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  • 1. Adolfsson, Jan
    et al.
    Garmo, Hans
    Varenhorst, Eberhard
    Ahlgren, Göran
    Ahlstrand, Christer
    Andren, Ove
    Örebro University, School of Health and Medical Sciences.
    Bill-Axelson, Anna
    Bratt, Ola
    Damber, Jan-Erik
    Hellström, Karin
    Hellström, Magnus
    Holmberg, Erik
    Holmberg, Lars
    Hugosson, Jonas
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Petterson, Bill
    Törnblom, Magnus
    Widmark, Anders
    Stattin, Pär
    Clinical characteristics and primary treatment of prostate cancer in Sweden between 1996 and 2005: Data from the national prostate cancer register in Sweden2007In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 41, no 6, p. 456-477Article in journal (Refereed)
    Abstract [en]

    Objective. The incidence of prostate cancer is rising rapidly in Sweden and there is a need to better understand the pattern of diagnosis, tumor characteristics and treatment. Material and methods. Between 1996 and 2005, all new cases of adenocarcinoma of the prostate gland were intended to be registered in the National Prostate Cancer Register (NPCR). This register contains information on diagnosing unit, date of diagnosis, cause of diagnosis, tumor grade, tumor stage according to the TNM classification in force, serum prostate-specific antigen (PSA) levels at diagnosis and primary treatment given within the first 6 months after diagnosis. Results. In total, 72 028 patients were registered, comprising >97% of all pertinent incident cases of prostate cancer in the Swedish Cancer Register (SCR). During the study period there was a considerable decrease in median age at the time of diagnosis, a stage migration towards smaller tumors, a decrease in median serum PSA values at diagnosis, a decrease in the age-standardized incidence rate of men diagnosed with distant metastases or with a PSA level of >100 ng/ml at diagnosis and an increase in the proportion of tumors with Gleason score ≤6. Relatively large geographical differences in the median age at diagnosis and the age-standardized incidence of cases with category T1c tumors were observed. Treatment with curative intent increased dramatically and treatment patterns varied according to geographical region. In men with localized tumors and a PSA level of <20 ng/ml at diagnosis, expectant treatment was more commonly used in those aged ≥75 years than in those aged <75 years. Also, the pattern of endocrine treatment varied in different parts of Sweden. Conclusions. All changes in the register seen over time are consistent with increased diagnostic activity, especially PSA testing, resulting in an increased number of cases with early disease, predominantly tumors in category T1c. The patterns of diagnosis and treatment of prostate cancer vary considerably in different parts of Sweden. The NPCR continues to be an important source for research, epidemiological surveillance of the incidence, diagnosis and treatment of prostate cancer

  • 2.
    Ali, Imran
    et al.
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Julin, Bettina
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Glynn, Anders
    The National Food Agency, Uppsala, Sweden.
    Högberg, Johan
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Berglund, Marika
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Jan-Erik
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Giovannucci, Edward
    Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston MA, United States; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston MA, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, United States.
    Wolk, Alicja
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Stenius, Ulla
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Åkesson, Agneta
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Exposure to polychlorinated biphenyls and prostate cancer: population-based prospective cohort and experimental studies2016In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 37, no 12, p. 1144-1151Article in journal (Refereed)
    Abstract [en]

    Polychlorinated biphenyls (PCBs) are highly persistent environmental pollutants and are undesirable components of our daily food. PCBs are classified as human carcinogens, but the evidence for prostate cancer is limited and available data are inconsistent. We explored the link between non-dioxin-like PCB and grade of prostate cancer in a prospective cohort as well as in cell experiments. A population-based cohort of 32496 Swedish men aged 45-79 years was followed prospectively through 1998-2011, to assess the association between validated estimates of dietary PCB exposure and incidence of prostate cancer by grade (2789 cases, whereof 1276 low grade, 756 intermediate grade, 450 high grade) and prostate cancer mortality (357 fatal cases). In addition, we investigated a non-dioxin-like PCB153-induced cell invasion and related markers in normal prostate stem cells (WPE-stem) and in three different prostate cancer cell lines (PC3, DU145 and 22RV1) at exposure levels relevant to humans. After multivariable-adjustment, dietary PCB exposure was positively associated with high-grade prostate cancer, relative risk (RR) 1.35 [95% confidence interval (CI): 1.03-1.76] and with fatal prostate cancer, RR 1.43 (95% CI: 1.05-1.95), comparing the highest tertile with the lowest. We observed no association with low or intermediate grade of prostate cancer. Cell invasion and related markers, including MMP9, MMP2, Slug and Snail, were significantly increased in human prostate cancer cells as well as in prostate stem cells after exposure to PCB153. Our findings both from the observational and experimental studies suggest a role of non-dioxin-like PCB153 in the development of high-grade and fatal prostate cancer.

  • 3.
    Andersson, Swen-Olof
    et al.
    Örebro University, School of Health and Medical Sciences.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Lyth, J.
    Stark, JR
    Henriksson, M.
    Adami, HO
    Carlsson, P.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Managing localized prostate cancer by radical prostatectomy or watchful waiting: cost analysis of a randomized trial (SPCG-4)2011In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 45, no 3, p. 177-183Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The cost of radical prostatectomy (RP) compared to watchful waiting (WW) has never been estimated in a randomized trial. The goal of this study was to estimate long-term total costs per patient associated with RP and WW arising from inpatient and outpatient hospital care.

    MATERIAL AND METHODS: This investigation used the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial, comparing RP to WW, and included data from 212 participants living in two counties in Sweden from 1989 to 1999 (105 randomized to WW and 107 to RP). All costs were included from randomization date until death or end of follow-up in July 2007. Resource use arising from inpatient and outpatient hospital costs was measured in physical units and multiplied by a unit cost to come up with a total cost per patient.

    RESULTS: During a median follow-up of 12 years, the overall cost in the RP group was 34% higher (p < 0.01) than in the WW group, corresponding to €6123 in Sweden. The difference was driven almost exclusively by the cost of the surgical procedure. The cost difference between RP and WW was two times higher among men with low (2-6) than among those with high (7-10) Gleason score.

    CONCLUSION: In this economic evaluation of RP versus WW of localized prostate cancer in a randomized study, RP was associated with 34% higher costs. This difference, attributed exclusively to the cost of the RP procedure, was not overcome during extended follow-up.

  • 4.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Natural history and prognostic factors in localized prostate cancer2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The natural history of localized prostate cancer is not fully understood. In most patients the tumor will never progress to a lethal disease, while a subset of patients will ultimately die of the disease. Efficient tools to separate indolent from lethal disease is currently lacking which means that many patients will be offered treatment without any benefit, but still be at risk of experiencing treatment related side effects.

    The aims of these studies were to get more insight into the natural history of untreated localized prostate cancer, to assess the prognostic value of established clinical parameters such as Gleason score, nuclear grade and tumor volume and, moreover, some new prognostic markers Ki-67, AMACR and MUC-1. We also aimed to study time trends in the detection of incidental tumors in Sweden.

    Patients with localized disease (n=223) and no initial treatment were followed for 21 years. Most patients had a favorable outcome. However, a subset of patients developed lethal disease even beyond 15 years of follow-up and these patients define the group that may benefit most from treatment with curative intent. Patients with poorly differentiated tumors experienced a 9 time higher risk of dying in prostate cancer.

    The studies on prognostic markers are based on a cohort of patients (n=253) with incidental prostate cancer detected by transurethral resection for presumed benign hyperplasia. All patients were left without initial treatment. Gleason grade, nuclear grade and tumor volume turned all out to be independent prognostic factors. MUC-1, AMACR and Ki-67 also carried prognostic information. However, after adjustment for Gleason grade, nuclear grade and tumor volume only MUC-1 and AMACR remained as statistically significant prognostic factors. When tested for sensitivity and specificity they all failed and, consequently, they seem to be of less value in daily practice for cancelling an individual patient regarding the choice of treatment.

    Time trends in incidental prostate tumors in Sweden were analyzed in a cohort of patients with prostate tumors detected by transurethral resection (TUR-P). Through linkage of the national registration number (NRN) with several registers, e.g. the Swedish Cancer Registry, the National Inpatient registry and the Cause of Death Registry we identified, during the period 1970 through 2003, in total 23288 patients with incidental prostate cancer, who constituted the study group. As comparison group we choose all patients diagnosed with prostate cancer between 1970-2003 excluding those with incidental cancer, in total 112204 patients. Our result confirms earlier findings that there has been a dramatic change over time in incidence of incidental prostate cancers in Sweden, which parallels the introduction of prostate specific antigen. We also found that the cumulative incidence of prostate cancer death is high in the incidental group, opposing earlier findings that incidental tumours are a non-lethal disease.

    List of papers
    1. Natural history of early, localized prostate cancer
    Open this publication in new window or tab >>Natural history of early, localized prostate cancer
    Show others...
    2004 (English)In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 291, no 22, p. 2713-2719Article in journal (Refereed) Published
    Abstract [en]

    Context Among men with early prostate cancer, the natural history without initial therapy determines the potential for survival benefit following radical local treatment. However, little is known about disease progression and mortality beyond 10 to 15 years of watchful waiting. Objective To examine the long-term natural history of untreated, early stage prostatic cancer. Design Population-based, cohort study with a mean observation period of 21 years. Setting Regionally well-defined catchment area in central Sweden (recruitment March 1977 through February 1984). Patients A consecutive sample of 223 patients (98% of all eligible) with early-stage (T0-T2 NX MO classification), initially untreated prostatic cancer. Patients with tumor progression were hormonally treated (either by orchiectomy or estrogens) if they had symptoms. Main Outcome Measures Progression-free, cause-specific, and overall survival. Results After complete follow-up, 39 (17%) of all patients experienced generalized disease. Most cancers had an indolent course during the first 10 to 15 years. However, further follow-up from 15 (when 49 patients were still alive) to 20 years, revealed a substantial decrease in cumulative progression-free survival (from 45.0% to 36.0%), survival without metastases (from 76.9% to 51.2%), and prostate cancer-specific survival (from 78.7% to 54.4%). The prostate cancer mortality rate increased from 15 per 1000 person-years (95% confidence interval, 10-21) during the first 15 years to 44 per 1000 person-years (95% confidence interval, 22-88) beyond 15 years of follow-up (P=.01). Conclusion Although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. These findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.

    National Category
    Surgery
    Research subject
    Surgery esp. Urology Specific
    Identifiers
    urn:nbn:se:oru:diva-15599 (URN)10.1001/jama.291.22.2713 (DOI)000221862300025 ()
    Available from: 2011-05-18 Created: 2011-05-18 Last updated: 2017-12-11Bibliographically approved
    2. How well does the Gleason score predict prostate cancer death?: A 20-year followup of a population based cohort in Sweden
    Open this publication in new window or tab >>How well does the Gleason score predict prostate cancer death?: A 20-year followup of a population based cohort in Sweden
    Show others...
    2006 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 175, no 4, p. 1337-1340Article in journal (Refereed) Published
    Abstract [en]

    Purpose

    Adenocarcinoma of the prostate is the most common cancer among men in Western countries. Although the prognostic heterogeneity of prostate cancer is enormous, clinically insignificant aggressive prostate cancers cannot be reliably distinguished. Therefore, identifying prognostic factors is increasingly important, notably among men diagnosed with localized prostate cancer, because many of them may not require aggressive treatment.

