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  • 151.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Inhibition of the epidermal growth factor receptor enhances castration-induced prostate involution and reduces testosterone-stimulated prostate growth in adult rats.2007In: Prostate, ISSN 0270-4137, Vol. 67, no 6, p. 573-581Article in journal (Refereed)
  • 152.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Scherdin, Tove Dahl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hagglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersson, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Granfors, Torvald
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High Caveolin-1 Expression in Tumor Stroma Is Associated with a Favourable Outcome in Prostate Cancer Patients Managed by Watchful Waiting2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164016Article in journal (Refereed)
    Abstract [en]

    In the present study we have investigated whether Caveolin-1 expression in non-malignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients managed by watchful waiting. Caveolin-1 was measured in prostate tissues obtained through transurethral resection of the prostate from 395 patients diagnosed with prostate cancer. The majority of the patients (n = 298) were followed by watchful waiting after diagnosis. Tissue microarrays constructed from malignant and non-malignant prostate tissue were stained with an antibody against Caveolin-1. The staining pattern was scored and related to clinicopathologic parameters and outcome. Microdissection and qRT-PCR analysis of Cav-1 was done of the prostate stroma from non-malignant tissue and stroma from Gleason 3 and 4 tumors. Cav-1 RNA expression was highest in non-malignant tissue and decreased during cancer progression. High expression of Caveolin-1 in tumor stroma was associated with significantly longer cancer specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were combined with Caveolin-1 in a Cox regression model. High stromal Caveolin-1 immunoreactivity in prostate tumors is associated with a favourable prognosis in prostate cancer patients managed by watchful waiting. Caveolin-1 could possibly become a useful prognostic marker for prostate cancer patients that are potential candidates for active surveillance.

  • 153.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Winther, Johanna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Rudolfsson, Stina H
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Karalija, Amar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Egevad, Lars
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm.
    Granfors, Torvald
    Department of Urology, Central Hospital, Västerås, Sweden.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e105063Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: ErbB2 is a member of the epidermal growth factor family of tyrosine kinases that is centrally involved in the pathogenesis of prostate cancer and several studies have reported that a high expression of this protein has prognostic value. In the present study, we have investigated whether tumour ErbB2 immunoreactivity (ErbB2-IR) has clinically useful prognostic value, i.e. that it provides additional prognostic information to that provided by routine clinical tests (Gleason score, tumour stage).

    METHODOLOGY/PRINCIPAL FINDINGS: ErbB2-IR was measured in a well-characterised tissue microarray of tumour and non-malignant samples obtained at diagnosis. Additionally, mRNA levels of ErbB2-IR in the prostate were determined in the rat following manipulation of circulating androgen levels. Tumour ErbB2-IR was significantly associated with the downstream signalling molecule phosphorylated-Akt and with the cell proliferation marker Ki-67. The significant association of tumour ErbB2-IR with the Gleason score at diagnosis was lost when controlled for the association of both parameters with Ki-67. In the rat prostate, mRNA for ErbB2 was inversely associated with circulating androgen levels. There was no association between ErbB2-IR and the androgen receptor (AR)-IR in the tumours, but an interaction between the two parameters was seen with respect to their association with the tumour stage. Tumour ErbB2-IR was confirmed to be a prognostic marker for disease-specific survival, but it did not provide significant additive information to the Gleason score or to Ki-67.

    CONCLUSIONS/SIGNIFICANCE: It is concluded that tumour ErbB2-IR is of limited clinical value as a prognostic marker to aid treatment decisions, but could be of pathophysiological importance in prostate cancer.

  • 154. Hartana, C. A.
    et al.
    Ahlén Bergman, E.
    Broomé, A.
    Berglund, S.
    Johansson, M.
    Alamdari, F.
    Jakubczyk, T.
    Huge, Y.
    Aljabery, F.
    Palmqvist, K.
    Holmström, B.
    Glise, H.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, O.
    Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 39-53Article in journal (Refereed)
    Abstract [en]

    Tissue-resident memory T (TRM ) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin-expressing TRM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.

  • 155. Hartana, Ciputra Adijaya
    et al.
    Bergman, Emma Ahlén
    Zirakzadeh, A. Ali
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Krantz, David
    Winerdal, Malin E.
    Winerdal, Max
    Johansson, Markus
    Alamdari, Farhood
    Jakubczyk, Tomasz
    Glise, Hans
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Urothelial bladder cancer may suppress perforin expression in CD8+ T cells by an ICAM-1/TGFβ2 mediated pathway2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 7, article id e0200079Article in journal (Refereed)
    Abstract [en]

    The immune system plays a significant role in urothelial bladder cancer (UBC) progression, with CD8+ T cells being capable to directly kill tumor cells using perforin and granzymes. However, tumors avoid immune recognition by escape mechanisms. In this study, we aim to demonstrate tumor immune escape mechanisms that suppress CD8+ T cells cytotoxicity. 42 patients diagnosed with UBC were recruited. CD8+ T cells from peripheral blood (PB), sentinel nodes (SN), and tumor were analyzed in steady state and in vitro-stimulated conditions by flow cytometry, RT-qPCR, and ELISA. Mass spectrometry (MS) was used for identification of proteins from UBC cell line culture supernatants. Perforin was surprisingly found to be low in CD8+ T cells from SN, marked by 1.8-fold decrease of PRF1 expression, with maintained expression of granzyme B. The majority of perforin-deficient CD8+ T cells are effector memory T (TEM) cells with exhausted Tc2 cell phenotype, judged by the presence of PD-1 and GATA-3. Consequently, perforin-deficient CD8+ T cells from SN are low in T-bet expression. Supernatant from muscle invasive UBC induces perforin deficiency, a mechanism identified by MS where ICAM-1 and TGFβ2 signaling were causatively validated to decrease perforin expression in vitro. Thus, we demonstrate a novel tumor escape suppressing perforin expression in CD8+ T cells mediated by ICAM-1 and TGFβ2, which can be targeted in combination for cancer immunotherapy.

  • 156. Hartana, Ciputra Adijaya
    et al.
    Kinn, Johan
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Anania, Stefan
    Alamdari, Farhood
    Glise, Hans
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Detection of micrometastases by flow cytometry in sentinel lymph nodes from patients with renal tumours2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 8, p. 957-966Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Stage is an important prognostic factor in renal tumours and dissemination to regional lymph nodes is associated with poor outcomes. Lymph nodes are routinely assessed by immunohistochemistry and microscopic evaluation, a time-consuming process where micrometastases might go undiagnosed. We evaluate an alternative method for detecting metastatic cells in sentinel nodes (SNs) by flow cytometry.

    METHODS: A total of 15 nodes from 5 patients diagnosed with renal tumours were analysed by flow cytometry. Staining for the intracellular marker cytokeratin 18 (CK18) with the surface markers carbonic anhydrase IX (CA9) and Cadherin 6 were used in flow cytometry analysis. Peripheral blood mononuclear cells (PBMCs) with the addition of known concentrations of cancer cell lines were analysed to investigate the sensitivity of micrometastasis detection.

    RESULTS: Stability of the assay was marked by low intra-assay variability (coefficient of variance ⩽16%) and low inter-assay variability (R(2)=0.9996-1). Eight nodes in four patients were positive for metastasis; six of them were considered being micrometastatic. These metastases were undetected by routine pathology and the patients were restaged from pN0 to pN1.

    CONCLUSIONS: Flow cytometry is able to detect micrometastases in lymph nodes of renal tumour patients that were undetected under H&E examination.

