate cancer2017In: Medical research archives, ISSN 2375-1916, Vol. 4, no 8Article in journal (Refereed)
    Abstract [en]

    Background: Recent therapeutic strategies for different cancer types have focused on targeting immune check-points, such as programmed death-1 (PD-1) and its ligand PD-L1. However, it was recently reported that men with castration-resistant prostate cancer did not respond to PD-1 blockade as monotherapy. The unresponsiveness could potentially be explained by low expression of PD-L1 on prostate tumor cells. This study investigated the expression of PD-L1 on tumor cells and tumor infiltrating lymphocytes (TILs) in men with primary prostate cancer.

    Material and Methods: Immunohistochemical analysis of PD-L1 expression was performed in a cohort of men undergoing transurethral resection of the prostate and diagnosed with prostate cancer. The expression was evaluated in tissue microarrays from 522 patients with at least 25 years of follow-up.

    Results: Only four of the 522 evaluated cases were positive for PD-L1, positivity on tumor cells were found in three of the cases, of which one case also had positivity on TILs, while a fourth case only had positivity on TILs.

    Conclusion: Our data suggest that treatments targeting the PD-1/PD-L1 interaction may not be successful as monotherapy in patients diagnosed with localized prostate cancer due to low expression of PD-L1.

  • 16.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden .
    Mölling, Paula
    Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Rider, Jennifer R.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Unemo, Magnus
    Örebro University, School of Health Sciences. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Pathology, Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Elgh, Fredrik
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Söderquist, Bo
    Örebro University, School of Medical Sciences.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden; A Member of the Transdisciplinary Prostate Cancer Partnership (TopCaP), Örebro, Sweden.
    Erratum to: Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer2016In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 11, article id 36Article in journal (Refereed)
  • 17.
    Davidsson, Sabina
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Rider, Jennifer R.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA.
    Unemo, Magnus
    Örebro University, School of Health Sciences. Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Karlsson, Mats G.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Pathology, Örebro University Hospital, Örebro, Sweden; Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden .
    Andersson, Swen-Olof
    Örebro University, School of Health Sciences. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Elgh, Fredrik
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Söderquist, Bo
    Örebro University, School of Medical Sciences.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer2016In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 11, article id 26Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 18. Davidsson, Sabina
    et al.
    Sundqvist, Pernilla
    Örebro University, School of Medical Sciences.
    Giunchi, Francesca
    Erlandsson, Ann
    Örebro University, School of Medical Sciences.
    Fiorentiono, Michelangelo
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    M2 macrophages and regulatory T cells as prognostic markers in renal cell carcinoma2019Conference paper (Refereed)
  • 19.
    Deo, Ameya
    et al.
    Högskolan i Skövde, Skövde, Sweden.
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences.
    Lindlöf, Angelica
    Högskolan i Skövde, Skövde, Sweden.
    How to choose a normalization strategy for miRNA quantitative real-time (QPCR) arrays2011In: Journal of Bioinformatics and Computational Biology, ISSN 0219-7200, E-ISSN 1757-6334, Vol. 9, no 6, p. 795-812Article in journal (Refereed)
    Abstract [en]

    Low-density arrays for quantitative real-time PCR (qPCR) are increasingly being used as an experimental technique for miRNA expression profiling. As with gene expression profiling using microarrays, data from such experiments needs effective analysis methods to produce reliable and high-quality results. In the pre-processing of the data, one cruciala nalysis step is normalization, which aims to reduce measurement errors and technical variability among arrays that might have arisen during the execution of the experiments. However, there are currently a number of different approaches to choose among and an unsuitable applied method may induce misleading effects, which could affect the subsequent analysis steps and thereby any conclusions drawn from the results. The hoice of normalization method is hence an important issue to consider. In this study we present the comparison of a number of data-driven normalization methods for TaqManlow-density arrays for qPCR and different descriptive statistical techniques that can facilitate the choice of normalization method. The performance of the normalization methods was assessed and compared against each other as well as against standard normalization using endogenous controls. The results clearly show that the data-driven methods reduce variation and represent robust alternatives to using endogenous controls.

  • 20.
    Erlandsson, Ann
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden; Department of Environmental and Life Sciences/Biology, Karlstad University, Karlstad, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Sven-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Vyas, Chraig
    Department of Epidemiology, Boston University School of Public Health, Boston MA, USA.
    Wikström, Pernilla
    Department of Medical Biosciences, Umeå University, Umeå, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Rider, Jennifer R.
    Department of Epidemiology, Boston University School of Public Health, Boston MA, USA.
    High inducible nitric oxide synthase in prostate tumor epithelium is associated with lethal prostate cancer2018In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 52, no 2, p. 129-133Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to investigate the role of inducible nitric oxide synthase (iNOS) in lethal prostate cancer (PCa) by studying the iNOS immunoreactivity in tumor tissue from men diagnosed with localized PCa.

    MATERIALS AND METHODS: This study is nested within a cohort of men diagnosed with incidental PCa undergoing transurethral resection of the prostate (the Swedish Watchful Waiting Cohort). To investigate molecular determinants of lethal PCa, men who died from PCa (n = 132) were selected as cases; controls (n = 168) comprised men with PCa who survived for at least 10 years without dying from PCa during follow-up. The immunoreactivity of iNOS in prostate tumor epithelial cells and in cells of the surrounding stroma was scored as low/negative, moderate or high. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for lethal PCa according to iNOS category.

    RESULTS: There was no association between iNOS immunoreactivity in stroma and lethal disease. However, when comparing high versus low/negative iNOS immunoreactivity in epithelial cells, the OR for lethal PCa was 3.80 (95% CI 1.45-9.97).