    Materials and Methods

    We analyzed a population based cohort of 253 men with early stage (T1a-b, Nx, M0) initially untreated prostate cancer diagnosed between 1977 and 1991, before PSA screening was available. Tissue samples were available for 240 patients diagnosed with transurethral resection. During complete followup through September 2003, standardized criteria were used to classify histopathological characteristics, progression and causes of death.

    Results

    Higher Gleason grade, higher nuclear grade and larger tumor volume were independent predictors of death in prostate cancer with monotonous and statistically significant trends (p <0.05). In contrast, the level of Ki-67 – strongly correlated to Gleason score – was not an independent predictor of prostate cancer death. Given a Gleason score of 7 or greater, the probability of dying of prostate cancer was 29%. The corresponding predictive value for Gleason score 8 or greater was 48%.

    Conclusions

    Although a high Gleason score is a determinant of prostate cancer death, its PPV is relatively low. Thus, further efforts in finding other or complementary indicators of prostate cancer outcome are needed.

    Place, publisher, year, edition, pages
    Baltimore: Williams and Wilkins Co., 2006
    National Category
    Medical and Health Sciences Surgery Urology and Nephrology
    Research subject
    Surgery esp. Urology Specific
    Identifiers
    urn:nbn:se:oru:diva-5067 (URN)10.1016/S0022-5347(05)00734-2 (DOI)
    Available from: 2009-01-26 Created: 2009-01-26 Last updated: 2017-12-14Bibliographically approved
    3. Decreased alpha-methylacyl CoA racemase expression in localized prostate cancer is associated with an increased rate of biochemical recurrence and cancer-specific death
    Open this publication in new window or tab >>Decreased alpha-methylacyl CoA racemase expression in localized prostate cancer is associated with an increased rate of biochemical recurrence and cancer-specific death
    Show others...
    2005 (English)In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 14, no 6, p. 1424-1432Article in journal (Refereed) Published
    Abstract [en]

    alpha-Methylacyl CoA racemase (AMACR) is overexpressed in prostate cancer relative to benign prostatic tissue. AMACR expression is highest in localized prostate cancer and decreases in metastatic prostate cancer. Herein, we explored the use of AMACR as a biomarker for aggressive prostate cancer. AMACR protein expression was determined by immunohistochemistry using an image analysis system on two localized prostate cancer cohorts consisting of 204 men treated by radical prostatectomy and 188 men followed expectantly. The end points for the cohorts were time to prostate-specific antigen (PSA) failure (i.e., elevation > 0.2 ng/mL) and time to prostate cancer death in the watchful waiting cohort. Using a regression tree method, optimal AMACR protein expression cutpoints were determined to best differentiate prostate cancer outcome in each of the cohorts separately. Cox proportional hazard models were then employed to examine the effect of the AMACR cutpoint on prostate cancer outcome, and adjusted for clinical variables. Lower AMACR tissue expression was associated with worse prostate cancer outcome, independent of clinical variables (hazard ratio, 3.7 for PSA failure; P = 0.018; hazard ratio, 4.1 for prostate cancer death, P = 0.0006). Among those with both low AMACR expression and high Gleason score, the risk of prostate cancer death was 18-fold higher (P = 0.006). The AMACR cutpoint developed using prostate cancer-specific death as the end point predicted PSA failures independent of Gleason score, PSA, and margin status. This is the first study to show that AMACR expression is significantly associated with prostate cancer progression and suggests that not all surrogate end points may be optimal to define biomarkers of aggressive prostate cancer.

    National Category
    Surgery
    Research subject
    Surgery esp. Urology Specific
    Identifiers
    urn:nbn:se:oru:diva-15600 (URN)10.1158/1055-9965.EPI-04-0801 (DOI)000229766600017 ()
    Available from: 2011-05-18 Created: 2011-05-18 Last updated: 2017-12-11Bibliographically approved
    4. MUC-1 gene is associated with prostate cancer death: a 20-year follow-up of a population-based study in Sweden
    Open this publication in new window or tab >>MUC-1 gene is associated with prostate cancer death: a 20-year follow-up of a population-based study in Sweden
    Show others...
    2007 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 97, no 6, p. 730-734Article in journal (Refereed) Published
    Abstract [en]

    Anti-adhesion mucins have proven to play an important part in the biology of several types of cancer. Therefore, we test the hypothesis that altered expression of MUC-1 is associated with prostate cancer progression. We retrieved archival tumour tissue from a population-based cohort of 195 men with localised prostate cancer (T1a-b, Nx, M0) that has been followed for up to 20 years with watchful waiting. Semi-automated, quantitative immunohistochemistry was undertaken to evaluate MUC-1 expression. We modelled prostate cancer-specific death as a function of MUC-1 levels accounting for age, Gleason grade and tumour extent, and calculated age-adjusted and multivariate adjusted hazard ratios (HR). Men that had tumours with an MUC-intensity lower or higher than normal tissue had a higher risk of dying in prostate cancer, independent of tumour extent and Gleason score (HR 5.1 and 4.5, respectively). Adjustment for Gleason grade and tumour stage did not alter the results. Men with a Gleason score >=7 and MUC-1 deviating from the normal had a 17 (RR=17.1 95% confidence interval=2.3–128) times higher risk to die in prostate cancer compared with men with Gleason score <7 and normal MUC-1 intensity. In summary, our data show that MUC-1 is an independent prognostic marker for prostate cancer death.

    Place, publisher, year, edition, pages
    London: Harcourt Publishers, 2007
    National Category
    Medical and Health Sciences Surgery Cancer and Oncology
    Research subject
    Oncology; Surgery esp. Urology Specific
    Identifiers
    urn:nbn:se:oru:diva-5063 (URN)10.1038/sj.bjc.6603944 (DOI)
    Available from: 2009-01-26 Created: 2009-01-26 Last updated: 2017-12-14Bibliographically approved
    5. Time trends and survival among men diagnosed with incidental prostate cancer in Sweden: a register-based study between 1970 and 2003
    Open this publication in new window or tab >>Time trends and survival among men diagnosed with incidental prostate cancer in Sweden: a register-based study between 1970 and 2003
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Surgery
    Research subject
    Surgery esp. Urology Specific
    Identifiers
    urn:nbn:se:oru:diva-15601 (URN)
    Available from: 2011-05-18 Created: 2011-05-18 Last updated: 2017-10-17Bibliographically approved
  • 5.
    Andrén, Ove
    et al.
    Örebro University, School of Health and Medical Sciences.
    Fall, Katja
    Andersson, Swen-Olof
    Rubin, Mark A.
    Bismar, Tarek A.
    Karlsson, M.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Mucci, Lorelei A.
    MUC-1 gene is associated with prostate cancer death: a 20-year follow-up of a population-based study in Sweden2007In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 97, no 6, p. 730-734Article in journal (Refereed)
    Abstract [en]

    Anti-adhesion mucins have proven to play an important part in the biology of several types of cancer. Therefore, we test the hypothesis that altered expression of MUC-1 is associated with prostate cancer progression. We retrieved archival tumour tissue from a population-based cohort of 195 men with localised prostate cancer (T1a-b, Nx, M0) that has been followed for up to 20 years with watchful waiting. Semi-automated, quantitative immunohistochemistry was undertaken to evaluate MUC-1 expression. We modelled prostate cancer-specific death as a function of MUC-1 levels accounting for age, Gleason grade and tumour extent, and calculated age-adjusted and multivariate adjusted hazard ratios (HR). Men that had tumours with an MUC-intensity lower or higher than normal tissue had a higher risk of dying in prostate cancer, independent of tumour extent and Gleason score (HR 5.1 and 4.5, respectively). Adjustment for Gleason grade and tumour stage did not alter the results. Men with a Gleason score >=7 and MUC-1 deviating from the normal had a 17 (RR=17.1 95% confidence interval=2.3–128) times higher risk to die in prostate cancer compared with men with Gleason score <7 and normal MUC-1 intensity. In summary, our data show that MUC-1 is an independent prognostic marker for prostate cancer death.

  • 6.
    Andrén, Ove
    et al.
    Örebro University, Department of Clinical Medicine.
    Fall, Katja
    Franzén, Lennart
    Andersson, Swen-Olof
    Johansson, Jan-Erik
    Rubin, Mark A.
    How well does the Gleason score predict prostate cancer death?: A 20-year followup of a population based cohort in Sweden2006In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 175, no 4, p. 1337-1340Article in journal (Refereed)
    Abstract [en]

    Purpose

    Adenocarcinoma of the prostate is the most common cancer among men in Western countries. Although the prognostic heterogeneity of prostate cancer is enormous, clinically insignificant aggressive prostate cancers cannot be reliably distinguished. Therefore, identifying prognostic factors is increasingly important, notably among men diagnosed with localized prostate cancer, because many of them may not require aggressive treatment.

    Materials and Methods

    We analyzed a population based cohort of 253 men with early stage (T1a-b, Nx, M0) initially untreated prostate cancer diagnosed between 1977 and 1991, before PSA screening was available. Tissue samples were available for 240 patients diagnosed with transurethral resection. During complete followup through September 2003, standardized criteria were used to classify histopathological characteristics, progression and causes of death.

    Results

    Higher Gleason grade, higher nuclear grade and larger tumor volume were independent predictors of death in prostate cancer with monotonous and statistically significant trends (p <0.05). In contrast, the level of Ki-67 – strongly correlated to Gleason score – was not an independent predictor of prostate cancer death. Given a Gleason score of 7 or greater, the probability of dying of prostate cancer was 29%. The corresponding predictive value for Gleason score 8 or greater was 48%.

    Conclusions

    Although a high Gleason score is a determinant of prostate cancer death, its PPV is relatively low. Thus, further efforts in finding other or complementary indicators of prostate cancer outcome are needed.

