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  • 1.
    Ahlin, Rebecca
    et al.
    Department of Oncology, Division of Clinical Cancer Epidemiology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Nybacka, Sanna
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Stranne, Johan
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Urology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
    Steineck, Gunnar
    Department of Oncology, Division of Clinical Cancer Epidemiology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Box 423, Gothenburg, Sweden.
    Hedelin, Maria
    Department of Oncology, Division of Clinical Cancer Epidemiology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Box 423, Gothenburg, Sweden; Regional Cancer Center West, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
    The effect of a phytoestrogen intervention and impact of genetic factors on tumor proliferation markers among Swedish patients with prostate cancer: study protocol for the randomized controlled PRODICA trial2022In: Trials, E-ISSN 1745-6215, Vol. 23, no 1, article id 1041Article in journal (Refereed)
    Abstract [en]

    Background: A high intake of phytoestrogens, found in soy, rye, and seeds, is associated with a reduced risk of a prostate cancer diagnosis. Previously, we found that the overall decreased risk of prostate cancer diagnosis in males with a high intake of phytoestrogens was strongly modified by a nucleotide sequence variant in the estrogen receptor-beta (ERβ) gene. However, we do not know if phytoestrogens can inhibit the growth of prostate cancer in males with established diseases. If there is an inhibition or a delay, there is reason to believe that different variants of the ERβ gene will modify the effect. Therefore, we designed an intervention study to investigate the effect of the addition of foods high in phytoestrogens and their interaction with the ERβ genotype on prostate tumor proliferation in patients with prostate cancer.

    Method: The PRODICA trial is a randomized ongoing intervention study in patients with low- and intermediate-risk prostate cancer with a Gleason score < 8, prostate-specific antigen (PSA) < 20, and scheduled for radical prostatectomy. The study is conducted at Sahlgrenska University Hospital in Gothenburg, Sweden. The intervention consists of a daily intake of soybeans and flaxseeds (~ 200 mg of phytoestrogens) until the surgery, approximately 6 weeks. The aim is to recruit 200 participants. The primary outcome is the difference in the proliferation marker Ki-67 between the intervention and the control groups. The genotype of ERβ will be investigated as an effect-modifying factor. Secondary outcomes include, e.g., concentrations of PSA and steroid hormones in the blood.

    Discussion: The results of the PRODICA trial will contribute important information on the relevance of increasing the intake of phytoestrogens in patients with prostate cancer who want to make dietary changes to improve the prognosis of their cancer. If genetic factors turn out to influence the effect of the intervention diet, dietary advice can be given to patients who most likely benefit from it. Dietary interventions are cost-effective, non-invasive, and result in few mild side effects. Lastly, the project will provide basic pathophysiological insights which could be relevant to the development of treatment strategies for patients with prostate cancer.

    Trial registration. ClinicalTrials.gov NCT02759380. Registered on 3 May 2016.

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  • 2.
    Ahlin, Rebecca
    et al.
    Department of Oncology, Division of Clinical Cancer Epidemiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Nørskov, Natalja P.
    Department of Animal and Veterinary Sciences, Aarhus University, AU-Foulum, Tjele, Denmark.
    Nybacka, Sanna
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Landberg, Rikard
    Department of Life Sciences, Division of Food and Nutrition Science, Chalmers University of Technology, Gothenburg, Sweden.
    Skokic, Viktor
    Department of Oncology, Division of Clinical Cancer Epidemiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Pelvic Cancer, Karolinska University Hospital, Stockholm, Sweden.
    Stranne, Johan
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Region Västra Götaland, Department of Urology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Sahlgrenska Cancer Center, Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Steineck, Gunnar
    Department of Oncology, Division of Clinical Cancer Epidemiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Hedelin, Maria
    Department of Oncology, Division of Clinical Cancer Epidemiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Regional Cancer Center West, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.
    Effects on serum hormone concentrations after a dietary phytoestrogen intervention in patients with prostate cancer: a randomized controlled trial2023In: Nutrients, E-ISSN 2072-6643, Vol. 15, no 7, article id 1792Article in journal (Refereed)
    Abstract [en]