  • 157.
    Hedberg, Ylva
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Landberg, Göran
    Retinoblastoma protein in human renal cell carcinoma in relation to alterations in G1/S regulatory proteins.2004In: International journal of cancer, ISSN 0020-7136, Vol. 109, no 2, p. 189-93Article in journal (Refereed)
  • 158.
    Hedestig, Oliver
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Sandman, Per-Olof
    Umeå University, Faculty of Medicine, Nursing.
    Tomic, Radisa
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Living after external beam radiotherapy of localized prostate cancer: A qualitative analysis of patient narratives.2005In: Cancer Nursing, ISSN 0162-220X, E-ISSN 1538-9804, Vol. 28, no 4, p. 310-317Article in journal (Refereed)
  • 159.
    Hedestig, Oliver
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Sandman, Per-Olof
    Umeå University, Faculty of Medicine, Nursing.
    Tomic, Radisa
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Living after radical prostatectomy for localized prostate cancer.: A qualitative analysis of patient narratives.2005In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 44, no 7, p. 679-686Article in journal (Refereed)
  • 160. Hedlund, Per Olov
    et al.
    Damber, Jan-Erik
    Hagerman, Inger
    Haukaas, Svein
    Henriksson, Peter
    Iversen, Peter
    Johansson, Robert
    Klarskov, Peter
    Lundbeck, Finn
    Rasmussen, Finn
    Varenhorst, Eberhard
    Viitanen, Jouko
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5.2008In: Scand J Urol Nephrol, ISSN 0036-5599, Vol. 42, no 3, p. 220-9Article in journal (Refereed)
  • 161.
    Henriksson, Tobias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Impact of home adress and distance to nearest urological unit on survival in invasive urinary bladder cancer2017Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 162. Holl, Katsiaryna
    et al.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Surcel, Heljä-Marja
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Koskela, Pentti
    Dillner, Joakim
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Olafsdottir, Gudridur H
    Ogmundsdottir, Helga M
    Pukkala, Eero
    Lehtinen, Matti
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lukanova, Annekatrin
    Endogenous steroid hormone levels in early pregnancy and risk of testicular cancer in the offspring: A nested case-referent study.2009In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 124, no 12, p. 2923-2928Article in journal (Refereed)
    Abstract [en]

    According to the leading hypothesis on testicular cancer (TC) etiology exposure to a specific pattern of steroid hormones in utero, in particular, to high levels of estrogens and low levels of androgens is the major determinant of TC risk in the offspring. We performed a case-referent study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal endogenous steroid hormones with regard to the risk of TC. TC cases and referents were aged between 0 and 25 years. For each case-index mother pair, three or four matched referent-referent mother pairs were identified using national population registries. First trimester or early second trimester sera were retrieved from the index mothers of 73 TC cases and 286 matched referent mothers, and were tested for dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG). Offspring of mothers with high DHEAS levels had a significantly decreased risk of TC (OR for highest vs. lowest DHEAS quartile, 0.18 (95% CI 0.06-0.58). In contrast, offspring of mothers with high androstenedione levels had an increased risk of TC (OR 4.1; 95% CI 1.2-12.0). High maternal total estradiol level also tended to be associated with an increased risk of TC in the offspring (OR 32; 95% CI 0.98-1,090). We report the first direct evidence that interplay of maternal steroid hormones in the early pregnancy is important in the etiology of TC in the offspring. (c) 2009 UICC.

  • 163. Holl, Katsiaryna
    et al.
    Surcel, Helja-Marja
    Koskela, Pentti
    Dillner, Joakim
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Wadell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Kaasila, Marjo
    Olafsdottir, Gudridur H
    Ogmundsdottir, Helga M
    Pukkala, Eero
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lehtinen, Matti
    Maternal Epstein-Barr virus and cytomegalovirus infections and risk of testicular cancer in the offspring: a nested case-control study2008In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 116, no 9, p. 816-822Article in journal (Refereed)
    Abstract [en]

    During recent decades the incidence of testicular cancer (TC) has increased rapidly around the world. Associated exogenous etiological factors might therefore be identifiable. We performed a case-control study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of congenital or neonatal infections with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) as risk factors of TC in the offspring. For each case-index mother pair, three or four matched control-control mother pairs were identified using national population registries. First trimester sera were retrieved from the index mothers of 66 TC cases and 258 matched control mothers, and were tested for antibodies to EBV and CMV. High level of maternal EBV IgG antibodies was associated with significantly increased risk of TC in the offspring (odds ratio (OR), 2.50; 95% confidence interval (CI), 1.15, 5.40), especially with risk of non-seminoma TC (OR, 2.73; 950% CI, 1.25, 5.99) and non-seminoma TC diagnosed under 8 years of age (OR, 2.72; 95% CI, 1.05, 7.04). In contrast, offspring of CMV IgG-seropositive mothers had a decreased risk of TC diagnosed under 8 years of age (OR, 0.35; 95% CI, 0.14, 0.89). Our results suggest that EBV and CMV infections may be associated with TC.

  • 164.
    Holm, Alexander
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Patients’ perspective on prostate artery embolization2017Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 165.
    Holmström, Benny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Early diagnosis and treatment of prostate cancer: observational studies in the National Prostate Cancer Register of Sweden and the Västerbotten Intervention Project2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Prostate-specific antigen (PSA) testing has caused a steep increase in the incidence of prostate cancer, especially the incidence of localised low risk disease. In order to decrease the overdiagnosis accompanied by PSA testing, analysis of inherited genetic variants have been suggested as potential tools for clinical assessment of disease risk. With the aim of minimizing overtreatment and postpone side-effects of curative treatment for low risk prostate cancer, active surveillance, a treatment strategy with initial surveillance and deferred radical prostatectomy at the time of progression has evolved. 

    The aim of this thesis was to study the validity of PSA (paper I) and inherited genetic variants (paper II) for early diagnosis of prostate cancer, to assess the extent of PSA testing in Sweden (paper III), and to study the safety of deferred radical prostatectomy in localised low to intermediate risk prostate cancer (paper IV).

    The study designs were i) case-control studies nested within the Västerbotten intervention project (paper I and II), ii) observational study in the Cancer Register of Sweden (paper III), and iii) observational study in the NPCR Follow-up study (paper IV).

    PSA had a high validity in predicting a prostate cancer diagnosis with an area under the receiver operating characteristics (ROC) curve of 0.86 (95% CI, 0.84 to 0.88). A combined test, including PSA, the ratio of free to total PSA, and 33 single nucleotide polymorphisms (SNPs) in a genetic risk score, increased the area under curve to 0.87 (95% CI, 0.85 to 0.89). The estimated uptake of PSA testing among men aged 55 to 69 years increased from zero to 56% between 1997 and 2007 and there were large variations in the uptake of PSA testing between counties in Sweden. After a median follow-up time of eight years there was no significant difference in presence of any one or more adverse pathology features or prostate cancer specific mortality after primary compared to deferred radical prostatectomy in localised low to intermediate risk prostate cancer.

    Results from these studies indicate that PSA and the hitherto identified SNPs are not suitable biomarkers in single-test prostate cancer screening. It is possible to estimate the uptake of PSA testing on a population level. Initial surveillance and deferred radical prostatectomy represent a feasible treatment strategy in localised low to intermediate risk prostate cancer.

  • 166.
    Holmström, Benny
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Holmberg, Erik
    Egevad, Lars
    Adolfsson, Jan
    Johansson, Jan-Erik
    Hugosson, Jonas
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Outcome of primary versus deferred radical prostatectomy in the National Prostate Cancer Register of Sweden follow-up study2010In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 184, no 4, p. 1322-1327Article in journal (Refereed)
    Abstract [en]

    Purpose We assessed outcomes in terms of adverse pathology and prostate cancer specific mortality in men who underwent primary or deferred radical prostatectomy.

    Materials and Methods In the National Prostate Cancer Register of Sweden Follow-Up Study men 70 years old or younger at diagnosis with localized low to intermediate risk prostate cancer diagnosed from 1997 to 2002 were identified. Outcome in terms of adverse pathology, namely upgrading of Gleason score, positive surgical margins and extraprostatic extension, as well as prostate cancer specific mortality, was assessed in 2,344 men who underwent primary radical prostatectomy and 222 who underwent deferred radical prostatectomy after an initial period of surveillance.

    Results Upgrading of Gleason score in surgical specimens vs core biopsies was less frequent after primary (25%) vs deferred radical prostatectomy (38%), p <0.001. There was no significant difference in the percentage of men who underwent primary vs deferred radical prostatectomy for positive surgical margins (33% vs 24%) or extraprostatic extension (27% vs 25%), and there was no difference in any 1 or more of the 3 adverse pathology features (55% vs 56%). After a median followup of 8 years 0.7% of men in the primary radical prostatectomy group and 0.9% in the deferred radical prostatectomy group had died of prostate cancer.

    Conclusions There was no significant difference in the presence of any 1 or more adverse pathology features or in prostate cancer specific mortality after primary compared to deferred radical prostatectomy. However, longer followup is needed to conclusively evaluate the role of deferred radical prostatectomy.