  • 7.
    Andrén, Ove
    et al.
    Örebro University, School of Health and Medical Sciences.
    Garmo, Hans
    Mucci, Lorelei
    Andersson, Swen-Olof
    Johansson, Jan-Erik
    Fall, Katja
    Time trends and survival among men diagnosed with incidental prostate cancer in Sweden: a register-based study between 1970 and 2003Manuscript (preprint) (Other academic)
  • 8.
    Andrén, Ove
    et al.
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Widmark, A.
    Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    Fält, A.
    Ulvskog, E.
    Örebro University, School of Medical Sciences. Department of Oncology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Davidsson, Sabina
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Karlsson, C. Thellenberg
    Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
    Hjälm-Eriksson, M.
    Department of Oncology, Karolinska Institute, Stockholm, Sweden.
    Cabazitaxel followed by androgen deprivation therapy (ADT) significantly improves time to progression in patients with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC): A randomized, open label, phase III, multicenter trial2017In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no Suppl. 5, article id 811PArticle in journal (Other academic)
  • 9.
    Bill-Axelson, Anna
    et al.
    Dept Surg Sci, Univ Uppsala Hosp, Uppsala, Sweden.
    Holmberg, Lars
    Reg Canc Ctr Uppsala Orebro, Univ Uppsala Hosp, Uppsala, Sweden; Sch Med, Div Canc Studies, Kings Coll London, London, England.
    Garmo, Hans
    Reg Canc Ctr Uppsala Orebro, Univ Uppsala Hosp, Uppsala, Sweden; Sch Med, Div Canc Studies, Kings Coll London, London , England.
    Rider, Jennifer R.
    Dept Med, Channing Lab, Brigham & Womens Hosp, Boston MA, USA; Sch Med, Harvard Univ, Boston MA, USA; Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston MA, USA.
    Taari, Kimmo
    Cent Hosp, Dept Urol, Univ Helsinki, Helsinki, Finland.
    Busch, Christer
    Dept Immunol Genet & Pathol, Univ Uppsala Hosp, Uppsala, Sweden.
    Nordling, Stig
    Dept Pathol, Univ Helsinki, Helsinki, Finland.
    Häggman, Michael
    Dept Surg Sci, Univ Uppsala Hosp, Uppsala, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept Urol, Örebro University Hospital, Örebro, Sweden.
    Spångberg, Anders
    Dept Urol, Linköping, Linköping Univ Hosp, Linköping, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept Urol, Örebro University Hospital, Örebro, Sweden.
    Palmgren, Juni
    Dept Med Epidemiol & Biostat, Karolinska Inst, Stockholm, Sweden.
    Steineck, Gunnar
    Dept Pathol & Oncol, Div Clin Canc Epidemiol, Karolinska Inst, Stockholm, Sweden; Div Clin Canc Epidemiol, Sahlgrenska Academy, Gothenburg, Sweden.
    Adami, Hans-Olov
    Dept Med Epidemiol & Biostat, Karolinska Inst, Stockholm, Sweden; Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston MA, USA.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept Urol, Örebro University Hospital, Örebro, Sweden.
    Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer2014In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 370, no 10, p. 932-942Article in journal (Refereed)
    Abstract [en]

    Background: Radical prostatectomy reduces mortality among men with localized prostate cancer; however, important questions regarding long-term benefit remain.

    Methods: Between 1989 and 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy and followed them through the end of 2012. The primary end points in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) were death from any cause, death from prostate cancer, and the risk of metastases. Secondary end points included the initiation of androgen-deprivation therapy.

    Results: During 23.2 years of follow-up, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died. Of the deaths, 63 in the surgery group and 99 in the watchful-waiting group were due to prostate cancer; the relative risk was 0.56 (95% confidence interval [CI], 0.41 to 0.77; P=0.001), and the absolute difference was 11.0 percentage points (95% CI, 4.5 to 17.5). The number needed to treat to prevent one death was 8. One man died after surgery in the radical-prostatectomy group. Androgen-deprivation therapy was used in fewer patients who underwent prostatectomy (a difference of 25.0 percentage points; 95% CI, 17.7 to 32.3). The benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age (relative risk, 0.45) and in those with intermediate-risk prostate cancer (relative risk, 0.38). However, radical prostatectomy was associated with a reduced risk of metastases among older men (relative risk, 0.68; P=0.04).

    Conclusions: Extended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment. (Funded by the Swedish Cancer Society and others.)

    The randomized Swedish trial of prostatectomy versus watchful waiting in disease detected mainly clinically (not by PSA screening) continues to show a benefit for early prostatectomy. The number of men younger than 65 needed to treat to prevent one death is now four. The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), a randomized trial of radical prostatectomy versus watchful waiting in men with localized prostate cancer diagnosed before the era of prostate-specific antigen (PSA) testing, showed a survival benefit of radical prostatectomy as compared with observation at 15 years of follow-up.(1) By contrast, the Prostate Cancer Intervention versus Observation Trial (PIVOT), initiated in the early era of PSA testing, showed that radical prostatectomy did not significantly reduce prostate cancer-specific or overall mortality after 12 years.(2) PSA screening profoundly changes the clinical domain of study. Among other considerations, the substantial additional lead time ...

  • 10.
    Bill-Axelson, Anna
    et al.
    Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Holmberg, Lars
    Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden; School of Medicine, Division of Cancer Studies, Sweden hSchool of Cancer and Pharmaceutical Sciences, King’s College London, London, United Kingdom.
    Garmo, Hans
    Regional Cancer Center Uppsala, Uppsala University Hospital, Uppsala, Sweden; School of Medicine, Division of Cancer Studies, Sweden, London, United Kingdom.
    Taari, Kimmo
    Department of Urology, Helsinki University Hospital, Helsinki, Finland..
    Busch, Christer
    Uppsala University Hospital, Department of Pathology, Uppsala, Sweden.
    Nordling, Stig
    Department of Pathology, University of Helsinki, Helsinki, Finland.
    Häggman, Michael
    Department of Surgical Sciences, Uppsala University Hospital, Uppsala, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Steineck, Gunnar
    Division of Clinical Cancer Epidemiology, Sahlgrenska Academy, Gothenburg, Sweden.
    Adami, Hans-Olov
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T.C. Chan School of Public Health, Boston, United States; Clinical Effectiveness Research Group, Institute of Health and Society, University of Oslo, Oslo, Norway.
    Johansson, Jan-Erik
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Radical Prostatectomy or Watchful Waiting in Prostate Cancer-29-Year Follow-up2018In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, no 24, p. 2319-2329Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Radical prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from randomized trials with long-term followup is sparse.

    METHODS: We randomly assigned 695 men with localized prostate cancer to watchful waiting or radical prostatectomy from October 1989 through February 1999 and collected follow-up data through 2017. Cumulative incidence and relative risks with 95% confidence intervals for death from any cause, death from prostate cancer, and metastasis were estimated in intention-to-treat and per-protocol analyses, and numbers of years of life gained were estimated. We evaluated the prognostic value of histopathological measures with a Cox proportional-hazards model.

    RESULTS: By December 31, 2017, a total of 261 of the 347 men in the radical-prostatectomy group and 292 of the 348 men in the watchful-waiting group had died; 71 deaths in the radical-prostatectomy group and 110 in the watchful-waiting group were due to prostate cancer (relative risk, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001; absolute difference in risk, 11.7 percentage points; 95% CI, 5.2 to 18.2). The number needed to treat to avert one death from any cause was 8.4. At 23 years, a mean of 2.9 extra years of life were gained with radical prostatectomy. Among the men who underwent radical prostatectomy, extracapsular extension was associated with a risk of death from prostate cancer that was 5 times as high as that among men without extracapsular extension, and a Gleason score higher than 7 was associated with a risk that was 10 times as high as that with a score of 6 or lower (scores range from 2 to 10, with higher scores indicating more aggressive cancer).

    CONCLUSIONS: Men with clinically detected, localized prostate cancer and a long life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer.

  • 11.
    Blattner, Mirjam
    et al.
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York, USA.
    Lee, Daniel J.
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York, USA; Dept Urol, Weill Med Coll, Cornell Univ, New York, USA.
    O'Reilly, Catherine
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA.
    Park, Kyung
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA.
    MacDonald, Theresa Y.
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA.
    Khani, Francesca
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA.
    Turner, Kevin R.
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA.
    Chiu, Ya-Lin
    Dept Biostat & Epidemiol, Weill Med Coll, Cornell Univ, New York NY, USA.
    Wild, Peter J.
    Inst Surg Pathol, Univ Zurich Hosp, Zurich, Switzerland.
    Dolgalev, Igor
    Human Oncol & Pathogenesis Program, Mem Sloan Kettering Canc Ctr, New York NY, USA.
    Heguy, Adriana
    Human Oncol & Pathogenesis Program, Mem Sloan Kettering Canc Ctr, New York NY, USA.
    Sboner, Andrea
    Dept Pathol & Lab Med, Inst Precis Med, New York NY, USA; Weill Med Coll, Cornell Univ, Inst Computat Biomed, New York, NY, USA; Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA.
    Ramazangolu, Sinan
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA; Inst Computat Biomed, Weill Med Coll, Cornell Univ, New York NY, USA.
    Hieronymus, Haley
    Inst Computat Biomed, Weill Med Coll, Cornell Univ, New York NY, USA.
    Sawyers, Charles
    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York NY, USA.
    Tewari, Ashutosh K.
    Dept Urol, Weill Med Coll, Cornell Univ, New York NY, USA.
    Moch, Holger
    Inst Surg Pathol, Univ Zurich Hosp, Zurich, Switzerland.
    Yoon, Ghil Suk
    Sch Med, Dept Pathol, Kyungpook Natl Univ, Taegu, South Korea.
    Known, Yong Chul
    Sch Med, Dept Pathol, Catholic Univ Daegu, Taegu, South Korea.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Dept Urol, Örebro University Hospital, Örebro, Sweden.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Demichelis, Francecsa
    Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA; Ctr Integrat Biol, Univ Trento, Trento, Italy.
    Mosquera, Juan Miguel
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA.
    Robinson, Brian D.
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA; Dept Urol, Weill Med Coll, Cornell Univ, New York NY, USA .
    Barbieri, Christopher E.
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA; Dept Urol, Weill Med Coll, Cornell Univ, New York NY, USA .
    Rubin, Mark A.
    Dept Pathol & Lab Med, Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA; Dept Urol, Weill Med Coll, Cornell Univ, New York NY, USA; Inst Precis Med, Weill Med Coll, Cornell Univ, New York NY, USA .
    SPOP Mutations in Prostate Cancer across Demographically Diverse Patient Cohorts2014In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, no 1, p. 14-U34Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recurrent mutations in the Speckle-Type POZ Protein (SPOP) gene occur in up to 15% of prostate cancers. However, the frequency and features of cancers with these mutations across different populations is unknown.

    OBJECTIVE: To investigate SPOP mutations across diverse cohorts and validate a series of assays employing high-resolution melting (HRM) analysis and Sanger sequencing for mutational analysis of formalin-fixed paraffin-embedded material.

    DESIGN, SETTING, AND PARTICIPANTS: 720 prostate cancer samples from six international cohorts spanning Caucasian, African American, and Asian patients, including both prostate-specific antigen-screened and unscreened populations, were screened for their SPOP mutation status. Status of SPOP was correlated to molecular features (ERG rearrangement, PTEN deletion, and CHD1 deletion) as well as clinical and pathologic features.

    RESULTS AND LIMITATIONS: Overall frequency of SPOP mutations was 8.1% (4.6% to 14.4%), SPOP mutation was inversely associated with ERG rearrangement (P < .01), and SPOP mutant (SPOPmut) cancers had higher rates of CHD1 deletions (P < .01). There were no significant differences in biochemical recurrence in SPOPmut cancers. Limitations of this study include missing mutational data due to sample quality and lack of power to identify a difference in clinical outcomes.

    CONCLUSION: SPOP is mutated in 4.6% to 14.4% of patients with prostate cancer across different ethnic and demographic backgrounds. There was no significant association between SPOP mutations with ethnicity, clinical, or pathologic parameters. Mutual exclusivity of SPOP mutation with ERG rearrangement as well as a high association with CHD1 deletion reinforces SPOP mutation as defining a distinct molecular subclass of prostate cancer.