    Phytoestrogens have been suggested to have an anti-proliferative role in prostate cancer, potentially by acting through estrogen receptor beta (ERβ) and modulating several hormones. We primarily aimed to investigate the effect of a phytoestrogen intervention on hormone concentrations in blood depending on the ERβ genotype. Patients with low and intermediate-risk prostate cancer, scheduled for radical prostatectomy, were randomized to an intervention group provided with soybeans and flaxseeds (∼200 mg phytoestrogens/d) added to their diet until their surgery, or a control group that was not provided with any food items. Both groups received official dietary recommendations. Blood samples were collected at baseline and endpoint and blood concentrations of different hormones and phytoestrogens were analyzed. The phytoestrogen-rich diet did not affect serum concentrations of testosterone, insulin-like growth factor 1, or sex hormone-binding globulin (SHBG). However, we found a trend of decreased risk of increased serum concentration of estradiol in the intervention group compared to the control group but only in a specific genotype of ERβ (p = 0.058). In conclusion, a high daily intake of phytoestrogen-rich foods has no major effect on hormone concentrations but may lower the concentration of estradiol in patients with prostate cancer with a specific genetic upset of ERβ.

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  • 3. Anand, Aseem
    et al.
    Morris, Michael J.
    Larson, Steven M.
    Minarik, David
    Josefsson, Andreas
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden.
    Helgstrand, John T.
    Oturai, Peter S.
    Edenbrandt, Lars
    Røder, Martin Andreas
    Bjartell, Anders
    Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide2016In: EJNMMI Research, E-ISSN 2191-219X, Vol. 6, article id 23Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Having performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength of the automated BSI in predicting overall survival (OS) in mCRPC patients being treated with enzalutamide.

    METHODS: Retrospectively, we included patients who received enzalutamide as a clinically approved therapy for mCRPC and had undergone bone scan prior to starting therapy. Automated BSI, prostate-specific antigen (PSA), hemoglobin (HgB), and alkaline phosphatase (ALP) were obtained at baseline. Change in automated BSI and PSA were obtained from patients who have had bone scan at week 12 of treatment follow-up. Automated BSI was obtained using the analytically validated EXINI Bone(BSI) version 2. Kendall's tau (τ) was used to assess the correlation of BSI with other blood-based biomarkers. Concordance index (C-index) was used to evaluate the discriminating strength of automated BSI in predicting OS.

    RESULTS: Eighty mCRPC patients with baseline bone scans were included in the study. There was a weak correlation of automated BSI with PSA (τ = 0.30), with HgB (τ = -0.17), and with ALP (τ = 0.56). At baseline, the automated BSI was observed to be predictive of OS (C-index 0.72, standard error (SE) 0.03). Adding automated BSI to the blood-based model significantly improved the C-index from 0.67 to 0.72, p = 0.017. Treatment follow-up bone scans were available from 62 patients. Both change in BSI and percent change in PSA were predictive of OS. However, the combined predictive model of percent PSA change and change in automated BSI (C-index 0.77) was significantly higher than that of percent PSA change alone (C-index 0.73), p = 0.041.

    CONCLUSIONS: The upgraded and analytically validated automated BSI was found to be a strong predictor of OS in mCRPC patients. Additionally, the change in automated BSI demonstrated an additive clinical value to the change in PSA in mCRPC patients being treated with enzalutamide.

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  • 4.
    Bovinder Ylitalo, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thellenberg-Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Excellent cabazitaxel response in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of resistance development by anti-androgensManuscript (preprint) (Other academic)
  • 5.
    Bovinder Ylitalo, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thellenberg-Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marked response to cabazitaxel in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of acquired resistance by anti-androgens2020In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 80, no 2, p. 214-224Article in journal (Refereed)
    Abstract [en]

    Background: Taxane treatment may be a suitable therapeutic option for patients with castration‐resistant prostate cancer and high expression of constitutively active androgen receptor variants (AR‐Vs). The aim of the study was to compare the effects of cabazitaxel and androgen deprivation treatments in a prostate tumor xenograft model expressing high levels of constitutively active AR‐V7. Furthermore, mechanisms behind acquired cabazitaxel resistance were explored.

