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  • 1.
    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.

  • 2. Bill-Axelson, Anna
    et al.
    Holmberg, Lars
    Filén, Frej
    Ruutu, Mirja
    Garmo, Hans
    Busch, Christer
    Nordling, Stig
    Häggman, Michael
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Bratell, Stefan
    Spångberg, Anders
    Palmgren, Juni
    Adami, Hans-Olov
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial2008In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 100, no 16, p. 1144-1154Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up.

    METHODS: From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided.

    RESULTS: During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001).

    CONCLUSION: Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery. 

  • 3.
    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 ...

  • 4.
    Bill-Axelson, Anna
    et al.
    Dept. Urology, Uppsala University Hospital, Uppsala, Sweden; Dept, Pathology & Oncology, Div. Clinical Cancer Epidemiology, Karolinska Institute, Stockholm, Sweden.
    Holmberg, Lars
    Regional Oncology Center, Uppsala University Hospital, Uppsala, Sweden; School of Medicine, Division of Cancer Studies, Kings College London, London, England.
    Ruutu, Mirja
    Cent Hosp, Dept Urol, Univ Helsinki, Helsinki, Finland.
    Garmo, Hans
    Reg Oncol Ctr, Univ Uppsala Hospital, Uppsala, Sweden; Sch Med, Div Canc Studies, Kings College London, London, UK.
    Stark, Jennifer R
    Deptartment of Urology, Örebro University Hospital, Örebro, Sweden; Dept Med, Channing Lab, Brigham & Womens Hospital, Boston MA, USA; Sch Med, Harvard University, Boston MA, USA.
    Busch, Christer
    Dept Pathol, Uppsala University Hospital, Uppsala, Sweden.
    Nordling, Stig
    Cent Hosp, Dept Pathol, Univ Helsinki, Helsinki, Finland.
    Häggman, Michael
    Dept Urology, Uppsala University Hospital, Uppsala, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Bratell, Stefan
    Dept Urology, Borås Hospital, Borås, Sweden.
    Spångberg, Anders
    Dept Urology, Linköping University Hospital, Linköping, Sweden.
    Palmgren, Juni
    Dept Med Epidemiol & Biostat, Karolinska Institute, Stockholm, Sweden.
    Steineck, Gunnar
    Dept, Pathology & Oncology, Div. Clinical Cancer Epidemiology, Karolinska Institute, Stockholm, Sweden; Div Clin Canc Epidemiol, Sahlgrenska Academy, Gothenburg, Sweden.
    Adami, Hans-Olov
    Dept Med Epidemiol & Biostat, Karolinska Institute, Stockholm, Sweden; School of Publ Health, Dept Epidemiology, Harvard Univ, Boston MA, USA.
    Johansson, J-E
    Örebro University, School of Health and Medical Sciences. Dept Urol, Örebro University Hospital, Örebro, Sweden; Center of Assessment Med Technology, Örebro University Hospital, Örebro, Sweden.
    Radical prostatectomy versus watchful waiting in early prostate cancer2011In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 364, no 18, p. 1708-1717Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In 2008, we reported that radical prostatectomy, as compared with watchful waiting, reduces the rate of death from prostate cancer. After an additional 3 years of follow-up, we now report estimated 15-year results.

    METHODS: From October 1989 through February 1999, we randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy. Follow-up was complete through December 2009, with histopathological review of biopsy and radical-prostatectomy specimens and blinded evaluation of causes of death. Relative risks, with 95% confidence intervals, were estimated with the use of a Cox proportional-hazards model.

    RESULTS: During a median of 12.8 years, 166 of the 347 men in the radical-prostatectomy group and 201 of the 348 in the watchful-waiting group died (P=0.007). In the case of 55 men assigned to surgery and 81 men assigned to watchful waiting, death was due to prostate cancer. This yielded a cumulative incidence of death from prostate cancer at 15 years of 14.6% and 20.7%, respectively (a difference of 6.1 percentage points; 95% confidence interval [CI], 0.2 to 12.0), and a relative risk with surgery of 0.62 (95% CI, 0.44 to 0.87; P=0.01). The survival benefit was similar before and after 9 years of follow-up, was observed also among men with low-risk prostate cancer, and was confined to men younger than 65 years of age. The number needed to treat to avert one death was 15 overall and 7 for men younger than 65 years of age. Among men who underwent radical prostatectomy, those with extracapsular tumor growth had a risk of death from prostate cancer that was 7 times that of men without extracapsular tumor growth (relative risk, 6.9; 95% CI, 2.6 to 18.4).

    CONCLUSIONS: Radical prostatectomy was associated with a reduction in the rate of death from prostate cancer. Men with extracapsular tumor growth may benefit from adjuvant local or systemic treatment.

  • 5.
    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)
  • 6.
    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.

  • 7.
    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)
  • 8.
    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.

  • 9.
    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.

  • 10. 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.

  • 11.
    Downer, Mary K.
    et al.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston MA, United States; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, United States.
    Batista, Julie L.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, United States; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, United States.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, United States; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, United States.
    Stampfer, Meir J.
    Epstein, Mara Meyer
    Department of Medicine and the Meyers Primary Care Institute, University of Massachusetts Medical School, Worcester MA, United States.
    Håkansson, Niclas
    The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Wolk, Alicja
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Jan-Erik
    Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, United States; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Dairy intake in relation to prostate cancer survival2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 9, p. 2060-2069Article in journal (Refereed)
    Abstract [en]

    Dairy intake has been associated with increased risk of advanced prostate cancer. Two US cohort studies reported increased prostate cancer-specific mortality with increased high-fat milk intake. We examined whether dairy and related nutrient intake were associated with prostate cancer progression in a Swedish patient population with high dairy consumption. We prospectively followed 525 men with newly diagnosed prostate cancer (diagnosed 1989-1994). We identified and confirmed deaths through February 2011 (n = 222 prostate cancer-specific, n = 268 from other causes). Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between food or nutrient intake and prostate cancer-specific death. On average, patients consumed 5.0 servings/day of total dairy products at diagnosis. In the whole population, high-fat milk intake was not associated with prostate cancer-specific death (95% CI: 0.78, 2.10; p-trend = 0.32; multivariate-adjusted model). However, among patients diagnosed with localized prostate cancer, compared to men who consumed <1 servings/day of high-fat milk, those who drank >= 3 servings/day had an increased hazard of prostate cancer mortality (HR = 6.10; 95% CI: 2.14, 17.37; p-trend = 0.004; multivariate-adjusted model). Low-fat milk intake was associated with a borderline reduction in prostate cancer death among patients with localized prostate cancer. These associations were not observed among patients diagnosed with advanced stage prostate cancer. Our data suggest a positive association between high-fat milk intake and prostate cancer progression among patients diagnosed with localized prostate cancer. Further studies are warranted to investigate this association and elucidate the mechanisms by which high-fat milk intake may promote prostate cancer progression.

  • 12.
    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.

  • 13.
    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.

  • 14. 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.

  • 15.
    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.

  • 16.
    Fant, Federica
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Axelsson, Kjell
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Sandblom, Dag
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Magnuson, Anders
    Clinical Epidemiology and Biostatistical Unit, Örebro University Hospital, Örebro University, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Gupta, Anil
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Thoracic epidural analgesia or patient-controlled local analgesia for radical retropubic prostatectomy: a randomized, double-blind study2011In: British Journal of Anaesthesia, ISSN 0007-0912, E-ISSN 1471-6771, Vol. 107, no 5, p. 782-789Article in journal (Refereed)
    Abstract [en]

    Background.Postoperative pain after radical retropubic prostatectomy is moderate to severe. The primary aim of this study was to assess whether intra-abdominal local anaesthetics provide similar analgesia compared with thoracic epidural analgesia (TEA).