  • 12.
    Blattner, Mirjam
    et al.
    Weill Cornell Med Coll, New York NY, USA.
    Lee, Daniel
    Weill Cornell Med Coll, New York NY, USA.
    O'Reilly, Catherine
    Weill Cornell Med Coll, New York NY, USA.
    Park, Kyung
    Weill Cornell Med Coll, New York NY, USA.
    MacDonald, Theresa Y.
    Weill Cornell Med Coll, New York NY, USA.
    Khani, Francesca
    Weill Cornell Med Coll, New York NY, USA.
    Turner, Kevin
    Weill Cornell Med Coll, New York NY, USA.
    Wild, Peter J.
    Univ Zurich Hosp, Zurich, Switzerland.
    Hieronymus, Haley
    Mem Sloan Kettering Canc Ctr, New York NY, USA.
    Sawyers, Charles L.
    Mem Sloan Kettering Canc Ctr, New York NY, USA.
    Tewari, Ashutosh K.
    Weill Cornell Med Coll, New York, USA.
    Moch, Holger
    Univ Zurich Hosp, Zurich, Switzerland.
    Yoon, Ghil Suk
    Sch Med, Kyungpook Natl Univ, Daegu, South Korea.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Mosquera, Juan Miguel
    Weill Cornell Med Coll, New York NY, USA.
    Robinson, Brian D.
    Weill Cornell Med Coll, New York NY, USA.
    Sboner, Andrea
    Weill Cornell Med Coll, New York NY, USA.
    Barbierie, Christopher E.
    Weill Cornell Med Coll, New York NY, USA.
    Rubin, Mark A.
    Weill Cornell Med Coll, New York NY, USA.
    SPOP mutations in prostate cancer across demographically diverse patient cohorts2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19, article id 2244Article in journal (Other academic)
  • 13.
    Blomqvist, L.
    et al.
    Department of Diagnostic Radiology, Karolinska University Hospital, Solna, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden .
    Carlsson, S.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Urology, Karolinska University Hospital, Solna, Sweden.
    Gjertsson, P.
    Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Heintz, E.
    The Swedish Council on Health Technology Assessment, Stockholm, Sweden.
    Hultcrantz, M.
    The Swedish Council on Health Technology Assessment, Stockholm, Sweden.
    Mejare, I.
    The Swedish Council on Health Technology Assessment, Stockholm, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Limited evidence for the use of imaging to detect prostate cancer: a systematic review2014In: European Journal of Radiology, ISSN 0720-048X, E-ISSN 1872-7727, Vol. 83, no 9, p. 1601-1606Article, review/survey (Refereed)
    Abstract [en]

    Objective: To assess the diagnostic accuracy of imaging technologies for detecting prostate cancer in patients with elevated PSA-values or suspected findings on clinical examination.

    Methods: The databases Medline, EMBASE, Cochrane, CRD HTA/DARE/NHS EED and EconLit were searched until June 2013. Pre-determined inclusion criteria were used to select full text articles. Risk of bias in individual studies was rated according to QUADAS or AMSTAR. Abstracts and full text articles were assessed independently by two reviewers. The performance of diagnostic imaging was compared with systematic biopsies (reference standard) and sensitivity and specificity were calculated.

    Results: The literature search yielded 5141 abstracts, which were reviewed by two independent reviewers. Of these 4852 were excluded since they did not meet the inclusion criteria. 288 articles were reviewed in full text for quality assessment. Six studies, three using MRI and three using transrectal ultrasound were included. All were rated as high risk of bias. Relevant studies on PET/CT were not identified.

    Conclusion: Despite clinical use, there is insufficient evidence regarding the accuracy of imaging technologies for detecting cancer in patients with suspected prostate cancer using TRUS guided systematic biopsies as reference standard. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

  • 14.
    Bratt, Ola
    et al.
    Department of Urology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Holmberg, Erik
    Regional Cancer Centre, Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Gothenburg, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Carlsson, Stefan
    Section of Urology, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Drevin, Linda
    Regional Cancer Centre, Uppsala-Örebro, Uppsala, Sweden.
    Johansson, Eva
    Department of Urology, Academic Hospital, Uppsala, Sweden.
    Josefsson, Andreas
    Department of Urology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Nyberg, Maria
    Department of Urology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Sandberg, Jonas
    Department of Urology, Norrland University Hospital, Umeå, Sweden.
    Stattin, Pär
    Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Robinsson, David
    Department of Urology, Department of Urology, Jönköping County, Sweden.
    The Value of an Extensive Transrectal Repeat Biopsy with Anterior Sampling in Men on Active Surveillance for Low-risk Prostate Cancer: A Comparison from the Randomised Study of Active Monitoring in Sweden (SAMS)2019In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 76, no 4, p. 461-466Article in journal (Refereed)
    Abstract [en]

    Background: A systematic repeat biopsy is recommended for men starting on active surveillance for prostate cancer, but the optimal number and distribution of cores are unknown.

    Objective: To evaluate an extensive repeat transrectal biopsy with anterior sampling in men starting on active surveillance.

    Design, setting, and participants: Randomised multicentre trial. From 2012 to 2016, 340 Swedish men, aged 40-75 yr, with recently diagnosed low-volume Gleason grade group 1 prostate cancer were included.

    Intervention: Either an extensive transrectal biopsy with anterior sampling (median 19 cores) or a standard transrectal biopsy (median 12 cores).

    Outcome measurements and statistical analysis: Primary outcome measure: Gleason grade group >= 2 cancer. Secondary outcomes: Cancer in anteriorly directed biopsy cores and postbiopsy infection. Nonparametric statistical tests were applied.

    Results and limitations: Gleason grade group >= 2 cancer was detected in 16% of 156 men who had an extensive biopsy and in 10% of 164 men who had a standard biopsy, a 5.7% difference (95% confidence interval [CI]-0.2% to 13%, p = 0.09). There was a strong linear association between prostate-specific antigen (PSA) density and cancer in the anteriorly directed biopsy cores. The odds ratios for cancer in the anteriorly directed cores were for any cancer 2.2 (95% CI 1.3-3.9, p = 0.004) and for Gleason grade group >= 2 cancer 2.3 (95% CI 1.2-4.4, p = 0.015) per 0.1-ng/ml/cm(3) increments. Postbiopsy infections were equally common in the two groups. A limitation is that magnetic resonance imaging was not used.

    Conclusions: The trial did not support general use of the extensive transrectal repeat biopsy template, but cancer in the anteriorly directed cores was common, particularly in men with high PSA density. The higher the PSA density, the stronger the reason to include anterior sampling at a systematic repeat biopsy.

    Patient summary: This trial compared two different templates for transrectal prostate biopsy in men starting on active surveillance for low-risk prostate cancer. Cancer was often found in the front part of the prostate, which is not sampled on a standard prostate biopsy. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  • 15. Braun, M.
    et al.
    Shaikhibrahim, Z.
    Menon, R.
    Offermann, A.
    Queisser, A.
    Boehm, D.
    Vogel, W.
    Ruenauver, K.
    Ruiz, C.
    Zellweger, T.
    Svensson, Maria A.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Kristiansen, G.
    Wernert, N.
    Bubendorf, L.
    Perner, S.
    MED15, Encoding a Subunit of the Mediator Complex, Is Overexpressed at High Frequency in Castration-Resistant Prostate Cancer2014In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 27, p. 219A-219AArticle in journal (Other academic)
  • 16.
    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.

  • 17.
    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.

  • 18.
    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.

  • 19.
    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.

  • 20.
    Chetta, Paolo
    et al.
    Dana - Farber Cancer Institute, Boston MA, USA.
    Zadra, Giorgia
    Dana - Farber Cancer Institute, Boston MA, USA.
    Cangi, Maria Giulia
    IRCCS San Raffaele Scientific Institute, Milan, Italy.
    Francaviglia, Ilaria
    IRCCS San Raffaele Scientific Institute, Milan, Italy.
    Luciano, Roberta
    IRCCS San Raffaele Scientific Institute, Milan, Italy.
    Davidsson, Sabina
    Örebro University, Faculty of Medicine and Health, Örebro, Sweden.
    Tyekucheva, Svitlana
    Dana - Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston MA, USA.
    Bosari, Silvano
    Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
    Andrén, Ove
    Örebro University, School of Medical Sciences.
    Doglioni, Claudio
    University Vita - Salute San Raffaele, Milano, Italy.
    Loda, Massimo
    Dana - Farber Cancer Institute, Boston MA, USA.
    IDH1 Mutations Mark a High-Grade, Potentially Aggressive Variant of Prostate Cancer2019In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 32, no Suppl. 2Article in journal (Other academic)
  • 21.
    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.

  • 22.
    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.

  • 23.
    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.

  • 24.
    Davidsson, Sabina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fiorentino, Michelangelo
    Mol Pathol Lab, Addarii Inst Oncol, Dept Hematol Oncol, Univ Bologna, Bologna, Italy; Sch Med, Dana Farber Canc Inst, Dept Pathol, Brigham & Womens Hosp & Adult Oncol, Harvard Univ, Boston MA, USA.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fang, Fang
    Sch Med, Channing Lab, Dept Med, Brigham & Womens Hosp, Harvard Univ, Boston MA, USA; Dept Med Epidemiol & Biostat, Karolinska Inst, Stockholm, Sweden.
    Mucci, Lorelei A.
    Sch Publ Hlth, Dept Epidemiol, Harvard Univ, Boston MA, USA; Sch Med, Channing Lab, Dept Med, Brigham & Womens Hosp, Harvard Univ, Boston MA, USA.
    Varenhorst, Eberhard
    Dept Urol, Linköping Univ Hosp, Linköping, Sweden.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rider, Jennifer R.
    Dept Urol, Örebro Univ Hosp, Örebro, Sweden; Sch Med, Dana Farber Canc Inst, Dept Pathol, Brigham & Womens Hosp & Adult Oncol, Harvard Univ, Boston MA, USA.
    Inflammation, focal atrophic lesions, and prostatic intraepithelial neoplasia with respect to risk of lethal prostate cancer2011In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, no 10, p. 2280-2287Article in journal (Refereed)
    Abstract [en]

    Background: A challenge in prostate cancer (PCa) management is identifying potentially lethal disease at diagnosis. Inflammation, focal prostatic atrophy, and prostatic intraepithelial neoplasia (PIN) are common in prostate tumor specimens, but it is not clear whether these lesions have prognostic significance. Methods: We conducted a case-control study nested in a cohort of men diagnosed with stage T1a-b PCa through transurethral resection of the prostate in Sweden. Cases are men who died of PCa (n = 228). Controls are men who survived more than 10 years after PCa diagnosis without metastases (n = 387). Slides were assessed for Gleason grade, inflammation, PIN, and four subtypes of focal prostatic atrophy: simple atrophy (SA), postatrophic hyperplasia (PAH), simple atrophy with cyst formation, and partial atrophy. We estimated OR and 95% CI for odds of lethal PCa with multivariable logistic regression. Results: Chronic inflammation and PIN were more frequently observed in tumors with PAH, but not SA. No specific type of atrophy or inflammation was significantly associated with lethal PCa overall, but there was a suggestion of a positive association for chronic inflammation. Independent of age, Gleason score, year of diagnosis, inflammation, and atrophy type, men with PIN were 89% more likely to die of PCa (95% CI: 1.04-3.42). Conclusion: Our data show that PIN, and perhaps presence of moderate or severe chronic inflammation, may have prognostic significance for PCa. Impact: Lesions in tumor adjacent tissue, and not just the tumor itself, may aid in identification of clinically relevant disease. Cancer Epidemiol Biomarkers Prev; 20(10); 2280-7. (C) 2011 AACR.

  • 25.
    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)
  • 26.
    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.