    Methods: Mice were subcutaneously inoculated with 22Rv1 cells and treated with surgical castration (n = 7), abiraterone (n = 9), cabazitaxel (n = 6), castration plus abiraterone (n = 8), castration plus cabazitaxel (n = 11), or vehicle and/or sham operation (n = 23). Tumor growth was followed for about 2 months or to a volume of approximately 1000 mm3. Two cabazitaxel resistant cell lines; 22Rv1‐CabR1 and 22Rv1‐CabR2, were established from xenografts relapsing during cabazitaxel treatment. Differential gene expression between the cabazitaxel resistant and control 22Rv1 cells was examined by whole‐genome expression array analysis followed by immunoblotting, immunohistochemistry, and functional pathway analysis.

    Results: Abiraterone treatment alone or in combination with surgical castration had no major effect on 22Rv1 tumor growth, while cabazitaxel significantly delayed and in some cases totally abolished 22Rv1 tumor growth on its own and in combination with surgical castration. The cabazitaxel resistant cell lines; 22Rv1‐CabR1 and 22Rv1‐CabR2, both showed upregulation of the ATP‐binding cassette sub‐family B member 1 (ABCB1) efflux pump. Treatment with ABCB1 inhibitor elacridar completely restored susceptibility to cabazitaxel, while treatment with AR‐antagonists bicalutamide and enzalutamide partly restored susceptibility to cabazitaxel in both cell lines. The cholesterol biosynthesis pathway was induced in the 22Rv1‐CabR2 cell line, which was confirmed by reduced sensitivity to simvastatin treatment.

    Conclusions: Cabazitaxel efficiently inhibits prostate cancer growth despite the high expression of constitutively active AR‐V7. Acquired cabazitaxel resistance involving overexpression of efflux transporter ABCB1 can be reverted by bicalutamide or enzalutamide treatment, indicating the great clinical potential for combined treatment with cabazitaxel and anti‐androgens.

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

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

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

    DESIGN, SETTING, AND PARTICIPANTS: Randomised multicentre trial. From 2012 to 2016, 340 Swedish men, aged 40-75yr, with recently diagnosed low-volume Gleason grade group 1 prostate cancer were included.

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

    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome measure: Gleason grade group ≥2 cancer.

    SECONDARY OUTCOMES: Cancer in anteriorly directed biopsy cores and postbiopsy infection. Nonparametric statistical tests were applied.

    RESULTS AND LIMITATIONS: Gleason grade group ≥2 cancer was detected in 16% of 156 men who had an extensive biopsy and in 10% of 164 men who had a standard biopsy, a 5.7% difference (95% confidence interval [CI]-0.2% to 13%, p=0.09). There was a strong linear association between prostate-specific antigen (PSA) density and cancer in the anteriorly directed biopsy cores. The odds ratios for cancer in the anteriorly directed cores were for any cancer 2.2 (95% CI 1.3-3.9, p=0.004) and for Gleason grade group ≥2 cancer 2.3 (95% CI 1.2-4.4, p=0.015) per 0.1-ng/ml/cm3 increments. Postbiopsy infections were equally common in the two groups. A limitation is that magnetic resonance imaging was not used.

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

    PATIENT SUMMARY: This trial compared two different templates for transrectal prostate biopsy in men starting on active surveillance for low-risk prostate cancer. Cancer was often found in the front part of the prostate, which is not sampled on a standard prostate biopsy.