    Methods.Fifty patients, ASA I–II, participated in this prospective, doubleblinded study. All patients had TEA. After operation, they were randomized into two groups of 25 patients: Group PCLA (patient- ontrolled local analgesia): self-administration of 10 ml of ropivacaine 2 mg ml21 via the intra-abdominal catheter for 48 h. Group TEA: infusion of 10 ml h–1 of ropivacaine 1 mg ml–1, fentanyl 2mg ml21, and epinephrine 2mg ml21 epidurally for 48 h. The primary endpoint was pain on coughing at 4 h after operation. Rescue medication was morphine i.v. as required.

    Results.Pain on coughing at 4, 24, and 48 h was significantly lower in Group TEA [0 (0–10)] compared with Group PCLA [4 (0–10)] (P,0.05). Significantly lower pain intensity was also found in Group TEA compared with Group PCLA at the incision site, deep pain, and pain on coughing at 4 and 24 h (P,0.05). Morphine consumption was significantly greater in Group PCLA [12 (0–46)] compared with Group TEA [0 (0–20)] at 0–48 h after operation [median (range)] (P¼0.015). Maximum expiratory pressure was higher in Group TEA compared with Group PCLA at 24 h (P,0.01).Conclusions.TEA provides superior postoperative pain relief with better preservation of expiratory muscle strength compared with PCLA.

  • 17.
    Fant, Federica
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, E.
    Clinical Reaserch Centre, Örebro University, Sweden.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Magnuson, Anders
    Clinical Epidemiology and Biostatistical Unit, Örebro University Hospita.
    Sandblom, Dag
    Örebro University, School of Health and Medical Sciences.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Axelsson, Kjell
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Gupta, Anil
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Thoracic epidural analgesia inhibits the neuro-hormonal but not the acute inflammatory stress response following radical retropubic prostatectomyManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Epidural anesthesia and analgesia has been shown to suppress the neurohormonalstress response in certain types of surgery, but its role in the inflammatory responseto surgery is unclear. The primary aim of this study was to assess whether the choice ofanalgesic technique influences these processes in patients undergoing radical retropubicprostatectomy (RRP).

    Method: 26 patients undergoing RRP were randomized to Group P (systemic opioid-basedanalgesia) or Group E (thoracic epidural-based analgesia) perioperatively. Induction andmaintenance of anesthesia in both groups followed a standardized protocol. The followingmeasurements were made perioperatively : plasma cortisol, glucose, insulin, plasma cytokines(IL-6, TNF-a) and pokeweed mitogen-stimulated cytokines (IFN-g, IL-2, IL-12p70, IL-10,IL-4, and IL-17), C-reactive proteins and leucocyte count. Other parameters recordedincluded pain, morphine consumption and perioperative complications during 72 hours.

    Results: Plasma concentration of cortisol and glucose were significantly higher in Group Pcompared to Group E at the end of surgery with a mean difference between groups of 232nmol/L (95% CI 84-381) (P=0.004) and 1.6 mmol/L (95% CI 0.6-2.5) (P=0.003) respectively.No significant differences were seen in any plasma cytokine except IL-17, which was higherin Group P compared with Group E, both at 24 h (P< 0.001) and 72 h (P=0.018)postoperatively. Significantly higher pain intensity was seen up to 24 hours postoperatively inGroup P compared to Group E (p < 0.05).

    Conclusion: Thoracic epidural analgesia reduces the early postoperative stress response butnot the acute inflammatory response to radical retrobupic prostatectomy suggesting that otherpathways are involved during the acute phase reaction.

  • 18.
    Fant, Federica
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, E.
    Sandblom, Dag
    Örebro University, School of Health and Medical Sciences.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Magnuson, Anders
    Clinical Epidemiology and Biostatistical Unit, Örebro University Hospital.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Gupta, Anil
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Early perioperative immunological effects of anesthesia and analgesia in patients undergoing prostate cancer surgeryManuscript (preprint) (Other academic)
    Abstract [en]

    Background:Clinical studies in humans as well as experimental evidence from animal studiessuggests that the immune system plays an important role in perioperative metastases following cancer surgery. However, the precise role of the different components of the immune system in this process appears conflicting. Our primary aim was to assess T cell activity and natural killer (NK) cell toxicity in patients undergoing prostate cancer surgery and randomized to epidural or intravenous analgesia.

    Methods:26 patients were randomized to receive general anaesthesia and patient controlled analgesia (PCA) with morphine postoperatively (Group P) or combined, general and epidural anaestesia with patient-controlled thoracic epidural analgesia postoperatively (Group E). Blood sample were obtained perioperatively at different time points for analyses of: subpopulations of leukocytes, cell- ediated immune response after mitogen stimulation, NK cell cytotoxicity, vascular endothelial growth factor (VEGF), IFN-g/IL-10 ratio, C-reactive protein (CRP) and white blood cell (WBC) count. In addition, pain and morphine consumtion were also determined.

    Results: T lymphocytes decreased more in Group P compared to Group E at 24 hours postoperatively while T-helper lymphocytes decreased more in Group E compared to Group P at the same time point without reaching statistically significant difference.No differences were seen in NK cells or cytotoxic T lymphocytes between the groups. The CD4+/CD8+ ratio remained constant between the groups over time. Natural Killer Cell cytotoxicity did not show statistically significant differences between the groups at the different postoperative time points. No other differences ere found between the groups except in pain intensity which was lower in Group E, and morphine consumption which was greater in Group P. Conclusions:Our findings suggest that regional anaesthesia and analgesia appears to play a minor role in immunomodulation following surgery for prostate cancer. If regional anesthesia does prevent tumour growth or metastases perioperatively, the mechanism for this needs to be further elucidated.

  • 19.
    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.

  • 20. 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.

  • 21. 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

  • 22.
    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.

  • 23.
    Gupta, Anil
    et al.
    Örebro University, School of Health and Medical Sciences.
    Fant, Federica
    Örebro University, School of Health and Medical Sciences.
    Axelsson, Kjell
    Örebro University, School of Health and Medical Sciences.
    Sandblom, Dag
    Rykowski, Jan
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Postoperative analgesia after radical retropubic prostatectomy: a double-blind comparison between low thoracic epidural and patient-controlled intravenous analgesia2006In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 105, no 4, p. 784-793Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Postoperative pain after radical retropubic prostatectomy can be severe unless adequately treated. Low thoracic epidural analgesia and patient-controlled intravenous analgesia were compared in this double-blind, randomized study.

    METHODS: Sixty patients were randomly assigned to receive either low thoracic epidural analgesia (group E) or patient-controlled intravenous analgesia (group P) for postoperative pain relief. All patients had general anesthesia combined with thoracic epidural analgesia during the operation. Postoperatively, patients in group E received an infusion of 1 mg/ml ropivacaine, 2 microg/ml fentanyl, and 2 microg/ml adrenaline, 10 ml/h during 48 h epidurally, and a placebo patient-controlled intravenous analgesia pump intravenously. Patients in group P received a patient-controlled intravenous analgesia pump with morphine intravenously and 10 ml/h placebo epidurally. Pain, the primary outcome variable, was measured using the numeric rating scale at rest (incision pain and "deep" visceral pain) and on coughing. Secondary outcome variables included gastrointestinal function, respiratory function, mobilization, and full recovery. Health-related quality of life was measured using the Short Form-36 questionnaire, and plasma concentration of fentanyl was measured in five patients to exclude a systemic effect of fentanyl.