  • 27.
    Davidsson, Sabina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Mölling, Paula
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Rider, Jennifer R.
    Karlsson, Mats G.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Elgh, Fredrik
    Andrén, Ove
    Örebro University, School of Medicine, Örebro University, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden.
    Prevalence and typing of Propionibacterium acnes in prostate tissue obtained from men with prostate cancer and from health controlsManuscript (preprint) (Other academic)
  • 28.
    Davidsson, Sabina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Ohlson, Anna-Lena
    Dept Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Meisner, Allison
    School of Public Health, Dept Epidemiology, Harvard University, Boston MA, USA.
    Fiorentino, Michelangelo
    School of Public Health, Dept Epidemiology, Harvard University, Boston MA, USA; Molecular Pathology Lab, Dept Hematological Oncology, Addarii Institute of Oncology, University of Bologna, Bologna, Italy.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Rider, Jennifer R
    School of Public Health, Dept Epidemiology and School of Medicine, Harvard Univ, Boston MA, USA; Dept Med, Channing Lab, Brigham & Womens Hosp, Boston MA, USA.
    CD4 helper T cells, CD8 cytotoxic T cells, and FOXP3(+) regulatory T cells with respect to lethal prostate cancer2013In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 26, no 3, p. 448-455Article in journal (Refereed)
    Abstract [en]

    Prostate cancer represents a major contributor to cancer mortality, but the majority of men with prostate cancer will die of other causes. Thus, a challenge is identifying potentially lethal disease at diagnosis. Conflicting results have been reported when investigating the relationship between infiltration of lymphocytes and survival in prostate cancer. One of the mechanisms suggested is the recruitment of regulatory T cells (T(regs)), a subpopulation of T cells that have a role in promoting tumor growth. T(regs) counteract tumor rejection through suppressive functions on the anti-immune response but their prognostic significance is still unknown. We report here the results of a conducted case-control study nested in a cohort of men treated with transurethral resection of the prostate and diagnosed incidentally with prostate cancer. Cases are men who died of prostate cancer (n=261) and controls are men who survived >10 years after their diagnosis (n=474). Infiltration of both T(helper) and T(cytotoxic) cells was frequently observed and the majority of the T(regs) were CD4(+). T(helper) or T(cytotoxic) cells were not associated with lethal prostate cancer. However, we found a nearly twofold increased risk of lethal prostate cancer when comparing the highest with the lowest quartile of CD4(+) T(reg) cells (95% confidence interval: 1.3-2.9). Our conclusion is that men with greater numbers of CD4(+) T(regs) in their prostate tumor environment have an increased risk of dying of prostate cancer. Identification of CD4(+) T(regs) in tumor tissue may predict clinically relevant disease at time of diagnosis independently of other clinical factors.Modern Pathology advance online publication, 5 October 2012; doi:10.1038/modpathol.2012.164.

  • 29.
    Davidsson, Sabina
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Elgh, Fredrik
    Örebro University, School of Health and Medical Sciences. Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Olsson, Jan
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Multilocus sequence typing and repetitive-sequence-based PCR (DiversiLab) for molecular epidemiological characterization of Propionibacterium acnes isolates of heterogeneous origin2012In: Anaerobe, ISSN 1075-9964, E-ISSN 1095-8274, Vol. 18, no 4, p. 392-399Article in journal (Refereed)
    Abstract [en]

    Propionibacterium acnes is a gram-positive bacillus predominantly found on the skin. Although it is considered an opportunistic pathogen it is also been associated with severe infections. Some specific P. acnes subtypes are hypothesized to be more prone to cause infection than others. Thus, the aim of the present study was to investigate the ability to discriminate between P. acnes isolates of a refined multilocus sequence typing (MLST) method and a genotyping method, DiversiLab, based on repetitive-sequence-PCR technology.

    The MLST and DiversiLab analysis were performed on 29 P. acnes isolates of diverse origins; orthopedic implant infections, deep infections following cardiothoracic surgery, skin, and isolates from perioperative tissue samples from prostate cancer. Subtyping was based on recA, tly, and Tc12S sequences.

    The MLST analysis identified 23 sequence types and displayed a superior ability to discriminate P. acnes isolates compared to DiversiLab and the subtyping. The highest discriminatory index was found when using seven genes. DiversiLab was better able to differentiate the isolates compared to the MLST clonal complexes of sequence types.

    Our results suggest that DiversiLab can be useful as a rapid typing tool for initial discrimination of P. acnes isolates. When better discrimination is required, such as for investigations of the heterogeneity of P. acnes isolates and its involvement in different pathogenic processes, the present MLST protocol is valuable.

  • 30. Demichelis, F.
    et al.
    Fall, K.
    Perner, S.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Schmidt, F.
    Setlur, S.R.
    Hoshida, Y.
    Mosquera, J-M.
    Pawitan, Y.
    Lee, C.
    Adami, H-O.
    Mucci, L.A.
    Kantoff, P.W.
    Andersson, S-O.
    Chinnaiyan, A.M.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Rubin, M.A.
    TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort2007In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 26, no 31, p. 4596-4599Article in journal (Refereed)
    Abstract [en]

    The identification of the TMPRSS2:ERG fusion in prostate cancer suggests that distinct molecular subtypes may define risk for disease progression. In surgical series, TMPRSS2:ERG fusion was identified in 50% of the tumors. Here, we report on a population-based cohort of men with localized prostate cancers followed by expectant (watchful waiting) therapy with 15% (17/111) TMPRSS2:ERG fusion. We identified a statistically significant association between TMPRSS2:ERG fusion and prostate cancer specific death (cumulative incidence ratio=2.7, P<0.01, 95% confidence interval=1.3–5.8). Quantitative reverse-transcription–polymerase chain reaction demonstrated high estrogen-regulated gene (ERG) expression to be associated with TMPRSS2:ERG fusion (P<0.005). These data suggest that TMPRSS2:ERG fusion prostate cancers may have a more aggressive phenotype, possibly mediated through increased ERG expression.

  • 31.
    Discacciati, A.
    et al.
    Unit of Nutritional Epidemiology, Division of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Orsini, N.
    Unit of Nutritional Epidemiology, Division of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Mantzoros, C. S.
    Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, United States.
    Wolk, A.
    Unit of Nutritional Epidemiology, Division of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Coffee consumption and risk of localized, advanced and fatal prostate cancer: a population-based prospective study2013In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, no 7, p. 1912-1918Article in journal (Refereed)
    Abstract [en]

    Background: The epidemiological evidence on possible relationships between coffee consumption and prostate cancer (PCa) risk by subtype of the disease (localized, advanced) and fatal PCa risk is limited.

    Materials and methods: A population-based cohort of 44 613 Swedish men aged 45-79 years was followed up from January 1998 through December 2010 for incidence of localized (n = 2368), advanced (n = 918) and fatal (n = 515) PCa. We assessed the associations between coffee consumption and localized, advanced and fatal PCa risk using competing-risk regressions. We examined possible effect modification by body mass index (BMI).

    Results: For localized PCa, each one cup increase in daily coffee consumption was associated with a 3% reduced risk [sub-hazard ratio (SHR) = 0.97, 95% confidence interval (CI) = 0.95-0.99]. For advanced and fatal PCa, we found a non-significant inverse association; each one cup increase was associated with a 2% reduced risk of advanced [SHR (95% CI) = 0.98 (0.95-1.02)] and fatal PCa [SHR (95% CI) = 0.98 (0.93-1.03)]. We observed evidence of effect modification by BMI for localized PCa (P-interaction = 0.03); the inverse association was stronger among overweight and obese men (BMI >= 25 kg/m(2)) compared with normal-weight men (BMI < 25 kg/m(2)).

    Conclusions: We observed a clear inverse association between coffee consumption and risk of localized PCa, especially among overweight and obese men.

  • 32. Discacciati, A.
    et al.
    Orsini, N.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Johansson, J-E
    Wolk, A.
    Body mass index in early and middle-late adulthood and risk of localised, advanced and fatal prostate cancer: a population-based prospective study2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 105, no 7, p. 1061-1068Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The relationships between body mass index (BMI) during early and middle-late adulthood and incidence of prostate cancer (PCa) by subtype of the disease (localised, advanced) and fatal PCa is unclear.

    METHODS: A population-based cohort of 36,959 Swedish men aged 45-79 years was followed up from January 1998 through December 2008 for incidence of PCa (1530 localised and 554 advanced cases were diagnosed) and through December 2007 for PCa mortality (225 fatal cases).

    RESULTS: From a competing-risks analysis, incidence of localised PCa was observed to be inversely associated with BMI at baseline (middle-late adulthood; rate ratio (RR) for 35 kg m(-2) when compared with 22 kg m(-2) was 0.69 (95% CI 0.52-0.92)), but not at age 30. For fatal PCa, BMI at baseline was associated with a nonstatistically significant increased risk (RR for every five-unit increase: 1.12 (0.88-1.43)) and BMI at age 30 with a decreased risk (RR for every five-unit increase: 0.72 (0.51-1.01)).

    CONCLUSION: Our results indicate an inverse association between obesity during middle-late, but not early adulthood, and localised PCa. They also suggest a dual association between BMI and fatal PCa--a decreased risk among men who were obese during early adulthood and an increased risk among those who were obese during middle-late adulthood.

  • 33.
    Epstein, Mara M
    et al.
    Department of Epidemiology, Harvard School of Public Health, Boston MA, United States; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, United States.
    Andrén, Ove
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Kasperzyk, Julie L
    Department of Epidemiology, Harvard School of Public Health, Boston MA, United States; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, United States.
    Shui, Irene M
    Department of Epidemiology, Harvard School of Public Health, Boston MA, United States.
    Penney, Kathryn L
    Department of Epidemiology, Harvard School of Public Health, Boston MA, United States; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, United States.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Clinical Epidemiology and Biostatistics, Örebro University Hospital, Örebro, Sweden.
    Rider, Jennifer R
    Department of Epidemiology, Harvard School of Public Health, Boston MA, United States; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, United States.
    Stampfer, Meir J
    Department of Epidemiology, Harvard School of Public Health, Boston MA, United States; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, United States.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Giovannucci, Edward
    Department of Epidemiology, Harvard School of Public Health, Boston MA, United States; Department of Nutrition, Harvard School of Public Health, Boston MA, United States.
    Mucci, Lorelei A
    Department of Epidemiology, Harvard School of Public Health, Boston MA, United States; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, United States; Centre for Public Health Services, University of Iceland, Reykjavik, Iceland.
    Seasonal variation in expression of markers in the vitamin D pathway in prostate tissue2012In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 23, no 8, p. 1359-1366Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Recent studies suggest variation in genes along the vitamin D pathway, as well as vitamin D receptor (VDR) protein levels, may be associated with prostate cancer. As serum vitamin D levels vary by season, we sought to determine whether the expression of genes on the vitamin D pathway, assessed in prostate tumor tissue, do the same.

    METHODS: Our study incorporates mRNA expression data from 362 men in the Swedish Watchful Waiting cohort, diagnosed between 1977 and 1999, and 106 men enrolled in the US Physicians' Health Study (PHS) diagnosed between 1983 and 2004. We also assayed for VDR protein expression among 832 men in the PHS and Health Professionals Follow-up Study cohorts. Season was characterized by date of initial tissue specimen collection categorically and by average monthly ultraviolet radiation levels. One-way analysis of variance was used to examine variation in the expression levels of six genes on the vitamin D pathway-VDR, GC, CYP27A1, CYP27B1, RXRα, CYP24A1-and VDR protein by season, adjusted for age at diagnosis and Gleason grade. Variation was also examined separately among lethal and nonlethal cases.