  • 7.
    Cheng, Tuck Seng
    et al.
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building ,Old Road Campus, Oxford, United Kingdom.
    Noor, Urwah
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building ,Old Road Campus, Oxford, United Kingdom.
    Watts, Eleanor
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, MD, Rockville, United States.
    Pollak, Michael
    Oncology Department, McGill University and Segal Cancer Centre, Jewish General Hospital, QC, Montreal, Canada.
    Wang, Ye
    Oncology Department, McGill University and Segal Cancer Centre, Jewish General Hospital, QC, Montreal, Canada.
    McKay, James
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Atkins, Joshua
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Masala, Giovanna
    Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.
    Sánchez, Maria-Jose
    Escuela Andaluza de Salud Pública (EASP), Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain.
    Agudo, Antonio
    Unit of Nutrition and Cancer, Catalan Institute of Oncology - ICO, L'Hospitalet de Llobregat, Barcelona, Spain; Nutrition and Cancer Group; Epidemiology, Public Health, Cancer Prevention and Palliative Care Program; Bellvitge Biomedical Research Institute - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
    Castilla, Jesús
    Instituto de Salud Pública de Navarra - IdiSNA, Pamplona, Spain; CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain.
    Aune, Dagfinn
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Department of Nutrition, Oslo New University College, Oslo, Norway; Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital Ullevå, Oslo, Norway.
    Colorado-Yohar, Sandra M.
    Department of Epidemiology, Murcia Regional Health Council-IMIB, Murcia, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia.
    Manfredi, Luca
    Centre for Biostatistics, Epidemiology, Public Health (C-BEPH), Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.
    Gunter, Marc J.
    Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC- WHO), Lyon, France.
    Pala, Valeria
    Epidemiology and Prevention Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Key, Timothy J.
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building ,Old Road Campus, Oxford, United Kingdom.
    Smith-Byrne, Karl
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building ,Old Road Campus, Oxford, United Kingdom.
    Travis, Ruth C.
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building ,Old Road Campus, Oxford, United Kingdom.
    Circulating free insulin-like growth factor-I and prostate cancer: a case-control study nested in the European prospective investigation into cancer and nutrition2024In: BMC Cancer, E-ISSN 1471-2407, Vol. 24, no 1, article id 676Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Circulating total insulin-like growth factor-I (IGF-I) is an established risk factor for prostate cancer. However, only a small proportion of circulating IGF-I is free or readily dissociable from IGF-binding proteins (its bioavailable form), and few studies have investigated the association of circulating free IGF-I with prostate cancer risk.

    METHODS: We analyzed data from 767 prostate cancer cases and 767 matched controls nested within the European Prospective Investigation into Cancer and Nutrition cohort, with an average of 14-years (interquartile range = 2.9) follow-up. Matching variables were study center, length of follow-up, age, and time of day and fasting duration at blood collection. Circulating free IGF-I concentration was measured in serum samples collected at recruitment visit (mean age 55 years old; standard deviation = 7.1) using an enzyme-linked immunosorbent assay (ELISA). Conditional logistic regressions were performed to examine the associations of free IGF-I with risk of prostate cancer overall and subdivided by time to diagnosis (≤ 14 and > 14 years), and tumor characteristics.

    RESULTS: Circulating free IGF-I concentrations (in fourths and as a continuous variable) were not associated with prostate cancer risk overall (odds ratio [OR] = 1.00 per 0.1 nmol/L increment, 95% CI: 0.99, 1.02) or by time to diagnosis, or with prostate cancer subtypes, including tumor stage and histological grade.

    CONCLUSIONS: Estimated circulating free IGF-I was not associated with prostate cancer risk. Further research may consider other assay methods that estimate bioavailable IGF-I to provide more insight into the well-substantiated association between circulating total IGF-I and subsequent prostate cancer risk.

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  • 8. Chung, Sui Chu
    et al.
    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.
    Granfors, Torvald
    Egevad, Lars
    Mancini, Giacomo
    Lutz, Beat
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    A high cannabinoid CB(1) receptor immunoreactivity is associated with disease severity and outcome in prostate cancer2009In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 45, no 1, p. 174-182Article in journal (Refereed)
    Abstract [en]