    RESULTS: Incisional pain and pain on coughing were lower in group E compared with group P at 2-24 h, as was deep pain between 3 and 24 h postoperatively (P < 0.05). Maximum expiratory pressure was greater in group E at 4 and 24 h (P < 0.05) compared with group P. No difference in time to home discharge was found between the groups. The mean plasma fentanyl concentration varied from 0.2 to 0.3 ng/ml during 0-48 h postoperatively. At 1 month, the scores on emotional role, physical functioning, and general health of the Short Form-36 were higher in group E compared with group P. However, no group x time interaction was found in the Short Form-36.

    CONCLUSIONS: The authors found evidence for better pain relief and improved expiratory muscle function in patients receiving low thoracic epidural analgesia compared with patient-controlled analgesia for radical retropubic prostatectomy. Low thoracic epidural analgesia can be recommended as a good method for postoperative analgesia after abdominal surgery.

  • 24. Hedelin, Maria
    et al.
    Klint, Åsa
    Chang, Ellen T.
    Bellocco, Rino
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Heinonen, Satu-Maarit
    Adlercreutz, Herman
    Adami, Hans-Olov
    Grönberg, Henrik
    Bälter, Katarina Augustsson
    Dietary phytoestrogen, serum enterolactone and risk of prostate cancer: the cancer prostate Sweden study (Sweden)2006In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 17, no 2, p. 169-180Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Based on evidence that phytoestrogens may protect against prostate cancer, we evaluated the associations between serum enterolactone concentration or dietary phytoestrogen intake and risk of prostate cancer. METHODS: In our Swedish population-based case-control study, questionnaire-data were available for 1,499 prostate cancer cases and 1,130 controls, with serum enterolactone levels in a sub-group of 209 cases and 214 controls. Unconditional logistic regression was performed to estimate multivariate odds ratios (ORs) and 95% confidence intervals (CIs) for associations with risk of prostate cancer. RESULTS: High intake of food items rich in phytoestrogens was associated with a decreased risk of prostate cancer. The OR comparing the highest to the lowest quartile of intake was 0.74 (95% CI: 0.57-0.95; p-value for trend: 0.01). In contrast, we found no association between dietary intake of total or individual lignans or isoflavonoids and risk of prostate cancer. Intermediate serum levels of enterolactone were associated with a decreased risk of prostate cancer. The ORs comparing increasing quartiles of serum enterolactone concentration to the lowest quartile were, respectively, 0.28 (95% CI: 0.15-0.55), 0.63 (95% CI: 0.35-1.14) and 0.74 (95% CI: 0.41-1.32). CONCLUSIONS: Our results support the hypothesis that certain foods high in phytoestrogens are associated with a lower risk of prostate cancer.

  • 25.
    Ilicki, Jonathan
    et al.
    Department of Urology, Örebro University Hospital, Örebro University, Örebro, Sweden.
    Krauss, Wolfgang
    Department of Radiology, Örebro University Hospital, Örebro University, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro University, Örebro, Sweden.
    Partial Segmental Thrombosis of the Corpus Cavernosum: A Case Report and a Review of the Literature2012In: Urology, ISSN 0090-4295, E-ISSN 1527-9995, Vol. 79, no 3, p. 708-712Article, review/survey (Refereed)
    Abstract [en]

    Partial segmental thrombosis of the corpus cavernosum (PSTCC) is a rare urological condition characterized by a painful, firm mass in the proximal part of the corpus cavernosum. The underlying pathophysiology of this condition is not fully understood. We present a case diagnosed by magnetic resonance imaging with complete clinical recovery after conservative treatment and novel associated findings, such as excessive alcohol intake. We also review the previous cases of PSTCC and propose a two hit model explaining PSTCC's etiology. UROLOGY 79: 708-712, 2012.

  • 26.
    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.

  • 27. Karypidis, A.-H.
    et al.
    Olsson, M.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Rane, A.
    Ekström, L.
    Deletion polymorphism of the UGT2B17 gene is associated with increased risk for prostate cancer and correlated to gene expression in the prostate2008In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 8, no 2, p. 147-151Article in journal (Refereed)
    Abstract [en]

    Metabolism of androgens includes glucuronidation, the major pathway of steroid elimination in several steroid target tissues. Glucuronidation is catalysed by UDP-glucuronosyltransferases (UGTs). UGT2B17 has been shown to be particularly active against androgens and is highly abundant in the prostate. Recently, we discovered that deletion of the UGT2B17 gene is associated with low or undetectable urinary testosterone levels. Here, we determined the phenotypic outcome of the deletion by quantifying the UGT2B17 mRNA expression in normal prostate tissues in individuals with different genotypes. Additionally, the frequency of UGT2B17 deletion polymorphism was studied in a Swedish population-based case–control study including 176 patients diagnosed with prostate cancer and 161 controls. We found that the individuals homozygous for the insertion allele expressed 30 times more UGT2B17 mRNA in prostate tissue than the heterozygotes. Carriers of the deletion allele had a significantly increased risk of prostate cancer (OR=2.07; 95% CI=1.32–3.25). In conclusion, these results show the UGT2B17 deletion polymorphism is associated with prostate cancer risk. 

  • 28. 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.

  • 29. Landberg, Rikard
    et al.
    Kamal-Eldin, Afaf
    Andersson, Swen-Olof
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Zhang, Jie-Xian
    Hallmans, Göran
    Åman, Per
    Reproducibility of plasma alkylresorcinols during a 6-week rye intervention study in men with prostate cancer2009In: Journal of Nutrition, ISSN 0022-3166, E-ISSN 1541-6100, Vol. 139, no 5, p. 975-980Article in journal (Refereed)
    Abstract [en]

    Alkylresorcinols (AR), phenolic lipids exclusively present in the outer parts of wheat and rye grains, have been proposed as concentration biomarkers of whole-grain wheat and rye intake. A key feature of a good biomarker is high reproducibility, which indicates how accurately a single sample reflects the true mean biomarker concentration caused by a certain intake. In this study, the short- to medium-term reproducibility of plasma AR was determined using samples from a crossover intervention study, where men with prostate cancer (n = 17) were fed rye whole-grain/bran or refined wheat products for 6-wk periods. AR homologs C17:0 and C21:0 differed between the treatments (P < 0.001). The reproducibility determined by the intraclass correlation coefficient (ICC) was high (intervention period 1: ICC = 0.90 [95% CI = 0.82-0.98], intervention period 2: ICC = 0.88 [95% CI = 0.78-0.98]). The results show that a single fasting plasma sample could be used to estimate the mean plasma AR concentration during a 6-wk intervention period with constant intake at a precision of +/- 20% (80% CI). This suggests that the plasma AR concentration can be used as a reliable short- to medium-term biomarker for whole-grain wheat and rye under intervention conditions where intake is kept constant.

  • 30. Larsson, Susanna C.
    et al.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Wolk, Alicja
    Cultured milk, yogurt, and dairy intake in relation to bladder cancer risk in a prospective study of Swedish women and men2008In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 88, no 4, p. 1083-1087Article in journal (Refereed)
    Abstract [en]

    Background:Findings from epidemiologic studies of the effect of dairy foods (mainly milk) on the risk of bladder cancer have been inconsistent.

    Objective:We aimed to examine the association between the intake of cultured milk and other dairy foods and the incidence of bladder cancer in a prospective, population-based cohort.

    Design:We prospectively followed 82 002 Swedish women and men who were cancer-free and who completed a 96-item food-frequency questionnaire in 1997. Incident cases of bladder cancer were identified in the Swedish cancer registries.