  • 167.
    Holmström, Benny
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC), Lyon, France.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenman, Ulf-Håkan
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prostate specific antigen for early detection of prostate cancer: longitudinal study2009In: BMJ (Clinical research ed.), ISSN 1468-5833, Vol. 339, p. b3537-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate if prostate specific antigen test attains validity standards required for screening in view of recent prostate cancer screening trial results.

    DESIGN: Case-control study nested in longitudinal cohort.

    SETTING: Västerbotten Intervention Project cohort, Umeå, Sweden.

    PARTICIPANTS: 540 cases and 1034 controls matched for age and date of blood draw.

    MAIN OUTCOME MEASURE: Validity of prostate specific antigen for prediction of subsequent prostate cancer diagnosis by record linkage to cancer registry.

    RESULTS: Blood samples were drawn on average 7.1 (SD 3.7) years before diagnosis. The area under the curve for prostate specific antigen was 0.84 (95% confidence interval 0.82 to 0.86). At prostate specific antigen cut-off values of 3, 4, and 5 ng/ml, sensitivity estimates were 59%, 44%, and 33%, and specificity estimates were 87%, 92%, and 95%. The positive likelihood ratio commonly considered to "rule in disease" is 10; in this study the positive likelihood ratios were 4.5, 5.5, and 6.4 for prostate specific antigen cut-off values of 3, 4, and 5 ng/ml. The negative likelihood ratio commonly considered to "rule out disease" is 0.1; in this study the negative likelihood ratios were 0.47, 0.61, and 0.70 for prostate specific antigen cut-off values of 3, 4, and 5 ng/ml. For a cut-off of 1.0 ng/ml, the negative likelihood ratio was 0.08.

    CONCLUSIONS: No single cut-off value for prostate specific antigen concentration attained likelihood ratios formally required for a screening test. Prostate specific antigen concentrations below 1.0 ng/ml virtually ruled out a prostate cancer diagnosis during the follow-up. Additional biomarkers for early detection of prostate cancer are needed before population based screening for prostate cancer should be introduced.

  • 168.
    Holmström, Benny
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Mattias
    International Agency for Research on Cancer (IARC), Lyon, France.
    Bratt, Ola
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    PSA-testet håller inte för screening: bra – men inte tillräckligt bra2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 7, p. 436, 438-439Article in journal (Refereed)
    Abstract [sv]

    Prostatacancer är den vanligaste cancersjukdomen och den vanligaste cancerrelaterade dödsorsaken bland män i Sverige. Screening för prostataspecifikt antigen (PSA) minskade dödligheten i prostatacancer med 20 procent i en stor randomiserad studie. En utvärdering av PSA-test med sannolikhetskvot (likelihood ratio) visade att det inte uppfyller kriterierna för ett screeningtest. Män ska ha information om PSA-testets för- och nackdelar innan testet utförs. En broschyr med sådan information finns tillgänglig på <http://www.socialstyrelsen.se/publikationer2007/2007-114-90>.

  • 169. Hosen, Ismail
    et al.
    Rachakonda, P. Sivaramakrishna
    Heidenreich, Barbara
    Sitaram, Raviprakash T.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hemminki, Kari
    Kumar, Rajiv
    TERT promoter mutations in clear cell renal cell carcinoma2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 10, p. 2448-2452Article in journal (Refereed)
    Abstract [en]

    We screened promoter region of the telomerase reverse transcriptase (TERT) for activating somatic mutations in 188 tumors from patients with clear cell renal cell carcinoma (ccRCC). Twelve tumors (6.4%) carried a mutation within the core promoter region of the gene. The mutations were less frequent in high grade tumors compared to low grade tumors [odds ratio (OR)=0.15, 95% confidence interval (CI)=0.03-0.72, p=0.02]. Multivariate analysis for cause specific survival showed statistically significant poor outcome in patients with TERT promoter mutations [hazard ratio (HR)=2.90, 95% CI=1.13-7.39, p=0.03]. A common polymorphism (rs2853669) within the locus seemed to act as a modifier of the effect of the mutations on patient survival as the noncarriers of the variant allele with the TERT promoter mutations showed worst survival (HR=3.34, 95% CI=1.24-8.98, p=0.02). We also measured relative telomere length (RTL) in tumors and difference between tumors with and without the TERT promoter mutations was not statistically significant. Similarly, no difference in patient survival based on RTL in tumors was observed. Our study showed a relatively low frequency of TERT promoter mutations in ccRCC. Nevertheless, patients with the mutations, particularly in the absence of the rs2853669 variant showed the worst disease-specific survival. Thus, it is possible that the TERT promoter mutations define a small subset of tumors with an aggressive behavior. What's new? The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase, a ribonucleoprotein complex that maintains genomic integrity. Activating somatic mutations in the promoter region of the TERT gene have been reported in many cancers. Here, the authors describe new TERT promoter mutations in clear cell renal cell carcinoma. Although present only in a proportion of the tumors, the TERT promoter mutations were independently associated with poor patient survival. The effect was enhanced by a common polymorphism within the core TERT promoter. The TERT promoter mutations may thus define a small subset of tumors with an aggressive behavior.

  • 170. Hotakainen, Kristina
    et al.
    Lintula, Susanna
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Finne, Patrik
    Paju, Annukka
    Stenman, Ulf-Håkan
    Stenman, Jakob
    Expression of human chorionic gonadotropin beta-subunit type I genes predicts adverse outcome in renal cell carcinoma.2006In: J Mol Diagn, ISSN 1525-1578, Vol. 8, no 5, p. 598-603Article in journal (Refereed)
  • 171. Hsu, Fang-Chi
    et al.
    Lindström, Sara
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Sun, Jielin
    Wiklund, Fredrik
    Chen, Shyh-Huei
    Adami, Hans-Olov
    Turner, Aubrey R
    Liu, Wennuan
    Bälter, Katarina
    Kim, Jin Woo
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Chang, Bao-Li
    Isaacs, William B
    Xu, Jianfeng
    Grönberg, Henrik
    Zheng, S Lilly
    A multigenic approach to evaluating prostate cancer risk in a systematic replication study.2008In: Cancer Genet Cytogenet, ISSN 1873-4456, Vol. 183, no 2, p. 94-8Article in journal (Refereed)
  • 172. Hsu, Fang-Chi
    et al.
    Sun, Jielin
    Wiklund, Fredrik
    Isaacs, Sarah D
    Wiley, Kathleen E
    Purcell, Lina D
    Gao, Zhengrong
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Zhu, Yi
    Kim, Seong-Tae
    Zhang, Zheng
    Liu, Wennuan
    Chang, Bao-Li
    Walsh, Patrick C
    Duggan, David
    Carpten, John D
    Isaacs, William B
    Grönberg, Henrik
    Xu, Jianfeng
    Zheng, S Lilly
    A novel prostate cancer susceptibility locus at 19q13.2009In: Cancer research, ISSN 1538-7445, Vol. 69, no 7, p. 2720-3Article in journal (Refereed)
    Abstract [en]

    A two-stage genome-wide association study (GWAS) of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative identified single nucleotide polymorphisms (SNP) in 150 regions across the genome that may be associated with prostate cancer (PCa) risk. We filtered these results to identify 43 independent SNPs where the frequency of the risk allele was consistently higher in cases than in controls in each of the five CGEMS study populations. Genotype information for 22 of these 43 SNPs was obtained either directly by genotyping or indirectly by imputation in our PCa GWAS of 500 cases and 500 controls selected from a population-based case-control study in Sweden [Cancer of the Prostate in Sweden (CAPS)]. Two of these 22 SNPs were significantly associated with PCa risk (P<0.05). We then genotyped these two SNPs in the remaining cases (n=2,393) and controls (n=1,222) from CAPS and found that rs887391 at 19q13 was highly associated with PCa risk (P=9.4 x 10(-4)). A similar trend of association was found for this SNP in a case-control study from Johns Hopkins Hospital (JHH), albeit the result was not statistically significant. Altogether, the frequency of the risk allele of rs887391 was consistently higher in cases than controls among each of seven study populations examined, with an overall P=3.2 x 10(-7) from a combined allelic test. A fine-mapping study in a 110-kb region at 19q13 among CAPS and JHH study populations revealed that rs887391 was the most strongly associated SNP in the region. Additional confirmation studies of this region are warranted.