    In the light of findings indicating that cannabinoids can affect the proliferation of a number of cancer cell types and that cannabinoid receptor expression is higher in prostate cancer cell lines than in non-malignant cells, we investigated whether the level of cannabinoid 1 receptor immunoreactivity (CB(1)IR) in prostate cancer tissues is associated with disease severity and outcome. Formalin-fixed paraffin-embedded non-malignant and tumour tissue samples from patients who were diagnosed with prostate cancer at a transurethral resection for voiding problems were used. CB(1)IR, which was scored in a total of 399 cases, was associated with the epithelial cell membranes, with little staining in the stroma. Patients with a tumour CB(1)IR score greater or equal to the median (2) had a significantly higher proportion of Gleason scores 8-10, metastases at diagnosis, tumour size and rate of cell proliferation at diagnosis than patients with a score<2. For 269 cases, tumour CB(1)IR was measured for patients who only received palliative therapy at the end stages of the disease, allowing the influence of CB(1)IR upon the disease outcome to be determined. Receiver operating characteristic (ROC) curves showed an area under the curve of 0.67 (95% confidence limits 0.59-0.74) for CB(1)IR in the tumour. CB(1)IR in non-malignant tissue was not associated with disease outcome. A tumour CB(1)IR score >or=2 was associated with a significantly lower disease specific survival. A Cox proportional hazards regression indicated that the tumour CB(1)IR score and the Gleason score were independent prognostic variables. It is concluded that a high tumour CB(1)IR score is associated with prostate cancer severity and outcome.

  • 9.
    Fowler, Christopher J.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thors, Lina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Chung, Sui Chu
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hammarsten, Peter
    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.
    Tumour epithelial expression levels of endocannabinoid markers modulate the value of endoglin-positive vascular density as a prognostic marker in prostate cancer2013In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, ISSN 1388-1981, E-ISSN 1879-2618, Vol. 1831, no 10, p. 1579-1587Article in journal (Refereed)
    Abstract [en]

    Fatty acid amide hydrolase (FAAH) is responsible for the hydrolysis of the endogenous cannabinoid (CB) receptor ligand anandamide. Here we have investigated whether the expression levels of FAAH and CB1 receptors influence the prognostic value of markers of angiogenesis in prostate cancer. Data from a cohort of 419 patients who were diagnosed with prostate cancer at transurethral resection for lower urinary tract symptoms, of whom approximately 2/3 had been followed by expectancy, were used. Scores for the angiogenesis markers endoglin and von Willebrand factor (vWf), the endocannabinoid markers fatty acid amide hydrolase (FAAH) and cannabinoid CB1 receptors and the cell proliferation marker Ki-67 were available in the database. For the cases followed by expectancy, the prognostic value of endoglin was dependent upon the tumour epithelial FAAH immunoreactivity (FAAH-IR) and CB1IR scores, and the non-malignant epithelial FAAH-IR scores, but not the non-malignant CB1IR scores or the tumour blood vessel FAAH-IR scores. This dependency upon the tumour epithelial FAAH-IR or CB1IR scores was less apparent for vWf, and was not seen for Ki-67. Using an endoglin cut-off value of 10 positively stained vessels per core and a median split of tumour FAAH-IR, four groups could be generated, with 15 year of disease-specific survival (%) of 68 +/- 7 (low endoglin, low FAAH), 45 +/- 11 (high endoglin, low FAAH), 77 +/- 6 (low endoglin, high FAAH) and 21 +/- 10 (high endoglin, high FAAH). Thus, the cases with high endoglin and high FAAH scores have the poorest rate of disease-specific survival. At diagnosis, the number of cases with tumour stages 1a-1b relative to stages 2-4 was sensitive to the endoglin score in a manner dependent upon the tumour FAAH-IR. It is concluded that the prognostic value of endoglin as a marker of neovascularisation in prostate cancer can be influenced by the expression level of markers of the endocannabinoid system. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.