    Results:During a mean follow-up of 9.4 y, 485 participants (76 women and 409 men) were diagnosed with bladder cancer. Total dairy intake was not significantly associated with risk of bladder cancer [7.0 servings/d compared with < 3.5 servings/d: multivariate rate ratio (RR) = 0.87; 95% CI: 0.66, 1.15; P for trend = 0.33]. However, a statistically significant inverse association was observed for the intake of cultured milk (sour milk and yogurt). The multivariate RRs for the highest category of cultured milk intake (2 servings/d) compared with the lowest category (0 serving/d) were 0.62 (95% CI: 0.46, 0.85; P for trend = 0.006) in women and men combined, 0.55 (95% CI: 0.25, 1.22; P for trend = 0.06) in women, and 0.64 (95% CI: 0.46, 0.89; P for trend = 0.03) in men. The intake of milk or cheese was not associated with bladder cancer risk.

  • 31. Larsson, Susanna C.
    et al.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Wolk, Alicja
    Diabetes mellitus, body size and bladder cancer risk in a prospective study of Swedish men2008In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 44, no 17, p. 2655-2660Article in journal (Refereed)
    Abstract [en]

    Epidemiologic studies on diabetes and body size in relation to risk of bladder cancer have yielded inconsistent results. We examined prospectively the associations between a history of diabetes, height, weight, body mass index and waist circumference, and the incidence of bladder cancer in the Cohort of Swedish Men, a prospective study of 45,906 men aged 45–79 years at baseline. During follow-up from 1998 through December 2007, 414 incident cases of bladder cancer were ascertained. A history of diabetes was not associated with risk of bladder cancer (multivariate rate ratio=1.16; 95% confidence interval=0.81–1.64). Similarly, no associations were observed for height, weight, body mass index or waist circumference. These findings in men do not support a role for diabetes, height or excess body mass in the aetiology of bladder cancer. 

  • 32. Larsson, Susanna C.
    et al.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Wolk, Alicja
    Fruit and vegetable consumption and risk of bladder cancer: a prospective cohort study2008In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 17, no 9, p. 2519-2522Article in journal (Refereed)
    Abstract [en]

    Fruit and vegetable consumption has been inconsistently associated with risk of bladder cancer. We used data from a prospective population-based cohort study of 82,002 Swedish women and men to examine the association between fruit and vegetable consumption and bladder cancer incidence. Diet was assessed with a validated food frequency questionnaire. During a mean follow-up of 9.4 years, 485 incident cases of bladder cancer were identified in the Swedish cancer registries. We found no statistically significant association between intakes of total fruits and vegetables, total fruits, or total vegetables and bladder cancer risk after adjustment for age, sex, education, and cigarette smoking. The multivariate rate ratios (95% confidence intervals) comparing the highest with the lowest quartile of intake were 0.80 (0.60-1.05) for total fruits and vegetables, 0.93 (0.69-1.25) for fruits, and 0.89 (0.67-1.19) for vegetables. Likewise, no associations were observed for citrus fruits, cruciferous vegetables, or green leafy vegetables. The associations did not differ by sex or smoking status. In conclusion, findings from this prospective study suggest that fruit and vegetable intakes are not likely to be appreciably associated with the risk of bladder cancer.

  • 33. Larsson, Susanna C.
    et al.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Wolk, Alicja
    Meat intake and bladder cancer risk in a Swedish prospective cohort2009In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 20, no 1, p. 35-40Article in journal (Refereed)
    Abstract [en]

    Background  High meat consumption could potentially increase the risk of bladder cancer, but findings from epidemiologic studies are inconsistent. We prospectively examined the association between meat intake and bladder cancer risk in a population-based cohort study. Methods  We prospectively followed 82,002 Swedish women and men who were free from cancer and completed a food-frequency questionnaire in 1997. Incident cases of bladder cancer were identified in the Swedish cancer registries. Cox proportional hazards models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI), adjusted for age, sex, education, smoking status, pack-years of smoking, and total energy intake. Results  During a mean follow-up of 9.4 years, 485 incident cases of bladder cancer (76 women and 409 men) were ascertained in the cohort. We observed no association between the intake of total or any specific type of meat and the risk of bladder cancer. The multivariate HRs (95% CIs) comparing the highest and the lowest category of intake were 1.05 (0.71–1.55) for total meat, 1.00 (0.71–1.41) for red meat, 1.01 (0.80–1.28) for processed meats, 0.96 (0.70–1.30) for chicken/poultry, and 0.92 (0.65–1.30) for fried meats/fish. The associations did not vary by sex or smoking status. Conclusions  These results do not support the hypothesis that intake of red meat, processed meat, poultry, or fried meats/fish is associated with the risk of developing bladder cancer.

  • 34. Laven, Brett A.
    et al.
    Orsini, Nicola
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Gerber, Glenn S.
    Wolk, Alicja
    Birth weight, abdominal obesity and the risk of lower urinary tract symptoms in a population based study of Swedish men2008In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 179, no 5, p. 1891-1896Article in journal (Refereed)
    Abstract [en]

    Purpose

    Lower urinary tract symptoms and obesity are prominent health problems. Low birth weight increases the adult risk of adiposity and insulin resistance, which may increase sympathetic activity and potentially lower urinary tract symptoms. Results of obesity and lower urinary tract symptoms studies are conflicting, and low birth weight and lower urinary tract symptoms relationships have not been investigated.

    Materials and Methods

    This cross-sectional study examines lower urinary tract symptoms, body measures, activity, birth weight and lifestyle data collected by questionnaire from 1997 to 1998. Overall 27,858 men were analyzed and odds ratios calculated after excluding those with cancer, cerebrovascular accident, diabetes and incomplete information.

    Results

    After adjustment for age, activity level, smoking, alcohol, coffee intake and body mass index, a significant positive association was seen between abdominal obesity (waist-to-hip ratio) and moderate to severe lower urinary tract symptoms. The risks of moderate to severe and severe lower urinary tract symptoms were 22% (95% CI 1.09–1.37) and 28% (95% CI 1.01–1.63) higher, respectively, for the top vs the lowest abdominal obesity quartile. The risk of nocturia (twice or more per night) was 1.16 (95% CI 1.02–1.33) in men in the top compared to the bottom waist-to-hip ratio quartile. Men with low birth weight (less than 2,500 gm) had a 61% (95% CI 1.12–2.30) higher risk of severe lower urinary tract symptoms compared to men with normal birth weight (2,500 to 3,999 gm). Men in the top waist-to-hip ratio quartile who had low birth weight had twice the risk of severe lower urinary tract symptoms (95% CI 1.29–3.02) compared to men with normal birth weight and in the lowest waist-to-hip ratio quartile.

    Conclusions

    Low birth weight and abdominal adiposity are associated with increased risk of moderate to severe lower urinary tract symptoms in adults. Further investigations are needed to determine if decreases in obesity can ameliorate lower urinary tract symptoms.

  • 35.
    Lu, Donghao
    et al.
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Carlsson, Jessica
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Penney, Kathryn L.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, USA.
    Davidsson, Sabina
    Örebro University Hospital. Örebro University, School of Medical Sciences. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston MA, USA.
    Valdimarsdóttir, Unnur
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Faculty of Medicine, Center of Public Health Sciences, School of Health Sciences, University of Iceland, Reykjavík, Iceland.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Fang, Fang
    Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Fall, Katja
    Örebro University, School of Medical Sciences. Department of Medical Epidemiology & Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Expression and Genetic Variation in Neuroendocrine Signaling Pathways in Lethal and Nonlethal Prostate Cancer among Men Diagnosed with Localized Disease2017In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 26, no 12, p. 1781-1787Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 36.
    Lyth, J.
    et al.
    Department of Biomedical Engineering, Division of Medical Informatics, Linköping University, Linköping, Sweden; Regional Cancer Center Southeast, Linköping University, Linköping, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    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.
    Carlsson, P.
    Center for Medical Technology Assessment, Linköping University, Linköping, Sweden.
    Shahsavar, N.
    Department of Biomedical Engineering, Division of Medical Informatics, Linköping University, Linköping, Sweden; Regional Cancer Center Southeast, Linköping University, Linköping, Sweden.
    A decision support model for cost-effectiveness of radical prostatectomy in localized prostate cancer2012In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, no 1, p. 19-25Article in journal (Refereed)
    Abstract [en]

    Objective: This study aimed to develop a probabilistic decision support model to calculate the lifetime incremental cost-effectiveness ratio (ICER) between radical prostatectomy and watchful waiting for different patient groups.