  • 173. Hu, J.
    et al.
    Kinn, J.
    Zirakzadeh, A. A.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Norstedt, G.
    Wikstrom, A. -C
    Winqvist, O.
    The effects of chemotherapeutic drugs on human monocyte-derived dendritic cell differentiation and antigen presentation2013In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 172, no 3, p. 490-499Article in journal (Refereed)
    Abstract [en]

    Recent studies indicate that chemotherapeutic agents may increase the anti-tumoral immune response. Based on the pivotal role of dendritic cells (DCs) in host tumour-specific immune responses, we investigated the effect of commonly used chemotherapeutic drugs dexamethasone, doxorubicin, cisplatin and irinotecan and glucocorticoids on monocyte-derived DCs (moDCs). Dexamethasone displayed the strongest inhibitory effect on DC differentiation. The effect of cisplatin and irinotecan was moderate, while only weak effects were noticed for doxorubicin. Surprisingly, when the functional consequence of chemotherapy-treated CD14+ monocytes and their capacity to activate CD4+ T responders cells were investigated, cisplatin-treated monocytes gave rise to increased T cell proliferation. However, dexamethasone, doxorubicin and irinotecan-pretreated monocytes did not stimulate any increased T cell proliferation. Further investigation of this observation revealed that cisplatin treatment during DC differentiation up-regulated significantly the interferon (IFN)- transcript. By contrast, no effect was evident on the expression of interleukin (IL)-1, tumour necrosis factor (TNF)-, IL-6 or IFN- transcripts. Blocking IFN- attenuated the cisplatin-enhanced T cell proliferation significantly. In conclusion, cisplatin treatment enhanced the immune stimulatory ability of human monocytes, a mechanism mediated mainly by the increased production of IFN-.

  • 174.
    Hultdin, Johan
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Nutritional Research.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study.2005In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 113, no 5, p. 819-824Article in journal (Refereed)
    Abstract [en]

    The role of folate metabolism in cancer development is a topic of much current interest, with maintenance of adequate folate status tending to show a protective effect. Aberrant methylation, primarily hypermethylation of certain genes including tumor suppressors, has been implicated in prostate cancer development. Folate, vitamin B12 and homocysteine are essential for methyl group metabolism and thus also for DNA methylation. We related plasma levels of these factors to prostate cancer risk in a prospective study of 254 case subjects and 514 matched control subjects. Increasing plasma levels of folate and vitamin B12 were statistically significantly associated with increased prostate cancer risk, with an odds ratio of 1.60 (95% CI = 1.03-2.49; p(trend) = 0.02) for folate and 2.63 (95% CI = 1.61-4.29; p(trend) < 0.001) for vitamin B12 for highest vs. lowest quartile. Increasing plasma homocysteine levels were associated with a reduced risk of borderline significance (OR = 0.67; 95% CI = 0.43-1.04; p(trend) = 0.08). After adjustment for the other 2 plasma variables, body mass index and smoking, a statistically significant increased risk remained only for vitamin B12 (OR = 2.96; 95% CI = 1.58-5.55; p(trend) = 0.001). Adjusted OR for folate and homocysteine were 1.30 (95% CI = 0.74-2.24; p(trend) = 0.17) and 0.91 (95% CI = 0.51-1.58; p(trend) = 0.60), respectively. Our results suggest that factors contributing to folate status are not protective against prostate cancer. On the contrary, vitamin B12, associated with an up to 3-fold increase in risk, and possibly also folate, may even stimulate prostate cancer development. These findings are novel and should be explored further in future studies. (c) 2004 Wiley-Liss, Inc.

  • 175. Hunt, Kelly J
    et al.
    Lukanova, Annekatrin
    Rinaldi, Sabina
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norat, Teresa
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Riboli, Elio
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Kaaks, Rudolf
    A potential inverse association between insulin-like growth factor I and hypertension in a cross-sectional study.2006In: Annals of Epidemiology, ISSN 1047-2797, E-ISSN 1873-2585, Vol. 16, no 7, p. 563-571Article in journal (Refereed)
  • 176.
    Hägglöf, Christina
    et al.
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Paulsson, Janna
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Östman, Arne
    Stromal PDGFRbeta expression in prostate tumors and non-malignant prostate tissue predicts prostate cancer survival2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 5, p. e10747-Article in journal (Refereed)
    Abstract [en]

    The study revealed a number of novel associations between stromal PDGFRbeta expression in prostate tumors and several important clinical characteristics, including survival.

  • 177.
    Hägglöf, Christina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Strömvall, Kerstin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Egevad, Lars
    Josefsson, Andreas
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Granfors, Torvald
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TMPRSS2-ERG Expression Predicts Prostate Cancer Survival and Associates with Stromal Biomarkers2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e86824-Article in journal (Refereed)
    Abstract [en]

    The TMPRSS2-ERG gene fusion is found in approximately half of all prostate cancers. The functional and prognostic significance of TMPRSS2-ERG is, however, not fully understood. Based on a historical watchful waiting cohort, an association between TMPRSS2-ERG, evaluated as positive immune staining, and shorter survival of prostate cancer patients was identified. Expression of ERG was also associated with clinical markers such as advanced tumor stage, high Gleason score, presence of metastasis and prognostic tumor cell markers such as high Ki67, pEGFR and pAkt. Novel associations between TMPRSS2-ERG and alterations in the tumor stroma, for example, increased vascular density, hyaluronan and PDGFR beta and decreased Caveolin-1, all known to be associated with an aggressive disease, were found. The present study suggests that the TMPRSS2-ERG fusion gene is associated with a more aggressive prostate cancer phenotype, supported by changes in the tumor stroma.

  • 178.
    Häggstrom, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ulmert, David
    Lund Univ, Skåne Univ Hosp, Dept Clin Sci, Malmö, Sweden.
    Bjørge, Tone
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Ulmer, Hanno
    nnsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, Innsbruck, Austria.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Manjer, Jonas
    Lund Univ, Dept Plast Surg, Skåne Univ Hosp, Malmö, Sweden.
    Engeland, Anders
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Nagel, Gabriele
    Univ Ulm, Inst Epidemiol & Med Biometry, Ulm, Germany.
    Almqvist, Martin
    Lund Univ, Skåne Univ Hosp, Dept Surg, Malmö, Sweden.
    Selmer, Randi
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Concin, Hans
    Agcy Prevent & Social Med, Bregenz, Austria.
    Tretli, Steinar
    Canc Registry Norway, Inst Populat Based Canc Res, Oslo, Norway.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prospective study on metabolic factors and risk of prostate cancer2012In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 118, no 24, p. 6199-6206Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There are inconsistent data regarding the association between metabolic factors, separately and combined, and the risk of prostate cancer and death from prostate cancer.

    METHODS: In the Metabolic Syndrome and Cancer Project (Me-Can), data on body mass index (BMI); blood pressure; and blood levels of glucose, cholesterol, and triglycerides were collected for 289,866 men. Cox proportional hazard models were used to calculate relative risks (RRs) by exposures in quintiles as well as for z scores (with a mean of 0 and a standard deviation of 1) together with a composite sum of scores to assess the combined effect of metabolic factors. RRs were corrected for random errors in measurement.

    RESULTS: During a mean follow-up of 12 years, 6673 men were diagnosed with prostate cancer and 961 died of the disease. Men with high levels of glucose and triglycerides were found to have a decreased risk of prostate cancer: top versus bottom quintile of glucose: RR, 0.82 (95% confidence interval [95% CI], 0.62-1.08; P value for trend = .03) and top versus bottom quintile of triglycerides: RR, 0.88 (95% CI, 0.74-1.04; P value for trend = .001). High BMI, elevated blood pressure, and a high composite z score were found to be associated with an increased risk of death from prostate cancer: top versus bottom quintile of BMI: RR, 1.36 (95% CI, 1.08-1.71); systolic blood pressure: RR, 1.62 (95% CI, 1.07-2.45); and per 1-unit increase of the composite z score: RR, 1.13 (95% CI, 1.03-1.25).