    CONCLUSION: Patients with localized PCa have variable outcomes, especially those with moderately differentiated tumors. Identifying factors associated with long-term PCa outcomes can elucidate PCa tumor biology and identify new candidate prognostic markers. These findings support the hypothesis that high iNOS in tumor epithelium of the prostate is associated with lethal disease.

  • 21.
    Erlandsson, Ann
    et al.
    Örebro University, School of Medical Sciences. Department of Urology.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology.
    Lundholm, Marie
    Department of Medical Biosciences, Umeå University, Umeå, Sweden.
    Fält, Anna
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Andersson, Sven-Olof
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology.
    M2 macrophages and regulatory T cells in lethal prostate cancer2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 4, p. 363-369Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prostate cancer (PCa) is one of the most frequently diagnosed cancers in the world. Emerging evidence suggests that inflammatory cells such as M2 macrophages and regulatory T cells (Tregs) can contribute to cancer progression by suppressing the anti‐tumor immune response. This study investigated the number of CD163‐positive M2 macrophages in PCa tissue. It also investigated the correlation and interaction of M2 macrophages and Tregs.

    METHODS: were assessed using Spearman's rank-order correlation and a likelihood test, respectively. Logistic regression was used to estimate odds ratios (ORs) for lethal PCa and macrophage counts.

    RESULTS: showed a significant correlation (P < 0.001) but no interactions. The OR for lethal PCa was 1.93 (95%CI: 1.23-3.03) for men with high numbers of M2 macrophages. Also for cases with uncertain outcome (GS categories 3 + 4 and 4 + 3) high numbers of M2 macrophages does predict a poorer prognosis.

    CONCLUSIONS: Our data showed that men with high numbers of M2 macrophages in the prostate tumor environment had increased odds of dying of PCa. It is possible that M2 macrophages, together with other suppressor cells such as Tregs , promote an immunosuppressive environment.

  • 22.
    Falck, Eva
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Karlsson, Sandra
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Helenius, Gisela
    Karlsson, Mats G.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Klinga-Levan, Karin
    Loss of glutathione peroxidase 3 expression is correlated with epigenetic mechanisms in endometrial adenocarcinoma2010In: Cancer cell international, ISSN 1475-2867, Vol. 10, article id 46Article in journal (Refereed)
    Abstract [en]

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

  • 23.
    Grabowska, Beata
    et al.
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Ulvskog, Emma
    Örebro University, School of Medical Sciences. Department of Oncology, University Hospital Örebro, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Fiorentino, Michelangelo
    Department of Pathology, F. Addari Institute of Oncology, S. Orsola Hospital, Bologna, Italy.
    Giunchi, Francesca
    Department of Pathology, F. Addari Institute of Oncology, S. Orsola Hospital, Bologna, Italy.
    Lindblad, Per
    Örebro University, School of Medical Sciences. Department of Urology.
    Sundqvist, Pernilla
    Örebro University, School of Medical Sciences. Department of Urology.
    Clinical outcome and time trends of surgically treated renal cell carcinoma between 1986 and 2010: results from a single centre in Sweden2018In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 52, no 3, p. 206-212Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aims of this study were to create a cohort of retrospectively collected renal cell carcinoma (RCC) specimens to be used a basis for prognostic molecular studies, and to investigate the outcome and time trends in patients surgically treated for RCC in a single-centre cohort.

    MATERIALS AND METHODS: Patients undergoing surgery for RCC between 1986 and 2010 were included in the study. Medical records were reviewed, and the diagnostic tissue was re-evaluated according to a modern classification. The change in patient and tumour characteristics over time was analysed.

    RESULTS: The study included 345 patients. Smaller tumours, as indicated by primary tumour diameter, tumour (T) stage and American Joint Committee on Cancer (AJCC) stage, were found more frequently in later years compared to the early 1990s. No changes in the clinical outcome for the patients were seen among the time periods investigated. Increasing T stage, AJCC stage, primary tumour diameter and decreasing haemoglobin levels were associated with cancer-specific mortality in univariate analysis. A high calcium level was significantly associated with increased cancer-specific mortality (hazard ratio = 4.25, 95% confidence interval 1.36-13.28) in multivariate analysis.

    CONCLUSIONS: This study on patients who underwent surgery for RCC from 1986 to 2010 at a single institution in Sweden indicates that there has been a change in tumour characteristics of patients diagnosed with RCC over time. It was also shown that calcium levels were an independent prognostic factor for cancer-specific mortality in this cohort. This cohort could provide a valuable basis for further molecular studies.

  • 24.
    Iglesias-Gato, Diego
    et al.
    IVS, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Centre for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Danish Cancer Society, Copenhagen, Denmark.
    Wikström, Pernilla
    Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
    Tyanova, Stefka
    Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried, Germany.
    Lavallee, Charlotte
    IVS, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Centre for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Danish Cancer Society, Copenhagen, Denmark.
    Thysell, Elin
    Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology.
    Hägglöf, Christina
    Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
    Cox, Jürgen
    Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried, Germany.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Stattin, Pär
    Departments of Surgery and Perioperative Sciences, Umeå University, Umeå, Sweden.
    Egevad, Lars
    Section of Urology, Department of Surgical Science, Karolinska Institutet, Stockholm, Sweden.
    Widmark, Anders
    Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    Bjartell, Anders
    Department of Translational Medicine, Division of Urological Cancers, University of Lund, Lund, Sweden.
    Collins, Colin C.
    Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
    Bergh, Anders
    Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
    Geiger, Tamar
    Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
    Mann, Matthias
    Novo Nordisk Foundation Centre for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Proteomics and Signal Transduction, Max Planck Institute for Biochemistry, Martinsried, Germany.
    Flores-Morales, Amilcar
    IVS, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Centre for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; Danish Cancer Society, Copenhagen, Denmark.
    The Proteome of Primary Prostate Cancer2016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 69, no 5, p. 942-952Article in journal (Refereed)
    Abstract [en]

    Background: Clinical management of the prostate needs improved prognostic tests and treatment strategies. Because proteins are the ultimate effectors of most cellular reactions, are targets for drug actions and constitute potential biomarkers; a quantitative systemic overview of the proteome changes occurring during prostate cancer (PCa) initiation and progression can result in clinically relevant discoveries.