    Material and methods: A randomized trial (SPCG-4) provided most data for this study. Data on survival, costs and quality of life were inputs in a decision analysis, and a decision support model was developed. The model can generate cost-effectiveness information on subgroups of patients with different characteristics.

    Results: Age was the most important independent factor explaining cost-effectiveness. The cost-effectiveness value varied from 21,026 Swedish kronor (SEK) to 858,703 SEK for those aged 65 to 75 years, depending on Gleason scores and prostate-specific antigen (PSA) values. Information from the decision support model can support decision makers in judging whether or not radical prostatectomy (RP) should be used to treat a specific patient group.

    Conclusions: The cost-effectiveness ratio for RP varies with age, Gleason scores, and PSA values. Assuming a threshold value of 200,000 SEK per quality-adjusted life-year (QALY) gained, for patients aged ≤70 years the treatment was always cost-effective, except at age 70, Gleason 0-4 and PSA ≤10. Using the same threshold value at age 75, Gleason 7-9 (regardless of PSA) and Gleason 5-6 (with PSA >20) were cost-effective. Hence, RP was not perceived to be cost-effective in men aged 75 years with low Gleason and low PSA. Higher threshold values for patients with clinically localized prostate cancer could be discussed

  • 37.
    Martin, Neil E.
    et al.
    Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, USA.
    Gerke, Travis
    Department of Epidemiology, Harvard School of Public Health, Boston MA, USA.
    Sinnott, Jennifer A.
    Department of Epidemiology, Harvard School of Public Health, Boston MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, USA.
    Stack, Edward C.
    Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, USA.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Andersson, Swen-Olof
    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
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Fiorentino, Michelangelo
    Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, 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; Department of Pathology, Trinity College, Dublin, Ireland.
    Fedele, Giuseppe
    Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston MA, USA.
    Stampfer, Meir
    Department of Epidemiology, Harvard School of Public Health, Boston MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, USA.
    Kantoff, Philip W.
    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, USA.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard School of Public Health, Boston MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, USA.
    Loda, Massimo
    Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston MA, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA, USA; Broad Institute of Harvard and MIT, Cambridge MA, USA; Division of Cancer Studies, King's College London, London, United Kingdom.
    Measuring PI3K Activation: Clinicopathologic, Immunohistochemical, and RNA Expression Analysis in Prostate Cancer2015In: Molecular Cancer Research, ISSN 1541-7786, E-ISSN 1557-3125, Vol. 13, no 10, p. 1431-1440Article in journal (Refereed)
    Abstract [en]

    Assessing the extent of PI3K pathway activity in cancer is vital to predicting sensitivity to PI3K-targeting drugs, but the best biomarker of PI3K pathway activity in archival tumor specimens is unclear. Here, PI3K pathway activation was assessed, in clinical tissue from 1,021 men with prostate cancers, using multiple pathway nodes that include PTEN, phosphorylated AKT (pAKT), phosphorylated ribosomal protein S6 (pS6), and stathmin. Based on these markers, a 9-point score of PI3K activation was created using the combined intensity of the 4-markers and analyzed its association with proliferation (Ki67), apoptosis (TUNEL), and androgen receptor (AR) status, as well as pathologic features and cancer-specific outcomes. In addition, the PI3K activation score was compared with mRNA expression profiling data for a large subset of men. Interestingly, those tumors with higher PI3K activation scores also had higher Gleason grade (P = 0.006), increased AR (r = 0.37; P < 0.001) and Ki67 (r = 0.24; P < 0.001), and decreased TUNEL (r = -0.12; P = 0.003). Although the PI3K activation score was not associated with an increased risk of lethal outcome, a significant interaction between lethal outcome, Gleason and high PI3K score (P = 0.03) was observed. Finally, enrichment of PI3K-specific pathways was found in the mRNA expression patterns differentiating the low and high PI3K activation scores; thus, the 4-marker IHC score of PI3K pathway activity correlates with features of PI3K activation.

  • 38.
    Moazzami, A.
    et al.
    Department of Food Science, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Zhang, J. X.
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Kamal-Eldin, A.
    Department of Food Science, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Åman, P.
    Department of Food Science, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Hallmans, G.
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Johansson, J-E
    Örebro University, School of Health and Medical Sciences. Department of Urology, Örebro County Council, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences. Department of Urology, Örebro County Council, Örebro, Sweden.
    Nuclear magnetic resonance-based metabolomics enable detection of the effects of a whole grain rye and rye bran diet on the metabolic profile of plasma in prostate cancer patients2011In: Journal of Nutrition, ISSN 0022-3166, E-ISSN 1541-6100, Vol. 141, no 12, p. 2126-2132Article in journal (Refereed)
    Abstract [en]

    Prostate cancer (PC) is the most common cancer in the Western world and the second most important cancer causing male deaths, after lung cancer, in the United States and Britain. Lifestyle and dietary changes are recommended for men diagnosed with early-stage PC. It has been shown that a diet rich in whole grain (WG) rye reduces the progression of early-stage PC, but the underlying mechanism is not clear. This study sought to identify changes in the metabolic signature of plasma in patients with early-stage PC following intervention with a diet rich in WG rye and rye bran product (RP) compared with refined white wheat product (WP) as a tool for mechanistic investigation of the beneficial health effects of RP on PC progression. Seventeen PC patients received 485 g RP or WP in a randomized, controlled, crossover design during a period of 6 wk with a 2-wk washout period. At the end of each intervention period, plasma was collected after fasting and used for (1)H NMR-based metabolomics. Multilevel partial least squares discriminant analysis was used for paired comparisons of multivariate data. A metabolomics analysis of plasma showed an increase in 5 metabolites, including 3-hydroxybutyric acid, acetone, betaine, N,N-dimethylglycine, and dimethyl sulfone, after RP. To understand these metabolic changes, fasting plasma homocysteine, leptin, adiponectin, and glucagon were measured separately. The plasma homocysteine concentration was lower (P = 0.017) and that of leptin tended to be lower (P = 0.07) after RP intake compared to WP intake. The increase in plasma 3-hydroxybutyric acid and acetone after RP suggests a shift in energy metabolism from anabolic to catabolic status, which could explain some of the beneficial health effects of WG rye, i.e., reduction in prostate-specific antigen and reduced 24-h insulin secretion. In addition, the increase in betaine and N,N-dimethylglycine and the decrease in homocysteine show a favorable shift in homocysteine metabolism after RP intake.