    CONCLUSIONS: The authors found no evidence of an association between high levels of metabolic factors and the risk of prostate cancer, but high BMI, elevated blood pressure, and a composite score of all metabolic factors were associated with an increased risk of death from prostate cancer. 

  • 179.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Metabolic factors and risk of prostate, kidney, and bladder cancer2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Prostate cancer is the most common cancer in Sweden with around 10,000 new cases every year. Kidney and bladder cancer are less common with 1,000 and 2,000 new cases annually, respectively. The incidence of these cancer sites is higher in developed, than in developing countries, suggesting an association between lifestyle and cancer risk. The aims of this thesis were to investigate body mass index (BMI), blood pressure, and blood levels of glucose, total cholesterol, and triglycerides as risk factors for prostate, kidney, and bladder cancer. Furthermore, we aimed at assess probabilities of prostate cancer and competing events, all-cause death, for men with normal and high levels of metabolic factors.

    Material and methods: This thesis was conducted within the Metabolic Syndrome and Cancer project (Me-Can), a pooled cohort study with data from 578,700 participants from Norway, Sweden, and Austria. Data from metabolic factors were prospectively collected at health examinations and linked to the Cancer and Cause of Death registers in each country. 

    Results: High levels of metabolic factors were not associated with increased risk of prostate cancer, but high levels of BMI and blood pressure were associated with risk of prostate cancer death. The probability of prostate cancer was higher for men with normal levels of metabolic factors compared to men with high levels, but the probability of all-cause death, was higher for men with high levels than for those with normal levels. For both men and women, high levels of metabolic factors were associated with increased risk of kidney cancer (renal cell carcinoma). Furthermore, blood pressure for men and BMI for women were found as independent risk factors of kidney cancer. High blood pressure was associated with an increased risk of bladder cancer for men.

    Conclusions: High levels of metabolic factors were associated to risk of kidney and bladder cancer and to death from kidney, bladder, and prostate cancer. Compared to men with normal levels, men with high levels of metabolic factors had a decreased probability of prostate cancer but an increased probability of all-cause death.

  • 180.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Liedberg, Fredrik
    Hagberg, Oskar
    Aljabery, Firas
    Ströck, Viveka
    Hosseini, Abolfazl
    Gårdmark, Truls
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Malmström, Per-Uno
    Garmo, Hans
    Jahnson, Staffan
    Holmberg, Lars
    Cohort profile: The Swedish National Register of Urinary Bladder Cancer (SNRUBC) and the Bladder Cancer Data Base Sweden (BladderBaSe)2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 9, article id e016606Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To monitor the quality of bladder cancer care, the Swedish National Register of Urinary Bladder Cancer (SNRUBC) was initiated in 1997. During 2015, in order to study trends in incidence, effects of treatment and survival of men and women with bladder cancer, we linked the SNRUBC to other national healthcare and demographic registers and constructed the Bladder Cancer Data Base Sweden (BladderBaSe).

    PARTICIPANTS: The SNRUBC is a nationwide register with detailed information on 97% of bladder cancer cases in Sweden as compared with the Swedish Cancer Register. Participants in the SNRUBC have registered data on tumour characteristics at diagnosis, and for 98% of these treatment data have been captured. From 2009, the SNRUBC holds data on 88% of eligible participants for follow-up 5 years after diagnosis of non-muscle invasive bladder cancer, and from 2011, data on surgery details and complications for 85% of participants treated with radical cystectomy. The BladderBaSe includes all data in the SNRUBC from 1997 to 2014, and additional covariates and follow-up data from linked national register sources on comorbidity, socioeconomic factors, detailed information on readmissions and treatment side effects, and causes of death.

    FINDINGS TO DATE: Studies based on data in the SNRUBC have shown inequalities in survival and treatment indication by gender, regions and hospital volume. The BladderBaSe includes 38 658 participants registered in SNRUBC with bladder cancer diagnosed from 1 January 1997 to 31 December 2014. The BladderBaSe initiators are currently in collaboration with researchers from the SNRUBC investigating different aspects of bladder cancer survival.

    FUTURE PLANS: The SNRUBC and the BladderBaSe project are open for collaborations with national and international research teams. Collaborators can submit proposals for studies and study files can be uploaded to servers for remote access and analysis. For more information, please contact the corresponding author.

  • 181.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Rapp, Kilian
    Univ Ulm, Inst Epidemiol & Med Biometry, D-89069 Ulm, Germany.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Manjer, Jonas
    Lund Univ, Skåne Univ Hosp, Dept Surg, Malmö, Sweden.
    Bjørge, Tone
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Ulmer, Hanno
    Med Univ Innsbruck, Dept Med Stat Informat & Hlth Econ, A-6020 Innsbruck, Austria.
    Engeland, Anders
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Almqvist, Martin
    Lund Univ, Skåne Univ Hosp, Dept Surg, Malmö, Sweden.
    Concin, Hans
    Agcy Prevent & Social Med, Bregenz, Australia.
    Selmer, Randi
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tretli, Steinar
    Canc Registry Norway, Inst Populat Based Canc Res, Oslo, Norway.
    Nagel, Gabriele
    Univ Ulm, Inst Epidemiol & Med Biometry, D-89069 Ulm, Germany.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Metabolic factors associated with risk of renal cell carcinoma2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, p. e57475-Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that obesity and hypertension are associated with increased risk of renal cell carcinoma (RCC), but less is known about the association to other metabolic factors. In the Metabolic Syndrome and Cancer project (Me-Can) data on body mass index (BMI, kg/m2), blood pressure, and circulating levels of glucose, cholesterol, and triglycerides were collected from 560,388 men and women in cohorts from Norway, Austria, and Sweden. By use of Cox proportional hazard models, hazard ratios (HR) were calculated for separate and composite metabolic exposures. During a median follow-up of 10 years, 592 men and 263 women were diagnosed with RCC. Among men, we found an increased risk of RCC for BMI, highest vs. lowest quintile, (HR = 1.51, 95% CI 1.13-2.03), systolic blood pressure, (HR = 3.40, 95% CI 1.91-6.06), diastolic blood pressure, (HR = 3.33, 95% CI 1.85-5.99), glucose, (HR = 3.75, 95% CI 1.46-9.68), triglycerides, (HR = 1.79, 95% CI 1.00-3.21) and a composite score of these metabolic factors, (HR = 2.68, 95% CI 1.75-4.11). Among women we found an increased risk of RCC for BMI, highest vs. lowest quintile, (HR = 2.21, 95% CI 1.32-3.70) and the composite score, (HR = 2.29, 95% CI 1.12-4.68). High levels of the composite score were also associated with risk of death from RCC among both men and women. No multiplicative statistical or biological interactions between metabolic factors on risk of RCC were found. High levels of BMI, blood pressure, glucose and triglycerides among men and high BMI among women were associated with increased risk of RCC.

  • 182.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Clinical Sciences, Diabetes and Cardiovascular Diseases, Genetic Epidemiology, Lund University, Lund, Sweden.
    Garmo, Hans
    Holmberg, Lars
    Van Hemelrijck, Mieke
    Interpretation of conventional survival analysis and competing-risk analysis: an example of hypertension and prostate cancer2016In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 118, no 6, p. 850-852Article in journal (Refereed)
  • 183.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Nagel, Gabriele
    Manjer, Jonas
    Bjørge, Tone
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Engeland, Anders
    Ulmer, Hanno
    Lindkvist, Bjorn
    Selmer, Randi
    Concin, Hans
    Tretli, Steinar
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prostate Cancer, Prostate Cancer Death, and Death from Other Causes, Among Men with Metabolic Aberrations2014In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 25, no 6, p. 823-828Article in journal (Refereed)
    Abstract [en]

    Background: Few previous studies of metabolic aberrations and prostate cancer risk have taken into account the fact that men with metabolic aberrations have an increased risk of death from causes other than prostate cancer. The aim of this study was to calculate, in a real-life scenario, the risk of prostate cancer diagnosis, prostate cancer death, and death from other causes.

    Methods: In the Metabolic Syndrome and Cancer Project, prospective data on body mass index, blood pressure, glucose, cholesterol, and triglycerides were collected from 285,040 men. Risks of prostate cancer diagnosis, prostate cancer death, and death from other causes were calculated by use of competing risk analysis for men with normal (bottom 84%) and high (top 16%) levels of each factor, and a composite score.