    Objectives: To study cellular processes altered in PCa using system-wide quantitative analysis of changes in protein expression in clinical samples and to identify prognostic biomarkers for disease aggressiveness.

    Design, setting, and participants: Mass spectrometry was used for genome-scale quantitative proteomic profiling of 28 prostate tumors (Gleason score 6-9) and neighboring nonmalignant tissue in eight cases, obtained from formalin-fixed paraffin-embedded prostatectomy samples. Two independent cohorts of PCa patients (summing 752 cases) managed by expectancy were used for immunohistochemical evaluation of proneuropeptide-Y (pro-NPY) as a prognostic biomarker.

    Results and limitations: Over 9000 proteins were identified as expressed in the human prostate. Tumor tissue exhibited elevated expression of proteins involved in multiple anabolic processes including fatty acid and protein synthesis, ribosomal biogenesis and protein secretion but no overt evidence of increased proliferation was observed. Tumors also showed increased levels of mitochondrial proteins, which was associated with elevated oxidative phosphorylation capacity measured in situ. Molecular analysis indicated that some of the proteins overexpressed in tumors, such as carnitine palmitoyltransferase 2 (CPT2, fatty acid transporter), coatomer protein complex, subunit alpha (COPA, vesicle secretion), and mitogen-and stress-activated protein kinase 1 and 2 (MSK1/2, protein kinase) regulate the proliferation of PCa cells. Additionally, pro-NPY was found overexpressed in PCa (5-fold, p < 0.05), but largely absent in other solid tumor types. Pro-NPY expression, alone or in combination with the ERG status of the tumor, was associated with an increased risk of PCa specific mortality, especially in patients with Gleason score <= 7 tumors.

    Conclusions: This study represents the first system-wide quantitative analysis of proteome changes associated to localized prostate cancer and as such constitutes a valuable resource for understanding the complex metabolic changes occurring in this disease. We also demonstrated that pro-NPY, a protein that showed differential expression between high and low risk tumors in our proteomic analysis, is also a PCa specific prognostic biomarker associated with increased risk for disease specific death in patients carrying low risk tumors.

    Patient summary: The identification of proteins whose expression change in prostate cancer provides novel mechanistic information related to the disease etiology. We hope that future studies will prove the value of this proteome dataset for development of novel therapies and biomarkers. (C) 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  • 25.
    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.

  • 26.
    Lu, Donghao
    et al.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Penney, Kathryn L.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, USA.
    Davidsson, Sabina
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, USA.
    Valdimarsdóttir, Unnur
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Faculty of Medicine, Center of Public Health Sciences, School of Health Sciences, University of Iceland, Reykjavík, Iceland.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Fang, Fang
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Expression and Genetic Variation in Neuroendocrine Signaling Pathways in Lethal and Nonlethal Prostate Cancer among Men Diagnosed with Localized Disease2017In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 26, no 12, p. 1781-1787Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recent data suggest that neuroendocrine signaling pathways may play a role in the progression of prostate cancer, particularly for early-stage disease. We aimed to explore whether expression of selected genes in the adrenergic, serotoninergic, glucocorticoid, and dopaminergic pathways differs in prostate tumor tissue from men with lethal disease compared to men with nonlethal disease.

    METHODS: Based on the Swedish Watchful Waiting Cohort, we included 511 men diagnosed with incidental prostate cancer through TURP during 1977-1998 with follow-up up to 30 years. For those with tumor tissue (N=262), we measured mRNA expression of 223 selected genes included in neuroendocrine pathways. Using DNA from normal prostate tissue (N=396), we genotyped 36 SNPs from 14 receptor genes. Lethal prostate cancer was the primary outcome in analyses with pathway gene expression and genetic variants.

    RESULTS: Differential expression of genes in the serotoninergic pathway was associated with risk of lethal prostate cancer (P=0.007); similar but weaker associations were noted for the adrenergic (P=0.014) and glucocorticoid (P=0.020) pathways. Variants of the HTR2A (rs2296972; P=0.002) and NR3CI (rs33388; P=0.035) genes (within the serotoninergic and glucocorticoid pathways) were associated with lethal cancer in over-dominant models. These genetic variants were correlated with expression of several genes in corresponding pathways (P<0.05).

    CONCLUSIONS: Our findings lend support to hypothesis that the neuroendocrine pathways, particularly serotoninergic pathway, are associated with lethal outcome in the natural course of localized prostate cancer.

    IMPACT: The current study provides evidence of the role of neuroendocrine pathways in prostate cancer progression which may have clinical utility.

  • 27.
    Nowak, Michael
    et al.
    Inst Pathol, Univ Hosp Bonn, Bonn, Germany.; Dept Prostate Canc Res, Univ Hosp Bonn, Bonn, Germany..
    Svensson, Maria A.
    Örebro University Hospital. Dept Lab Med, Univ Hosp Örebro, Örebro, Sweden; Dept Urol, Univ Hosp Örebro, Örebro, Sweden; Inst Hlth & Med Sci, Univ Örebro, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept Urol, Örebro, Örebro University Hospital, Örebro, Sweden.
    Vogel, Wenzel
    Inst Pathol, Univ Hosp Bonn, Bonn, Germany; Dept Prostate Canc Res, Univ Hosp Bonn, Bonn, Germany.
    Kebschull, Moritz
    Dept Periodontol Operat & Prevent Dent, Univ Bonn, Bonn, Germany.
    Wernert, Nicolas
    Inst Pathol, Univ Hosp Bonn, Bonn, Germany.
    Kristiansen, Glen
    Inst Pathol, Univ Hosp Bonn, Bonn, Germany.
    Andren, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept Urol, Örebro University Hospital, Örebro, Sweden.
    Braun, Martin
    Inst Pathol, Univ Hosp Bonn, Bonn, Germany.; Dept Prostate Canc Res, Univ Hosp Bonn, Bonn, Germany.
    Perner, Sven
    Inst Pathol, Univ Hosp Bonn, Bonn, Germany.; Dept Prostate Canc Res, Univ Hosp Bonn, Bonn, Germany.
    Prognostic significance of phospho-histone H3 in prostate carcinoma2014In: World journal of urology, ISSN 0724-4983, E-ISSN 1433-8726, Vol. 32, no 3, p. 703-707Article in journal (Refereed)
    Abstract [en]