    RESULTS: Tumor expression levels of the six genes did not vary significantly by season of tissue collection. No consistent patterns emerged from subgroup analyses by lethal versus nonlethal cases.

    CONCLUSIONS: Unlike circulating levels of 25(OH) vitamin D, expression levels of genes on the vitamin D pathway and VDR protein did not vary overall by season of tissue collection. Epidemiological analyses of vitamin D gene expression may not be biased by seasonality.

  • 34.
    Epstein, Mara M.
    et al.
    Channing Lab, Dept Medicine, Brigham & Womens Hosp, Harvard University, Boston MA, USA; School of Public Health, Dept. of Epidemiology, Harvard University, Boston MA, USA.
    Kasperzyk, Julie L.
    Channing Lab, Dept Medicine, Brigham & Womens Hosp, Harvard University, Boston MA, USA; School of Public Health, Dept. of Epidemiology, Harvard University, Boston MA, USA.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Giovannucci, Edward L.
    Channing Lab, Dept Medicine, Brigham & Womens Hosp, Harvard University, Boston MA, USA; School of Public Health, Dept. of Epidemiology and Dept. of Nutrition, Harvard University, Boston MA, USA.
    Wolk, Alicja
    Inst. Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Håkansson, Niclas
    Inst. Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Andersson, Swen-Olof
    Örebro County Council, Örebro, Sweden.
    Johansson, Jan-Erik
    Örebro County Council, Örebro, Sweden.
    Fall, Katja
    School of Public Health, Dept. Epidemiology, Harvard University, Boston MA, USA; Dept. Genetics & Pathology, Uppsala University Hospital, Uppsala, Sweden; Center for Public Health Services, University of Iceland, Reykjavik, Iceland.
    Mucci, Lorelei A.
    Channing Lab, Dept. of Medicine, School of Medicine, Brigham & Womens Hospital, Harvard University, Boston MA, USA; School of Public Health, Dept. Epidemiology, Harvard University, Boston MA, USA; Center for Public Health Services, Univ Iceland, Reykjavik, Iceland.
    Dietary zinc and prostate cancer survival in a Swedish cohort2011In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 93, no 3, p. 586-593Article in journal (Refereed)
    Abstract [en]

    Background: Zinc is involved in many essential cellular functions, including DNA repair and immune system maintenance. Although experimental evidence supports a role for zinc in prostate carcinogenesis, epidemiologic data are inconsistent; no data on cancer-specific survival have been reported.

    Objective: Our objective was to determine whether dietary zinc assessed near the time of prostate cancer diagnosis is associated with improved disease-specific survival.

    Design: This population-based cohort consists of 525 men aged < 80 y from Orebro County, Sweden, with a diagnosis of prostate cancer made between 1989 and 1994. Study participants completed self-administered food-frequency questionnaires, and zinc intake was derived from nutrient databases. Cox proportional hazards regression was used to estimate multivariate hazard ratios (HRs) and 95% CIs for time to death from prostate cancer as well as death from all causes through February 2009 by quartile (Q) of dietary zinc intake. Models were also stratified by disease stage at diagnosis (localized or advanced).

    Results: With a median follow-up of 6.4 y, 218 (42%) men died of prostate cancer and 257 (49%) died of other causes. High dietary zinc intake was associated with a reduced risk of prostate cancer-specific mortality (HR(Q4 vs Q1): 0.64; 95% CI: 0.44, 0.94; P for trend = 0.05) in the study population. The association was stronger in men with localized tumors (HR: 0.24; 95% CI: 0.09, 0.66; P for trend = 0.005). Zinc intake was not associated with mortality from other causes.

    Conclusion: These results suggest that high dietary intake of zinc is associated with lower prostate cancer-specific mortality after diagnosis, particularly in men with localized disease. Am J Clin Nutr 2011;93:586-93.

  • 35. Epstein, Mara M
    et al.
    Kasperzyk, Julie L
    Mucci, Lorelei A
    Giovannucci, Edward
    Price, Alkes
    Wolk, Alicja
    Håkansson, Niclas
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Andersson, Swen-Olof
    Andrén, Ove
    Dietary fatty acid intake and prostate cancer survival in Örebro county, Sweden2012In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 176, no 3, p. 240-252Article in journal (Refereed)
    Abstract [en]

    Although dietary fat has been associated with prostate cancer risk, the association between specific fatty acids and prostate cancer survival remains unclear. Dietary intake of 14 fatty acids was analyzed in a population-based cohort of 525 Swedish men with prostate cancer in Örebro County (1989-1994). Multivariable hazard ratios and 95% confidence intervals for time to prostate cancer death by quartile and per standard deviation increase in intake were estimated by Cox proportional hazards regression. Additional models examined the association by stage at diagnosis (localized: T0-T2/M0; advanced: T0-T4/M1, T3-T4/M0). Among all men, those with the highest omega-3 docosahexaenoic acid and total marine fatty acid intakes were 40% less likely to die from prostate cancer (P(trend) = 0.05 and 0.04, respectively). Among men with localized prostate cancer, hazard ratios of 2.07 (95% confidence interval: 0.93, 4.59; P(trend) = 0.03) for elevated total fat, 2.39 (95% confidence interval: 1.06, 5.38) for saturated myristic acid, and 2.88 (95% confidence interval: 1.24, 6.67) for shorter chain (C4-C10) fatty acid intakes demonstrated increased risk for disease-specific mortality for the highest quartile compared with the lowest quartile. This study suggests that high intake of total fat and certain saturated fatty acids may worsen prostate cancer survival, particularly among men with localized disease. In contrast, high marine omega-3 fatty acid intake may improve disease-specific survival for all men.

  • 36.
    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.

  • 37.
    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.

  • 38.
    Fall, Katja
    et al.
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
    Fang, Fang
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America; Channing Laboratory, Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
    Ye, Weimin
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Andrén, Ove
    Örebro University Hospital, Örebro, Sweden.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences. Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University Hospital, Örebro, Sweden.
    Sparén, Pär
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Klein, Georg
    The Microbiology Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden.
    Stampfer, Meir
    Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America; Channing Laboratory, Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America.
    Adami, Hans-Olov
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America.
    Valdimarsdóttir, Unnur
    Centre of Public Health Sciences, University of Iceland, Reykjavík, Iceland.
    Immediate risk for cardiovascular events and suicide following a prostate cancer diagnosis: prospective cohort study2009In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 6, no 12, p. e1000197-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Stressful life events have been shown to be associated with altered risk of various health consequences. The aim of the present study was to investigate whether the emotional stress evoked by a prostate cancer diagnosis increases the immediate risks of cardiovascular events and suicide.

    METHODS AND FINDINGS: We conducted a prospective cohort study by following all men in Sweden who were 30 y or older (n = 4,305,358) for a diagnosis of prostate cancer (n = 168,584) and their subsequent occurrence of cardiovascular events and suicide between January 1, 1961 and December 31, 2004. We used Poisson regression models to calculate relative risks (RRs) and 95% confidence intervals (CIs) of cardiovascular events and suicide among men who had prostate cancer diagnosed within 1 y to men without any cancer diagnosis. The risks of cardiovascular events and suicide were elevated during the first year after prostate cancer diagnosis, particularly during the first week. Before 1987, the RR of fatal cardiovascular events was 11.2 (95% CI 10.4-12.1) during the first week and 1.9 (95% CI 1.9-2.0) during the first year after diagnosis. From 1987, the RR for cardiovascular events, nonfatal and fatal combined, was 2.8 (95% CI 2.5-3.2) during the first week and 1.3 (95% CI 1.3-1.3) during the first year after diagnosis. While the RR of cardiovascular events declined, the RR of suicide was stable over the entire study period: 8.4 (95% CI 1.9-22.7) during the first week and 2.6 (95% CI 2.1-3.0) during the first year after diagnosis. Men 54 y or younger at cancer diagnosis demonstrated the highest RRs of both cardiovascular events and suicide. A limitation of the present study is the lack of tumor stage data, which precluded possibilities of investigating the potential impact of the disease severity on the relationship between a recent diagnosis of prostate cancer and the risks of cardiovascular events and suicide. In addition, we cannot exclude residual confounding as a possible explanation.

    CONCLUSIONS: Men newly diagnosed with prostate cancer are at increased risks for cardiovascular events and suicide. Future studies with detailed disease characteristic data are warranted.

  • 39. Fall, Katja
    et al.
    Garmo, Hans
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Bill-Axelson, Anna
    Adolfsson, Jan
    Adami, Hans-Olov
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Holmberg, Lars
    Prostate-specific antigen levels as a predictor of lethal prostate cancer2007In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 99, no 7, p. 526-532Article in journal (Refereed)
    Abstract [en]

    Background: Rates of long-term survival among patients with untreated localized prostate cancer are high. To avoid unnecessary treatment, tools are needed to identify the small proportion of patients who are destined to develop lethal prostate cancer.

    Methods: To evaluate the accuracy of early changes in prostate-specific antigen (PSA) levels as predictors of prostate cancer outcome, we assessed serial measurements of PSA level among 267 men with localized prostate cancer in a Scandinavian cohort of men who were diagnosed between 1989 and 1999 and who were managed by watchful waiting. We then 1) fitted individual regression lines to the PSA values assessed for each patient during the first 2 years of follow-up by using three different models, 2) evaluated early PSA curve characteristics as determinants of the cumulative incidence of lethal prostate cancer and calculated hazard ratios for baseline PSA value and rate of change in PSA level to prostate cancer outcome, and 3) plotted time-dependent receiver operating characteristic (ROC) curves. All P values are two-sided.

    Results: During complete follow-up for a mean of 8.5 years, 34 patients (13%) died from prostate cancer, and 18 (7%) developed metastases but were still alive at end of follow-up. In a log-linear model, both PSA value at baseline (P = .05) and the rate of PSA change (P<.001) were associated with the development of lethal prostate cancer. In the ROC analysis, however, the accuracy of classifying the disease as either indolent or destined to progress was low, regardless of the cut point chosen for initial PSA level or rate of change in PSA level.

    Conclusions: Although baseline PSA value and rate of PSA change are prognostic factors for lethal prostate cancer, they are poor predictors of lethal prostate cancer among patients with localized prostate cancer who are managed by watchful waiting.

  • 40. Fall, Katja
    et al.
    Strömberg, Fredrik
    Rosell, Johan
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Varenhorst, Eberhard
    Reliability of death certificates in prostate cancer patients2008In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 42, no 4, p. 352-357Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the reliability of cause-of-death diagnoses among prostate cancer patients. MATERIAL AND METHODS: Information from death certificates obtained from the Swedish Death Register was compared with systematically reviewed medical records from the population-based Swedish Regional Prostate Cancer Register, South-East Region. In total, 5675 patients were included who had been diagnosed with prostate cancer between 1987 and 1999 and who had died before 1 January 2003. RESULTS: The proportion of prostate cancer cases classified as having died from prostate cancer was 3% higher in the official death certificates than in the reviewed records [0.03, 95% confidence interval (CI) 0.02 to 0.04]. Overall agreement between the official cause of death and the reviewed data was 86% (95% CI 85 to 87%). A higher accuracy was observed among men with localized disease (88%, 95% CI 87 to 89%), aged 60 years or younger at death (96%, 95% CI 93 to 100%), or who had undergone curative treatment (91%, 95% CI 88 to 95%). This study indicates a relatively high reliability of official cause-of-death statistics of prostate cancer patients in Sweden. CONCLUSION: Mortality data obtained from death certificates may be useful in the evaluation of large-scale prostate cancer intervention programmes, especially among younger patients with localized disease.