    Results: During a mean follow-up period of 12 years, 5,893 men were diagnosed with prostate cancer, 1,013 died of prostate cancer, and 26,328 died of other causes. After 1996, when prostate-specific antigen testing was introduced, men up to age 80 years with normal metabolic levels had 13% risk of prostate cancer, 2% risk of prostate cancer death, and 30% risk of death from other causes, whereas men with metabolic aberrations had corresponding risks of 11%, 2%, and 44%.

    Conclusions: In contrast to recent studies using conventional survival analysis, in a real-world scenario taking risk of competing events into account, men with metabolic aberrations had lower risk of prostate cancer diagnosis, similar risk of prostate cancer death, and substantially higher risk of death from other causes compared with men who had normal metabolic levels.

  • 184.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Nagel, Gabriele
    Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany.
    Manjer, Jonas
    Department of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden.
    Bjørge, Tone
    Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Engeland, Anders
    Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
    Ulmer, Hanno
    Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Innsbruck, Austria.
    Lindkvist, Björn
    Department of Surgery, Skåne University Hospital, Lund University, Malmö, Sweden.
    Selmer, Randi
    Norwegian Institute of Public Health, Oslo, Norway.
    Concin, Hans
    Agency for Preventive and Social Medicine, Bregenz, Austria.
    Tretli, Steinar
    Institute of Population-based Cancer Research, The Cancer Registry of Norway, Oslo, Norway.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Competing risk analysis of metabolic factors and prostate cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Men at risk of prostate cancer are also at risk of competing events but this has been ignored in most studies of metabolic aberrations and prostate cancer. The aim of this study was to assess probabilities of prostate cancer and prostate cancer death by use of competing risk analysis.

    Methods: In the Metabolic syndrome and Cancer project (Me-Can), data on body mass index, blood pressure, glucose, total cholesterol, and triglycerides were collected from 285 040 men. Probabilities of prostate cancer, prostate cancer death and competing events, i.e. all-cause death or death from other causes, respectively, were calculated for men with normal (bottom 84%) and high (top 16%) levels of each metabolic factor and a composite score based on all metabolic factors

    Results: During follow up, 5893 men were diagnosed with prostate cancer, 1013 men died of prostate cancer, and 26 328 men died of other causes. Men with high levels of metabolic factors had decreased probability of prostate cancer, similar probability of prostate cancer death, and increased probability of other causes of death compared to men with normal levels. After 1996, when prostate specific antigen was used for detection of prostate cancer, men up to 80 years with normal levels of metabolic factors had 13% probability of prostate cancer and 37% probability of death from all causes. For men with high levels of metabolic factors, corresponding probabilities were 12% and 47%.

    Conclusions: Men with metabolic aberrations had a decreased probability of prostate cancer but a substantially higher probability of death from all causes.

  • 185.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. null.
    Rapp, Kilian
    Univ Ulm, Inst Epidemiol, Ulm, Germany.
    Bjørge, Tone
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Lindkvist, Björn
    Univ Gothenburg, Sahlgrenska Acad, Dept Med, Gothenburg, Sweden.
    Concin, Hans
    Agcy Prevent & Social Med, Bregenz, Austria.
    Engeland, Anders
    Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Bergen, Norway.
    Manjer, Jonas
    Malmö Univ Hosp, Dept Surg, Malmö, Sweden.
    Ulmer, Hanno
    Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, Innsbruck, Austria.
    Selmer, Randi
    Norwegian Inst Publ Hlth, Oslo, Norway.
    Tretli, Steinar
    Canc Registry Norway, Inst Populat Based Canc Res, Oslo, Norway.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research. null.
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. null.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. null.
    Metabolic syndrome and risk of bladder cancer: prospective cohort study in the metabolic syndrome and cancer project (Me-Can)2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 128, no 8, p. 1890-1898Article in journal (Refereed)
    Abstract [en]

    There are little data on the putative association between factors in the metabolic syndrome (MetS) and risk of bladder cancer. In the Metabolic Syndrome and Cancer project (Me-Can), measurements of height, weight, blood pressure and circulating levels of glucose, cholesterol, and triglycerides had been collected from 578,700 subjects in cohorts in Norway, Austria, and Sweden. We used Cox proportional hazard models to calculate relative risks (RRs) of bladder cancer by exposures divided into quintiles, in categories according to the World Health Organisation (WHO) and as a continuous standardized variable (z-score with mean = 0 and standard deviation = 1) for each separate component and its standardized sum, a composite MetS score. RRs were corrected for random error in measurements. During a mean follow-up of 11.7 years (SD = 7.6), 1,587 men and 327 women were diagnosed with bladder cancer. Significant associations with risk were found among men per one unit increment of z-score for blood pressure, RR = 1.13 (95% CI 1.03-1.25), and the composite MetS score, RR = 1.10 (95% CI 1.01-1.18). Among women, glucose was nonsignificantly associated with risk, RR = 1.41 (95% CI 0.97-2.06). No statistically significant interactions were found between the components in the MetS in relation to bladder cancer risk. Hypertension and a composite MetS score were significantly but modestly associated with an increased risk of bladder cancer among men and elevated glucose was associated with a nonsignificant increase in risk among women.

  • 186.
    Häggström, Christel
    et al.
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Van Hemelrijck, Mieke
    Zethelius, Björn
    Robinson, David
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Grundmark, Birgitta
    Holmberg, Lars
    Gudbjörnsdottir, Soffia
    Garmo, Hans
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Prospective study of Type 2 diabetes mellitus, anti-diabetic drugs and risk of prostate cancer2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 3, p. 611-617Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes mellitus (T2DM) has consistently been associated with decreased risk of prostate cancer; however, if this decrease is related to the use of anti-diabetic drugs is unknown. We prospectively studied men in the comparison cohort in the Prostate Cancer data Base Sweden 3.0, with data on T2DM, use of metformin, sulfonylurea and insulin retrieved from national health care registers and demographic databases. Cox proportional hazards regression models were used to compute hazard ratios (HR) and 95% confidence intervals (CI) of prostate cancer, adjusted for confounders. The study consisted of 612,846 men, mean age 72 years (standard deviation; SD = 9 years), out of whom 25,882 men were diagnosed with prostate cancer during follow up, mean time of 5 years (SD = 3 years). Men with more than 1 year's duration of T2DM had a decreased risk of prostate cancer compared to men without T2DM (HR = 0.85, 95% CI = 0.82-0.88) but among men with T2DM, those on metformin had no decrease (HR = 0.96, 95% CI = 0.77-1.19), whereas men on insulin (89%) or sulfonylurea (11%) had a decreased risk (HR = 0.73, 95% CI = 0.55-0.98), compared to men with T2DM not on anti-diabetic drugs. Men with less than 1 year's duration of T2DM had no decrease in prostate cancer risk (HR = 1.11, 95% CI = 0.95-1.31). Our results gave no support to the hypothesis that metformin protects against prostate cancer as recently proposed. However, our data gave some support to an inverse association between T2DM severity and prostate cancer risk.

  • 187.
    Häggström Rudolfsson, Stina
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Franck Lissbrant, Ingela
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Localized expression of angiopoietin 1 and 2 may explain unique characteristics of the rat testicular microvasculature.2003In: Biology of Reproduction, ISSN 0006-3363, E-ISSN 1529-7268, Vol. 69, no 4, p. 1231-7Article in journal (Refereed)
    Abstract [en]

    The testicular vasculature is unique in several ways. The unfenestrated endothelial cells constitute one part of the blood-testis barrier, and testicular microvessels are normally resistant to inflammation mediators. At the same time that angiogenic factors and inflammation mediators are constitutively produced, the proportion of proliferating endothelial cells is considerably higher than in other organs, but new blood vessels are not formed. Hormonal stimulation of the testis with hCG increase endothelial cell proliferation, vascular permeability, and sensitivity to locally injected inflammation mediators. In the present study, we examined whether local expression of angiopoietin (ang) 1, an inhibitor of vascular leakage and sprouting angiogenesis, and its antagonist, ang 2, could be involved in establishing this vascular phenotype. Using reverse transcription-polymerase chain reaction and immunohistochemistry, we demonstrate that testicular vascular endothelial growth factor-A (VEGF-A), ang 1, ang 2, and the ang-receptor tie 2 are expressed in the testis and that hormonal stimulation with hCG is accompanied by increased expression of VEGF-A and ang 2. The ang 1 protein is expressed in testicular microvessels under basal conditions, and it is largely unaffected after hCG stimulation. Expression of ang 2 in microvessels, in contrast, is low under basal conditions and is up-regulated by hCG. Intratesticular injection of human recombinant ang 1 protein inhibits hCG-induced increase in vascular permeability. Injection of ang 2 in the testis increases endothelial cell proliferation and the volume of the interstitial space. We therefore suggest that ang 1 stabilizes testicular microvessels under basal conditions and that a shift in this balance caused by increased ang 2, together with increased VEGF-A, allows vascular leakage, high endothelial cell proliferation, and presumably, vascular growth after hormonal stimulation.