    Prostate cancer is the second most common cancer in men and the sixth most common cause of death from cancer in men worldwide. Currently, a sufficient pathological distinction between patients requiring further treatment and those for which active surveillance remains an option is still lacking, which leads to the problem of overtreatment. Cell proliferation is routinely assessed by detecting Ki-67 antigen. While Ki-67 is expressed throughout the interphase of proliferating cells, phosphorylation of the chromatin constituent histone H3 occurs only during the late G2 phase and mitosis thus providing a more strict assessment of the mitotic activity. We undertook this study to test whether expression of the recently introduced proliferation marker phospho-histone H3 (pHH3) in prostate carcinoma tissue sections exhibits prognostic significance in comparison with Ki-67. Protein expression of pHH3 and Ki-67 was assessed on TMA consisting of paraffin-embedded tissue from men that had undergone radical prostatectomy. The analysis included triplicate tissue cores of a total of 339 tumor foci. Immunohistochemical staining of pHH3 and Ki-67 was performed and analyzed using Definiens imaging software. Prostate cancer tissue exhibited a significantly higher frequency of pHH3-positive cells compared to benign prostate tissue. pHH3 expression was significantly correlated with Ki-67 expression. Furthermore, statistical analysis revealed positive correlation between pHH3 expression and PSA levels at diagnosis and in addition negatively correlated with overall survival. In contrast to Ki-67 staining, pHH3 expression did not correlate with Gleason grade. Our data point to a conceivable role of pHH3 as prognostic biomarker in prostate carcinoma.

  • 28.
    Offermann, Anne
    et al.
    Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck, Germany; Pathology of the Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
    Roth, Doris
    Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck, Germany; Pathology of the Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
    Hupe, Marie Christine
    Department of Urology, University Hospital Schleswig-Holstein, Germany.
    Hohensteiner, Silke
    Department of Urology, University Hospital Schleswig-Holstein, Germany.
    Becker, Finn
    Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck, Germany; Pathology of the Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
    Joerg, Vincent
    Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck, Germany; Pathology of the Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Kuempers, Christiane
    Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck, Germany; Pathology of the Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
    Ribbat-Idel, Julika
    Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck, Germany; Pathology of the Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
    Tharun, Lars
    Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck, Germany; Pathology of the Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
    Sailer, Verena
    Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck, Germany; Pathology of the Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
    Kirfel, Jutta
    Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck, Germany; Pathology of the Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
    Svensson, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Research and Education.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Lubczyk, Verena
    Department of Urology, University Hospital Schleswig-Holstein, Germany.
    Kuefer, Rainer
    Department of Urology, Klinik am Eichert Alb Fils Kliniken, Goeppingen, Germany.
    Merseburger, Axel S.
    Univ Hosp Schleswig Holstein, Dept Urol, Lubeck, Germany..
    Perner, Sven
    Institute of Pathology, University Hospital Schleswig-Holstein, Luebeck, Germany; Pathology of the Research Center Borstel, Leibniz Lung Center, Borstel, Germany.
    TRIM24 as an independent prognostic biomarker for prostate cancer2019In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 37, no 9, article id 576.e1Article in journal (Refereed)
    Abstract [en]

    Introduction: Simply applicable biomarkers for prostate cancer patients predicting the clinical course are urgently needed. Recently, TRIM24 has been identified to promote androgen receptor signaling and to correlate with an aggressive prostate cancer phenotype. Based on these data, we proofed TRIM24 as a prognostic biomarker for risk stratification.

    Materials and Methods: We performed TRIM24 immunohistochemistry on 2 independent cohorts including a total of 806 primary tumors, 26 locally advanced/recurrent tumors, 30 lymph node metastases, 30 distant metastases, and 129 benign prostatic samples from 497 patients as well as on 246 prostate needle biopsies. Expression data were correlated with clinic-pathological data including biochemical recurrence-free survival (bRFS) as endpoint.

    Results: Benign samples show no or low TRIM24 expression in 94%, while tumor tissues demonstrate significant higher levels. Strongest expression is observed in advanced and metastatic tumors. In multivariate analyses, TRIM24 up-regulation on radical prostatectomy specimens correlates with shorter bRFS independent of other prognostic parameters. 5-(10-) year bRFS rates for TRIM24 negative, low, medium and high expressing tumors are 93.1(93.1)%, 75.4(68.5)%, 54.9(47.5)% and 43.1(32.3)%, respectively. Of interest, tumors diagnosed as indolent disease, TRIM24 expression stratifies patients into specific risk groups. Increased TRIM24 expression associates with higher grade group, positive nodal status and extraprostatic tumor growth. TRIM24 assessment on prostate needle biopsies taken prior to treatment decision at time of initial diagnosis significantly correlates with recurrence after surgery.

    Conclusion: Using 2 large independent radical prostatectomy specimen cohorts, we found that TRIM24 expression predicts patients' risk to develop disease recurrence with high accuracy and independent from other established biomarkers. Further, this is the first study exploring TRIM24 expression on prostate needle biopsies which represents the clinically relevant tissue type on which biomarkers guide treatment decisions. Thus, we strongly suggest introducing TRIM24 evaluation in prostate needle biopsies in clinical routine as an inexpensive and simple immunohistochemical test.