  • 39. Mucci, Lorelei A.
    et al.
    Pawitan, Yudi
    Demichelis, Francesca
    Fall, Katja
    Stark, Jennifer R.
    Adami, Hans-Olov
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Andrén, Ove
    Eisenstein, Anna
    Holmberg, Lars
    Huang, Wei
    Kantoff, Philip W.
    Kim, Robert
    Perner, Sven
    Stampfer, Meir J.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Rubin, Mark A.
    Testing a multigene signature of prostate cancer death in the Swedish Watchful Waiting Cohort2008In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 17, no 7, p. 1682-1688Article in journal (Refereed)
    Abstract [en]

    Although prostate cancer is a leading cause of cancer death, most men die with and not from their disease, underscoring the urgency to distinguish potentially lethal from indolent prostate cancer. We tested the prognostic value of a previously identified multigene signature of prostate cancer progression to predict cancer-specific death. The Örebro Watchful Waiting Cohort included 172 men with localized prostate cancer of whom 40 died of prostate cancer. We quantified protein expression of the markers in tumor tissue by immunohistochemistry and stratified the cohort by quintiles according to risk classification. We accounted for clinical variables (age, Gleason, nuclear grade, and tumor volume) using Cox regression and calculated receiver operator curves to compare discriminatory ability. The hazard ratio of prostate cancer death increased with increasing risk classification by the multigene model, with a 16-fold greater risk comparing highest-risk versus lowest-risk strata, and predicted outcome independent of clinical factors (P = 0.002). The best discrimination came from combining information from the multigene markers and clinical data, which perfectly classified the lowest-risk stratum where no one developed lethal disease; using the two lowest-risk groups as reference, the hazard ratio (95% confidence interval) was 11.3 (4.0-32.8) for the highest-risk group and difference in mortality at 15 years was 60% (50-70%). The combined model provided greater discriminatory ability (area under the curve = 0.78) than the clinical model alone (area under the curve = 0.71; P = 0.04). Molecular tumor markers can add to clinical variables to help distinguish lethal and indolent prostate cancer and hold promise to guide treatment decisions. 

  • 40. Mucci, Lorelei A.
    et al.
    Pawitan, Yudi
    Demichelis, Francesca
    Fall, Katja
    Stark, Jennifer R.
    Adami, Hans-Olov
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Eisenstein, Anna S.
    Holmberg, Lars
    Huang, Wei
    Kantoff, Philip W.
    Perner, Sven
    Stampfer, Meir J.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Rubin, Mark A.
    Nine-gene molecular signature is not associated with prostate cancer death in a watchful waiting cohort2008In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 17, no 1, p. 249-251Article in journal (Refereed)
    Abstract [en]

    Tumor molecular markers hold promise to distinguish potentially lethal from indolent prostate cancer and to guide treatment choices. A previous study identified a nine-gene molecular signature in tumors associated with prostate-specific antigen relapse after prostatectomy. We examined this molecular model in relation to prostate cancer death among 172 men with initially localized disease. We quantified protein expression of the nine genes in tumors to classify progression risk. Accounting for clinical prognostic factors, the nine-gene model did not provide discrimination to predict lethal and indolent prostate cancer.

  • 41.
    Olsson, Jan
    et al.
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Davidsson, Sabina
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Molling, Paula
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olov
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andrén, Ove
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Söderquist, Bo
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Sellin, Mats
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Elgh, Fredrik
    Department of Clinical Microbiology, Umeå University, Umeå, Sweden.
    Antibiotic susceptibility in prostate-derived Propionibacterium acnes isolates2012In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 120, no 10, p. 778-785Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to determine antibiotic susceptibility of Propionibacterium acnes isolates from prostate. Prostate-derived P. acnes isolates (n = 24, Umea & Orebro, Sweden, 20072010) and a panel of control strains (n = 25, Sweden) collected from skin and deep infections were assessed for resistance to penicillin G, piperacillintazobactam, imipenem, gentamicin, azithromycin, erythromycin, vancomycin, ciprofloxacin, moxifloxacin, tetracycline, tigecycline, fusidic acid, clindamycin, rifampicin, linezolid, daptomycin, trimethoprimsulfamethoxazole, and metronidazole. In addition, the isolates were tested for inducible clindamycin resistance. All prostate derived P. acnes isolates displayed wild-type distribution of MIC-values, without evidence of acquired resistance. In the reference panel, 5 of 25 isolates had acquired macrolide resistance with cross-resistance to azithromycin, clindamycin, and erythromycin. In addition, one of these isolates was resistant to tetracycline.

  • 42. Orsini, N
    et al.
    Bellocco, R
    Bottai, M
    Pagano, M
    Andersson, Swen-Olof
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Giovannucci, E
    Wolk, A
    A prospective study of lifetime physical activity and prostate cancer incidence and mortality2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 101, no 11, p. 1932-1938Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The possible benefit of lifetime physical activity (PA) in reducing prostate cancer incidence and mortality is unclear. METHODS: A prospective cohort of 45,887 men aged 45-79 years was followed up from January 1998 to December 2007 for prostate cancer incidence (n=2735) and to December 2006 for its subtypes and for fatal (n=190) prostate cancer. RESULTS: We observed an inverse association between lifetime (average of age 30 and 50 years, and baseline age) total PA levels and prostate cancer risk. Multivariate-adjusted incidence in the top quartile of lifetime total PA decreased by 16% (95% confidence interval (CI)=2-27%) compared with that in the bottom quartile. We also observed an inverse association between average lifetime work or occupational activity and walking or bicycling duration and prostate cancer risk. Compared with men who mostly sit during their main work or occupation, men who sit half of the time experienced a 20% lower risk (95% CI=7-31%). The rate ratio linearly decreased by 7% (95% CI=1-12%) for total, 8% (95% CI=0-16%) for localised and 12% (95% CI=2-20%) for advanced prostate cancer for every 30 min per day increment of lifetime walking or bicycling in the range of 30 to 120 min per day. CONCLUSIONS: Our results suggest that not sitting for most of the time during work or occupational activity and walking or bicycling more than 30 min per day during adult life is associated with reduced incidence of prostate cancer.

  • 43. Penney, K. L.
    et al.
    Sinnott, J. A.
    Fall, Katja
    Örebro University, School of Medical Sciences.
    Pawitan, Y.
    Hoshida, Y.
    Kraft, P.
    Stark, J. R.
    Fiorentino, M.
    Perner, S.
    Finn, S.
    Calza, S.
    Flavin, R.
    Freedman, M. L.
    Setlur, S.
    Sesso, H. D.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Martin, N.
    Kantoff, P. W.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Adami, H. O.
    Rubin, M.
    Loda, M.
    Golub, T. R.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Stampfer, M. J.
    Mucci, L. A.
    mRNA expression signature of Gleason grade predicts lethal prostate cancer2011In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 29, no 17, p. 2391-2396Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis.

    PATIENTS AND METHODS: Using the complementary DNA-mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases.

    RESULTS: We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006).

    CONCLUSION: Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment.

  • 44.
    Popiolek, Marcin
    et al.
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Rider, Jennifer R.
    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston MA, USA; Department of Epidemiology, Harvard School of Public Health, Boston MA, USA .
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Andersson, Sven-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Holmberg, Lars
    Regional Oncologic Center, University Hospital, Uppsala, Sweden; Medical School, Division of Cancer Studies, King's College London, London, UK.
    Adami, Hans-Olov
    Department of Epidemiology, Harvard School of Public Health, Boston MA, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Natural history of early, localized prostate cancer: A final report from three decades of follow-up2013In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 63, no 3, p. 428-435Article in journal (Refereed)
    Abstract [en]

    Background: Most localized prostate cancers are believed to have an indolent course. Within 15 yr of diagnosis, most deaths among men with prostate cancer (PCa) can be attributed to other competing causes. However, data from studies with extended follow-up are insufficient to determine appropriate treatment for men with localized disease.

    Objective: To investigate the long-term natural history of untreated, early-stage PCa.