  • 188.
    Häggström, S
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Damber, J E
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Vascular endothelial growth factor content in metastasizing and nonmetastasizing Dunning prostatic adenocarcinoma.2000In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 45, no 1, p. 42-50Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Tumor angiogenesis is important in progressive tumor growth and metastasis. In the normal rat prostate and in androgen-sensitive prostate tumors androgen ablation causes an involution of the vasculature and a decrease in the vascular endothelial growth factor (VEGF) levels before regression of the prostate gland. To examine whether angiogenesis and metastasis are regulated by VEGF in androgen-insensitive and metastasizing prostate tumors, five Dunning rat prostate cancer sublines were tested; the androgen-sensitive, nonmetastasizing R3327 PAP, and the androgen-insensitive, low metastasizing AT-1, and the three androgen-insensitive, metastasizing AT-2, AT-3, and MatLyLu Dunning prostatic adenocarcinomas.

    METHODS: VEGF levels were quantified in the rat dorsolateral prostate and in the five Dunning sublines using competitive RT-PCR, Western blot, and Elisa. Vascular density was determined by factor VIII staining.

    RESULTS: VEGF mRNA was increased in all tumors compared with normal prostates. The two metastatic sublines AT-3 and MatLyLu and the nonmetastatic subline AT-1 showed the highest VEGF mRNA expression. VEGF protein levels in the prostate gland showed increased expression in the metastatic sublines, AT-2, AT-3, and MatLyLu, compared with the nonmetastatic AT-1 subline and the ventral prostate. VEGF proteins in serum were highest in the metastatic AT-3 subline. The vessel density was highest in the two highly metastatic sublines AT-3 and MatLyLu.

    CONCLUSIONS: Our results suggest that VEGF levels are associated with microvessel density and the previously established metastatic pattern of these rat prostate tumor systems.

  • 189.
    Häggström, S
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lissbrant, I F
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Damber, J E
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Testosterone induces vascular endothelial growth factor synthesis in the ventral prostate in castrated rats.1999In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 161, no 5, p. 1620-5Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Recent studies suggest that the vasculature is important for the control of prostate growth. Castration induces an involution of the prostate gland and its vasculature. Replacement of testosterone stimulates endothelial cell proliferation and normalizes vascular volumes and blood flow several days before organ regrowth. Antiangiogenesis treatment inhibits the growth of prostate tumors. Understanding the regulation of the prostate vasculature may therefore provide important knowledge of the mechanisms responsible for the growth of non-malignant and malignant prostate tissue. Castration induced regression and testosterone stimulated regrowth of the prostatic vasculature have here been used to study the involvement of the angiogenic factor vascular endothelial growth factor (VEGF) and its receptors flt-1 and flk-1/KDR in the regulation of the prostatic vasculature.

    MATERIALS AND METHODS: VEGF, flt-1, and flk-1/KDR levels were quantified in the rat ventral prostate following castration and testosterone replacement. Methods used were competitive RT-PCR, Western blot and immunohistochemistry.

    RESULTS: VEGF mRNA and protein levels were significantly decreased by castration and testosterone treatment induced VEGF synthesis in the rat ventral prostate epithelium. Flt-1 and flk-1/KDR receptor levels were unaffected by castration and testosterone treatment.

    CONCLUSIONS: Castration down regulates VEGF and testosterone induces VEGF synthesis in epithelial cells in the rat ventral prostate.

  • 190.
    Häggström, S
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stattin, P
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Wikström, P
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Damber, J E
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Castration-induced reduction of vascular endothelial growth factor expression in benign human prostate tissue is lost in advanced prostate cancer.2001In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 88, no 1, p. 110-6Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine the role of vascular response in the castration-induced regression of benign and malignant human prostate tissue, as recent studies show that castration rapidly decreases blood flow and induces endothelial cell death, which may be important for subsequent epithelial cell death and involution of the glandular tissue of the prostate.

    MATERIALS AND METHODS: The expression of vascular endothelial growth factor (VEGF) and its receptors was analysed using the quantitative reverse transcriptase-polymerase chain reaction, in benign and tumour areas of core biopsies taken before, and approximately 1 week after castration therapy. The castration-induced VEGF response was related to therapy-induced changes in tumour cell apoptotic index and subsequent response in serum prostate-specific antigen (PSA). In another set of patients, serum VEGF was quantified by enzyme-linked immunosorbent assay before, and at 3--6 months after castration therapy.

    RESULTS: VEGF mRNA was down-regulated after castration in benign prostate tissue (P < or = 0.05), whereas in tumour tissue, VEGF levels were reduced in some of the patients but unchanged or increased in others. In most patients whose tumour tissue responded with VEGF reduction, there was a corresponding increase in tumour cell apoptosis. Serum VEGF levels were not significantly changed after castration. Almost all patients responded with a substantial reduction in serum PSA after castration.

    CONCLUSION: Castration reduces VEGF mRNA expression in benign prostate tissue and generally in those prostate tumours where castration also induces tumour cell apoptosis. This suggests that a therapy-induced down-regulation of VEGF could be important for tumour cell death.

  • 191.
    Häggström, S
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tørring, N
    Møller, K
    Jensen, E
    Lund, L
    Nielsen, J E
    Bergh, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Damber, J-E
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Effects of finasteride on vascular endothelial growth factor.2002In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 36, no 3, p. 182-7Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Finasteride has been shown to reduce prostate bleeding in patients with benign prostatic hyperplasia (BPH). The mechanisms behind this are not known, but it has been suggested that finasteride reduces bleeding by inhibiting angiogenesis in the prostate. Studies in animals have shown that castration rapidly induces involution of the prostate vasculature, and androgen-stimulated prostate growth may be angiogenesis dependent. The objective of this study was to explore the response to finasteride on the vasculature and the expression of vascular endothelial growth factor (VEGF), a potent regulatory factor of angiogenesis in human prostate tissue.

    MATERIAL AND METHODS: Patients with BPH were randomly assigned to 3 months of treatment either with finasteride (5 mg/day) or placebo before undergoing transurethral resection of the prostate (TURP). Prostate tissue VEGF expression was quantified by Western blot and the vascular density determined in Factor VIII immunostained tissue sections. Serum concentrations of VEGF were measured with ELISA technique.

    RESULTS: Patients treated with finasteride (n = 15) showed a decrease in prostate tissue VEGF(165) expression compared with placebo (n = 13) treated patients (p < 0.05), but the vascular density and the serum VEGF levels were unaffected.

    CONCLUSIONS: This study shows that finasteride treatment decreases VEGF expression in the human prostate.

  • 192.
    Häggström, S
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Wikström, P
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Damber, J E
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Expression of vascular endothelial growth factor and its receptors in the rat ventral prostate and Dunning R3327 PAP adenocarcinoma before and after castration.1998In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 36, no 2, p. 71-9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Angiogenesis is important for prostate organogenesis and prostate cancer progression. It is not yet known whether androgens promote part of their control of prostate structure and function by influencing angiogenesis. The aim of this study was to explore the possible androgenic regulation of the angiogenic factor vascular endothelial growth factor (VEGF) and its receptors flt-1 and flk-1/KDR in the rat ventral prostate (VP) and Dunning R3327 PAP adenocarcinoma.

    METHODS: RNA was prepared from VP and tumors of intact and castrated rats. VEGF, flt-1, and flk-1/KDR mRNA levels were determined using competitive RT-PCR.