  • 29.
    Offermann, Anne
    et al.
    University Medical Center Schleswig-Holstein, Leibniz Center for Medicine and Biosciences, Lübeck and Borstel, Germany.
    Schneider, Felix
    Klinik am Eicher Alb Fils Kliniken, Goeppingen, Germany.
    Hupe, Marie Christine
    University Hospital Schleswig-Holstein, Lübeck, Germany.
    Hohensteiner, Silke
    Klinik am Eichert Alb Fils Kliniken, Goeppingen, Germany.
    Becker, Finn
    University Medical Center Schleswig-Holstein, Leibniz Center for Medicine and Biosciences, Lübeck and Borstel, Germany.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Kirfel, Jutta
    University Hospital Schleswig-Holstein, Leibniz Center for Medicine and Biosciences, Lübeck and Borstel, Germany.
    Svensson, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Andrén, Ove
    Örebro University, School of Medical Sciences.
    Merseburger, Axel
    University Hospital Lübeck, Lübeck, Germany.
    Lubczyk, Verena
    Klinik am Eichert Alb Fils Kliniken, Goeppingen, Germany.
    Kuefer, Rainer
    Klinik am Eichert Alb Fils Kliniken, Goeppingen, Germany.
    Sven, Perner
    University Medical Center Schleswig-Holstein, Leibniz Center for Medicine and Biosciences, Lübeck and Borstel, Germany, Lübeck.
    TRIM24 as Independent Prognostic Marker in Prostate Cancer2018In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 31, no Suppl. 2, p. 372-373Article in journal (Other academic)
    Abstract [en]

    Background: Simply applicable biomarkers for prostate cancer (PCa) predicting the clinical course are urgently needed. Recently, TRIM24 has been identified to promote androgen-receptor signaling and to correlate with poor outcome. Based on these data, we validated TRIM24 as a prognostic biomarker for PCa.

    Design: We performed TRIM24 immunohistochemistry on two independent cohorts including a total of 806 primary tumors, 26 locally advanced/recurrent tumors, 30 lymph node metastases, 30 distant metastases and 129 benign prostatic samples from 497 patients. Expression data were correlated with clinic-pathological data including biochemical recurrence free survival (bRFS) as endpoint.

    Results: Benign samples show no/low TRIM24 expression in 94%, while tumors demonstrate significantly higher levels. Strongest expression is observed in metastatic tumors. In multivariate analyses, TRIM24 up-regulation correlates with shorter bRFS independent of other prognostic parameters. 5-(10-) year bRFS rates for TRIM24 negative, low, medium and high expressing tumors are 93.1(93.1)%, 75.4(68.5)%, 54.9(47.5)% and 43.1(32.3)%, respectively. Of interest, tumors diagnosed as indolent disease, TRIM24 expression stratifies patients into specific risk groups. Increased TRIM24 expression associates with higher Grade Group, positive nodal status and extraprostatic tumor growth.

    Conclusions: Using two large independent cohorts, we found that TRIM24 expression predicts patients’ risk to develop disease recurrence with high accuracy and independently from other established prognostic markers. To our knowledge, TRIM24 is the first prognostic biomarker to be independent, accurate and reproducible on three different primary PCa cohorts. Thus, we strongly suggest introducing TRIM24 in clinical routine as a simple immunohistochemical test.

  • 30.
    Rider, Jennifer R.
    et al.
    Boston University School of Public Health, Boston, MA, USA.
    Erlandsson, Ann
    Örebro University Hospital, Örebro, Sweden.
    Vyas, Chirag
    Boston University School of Public Health, Boston, MA, USA.
    Davidsson, Sabina
    Örebro University Hospital, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University Hospital, Örebro, Sweden.
    Andren, Ove
    Örebro University Hospital, Örebro, Sweden.
    iNOS expression and lethal prostate cancer in patients with localized disease2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, no 22S, article id B26Article in journal (Refereed)
    Abstract [en]

    Inducible nitric oxide synthase (iNOS) has demonstrated both tumor-promoting and tumor-inhibiting effects in prostate cancer. However, the relationship between iNOS protein expression and long-term prostate cancer outcomes is unclear. We evaluated iNOS expression in tumor epithelia and stroma in 300 men with localized tumors diagnosed incidentally by transurethral resection of the prostate (TURP) in Sweden. In this extreme case-control design, cases (N=132) died of prostate cancer and controls (N=168) survived at least 8 years following diagnosis without death from prostate cancer or a competing cause. Immunohistochemistry was undertaken with a polyclonal rabbit anti-human NOS2 antibody (Abcam) and the Ventana (Roche) semi-automated staining system. Two observers individually scored the staining according to intensity and number of positive cells from 0-3. The median value across cores in each patient were then categorized as <1, >1-<2, and >2, separately for epithelial and stromal compartments. Odds ratios for lethal prostate cancer were estimated with logistic regression controlling for the matching factors (age, calendar year of diagnosis), as well as tumor stage, Gleason score, and percent tumor. iNOS was expressed by stromal-associated M1 macrophages and fibroblasts, as well as tumor cells. Gleason score was positively associated with both stromal and epithelial iNOS staining. In the stroma, there was no statistically significant association between iNOS expression and lethal prostate cancer after adjustment for clinical covariates. However, the odds of lethal prostate cancer increased with tumor expression of iNOS in the fully adjusted model. Compared to patients with the lowest category of iNOS expression, the odds ratios for lethal prostate cancer were 2.96 (95% CI: 1.26-6.96) for patients in the second category and 3.80 (95% CI: 1.45-9.97) for patients in the top category. These results suggest that iNOS may help to identify patients with aggressive prostate cancer at the time of diagnosis, or may be a therapeutic target. Given previously reported in vitro data suggesting that iNOS promotes proliferation of androgen-independent prostate tumors, future analyses will investigate association between iNOS expression and time to castration-resistant prostate cancer in this patient population.