    Design, setting, and participants: We conducted a population-based, prospective-cohort study using a consecutive sample of 223 patients with untreated, localized PCa from a regionally well-defined catchment area in central Sweden. All subjects were initially managed with observation. Androgen deprivation therapy was administered when symptomatic tumor progression occurred.

    Outcome measurements and statistical analysis: Based on >30 yr of follow-up, the main outcome measures were: progression-free, cause-specific, and overall survival, and rates of progression and mortality per 1000 person-years.

    Results and limitations: After 32 yr of follow-up, all but 3 (1%) of the 223 men had died. We observed 90 (41.4%) local progression events and 41 (18.4%) cases of progression to distant metastasis. In total, 38 (17%) men died of PCa. Cause-specific survival decreased between 15 and 20 yr, but stabilized with further follow-up. All nine men with Gleason grade 8-10 disease died within the first 10 yr of follow-up, five (55%) from PCa. Survival for men with well-differentiated, nonpalpable tumors declined slowly through 20 yr, and more rapidly between 20 and 25 yr (from 75.2% [95% confidence interval, 48.4-89.3] to 25% [95% confidence interval, 22.0-72.5]). It is unclear whether these data are relevant for tumors detected by elevated prostate-specific antigen levels.

    Conclusions: Although localized PCa most often has an indolent course, local progression and distant metastasis can develop over the long term, even among patients considered low risk at diagnosis.

  • 45.
    Sboner, Andrea
    et al.
    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven CT, USA.
    Demichelis, Francesca
    Department of Pathology and LaboratoryMedicine, Weill Cornell Medical Center, New York, USA; Institute for Computational Biomedicine, Weill Cornell Medical Center, New York, USA.
    Calza, Stefano
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Biomedical Sciences and Biotechnologies, University of Brescia, Brescia, Italy.
    Pawitan, Yudi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Setlur, Sunita R.
    Department of Pathology, Brigham and Women's Hospital, Boston MA, USA.
    Hoshida, Yujin
    The Broad Institute of MIT and Harvard, Cambridge MA, USA; The Dana Farber Cancer Institute, Boston MA, USA.
    Perner, Sven
    Department of Pathology and LaboratoryMedicine, Weill Cornell Medical Center, New York, USA.
    Adami, Hans-Olov
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Fall, Katja
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Mucci, Lorelei A.
    Harvard Medical School, Boston MA, USA; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston MA, USA; Department of Epidemiology, Harvard School of Public Health, Boston MA, USA .
    Kantoff, Philip W.
    Harvard Medical School, Boston MA, USA; The Dana Farber Cancer Institute, Boston MA, USA .
    Stampfer, Meir
    Harvard Medical School, Boston MA, USA; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston MA, USA; Department of Epidemiology, Harvard School of Public Health, Boston MA, USA .
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Varenhorst, Eberhard
    Department of Urology, Linköping University Hospital, Linköping, Sweden.
    Johansson, Jan-Erik
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Gerstein, Mark B.
    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven CT, USA; Program in Computational Biology and Bioinformatics, Yale University, New Haven CT, USA; Department of Computer Science, Yale University, New Haven CT, USA .
    Golub, Todd R.
    The Howard Hughes Medical Institute at The Broad Institute of MIT and Harvard, Cambridge MA, USA; The Broad Institute of MIT and Harvard, Cambridge MA, USA; The Dana Farber Cancer Institute, Boston MA, USA .
    Rubin, Mark A.
    Medicine, Weill Cornell Medical Center, New York, USA; The Broad Institute of MIT and Harvard, Cambridge MA, USA .
    Andrén, Ove
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Molecular sampling of prostate cancer: a dilemma for predicting disease progression2010In: BMC Medical Genomics, ISSN 1755-8794, E-ISSN 1755-8794, Vol. 3, article id 8Article in journal (Refereed)
    Abstract [en]

    Background: Current prostate cancer prognostic models are based on pre-treatment prostate specific antigen (PSA) levels, biopsy Gleason score, and clinical staging but in practice are inadequate to accurately predict disease progression. Hence, we sought to develop a molecular panel for prostate cancer progression by reasoning that molecular profiles might further improve current clinical models.

    Methods: We analyzed a Swedish Watchful Waiting cohort with up to 30 years of clinical follow up using a novel method for gene expression profiling. This cDNA-mediated annealing, selection, ligation, and extension (DASL) method enabled the use of formalin-fixed paraffin-embedded transurethral resection of prostate (TURP) samples taken at the time of the initial diagnosis. We determined the expression profiles of 6100 genes for 281 men divided in two extreme groups: men who died of prostate cancer and men who survived more than 10 years without metastases (lethals and indolents, respectively). Several statistical and machine learning models using clinical and molecular features were evaluated for their ability to distinguish lethal from indolent cases.

    Results: Surprisingly, none of the predictive models using molecular profiles significantly improved over models using clinical variables only. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes is widespread in prostate cancer as compared to other types of tumors.

    Conclusions: The determination of the molecularly dominant tumor nodule may be limited by sampling at time of initial diagnosis, may not be present at time of initial diagnosis, or may occur as the disease progresses making the development of molecular biomarkers for prostate cancer progression challenging.

  • 46. Setlur, Sunita R.
    et al.
    Mertz, Kirsten D.
    Hoshida, Yujin
    Demichelis, Francesca
    Lupien, Mathieu
    Perner, Sven
    Sboner, Andrea
    Pawitan, Yudi
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Johnson, Laura A.
    Tang, Jeff
    Adami, Hans-Olov
    Calza, Stefano
    Chinnaiyan, Arul M.
    Rhodes, Daniel
    Tomlins, Scott
    Fall, Katja
    Mucci, Lorelei A.
    Kantoff, Philip W.
    Stampfer, Meir J.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Varenhorst, Eberhard
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Brown, Myles
    Golub, Todd R.
    Rubin, Mark A.
    Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer2008In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 100, no 11, p. 815-825Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The majority of prostate cancers harbor gene fusions of the 5'-untranslated region of the androgen-regulated transmembrane protease serine 2 (TMPRSS2) promoter with erythroblast transformation-specific transcription factor family members. The common fusion between TMPRESS2 and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) is associated with a more aggressive clinical phenotype, implying the existence of a distinct subclass of prostate cancer defined by this fusion. METHODS: We used complementary DNA-mediated annealing, selection, ligation, and extension to determine the expression profiles of 6144 transcriptionally informative genes in archived biopsy samples from 455 prostate cancer patients in the Swedish Watchful Waiting cohort (1987-1999) and the United States-based Physicians(') Health Study cohort (1983-2003). A gene expression signature for prostate cancers with the TMPRSS2-ERG fusion was determined using partitioning and classification models and used in computational functional analysis. Cell proliferation and TMPRSS2-ERG expression in androgen receptor-negative (NCI-H660) prostate cancer cells after treatment with vehicle or estrogenic compounds were assessed by viability assays and quantitative polymerase chain reaction, respectively. All statistical tests were two-sided. RESULTS: We identified an 87-gene expression signature that distinguishes TMPRSS2-ERG fusion prostate cancer as a discrete molecular entity (area under the curve = 0.80, 95% confidence interval [CI] = 0.792 to 0.81; P < .001). Computational analysis suggested that this fusion signature was associated with estrogen receptor (ER) signaling. Viability of NCI-H660 cells decreased after treatment with estrogen (viability normalized to day 0, estrogen vs vehicle at day 8, mean = 2.04 vs 3.40, difference = 1.36, 95% CI = 1.12 to 1.62) or ERbeta agonist (ERbeta agonist vs vehicle at day 8, mean = 1.86 vs 3.40, difference = 1.54, 95% CI = 1.39 to 1.69) but increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at day 8, mean = 4.36 vs 3.40, difference = 0.96, 95% CI = 0.68 to 1.23). Similarly, expression of TMPRSS2-ERG decreased after ERbeta agonist treatment (fold change over internal control, ERbeta agonist vs vehicle at 24 hours, NCI-H660, mean = 0.57- vs 1.0-fold, difference = 0.43-fold, 95% CI = 0.29- to 0.57-fold) and increased after ERalpha agonist treatment (ERalpha agonist vs vehicle at 24 hours, mean = 5.63- vs 1.0-fold, difference = 4.63-fold, 95% CI = 4.34- to 4.92-fold). CONCLUSIONS: TMPRSS2-ERG fusion prostate cancer is a distinct molecular subclass. TMPRSS2-ERG expression is regulated by a novel ER-dependent mechanism.