    RESULTS: VEGF121, VEGF165, and VEGF189 together with flt-1 and flk-1/KDR mRNA were detected. The VEGF, but not flt-1 mRNA levels were significantly decreased in the VP after castration. The Dunning tumor expressed high levels of mRNA for VEGF and its receptors compared to the VP. The flt-1 mRNA level in the tumor increased after castration, while the VEGF mRNA levels were unchanged.

    CONCLUSIONS: Decreased mRNA expression of VEGF, but not flt-1, was found in the rat VP after castration. However, in the Dunning tumor, castration did not alter the expression of VEGF mRNA. Moreover, elevated levels of both mRNA for VEGF and its receptors relative to the VP were observed, indicating that the VEGF system may be important for Dunning tumor development.

  • 193.
    Hörnberg, Emma
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bovinder Ylitalo, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 4, p. e19059-Article in journal (Refereed)
    Abstract [en]

    Background: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote  the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival.

    Methodology/Principal Findings: Hormone-naı¨ve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from  40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival.

    Conclusions/Significance: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.

  • 194.
    Idahl, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Obstetrik och gynekologi.
    Abramsson, Leif
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Kumlin, U
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Liljeqvist, J A
    Olofsson, J I
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Obstetrik och gynekologi.
    Male serum Chlamydia trachomatis IgA and IgG, but not heat shock protein 60 IgG, correlates with negatively affected semen characteristics and lower pregnancy rates in the infertile couple2007In: International Journal of Andrology, ISSN 0105-6263, E-ISSN 1365-2605, Vol. 30, no 2, p. 99-107Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The objective of this study was to evaluate whether serum Chlamydia trachomatis immunoglobulin-A (IgA), IgM and C. trachomatis heat shock protein 60 (CHSP60) IgG are of additional value to C. trachomatis IgG regarding the impact on fecundity in infertile couples, and to relate C. trachomatis serum antibodies to semen characteristics, diagnoses and pregnancy outcome.

    METHODS: A total of 226 infertile couples, previously tested for C. trachomatis IgG, were tested for C. trachomatis IgA, IgM and CHSP60 IgG, and semen samples from all men were analysed.

    RESULTS: Chlamydia trachomatis serum IgA in men (but not in women) correlated with reduced chances of achieving pregnancy [p = 0.021, relative risk (RR) =0.65, 95% confidence interval (CI) 0.42-1.005] and in combination with C. trachomatis IgG the chance was further reduced (p =0.001, RR = 0.35, 95% CI 0.15-0.84). Chlamydia trachomatis serum IgA was also significantly correlated with reduced motility of the spermatozoa (-8.7%, p = 0.023), increased number of dead spermatozoa (+10.5%, p = 0.014) and higher prevalence of leucocytes in semen (+122%, p = 0.005), and in combination with C. trachomatis IgG positivity, there was also a decrease in sperm concentration (-35%, p = 0.033), the number of progressive spermatozoa (-14.8%, p = 0.029) and a rise in the teratozoospermia index (+4.4%, p = 0.010). CHSP60 IgG correlated with reduced motility (-5.6%, p = 0.033), and in the women to tubal factor infertility (p = 0.033), but no correlations of C. trachomatis serum IgM or CHSP60 IgG with pregnancy rates were found.

    CONCLUSIONS: Chlamydia trachomatis serum IgA in the male partner of the infertile couple has an additive value to IgG in predicting pregnancy chances, and serum IgA and IgG are associated with subtle negative changes in semen characteristics.

  • 195.
    Inghammar, M
    et al.
    Dept of Clinical Sciences Lund, Lund University.
    Löfdahl, C-G
    Dept of Clinical Sciences Lund, Lund University.
    Winqvist, N
    Dept of Clinical Sciences Malmö , Lund University.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egesten, A
    Dept of Clinical Sciences Lund, Lund University.
    Engström, G
    Dept of Clinical Sciences Malmo¨ , Lund University.
    Impaired pulmonary function and the risk of tuberculosis: a population-based cohort study2011In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 37, no 5, p. 1285-1287Article in journal (Refereed)
  • 196.
    Inkiläinen, Aapo
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Styrke, Johan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Sundsvall Hospital, Sundsvall, Sweden .
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Strigård, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Occurrence of abdominal bulging and hernia after open partial nephrectomy: a retrospective cohort study2018In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 52, no 1, p. 54-58Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Abdominal bulging and incisional hernia are known sequelae after open partial nephrectomy (OPN) via a flank incision. Precise rates are not known. The aims of this study were to determine the rates of bulging and hernia after OPN, and to examine potential risk factors.

    MATERIALS AND METHODS: A retrospective review was undertaken of 197 consecutive patients operated on with OPN via a flank incision between 2004 and 2014. After exclusion, 184 patients remained. Medical records and radiological images from the preoperative work-up, and follow-up after surgery at 3, 12 and 24 months, were reviewed.

    RESULTS: A visible bulge was noted in 36 of the 184 patients at clinical examination. Only 20 cases (12%) remained at the last follow-up. Radiological changes interpreted as a bulge were initially seen in 50 patients, while only 35 (19%) remained at the last radiological examination. Clinical incisional hernia was reported in five patients (3%), and radiological hernia was seen in 10 patients (5%). Patients who developed a hernia had a higher body mass index (30 vs 26 kg/m(2), p = 0.02). Other demographic variables showed no significant correlation.

    CONCLUSIONS: Bulging is a common sequela after flank incision. The rate of incisional hernia after flank incision is comparable to rates after other forms of abdominal surgery. Further studies are required to evaluate the psychological and physiological effects of bulging, the pain and weakness caused, and the cosmetic embarrassment suffered by the patient.

  • 197.
    Jacobsen, Jan
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Landberg, G
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Expression of vascular endothelial growth factor protein in human renal cell carcinoma2004In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 93, no 3, p. 297-302Article in journal (Refereed)
  • 198.
    Jacobsen, Jan
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Different isoform patterns for vascular endothelial growth factor between clear cell and papillary renal cell carcinoma.2006In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 97, no 5, p. 1102-1108Article in journal (Refereed)
  • 199. Jahnson, S.
    et al.
    Hagberg, O.
    Holmang, S.
    Liedberg, F.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Malmstrom, P. U.
    Wijkstrom, H.
    Mansson, W.
    Higher excess mortality rate in women than in men with invasive bladder cancer2012In: European urology. Supplement, ISSN 1569-9056, E-ISSN 1878-1500, Vol. 11, no 1, p. E870-U832Article in journal (Other academic)
  • 200. Jahnson, Staffan
    et al.
    Damm, Ole
    Hellsten, Sverker
    Holmäng, Sten
    Liedberg, Fredrik
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Malmström, Per-Uno
    Månsson, Wiking
    Rosell, Johan
    Wijkstöm, Hans
    Urinary diversion after cystectomy for bladder cancer: a population-based study in Sweden.2010In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 44, no 2, p. 69-75Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the type of urinary diversion performed after cystectomy in patients with muscle-invasive bladder cancer in Sweden, using data from a population-based national register. MATERIAL AND METHODS: Since 1997, the Swedish Bladder Cancer Register has included more than 90% of all patients with newly diagnosed bladder cancer. The different types of urinary diversion performed in 1997-2003 were analysed, comparing non-continent diversion (ileal conduit) with continent reconstruction (bladder substitution or continent cutaneous diversion). RESULTS: During the study period, 3463 patients were registered with clinical T2-T4 non-metastatic bladder cancer. Cystectomy was performed in 1141 patients with ileal conduit in 732 (64%) and continent reconstruction in 409 (36%). Ileal conduit was used more frequently in females than males (p = 0.019), in patients older than 75 years (p < 0.00001), and in those with less favourable TNM classification. Continent reconstruction was done more often at university hospitals than at county hospitals (p < 0.00001), but rarely in the northern and western healthcare regions compared with other regions (p < 0.00001). Nationwide, the proportion of registered continent reconstructions decreased, although the absolute number was relatively stable (50-60 per year). CONCLUSIONS: Continent reconstruction after cystectomy for muscle-invasive bladder cancer is performed more often in some healthcare regions and in patients at university hospitals than in county hospitals, indicating a substantial provider influence on the choice of urinary diversion. Over time, the proportion of these procedures has decreased, while the absolute number has remained low and stable; therefore, concentration in high-volume hospitals specialized in bladder cancer and continent reconstruction seems appropriate.

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