  • 10.
    Halin Bergström, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rudolfsson, Stina H.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High-grade tumours promote growth of other less-malignant tumours in the same prostate2021In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 253, no 4, p. 396-403Article in journal (Refereed)
    Abstract [en]

    Prostate cancer is a multifocal disease, but if and how individual prostate tumours influence each other is largely unknown. We therefore explored signs of direct or indirect tumour–tumour interactions in experimental models and patient samples. Low‐metastatic AT1 and high‐metastatic MatLyLu (MLL) Dunning rat prostate cancer cells were injected into separate lobes of the ventral prostate of immunocompetent rats. AT1 tumours growing in the same prostate as MLL tumours had increased tumour size and proliferation compared to AT1 tumours growing alone. In addition, the vasculature and macrophage density surrounding the AT1 tumours were increased by MLL tumour closeness. In patient prostatectomy samples, selected to contain an index tumour [tumour with the highest grade, International Society of Urological Pathology (ISUP) grade 1, 2, 3 or 4] and a low‐grade satellite tumour (ISUP grade 1), cell proliferation in low‐grade satellite tumours gradually increased with increasing histological grade of the index tumour. The density of blood vessels and CD68+ macrophages also increased around the low‐grade satellite tumour if a high‐grade index tumour was present. This suggests that high‐grade tumours, by changing the prostate microenvironment, may increase the aggressiveness of low‐grade lesions in the organ. Future studies are needed to explore the mechanisms behind tumour–tumour interactions and their clinical importance.

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  • 11.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Egevad, Lars
    Granfors, Torvald
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Phospho-Akt Immunoreactivity in Prostate Cancer: Relationship to Disease Severity and Outcome, Ki67 and Phosphorylated EGFR Expression2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 10, p. e47994-Article in journal (Refereed)
    Abstract [en]

    Background: In the present study, we have investigated the prognostic usefulness of phosphorylated Akt immunoreactivity (pAkt-IR) in prostate cancer using a well-characterised tissue microarray from men who had undergone transurethral resection due to lower urinary tract symptoms. Methodology/Principal Findings: pAkt-IR in prostate epithelial and tumour cells was assessed using a monoclonal anti-pAkt (Ser(473)) antibody. Immunoreactive intensity was determined for 282 (tumour) and 240 (non-mlignant tissue) cases. Tumour pAkt-IR scores correlated with Gleason score, tumour Ki67-IR (a marker of cell proliferation) and tumour phosphorylated epidermal growth factor receptor (pEGFR)-IR. For cases followed with expectancy, a high tumour pAkt-IR was associated with a poor disease-specific survival, and the prognostic information provided by this biomarker was additive to that provided by either (but not both) tumour pEFGR-IR or Ki67-IR. Upon division of the cases with respect to their Gleason scores, the prognostic value of pAkt-IR was seen for patients with Gleason score 8-10, but not for patients with Gleason score 6-7. Conclusions/Significance: Tumour pAkt-IR is associated with both disease severity and disease-specific survival. However, its clinical use as a biomarker is limited, since it does not provide prognostic information in patients with Gleason scores 6-7.

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    Phospho-Akt Immunoreactivity in Prostate Cancer
  • 12.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Karalija, Amar
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Rudolfsson, Stina Häggström
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Egevad, Lars
    Granfors, Torvald
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Low levels of phosphorylated epidermal growth factor receptor in nonmalignant and malignant prostate tissue predict favorable outcome in prostate cancer patients.2010In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 4, p. 1245-1255Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To explore if the expression of phosphorylated epidermal growth factor receptor (pEGFR) in nonmalignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients. EXPERIMENTAL DESIGN: We used formalin-fixed tissues obtained through the transurethral resection of the prostate from 259 patients diagnosed with prostate cancer after the transurethral resection of the prostate, and patients were then followed with watchful waiting. Tissue microarrays of nonmalignant and malignant prostate tissue were stained with an antibody against pEGFR. The staining pattern was scored and related to clinicopathologic parameters and to outcome. RESULTS: Low phosphorylation of EGFR in prostate epithelial cells, both in the tumor and surprisingly also in the surrounding nonmalignant tissue, was associated with significantly longer cancer-specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were added together with pEGFR to a Cox regression model. Tumor epithelial pEGFR immunoreactivity was significantly correlated to tumor cell proliferation, tumor vascular density, and nonmalignant epithelial pEGFR immunoreactivity. Patients with metastases had significantly higher immunoreactivity for tumor and nonmalignant epithelial pEGFR compared with patients without metastases. CONCLUSIONS: Low pEGFR immunoreactivity is associated with the favorable prognosis in prostate cancer patients and may provide information about which patients with Gleason score 6 and 7 tumors that will survive their disease even without treatment. Changes in the nonmalignant tissue adjacent to prostate tumors give prognostic information.