  • 31.
    Rueenauver, K.
    et al.
    Inst Pathol, Dept Prostate Canc Res, Univ Hosp Bonn, Bonn, Germany.
    Menon, R.
    Inst Pathol, Dept Prostate Canc Res, Univ Hosp Bonn, Bonn, Germany.
    Svensson, Maria A.
    Örebro University Hospital. Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, University Hospital of Örebro, Örebro, Sweden; Department of Urology, University Hospital of Örebro, Örebro, Sweden.
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Urology, University Hospital of Örebro, Örebro, Sweden.
    Vogel, W.
    Univ Hosp Bonn, Inst Pathol, Dept Prostate Canc Res, Bonn, Germany.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Urology, University Hospital of Örebro, Örebro, Sweden.
    Nowak, M.
    Univ Hosp Bonn, Inst Pathol, Dept Prostate Canc Res, Bonn, Germany.
    Perner, S.
    Univ Hosp Bonn, Inst Pathol, Dept Prostate Canc Res, Bonn, Germany.
    Transdiciplinary Prostate Cancer Partership (ToPCaP), Sweden (Andrén, Carlsson, Svensson, on behalf of or aff. to), Group author
    Prognostic significance of YWHAZ expression in localized prostate cancer2014In: Prostate Cancer and Prostatic Diseases, ISSN 1365-7852, E-ISSN 1476-5608, Vol. 17, no 4, p. 310-314Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prostate cancer (PCa) patients are often over-treated because of the lack of biomarkers needed to distinguish the lethal from the indolent form of PCa. YWHAZ was recently identified as a potential therapeutic target in castration-resistant PCa (CRPC). Therefore, this study focused on determining the prognostic significance of YWHAZ in localized PCa.

    METHODS: YWHAZ expression was assessed by immunohistochemistry on formalin-fixed paraffin-embedded tissue from 213 men who underwent radical prostatectomy. Kaplan-Meier analysis and Cox proportional-hazards models were, used to assess the prognostic value of YWHAZ intensity.

    RESULTS: High YWHAZ expression was strongly associated with high Gleason score at the time of diagnosis (P<0.001) and PSA relapse (P=0.001). Importantly, patients with high expression of YWHAZ had a higher risk of CRPC development (P=0.002) and reduced survival time (P=0.002).

    CONCLUSIONS: Our findings indicate that YWHAZ could serve as a promising prognostic biomarker in localized PCa to predict poor prognosis and to identify a subgroup of tumors, which might benefit from earlier adjuvant or YWHAZ-targeted therapy.

  • 32.
    Sinnott, Jennifer A.
    et al.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Department of Biostatistics, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
    Rider, Jennifer R.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Gerke, Travis
    Department of Epidemiology, College of Medicine and College of Public Health and Health Professions, University of Florida, Gainesville, USA.
    Tyekucheva, Svitlana
    Department of Biostatistics, Harvard School of Public Health, Boston, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA.
    Penney, Kathryn L.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
    Sesso, Howard D.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Loda, Massimo
    Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA; Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, USA.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Stampfer, Meir J.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Pawitan, Yudi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Andersson, Sven-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Molecular differences in transition zone and peripheral zone prostate tumors2015In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 36, no 6, p. 632-638Article in journal (Refereed)
    Abstract [en]

    Prostate tumors arise primarily in the peripheral zone (PZ) of the prostate, but 20-30% arise in the transition zone (TZ). Zone of origin may have prognostic value or reflect distinct molecular subtypes; however, it can be difficult to determine in practice. Using whole-genome gene expression, we built a signature of zone using normal tissue from five individuals and found that it successfully classified nine tumors of known zone. Hypothesizing that this signature captures tumor zone of origin, we assessed its relationship with clinical factors among 369 tumors of unknown zone from radical prostatectomies (RPs) and found that tumors that molecularly resembled TZ tumors showed lower mortality (P = 0.09) that was explained by lower Gleason scores (P = 0.009). We further applied the signature to an earlier study of 88 RP and 333 transurethral resection of the prostate (TURP) tumor samples, also of unknown zone, with gene expression on ~6000 genes. We had observed previously substantial expression differences between RP and TURP specimens, and hypothesized that this might be because RPs capture primarily PZ tumors, whereas TURPs capture more TZ tumors. Our signature distinguished these two groups, with an area under the receiver operating characteristic curve of 87% (P < 0.0001). Our findings that zonal differences in normal tissue persist in tumor tissue and that these differences are associated with Gleason score and sample type suggest that subtypes potentially resulting from different etiologic pathways might arise in these zones. Zone of origin may be important to consider in prostate tumor biomarker research.

  • 33. Svensson, Maria A.
    et al.
    Nowak, M.
    Vogel, W.
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Perner, S.
    Combination of Multiple Markers Predicts Prostate Cancer Outcome2014In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 27, p. 262A-262AArticle in journal (Other academic)
  • 34.
    Svensson, Maria A.
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Ohlson, A-L.
    Dept. of Laboratory Medicine, University Hospital of Örebro, Sweden.
    Sandblom, D.
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rider, JR.
    Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA; Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    ERG rearrangement status and castration resistant prostate cancer: a prospective,population-based studyManuscript (preprint) (Other academic)
    Abstract [en]

    Overtreatment is a major concern in prostate cancer (PCa) management, as no adequate prognostic tool exists to separate indolent from aggressive disease at time of diagnosis. Androgen deprivation therapy (ADT) is the standard treatment of locally recurrent or metastatic PCa and although most men respond well to ADT initially, inevitably a resistance to the treatment develops. Men with tumor growth despite the androgen-depleted environment are considered to have castration resistant PCa (CRPC). After developing CRPC, the median survival time is typically less than two years. Since the initial discovery of ERG rearrangement in PCa, several studies have investigated the association between ERG rearrangement and clinical outcome of PCa with discrepant results. Few studies have examined the association between ERG rearrangement and CRPC, despite the fact that the most common fusion partners to ERG are androgen regulated. In this study we investigated the association between ERG status and time to CRPC.