  • 47.
    Sinnott, Jennifer A.
    et al.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Department of Biostatistics, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
    Rider, Jennifer R.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
    Carlsson, Jessica
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Gerke, Travis
    Department of Epidemiology, College of Medicine and College of Public Health and Health Professions, University of Florida, Gainesville, USA.
    Tyekucheva, Svitlana
    Department of Biostatistics, Harvard School of Public Health, Boston, USA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA.
    Penney, Kathryn L.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.
    Sesso, Howard D.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Loda, Massimo
    Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA; Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, USA.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Stampfer, Meir J.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Pawitan, Yudi
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Andersson, Sven-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Molecular differences in transition zone and peripheral zone prostate tumors2015In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 36, no 6, p. 632-638Article in journal (Refereed)
    Abstract [en]

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

  • 48.
    Skeppner, Elisabet
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. 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.
    Windahl, Torgny
    Department of Urology, Örebro University Hospital, Örebro, Sweden.
    Initial symptoms and delay in patients with penile carcinoma2012In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, no 5, p. 319-325Article in journal (Refereed)
    Abstract [en]

    Objective: This study aimed to assess initial symptoms and factors associated with patients' and doctors' delay in penile carcinoma.

    Material and methods: Fifty consecutive patients with penile carcinoma treated with an organ-sparing technique and nine with partial amputation were enrolled in a prospective study at the Department of Urology, Örebro University Hospital, between 2005 and 2009. Face-to-face structured interviews in combination with self-assessment forms were used for the patients' descriptions of clinical symptoms, treatment seeking and reasons for delay. Data were also extracted from the medical records confirming time-lag between GP assessment, specialist care and time for diagnosis.

    Results: Erythema, rash and eczema were the most common initial symptoms (35%). In total, 65% had a patients' delay of more than 6 months, and among these there was a small, but not statistically significant, predominance for pT1 and pTis tumours. Living with a stable partner did not affect the delay. The most common reason for patients' delay was the feeling of embarrassment over symptoms localized in a sexual body area. Nine patients had a doctors' delay of more than 3 months from first special visit to diagnosis. Eight of these patients consulted dermatologists and were subjected to repeated biopsies, leaving premalignant results.

    Conclusions: A considerable proportion of the patients had a patients' delay of more than 6 months, perhaps due to benign initial symptoms as erythema, rash or eczema. Psychological factors such as embarrassment and denial may also be involved, as well as insufficient awareness or knowledge. 

  • 49.
    Skeppner, Elisabet
    et al.
    Örebro University, School of Health and Medical Sciences.
    Windahl, Torgny
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Sjögren Fugl-Meyer, Kerstin
    Treatment-seeking, aspects of sexual activity and life satisfaction in men with laser-treated penile carcinoma2008In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 54, no 3, p. 631-639Article in journal (Refereed)
    Abstract [en]

    ObjectivesThe aims were to assess the initial symptoms of penile carcinoma and patients’ time frame in treatment seeking, and to describe the effect of laser treatment on sexual activity and life satisfaction.Patients and methodsA retrospective face-to-face structured interview study of patients laser treated for localised penile carcinoma at the department of Urology in Örebro, Sweden, during 1986 to 2000. Sixty-seven was treated and 58 of them (mean age, 63 yr; range, 34–90) were alive at the time of this study. Forty-six (79%) agreed to participate.ResultsNinety-six percent of the patients recalled their first symptom of penile carcinoma. Superficial ulceration and fissures were the most common symptoms (39%). Thirty-seven percent delayed seeking treatment for more than 6 mo.The patients had a greater lifetime number of sexual partners and a greater lifetime prevalence of STIs than a Swedish representative comparator population.Some aspects of sexual life, such as manual stimulation/caressing and fellatio, decreased markedly after laser treatment.Patient satisfaction with life as a whole was approximately the same as that of the general population.ConclusionsPatients delayed seeking treatment for a considerable period, despite awareness of the first local symptoms. Men with laser-treated localised penile carcinoma resume their sexual activities to a large extent after the treatment. Except for satisfaction with somatic health, similar—or even higher—proportions of patients than comparators are satisfied with life as a whole and with other domains of life including satisfaction with sexual life.Take Home MessageIn this study of 46 men who received laser treatment for localised penile carcinoma, we found that they resumed their sexual activities to a great extent and coped well with nearly all aspects of life after the treatment.

  • 50.
    Stopsack, Konrad H.
    et al.
    Department of Internal Medicine, Mayo Clinic, Rochester MN, United States.
    Gerke, Travis A
    Department of Internal Medicine, Mayo Clinic, Rochester MN, United States.
    Andrén, Ove
    Örebro University, School of Medical Sciences. Department of Urology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden; School of Health and Medical Sciences, University of Örebro, Örebro, Sweden.
    Andersson, Swen-Olof
    Department of Urology, Örebro University Hospital, Örebro, Sweden; School of Health and Medical Sciences, University of Örebro, Örebro, Sweden.
    Giovannucci, Edward L.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston MA, USA.
    Mucci, Lorelei A.
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Department of Medicine, Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston MA, USA.
    Rider, Jennifer R
    Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston MA, USA; Department of Epidemiology, Boston University School of Public Health, Boston MA, USA.
    Cholesterol uptake and regulation in high-grade and lethal prostate cancers2017In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 38, no 8, p. 806-811Article in journal (Refereed)
    Abstract [en]

    Lethal prostate cancers have higher expression of squalene monooxygenase (SQLE), the second rate-limiting enzyme of cholesterol synthesis. Preclinical studies suggested that aberrant cholesterol regulators, receptors and transporters contribute to cholesterol accumulation uniformly. We assessed their association with features of aggressive cancers. In the prospective prostate cancer cohorts within the Health Professional Follow-up Study, the Physicians' Health Study and the Swedish Watchful Waiting Study, tumor mRNA expression profiling was performed. Lethal disease was defined as mortality or metastases from prostate cancer (n = 266) in contrast to non-lethal disease without metastases after >8 years of follow-up (n = 476). Associations with Gleason grade were additionally assessed using The Cancer Genome Atlas primary prostate cancer dataset (n = 333). Higher Gleason grade was associated with lower LDLR expression, lower SOAT1 and higher SQLE expression. Besides high SQLE expression, cancers that became lethal despite primary treatment were characterized by low LDLR expression (odds ratio for highest versus lowest quintile, 0.37; 95% CI 0.18-0.76) and by low SOAT1 expression (odds ratio, 0.41; 95% CI 0.21-0.83). The association of LDLR expression and lethality was not present in tumors with high IDOL expression. ABCA1, PCSK9 or SCARB1 expressions were not associated with Gleason grade or lethal cancer. In summary, prostate cancers that progress to lethal disease rely on de novo cholesterol synthesis (via SQLE), rather than transcellular uptake (via LDLR) or cholesterol esterification (via SOAT1). These results may help design pharmacotherapy for high-risk patients.

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