  • 41.
    Fiore, Christopher
    et al.
    Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston MA, USA; Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA.
    Bailey, Dyane
    Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston MA, USA; Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA.
    Conlon, Niamh
    Department of Pathology, Trinity College, Dublin, Ireland.
    Wu, Xiaoqiu
    Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston MA, USA; Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA.
    Martin, Neil
    Department of Radiation Oncology, Harvard Radiation Oncology Program, Boston MA, USA.
    Fiorentino, Michelangelo
    Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston MA, USA; Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA; Pathology Unit, Addarii Institute, S Orsola-Malpighi Hospital, Bologna, Italy.
    Finn, Stephen
    Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston MA, USA; Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA; Department of Pathology, Trinity College, Dublin, Ireland.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Harvard School of Public Health, Boston MA, USA.
    Andersson, Swen-Olof
    Harvard School of Public Health, Boston MA, USA.
    Andren, Ove
    Harvard School of Public Health, Boston MA, USA.
    Loda, Massimo
    Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston MA, USA; Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA.
    Flavin, Richard
    Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston MA, USA; Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA; Department of Pathology, Trinity College, Dublin, Ireland.
    Utility of multispectral imaging in automated quantitative scoring of immunohistochemistry2012In: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 65, no 6, p. 496-502Article in journal (Refereed)
    Abstract [en]

    Background: Automated scanning devices and image analysis software provide a means to overcome the limitations of manual semiquantitative scoring of immunohistochemistry. Common drawbacks to automated imaging systems include an inability to classify tissue type and an inability to segregate cytoplasmic and nuclear staining.

    Methods: Immunohistochemistry for the membranous marker a-catenin, the cytoplasmic marker stathmin and the nuclear marker Ki-67 was performed on tissue microarrays (TMA) of archival formalin-fixed paraffin-embedded tissue comprising 471 (alpha-catenin and stathmin) and 511 (Ki-67) cases of prostate adenocarcinoma. These TMA were quantitatively analysed using two commercially available automated image analysers, the Ariol SL-50 system and the Nuance system from CRi. Both systems use brightfield microscopy for automated, unbiased and standardised quantification of immunohistochemistry, while the Nuance system has spectral deconvolution capabilities. Results Overall concordance between scores from both systems was excellent (r=0.90; 0.83-0.95). The software associated with the multispectral imager allowed accurate automated classification of tissue type into epithelial glandular structures and stroma, and a single-step segmentation of staining into cytoplasmic or nuclear compartments allowing independent evaluation of these areas. The Nuance system, however, was not able to distinguish reliably between tumour and non-tumour tissue. In addition, variance in the labour and time required for analysis between the two systems was also noted.

    Conclusion: Despite limitations, this study suggests some beneficial role for the use of a multispectral imaging system in automated analysis of immunohistochemistry.

  • 42. Fiorentino, M.
    et al.
    Mucci, L.
    Fall, Katja
    Bailey, D.
    Fiore, C.
    Judson, G.
    Andrén, Ove
    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.
    Loda, M.
    Immunohistochemical Expression of BRCA1 in Prostate Cancer2009In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 89, p. 169A-169A, article id 760Article in journal (Other academic)
    Abstract [en]

    Background: BRCA1 is a multifunctional protein involved in DNA repair, gene transcription and the regulation of cell-cycle check-points. While germline mutations of BRCA1 are rare in prostate cancer and seem to play a limited role in tumor susceptibility, BRCA1 expression has not been investigated to date.

    Design: We analyzed the immunohistochemical expression of BRCA1 in paraffin embedded samples from 524 men with prostate cancer belonging to the Physicians’ Health Study and the Swedish Watchful Waiting cohorts of prostate cancer patients. High density tissue micro-arrays (TMA) including at least three tumor cores for each case were utilized for the immunohistochemical staining with the monoclonal MS110 antibody specific for the N-terminus of the 220 kDa BRCA1 protein. Cases were scored as negative or positive for BRCA1 immunostaining. The Ki67 proliferation index was also assessed on the same TMAs and evaluated by quantitative image analysis.

    Results: A positive nuclear immunostaining for BRCA1 was revealed in 62 of 524 (11.9%) patients while normal prostate control cores were all negative. BRCA1 positive tumors were associated with 4 times greater proliferation rate compared to BRCA1 negative tumors (p ∼ 0.0003). In addition, we found a linear trend such that tumors with greater number of TMA cores expressing BRCA1 had stronger extent of proliferation. Men with BRCA1 positive tumors had a slightly higher Gleason’s score (mean 7.5) compared to those negative for BRCA1 (mean 7) No significant correlation was found between BRCA1 staining and cancer-specific death.

    Conclusions: BRCA1 protein is expressed in a small subset of prostate cancers characterized by high proliferation index but not in normal prostate tissue. Expression of BRCA1 might be acquired in selected tumors to prevent DNA damage in actively replicating cells. A different role independent of germline mutations might be disclosed for BRCA1 as cell cycle regulator in prostate cancer.

  • 43. Fiorentino, M.
    et al.
    Mucci, L.
    Fall, Katja
    Bailey, D.
    Fiore, C.
    Judson, G.
    Andrén, Ove
    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.
    Loda, M.
    Immunohistochemical Expression of BRCA1 in Prostate Cancer2009In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 22, p. 169A-169A, article id 760Article in journal (Other academic)
    Abstract [en]

    Background: BRCA1 is a multifunctional protein involved in DNA repair, gene transcription and the regulation of cell-cycle check-points. While germline mutations of BRCA1 are rare in prostate cancer and seem to play a limited role in tumor susceptibility, BRCA1 expression has not been investigated to date.

    Design: We analyzed the immunohistochemical expression of BRCA1 in paraffin embedded samples from 524 men with prostate cancer belonging to the Physicians’ Health Study and the Swedish Watchful Waiting cohorts of prostate cancer patients. High density tissue micro-arrays (TMA) including at least three tumor cores for each case were utilized for the immunohistochemical staining with the monoclonal MS110 antibody specific for the N-terminus of the 220 kDa BRCA1 protein. Cases were scored as negative or positive for BRCA1 immunostaining. The Ki67 proliferation index was also assessed on the same TMAs and evaluated by quantitative image analysis.

    Results: A positive nuclear immunostaining for BRCA1 was revealed in 62 of 524 (11.9%) patients while normal prostate control cores were all negative. BRCA1 positive tumors were associated with 4 times greater proliferation rate compared to BRCA1 negative tumors (p ∼ 0.0003). In addition, we found a linear trend such that tumors with greater number of TMA cores expressing BRCA1 had stronger extent of proliferation. Men with BRCA1 positive tumors had a slightly higher Gleason’s score (mean 7.5) compared to those negative for BRCA1 (mean 7) No significant correlation was found between BRCA1 staining and cancer-specific death.

    Conclusions: BRCA1 protein is expressed in a small subset of prostate cancers characterized by high proliferation index but not in normal prostate tissue. Expression of BRCA1 might be acquired in selected tumors to prevent DNA damage in actively replicating cells. A different role independent of germline mutations might be disclosed for BRCA1 as cell cycle regulator in prostate canc

  • 44.
    Flaberg, E.
    et al.
    Department of Microbiology, Tumor and Cell Biology (MTC), Center for Integrative Recognition in the Immune System (IRIS), Karolinska Institutet, Stockholm, Sweden; Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institute, Stockholm, Sweden.
    Markasz, L.
    Department of Microbiology, Tumor and Cell Biology (MTC), Center for Integrative Recognition in the Immune System (IRIS), Karolinska Institutet, Stockholm, Sweden.
    Petranyi, Gabor
    Department of Microbiology, Tumor and Cell Biology (MTC), Center for Integrative Recognition in the Immune System (IRIS), Karolinska Institutet, Stockholm, Sweden.
    Stuber, G.
    Department of Microbiology, Tumor and Cell Biology (MTC), Center for Integrative Recognition in the Immune System (IRIS), Karolinska Institutet, Stockholm, Sweden.
    Dicsö, F.
    Division of Pediatrics, Jósa András County Hospital, Nyíregyháza, Hungary.
    Alchihabi, N.
    Division of Pediatrics, Jósa András County Hospital, Nyíregyháza, Hungary.
    Oláh, E.
    Department of Pediatrics, Medical and Health Science Center, Debrecen University, Debrecen, Hungary.
    Csízy, I.
    Department of Pediatrics, Medical and Health Science Center, Debrecen University, Debrecen, Hungary.
    Józsa, T.
    Department of Pediatrics, Medical and Health Science Center, Debrecen University, Debrecen, Hungary.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences. Clinic of Urology, Örebro County Council, Örebro, Sweden.
    Johansson, J-E
    Örebro University, School of Health and Medical Sciences. Clinic of Urology, Örebro County Council, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences. Clinic of Urology, Örebro County Council, Örebro, Sweden.
    Klein, G.
    Department of Microbiology, Tumor and Cell Biology (MTC), Center for Integrative Recognition in the Immune System (IRIS), Karolinska Institutet, Stockholm, Sweden.
    Szekely, L.
    Department of Microbiology, Tumor and Cell Biology (MTC), Center for Integrative Recognition in the Immune System (IRIS), Karolinska Institutet, Stockholm, Sweden.
    High-throughput live cell imaging reveals differential inhibition of tumor cell proliferation by human fibroblasts2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 128, no 12, p. 2793-2802Article in journal (Refereed)
    Abstract [en]

    Increasing evidence indicates that cancer development requires changes both in the precancerous cells and in their microenvironment. To study one aspect of the microenvironmental control, we departed from Michael Stoker's observation (Stroker et al, J Cell Sci 1966;1:297-310) that normal fibroblasts can inhibit the growth of admixed cancer cells (neighbour suppression). We have developed a high-throughput microscopy and image analysis system permitting the examination of live mixed cell cultures growing on 384-well plates, at the single cell level and over time. We have tested the effect of 107 samples of low passage number (<5) primary human fibroblasts from pediatric and adult donors, on the growth of six human tumor cell lines. Three of the lines were derived from prostate carcinomas, two from lung carcinomas and one was an EBV transformed lymphoblastoid line. Labeled tumor cells were grown in the presence of unlabeled fibroblasts. The majority of the tested fibroblasts inhibited the proliferation of the tumor cells, compared to the control cultures where labeled tumor cells were co-cultured with unlabeled tumor cells. The proliferation inhibiting effect of the fibroblasts differed depending on their site of origin and the age of the donor. Inhibition required direct cell contact. Mouse 3T3 fibroblasts inhibited the growth of SV40-transformed 3T3 cells and human tumor cells, showing that the inhibitory effect could prevail across the species barrier. Our high-throughput system allows the quantitative analysis of the inhibitory effect of fibroblasts on the population level and the exploration of differences depending on the source of the normal cells.