    We assessed the ERG status in a cohort of 220 men initially managed by watchful waiting and treated with ADT at disease progression. There was no statistically significant association between ERG status and time from start of ADT to CPRC, or start of ADT to PCa-specific death. However, men harboring the ERG rearrangement did have a significantly shorter time between time of diagnosis and start of hormonal treatment, compared to men without the rearrangement (HR: 1.81; 95% CI: 1.23- 2.65), suggesting that ERG rearrangement is indicative of a more aggressive subtype of PCa./p>

  • 35.
    Ugge, Henrik
    et al.
    Örebro University, School of Medical Sciences. Department of Urology.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Department of Urology.
    Söderquist, Bo
    Örebro University, School of Medical Sciences.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology.
    The influence of prostatic Cutibacterium acnes infection on serum levels of IL6 and CXCL8 in prostate cancer patients2018In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 13, article id 34Article in journal (Refereed)
    Abstract [en]

    Background: Chronic prostatic inflammation, caused by Cutibacterium acnes (C. acnes), has been proposed to influence the risk of prostate cancer development. In vitro studies have demonstrated the capacity of C. acnes to induce secretion of Interleukin 6 (IL6) and C-X-C motif chemokine ligand 8 (CXCL8) by prostate epithelial cells. Both these inflammatory mediators have been implicated in prostate cancer pathophysiology. In this cohort study, we aimed to investigate the influence of prostatic C. acnes on serum levels of IL6 and CXCL8.

    Methods: We recruited 99 prostate cancer patients who underwent radical prostatectomy at orebro University Hospital. The cultivation of pre-operatively obtained prostate biopsies identified C. acnes in 60 of the 99 patients. Levels of IL6 and CXCL8 in pre-operative serum samples were analyzed using ELISA, and concentrations were compared between prostate cancer patients with and without prostatic C. acnes infection using standard statistical methods.

    Results: No statistical differences were observed in serum levels of IL6 and CXCL8 between subjects with and without prostatic C. acnes infection.

    Conclusions: Our results indicate that prostatic C. acnes infection may give rise to low-grade inflammation with little effect on systemic levels of IL6 and CXCL8.

  • 36.
    Ugge, Henrik
    et al.
    Örebro University, School of Medical Sciences. Department of Urology.
    Downer, Mary K.
    Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, United States.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Bowden, Michaela
    Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, United States.
    Davidsson, Sabina
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Mucci, Lorelai A.
    Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, United States.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Sven-Olof
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Circulating inflammation markers and prostate cancerManuscript (preprint) (Other academic)
  • 37.
    Ugge, Henrik
    et al.
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Downer, Mary K.
    Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts, USA.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Bowden, Michaela
    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
    Davidsson, Sabina
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, Massachusetts, USA.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Sven-Olof
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Circulating inflammation markers and prostate cancer2019In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 11, p. 1338-1346Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Chronic inflammation is thought to influence the risk of prostate cancer. The purpose of this population-based case-control study was to evaluate the association of 48 circulating inflammation markers with prostate cancer, to identify candidate markers for further investigation.

    METHODS: Serum samples collected from 235 prostate cancer patients and 198 population-based controls recruited in Örebro County, Sweden, in 1989-1991, were assessed using a multiplex bead-based immunoassay to determine concentrations of 48 circulating inflammation markers. Logistic regression was first used to evaluate the association between individual markers (highest vs lowest concentration quartile) and prostate cancer in unadjusted and mutually adjusted models. Second, patients with inflammatory conditions, metastatic or advanced prostate cancer, were excluded to address the possible influence of systemic disease on inflammation markers.

    RESULTS: Individual analyses first identified 21 markers associated with prostate cancer (P < .05), which after mutual adjustment were reduced to seven markers. After the exclusion of men with conditions linked with systemic inflammation, associations between prostate cancer and deviant levels of C-X3-C motif chemokine ligand 1, platelet-derived growth factor subunit B homodimer, interleukin 10, C-C motif chemokine ligand (CCL) 21, and CCL11 remained statistically significant.

    CONCLUSIONS: In this explorative study, we identified candidate inflammation markers of possible importance for prostate cancer pathophysiology, for further evaluation in prospective studies.

  • 38.
    Ugge, Henrik
    et al.
    Örebro University, School of Medical Sciences. Department of Urology.
    Udumyan, Ruzan
    Örebro University, School of Medical Sciences.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, UK.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Acne in late adolescence and risk of prostate cancer2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, p. 1580-1585Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence suggest that Propionibacterium acnes may play a role in prostate carcinogenesis, but data are so far limited and inconclusive. The aim of this population-based cohort study was therefore to test whether presence of acne vulgaris during late adolescence is associated with an increased risk of prostate cancer later in life. We identified a large cohort of young men born in Sweden between 1952 and 1956, who underwent mandatory assessment for military conscription around the age of 18 (n= 243,187). Test information along with health data including medical diagnoses at time of conscription was available through the Swedish Military Conscription Register and the National Patient Register. The cohort was followed through linkages to the Swedish Cancer Register to identify the occurrence of prostate cancer until December 31st 2009. We used Cox regression to calculate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between acne in adolescence and prostate cancer risk. A total of 1,633 men were diagnosed with prostate cancer during a median follow-up of 36.7 years. A diagnosis of acne was associated with a statistically significant increased risk for prostate cancer (adjusted HR: 1.43 95%; CI: 1.06-1.92), particularly for advanced stage disease (HR: 2.37 95%; CI 1.19-4.73). A diagnosis of acne classified as severe conferred a 6-fold increased risk of prostate cancer (HR: 5.70 95% CI 1.42-22.85). Data from this large prospective population-based cohort add new evidence supporting a role of P acnes infection in prostate cancer.

  • 39.
    Ugge, Henrik
    et al.
    Örebro University, School of Medical Sciences. Department of Urology.
    Udumyan, Ruzan
    Örebro University, School of Medical Sciences.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, London, United Kingdom.
    Fall, Katja
    Örebro University, School of Medical Sciences.
    Appendicitis before age 20 years is associated with an increased risk of later prostate cancer2018In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 27, no 6, p. 660-664Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Appendicitis before age 20 years has been observed to influence the risk of several inflammatory conditions, possibly through underlying immunological mechanisms. Inflammation has further been suggested to be involved in prostate cancer development. We therefore hypothesized that immunological characteristics signaled by appendicitis before late adolescence might influence the risk of later prostate cancer, and aimed to evaluate this association in a population-based study.

    METHODS: We identified a large cohort of Swedish men who underwent assessment for military conscription around the age of 18 years (n= 242,573). Medical diagnoses at time of conscription were available through the Swedish Military Conscription Register. The Swedish Cancer Register was used to identify diagnoses of prostate cancer. Multivariable adjusted Cox regression analyses were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between appendicitis and prostate cancer.

    RESULTS: During a median of 36.7 years of follow-up, 1,684 diagnoses of prostate cancer occurred. We found a statistically significant association between appendicitis and overall prostate cancer (adjusted HR: 1.70; 95% CI: 1.08-2.67). The risk was notably increased for advanced (HR: 4.42; 95% CI: 1.74-11.22) and lethal (HR: 8.95; 95% CI: 2.98-26.91) prostate cancer.

    CONCLUSION: These results suggest that a diagnosis of appendicitis before adulthood potentially signals underlying immune characteristics and a pattern of inflammatory response relevant to prostate cancer risk.

    IMPACT: The study lends support to the proposed role of inflammation in prostate carcinogenesis, and adds another area of investigation potentially relevant to prostate cancer development.

  • 40.
    Zelic, Renata
    et al.
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Zugna, Daniela
    Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy ; Centro di Riferimento per l ’ Epidemiologia e la Prevenzione Oncologica (CPO) in Piemonte, Turin, Italy .
    Bottai, Matteo
    Unit of Biostatistics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden .
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Fridfeldt, Jonna
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden .
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology.
    Fiano, Valentina
    Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy; Centro di Riferimento per l ’ Epidemiologia e la Prevenzione Oncologica (CPO) in Piemonte, Turin, Italy .
    Fiorentino, Michelangelo
    Pathology Service, Addarii Institute of Oncology, Sant’ Orsola-Malpighi Hospital, Bologna, Italy.
    Giunchi, Francesca
    Pathology Service, Addarii Institute of Oncology, Sant’ Orsola-Malpighi Hospital, Bologna, Italy.
    Grasso, Chiara
    Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy; Centro di Riferimento per l ’ Epidemiologia e la Prevenzione Oncologica (CPO) in Piemonte, Turin, Italy .
    Lianas, Luca
    Data-Intensive Com puting Division, Center for Advanced Studies, Research and Development in Sardinia, Pula, Italy.
    Mascia, Cecilia
    Data-Intensive Com puting Division, Center for Advanced Studies, Research and Development in Sardinia, Pula, Italy.
    Molinaro, Luca
    Division of Pathology, Azienda Os pedaliero-Universitaria Città della Salute e della Scienza Hospital, Turin, Italy .
    Zanetti, Gianluigi
    Data-Intensive Com puting Division, Center for Advanced Studies, Research and Development in Sardinia, Pula, Italy.
    Richiardi, Lorenzo
    Cancer Epidemiology Unit, Department of Medical Sciences, University of Turin, Turin, Italy; Centro di Riferimento per l ’ Epidemiologia e la Prevenzione Oncologica (CPO) in Piemonte, Turin, Italy .
    Pettersson, Andreas
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Akre, Olof
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Urology, Karolinska University Hospital, Stockholm, Sweden.
    Estimation of Relative and Absolute Risks in a Competing-Risks Setting Using a Nested Case-Control Study Design: Example From the ProMort Study2019In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 188, no 6, p. 1165-1173Article in journal (Refereed)
    Abstract [en]

    In this paper, we describe the Prognostic Factors for Mortality in Prostate Cancer (ProMort) study and use it to demonstrate how the weighted likelihood method can be used in nested case-control studies to estimate both relative and absolute risks in the competing-risks setting. ProMort is a case-control study nested within the National Prostate Cancer Register (NPCR) of Sweden, comprising 1,710 men diagnosed with low- or intermediate-risk prostate cancer between 1998 and 2011 who died from prostate cancer (cases) and 1,710 matched controls. Cause-specific hazard ratios and cumulative incidence functions (CIFs) for prostate cancer death were estimated in ProMort using weighted flexible parametric models and compared with the corresponding estimates from the NPCR cohort. We further drew 1,500 random nested case-control subsamples of the NPCR cohort and quantified the bias in the hazard ratio and CIF estimates. Finally, we compared the ProMort estimates with those obtained by augmenting competing-risks cases and by augmenting both competing-risks cases and controls. The hazard ratios for prostate cancer death estimated in ProMort were comparable to those in the NPCR. The hazard ratios for dying from other causes were biased, which introduced bias in the CIFs estimated in the competing-risks setting. When augmenting both competing-risks cases and controls, the bias was reduced.

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