  • 45.
    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.

  • 46.
    Jerlström, Tomas
    et al.
    Örebro University, School of Medical Sciences. Department of Urology.
    Ruoqing, Chen
    Örebro University, School of Medical Sciences. Örebro University Hospital. Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Liedberg, Fredrik
    Department of Urology, Skåne University Hospital, Malmö, Sweden; Department of Translational Medicine, Lund University, Malmö, Sweden.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology.
    Ströck, Viveka
    Sahlgrenska Academy, Institute of Clinical Sciences, Gothenburg, Sweden; Sahlgrenska Academy, Institute of Clinical Sciences, Gothenburg, Sweden.
    Aljabery, Firas A. S.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Hosseini, Abolfazl
    Section of Urology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Sherif, Amir
    Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
    Malmström, Per-Uno
    Department of Urology, Institute of Surgical Sciences, Uppsala, Sweden.
    Ullén, Anders
    PO Bäckencancer, Theme Cancer, Karolinska University Hospital and Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
    Gårdmark, Truls
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    No increased risk of short-term complications after radical cystectomy for muscle-invasive bladder cancer among patients treated with preoperative chemotherapy: a nation-wide register-based study2019In: World journal of urology, ISSN 0724-4983, E-ISSN 1433-8726Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Preoperative chemotherapy is underused in conjunction with radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) due to concerns for complications and delay of surgery. Prospective data on short-term complications from population-based settings with frequent use of preoperative chemotherapy and standardised reporting of complications is lacking.

    METHODS: We identified 1,340 patients who underwent RC between 2011 and 2015 in Sweden due to MIBC according to the Swedish Cystectomy Register. These individuals were followed through linkages to several national registers. Propensity score adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for complications and death within 90 days of surgery, comparing patients receiving preoperative chemotherapy or not.

    RESULTS: Minimum two cycles of preoperative chemotherapy were given to 519 (39%) of the patients, who on average tended to be younger, have higher education, better physical status, and more advanced bladder cancer than patients not receiving chemotherapy. After adjusting for these and other parameters, there was no association between treatment with preoperative chemotherapy and short-term complications (OR 1.06 95% CI 0.82-1.39) or mortality (OR 0.75 95% CI 0.36-1.55). We observed a risk reduction for gastrointestinal complications among patients who received preoperative chemotherapy compared with those who did not (OR 0.49 95% CI 0.30-0.81).

    CONCLUSION: This nation-wide population-based observational study does not suggest that preoperative chemotherapy, in a setting with high utilisation of such treatment, is associated with an increased risk of short-term complications in MIBC patients treated with radical cystectomy.

  • 47. Johansson, Jan-Erik
    et al.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Andersson, Swen-Olof
    Dickman, Paul W.
    Holmberg, Lars
    Magnuson, Anders
    Adami, Hans-Olov
    Natural history of early, localized prostate cancer2004In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 291, no 22, p. 2713-2719Article in journal (Refereed)
    Abstract [en]

    Context Among men with early prostate cancer, the natural history without initial therapy determines the potential for survival benefit following radical local treatment. However, little is known about disease progression and mortality beyond 10 to 15 years of watchful waiting. Objective To examine the long-term natural history of untreated, early stage prostatic cancer. Design Population-based, cohort study with a mean observation period of 21 years. Setting Regionally well-defined catchment area in central Sweden (recruitment March 1977 through February 1984). Patients A consecutive sample of 223 patients (98% of all eligible) with early-stage (T0-T2 NX MO classification), initially untreated prostatic cancer. Patients with tumor progression were hormonally treated (either by orchiectomy or estrogens) if they had symptoms. Main Outcome Measures Progression-free, cause-specific, and overall survival. Results After complete follow-up, 39 (17%) of all patients experienced generalized disease. Most cancers had an indolent course during the first 10 to 15 years. However, further follow-up from 15 (when 49 patients were still alive) to 20 years, revealed a substantial decrease in cumulative progression-free survival (from 45.0% to 36.0%), survival without metastases (from 76.9% to 51.2%), and prostate cancer-specific survival (from 78.7% to 54.4%). The prostate cancer mortality rate increased from 15 per 1000 person-years (95% confidence interval, 10-21) during the first 15 years to 44 per 1000 person-years (95% confidence interval, 22-88) beyond 15 years of follow-up (P=.01). Conclusion Although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. These findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.

  • 48.
    Julin, B.
    et al.
    Unit of Nutritional Epidemiology, The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Wolk, A.
    Unit of Nutritional Epidemiology, The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Jan-Erik
    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. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Åkesson, A.
    Unit of Nutritional Epidemiology, The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Dietary cadmium exposure and prostate cancer incidence: a population-based prospective cohort study2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 21, no 5, p. 895-900Article in journal (Refereed)
    Abstract [en]

    Background: Experimental data convincingly propose the toxic metal cadmium as a prostate carcinogen. Cadmium is widely dispersed into the environment and, consequently, food is contaminated.

    Methods: A population-based cohort of 41 089 Swedish men aged 45-79 years was followed prospectively from 1998 through 2009 to assess the association between food frequency questionnaire-based estimates of dietary cadmium exposure (at baseline, 1998) and incidence of prostate cancer (3085 cases, of which 894 were localised and 794 advanced) and through 2008 for prostate cancer mortality (326 fatal cases).

    Results: Mean dietary cadmium exposure was 19 μg per day±s.d. 3.7. Multivariable-adjusted dietary cadmium exposure was positively associated with overall prostate cancer, comparing extreme tertiles; rate ratio (RR) 1.13 (95% confidence interval (CI): 1.03-1.24). For subtypes of prostate cancer, the RR was 1.29 (95% CI: 1.08-1.53) for localised, 1.05 (95% CI: 0.87-1.25) for advanced, and 1.14 (95% CI: 0.86-1.51) for fatal cases. No statistically significant difference was observed in the multivariable-adjusted risk estimates between tumour subtypes (P(heterogeneity)=0.27). For localised prostate cancer, RR was 1.55 (1.16-2.08) among men with a small waist circumference and RR 1.45 (1.15, 1.83) among ever smokers.

    Conclusion: Our findings provide support that dietary cadmium exposure may have a role in prostate cancer development.

  • 49. Kasperzyk, Julie L.
    et al.
    Fall, Katja
    Mucci, Lorelei A.
    Håkansson, Niclas
    Wolk, Alicja
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Andersson, Swen-Olof
    Andrén, Ove
    One-carbon metabolism-related nutrients and prostate cancer survival2009In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 90, no 3, p. 561-569Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Folate and other one-carbon metabolism nutrients may influence prostate cancer pathogenesis. Prior studies of these nutrients in relation to prostate cancer incidence have been inconclusive, and none have explored prostate cancer survival. OBJECTIVE: The objective was to assess whether dietary intakes of folate, riboflavin, vitamin B-6, vitamin B-12, and methionine measured around the time of prostate cancer diagnosis are associated with prostate cancer survival. DESIGN: This population-based prospective study comprised 525 men from Orebro, Sweden, who received a diagnosis of incident prostate cancer between 1989 and 1994 and completed a self-administered food-frequency questionnaire. Record linkages to the Swedish Death Registry enabled all cases to be followed for up to 20 y after diagnosis, and the cause of death was assigned via medical record review. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% CIs. During a median of 6.4 y of follow-up, 218 men (42%) died of prostate cancer and 257 (49%) of other causes. RESULTS: A comparison of the highest with the lowest quartile showed that vitamin B-6 intake was inversely associated with prostate cancer-specific death (HR: 0.71; 95% CI: 0.46, 1.10; P for trend = 0.08), especially in men with a diagnosis of localized-stage disease (HR; 0.05; 95% CI: 0.01, 0.26; P for trend = 0.0003). However, vitamin B-6 intake was not associated with improved prostate cancer survival among advanced-stage cases (HR: 1.04; 95% CI: 0.64, 1.72; P for trend = 0.87). Folate, riboflavin, vitamin B-12, and methionine intakes were not associated with prostate cancer survival. CONCLUSION: A high vitamin B-6 intake may improve prostate cancer survival among men with a diagnosis of localized-stage disease.

  • 50.
    Kirrander, Peter
    et al.
    Örebro University Hospital.
    Andrén, Ove
    Örebro University Hospital.
    Windahl, Torgny
    Örebro University Hospital. Örebro University Hospital, Region Örebro County, Örebro, Sweden.
    Dynamic sentinel node biopsy in penile cancer: initial experiences at a Swedish referral centre2013In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 111, no 3B, p. E48-E53Article in journal (Refereed)
    Abstract [en]

    Study Type Therapy (case series) Level of Evidence4 What's known on the subject? and What does the study add? According to the current European Association of Urology Guidelines, dynamic sentinel node biopsy is the recommended approach to assess lymph node status in men with cN0 intermediate and high risk penile cancer. Nevertheless, most encouraging results derive from a limited number of studies. The present study shows a false-negative rate of 15%, comparable with or better than several previous studies. Nevertheless, the aim should be a false-negative rate of no more than 5%. We conclude that increased overall experience and the use of the complete modern dynamic sentinel node biopsy protocol are paramount to improve results.

    OBJECTIVE center dot To evaluate the false-negative rate and complication rate of dynamic sentinel node biopsy (DSNB) in penile cancer.

    PATIENTS AND METHODS center dot In this retrospective study, 58 unilaterally or bilaterally clinically lymph node negative (cN0) patients with penile cancer (57 squamous cell carcinomas and one malignant melanoma), scheduled for DSNB at the orebro University Hospital, Sweden, between 1999 and 2011, were analysed. center dot Preoperative ultrasonography and fine-needle aspiration cytology of suspicious nodes were not introduced until 2008. center dot Patients were assessed by lymphoscintigraphy using 99mtechnetium nanocolloid on the day before surgery and the dissection of sentinel nodes was aided by the lymphoscintigraphic images and intraoperative detection of radiotracer and patent blue dye. center dot The false-negative rate and complication rate were calculated per groin.

    RESULTS center dot Of the 58 patients, 32 (55%) underwent preoperative ultrasonography. center dot Two patients had positive fine-needle aspiration cytology and discontinued further DSNB protocol. Of the remaining 56 patients, all but one were bilaterally cN0 and hence 111 cN0 groins were assessed by lymphoscintigraphy. center dot In the 55 bilaterally cN0 patients, lymphoscintigraphy visualized a bilateral sentinel node in 34 (62%). center dot At surgery, all excised sentinel nodes were radioactive while 43% were additionally blue. In total, at least one sentinel node was harvested in 96 (86%) of the DSNB staged groins. center dot A positive sentinel node was found in 11 groins (bilaterally in three patients). During a median follow-up of 21 months, two false-negative cases emerged, producing a false-negative rate of 15%. Both false-negative cases occurred during the first half of the study. The complication rate was 10%. The majority of complications were minor and transient.

    CONCLUSIONS center dot DSNB is a minimally invasive staging tool in men with cN0 penile cancer, enabling early detection of metastatic disease and thus optimal care. center dot Our false-negative rate of 15% is comparable or even favourable in comparison with several previous studies, but far from the 5% or less that we aim for. The complication rate found is somewhat higher than previously reported. center dot With increased overall experience and the continued use of the complete DSNB protocol, we believe our results will improve and the complication rate will decrease.

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