  • 13.
    Huang, Junchi
    et al.
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Freyhult, Eva
    Department of Cell and Molecular Biology, Science for Life Laboratory, National Bioinformatics Infrastructure Sweden, Uppsala University, Uppsala, Sweden.
    Buckland, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Urology, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Damber, Jan-Erik
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Welén, Karin
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Osteoclasts directly influence castration-resistant prostate cancer cells2022In: Clinical and Experimental Metastasis, ISSN 0262-0898, E-ISSN 1573-7276, Vol. 39, no 5, p. 801-814Article in journal (Refereed)
    Abstract [en]

    Metastasis to bone is the leading cause of death from prostate cancer. Interaction between tumor cells and bone cells can promote progression and influence tumor phenotype. It is known that prostate cancer cells support osteoclast differentiation, and degradation of bone matrix by osteoclasts releases growth factors stimulating tumor cell proliferation and invasion. In the present study osteolytic (PC-3) and osteoblastic (LNCaP-19) castration-resistant prostate cancer (CRPC) cells were co-cultured with mature osteoclasts or their precursor cells (RAW 264.7) to characterize direct effects of mature osteoclasts on CRPC cells. Osteoclasts increased proliferation and decrease apoptosis of CRPC cells as assessed with flow cytometry. RNA sequencing revealed that osteolytic CRPC cells were more responsive to osteoclast stimulation regarding gene expression, but the overall induced expression patterns were similar between the prostate cancer cell lines. Genes related to DNA repair were upregulated by osteoclasts, while genes related to endoplasmic reticulum stress-induced apoptosis and cholesterol synthesis were downregulated. The results of this study shows that osteoclasts directly influence CRPC cells, increasing proliferation, decreasing apoptosis, and affecting gene expression pathways that can affect sensitivity to DNA damage and endoplasmic reticulum function. This suggests targeting of osteoclasts to be a possible way to affect efficacy of other drugs by combination regimens in treating prostate cancer metastases.

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  • 14.
    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, 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.

  • 15.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Institute of Clinical Sciences, Department of Urology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Little support for a protective effect of ADT against COVID-192022In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 56, no 2, p. 112-113Article in journal (Other academic)
  • 16.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Prognostic markers in prostate cancer: studies of a watchful waiting cohort with long follow up2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Prostate Cancer (PC) is a common and highly variable disease. Using current diagnostic methods, the prostate specific antigen (PSA) blood test and histological grading of prostate tissue needle biopsies, it is often difficult to evaluate whether the patient has a PC that requires active treatment or not. The absolute majority of all 10,000 cases of PCs diagnosed annually in Sweden have tumours graded as Gleason score (GS) 6-7 and a PSA value in blood below 10. Many of these are harmless and can be left without active treatment and hence spared problematic post-therapy side-effects, others are highly malignant and require early diagnosis and treatment. Better prognostic markers are needed and the aim of this study was to evaluate prognostic markers and to test if these markers could identify patients with indolent tumours.

    Methods: We have studied tumour material from 419 men consecutively diagnosed with PC at transurethral resection (1975-1990). The majority of these patients (295) had no metastasis at diagnosis and was not given any curative treatment and only hormonal treatment upon symptoms from metastatic progression. Standard histological sections and tissue microarrays (TMA) from these tumours and surrounding normal prostate tissue were stained and evaluated for cell proliferation (Ki67), blood vessels (endoglin and von Willebrand factor, vWf) and the extracellular matrix component hyaluronan (HA). An orthotopic rat PC model was used to explore hyaluronan staining, hyaluronic acid synthase (HAS)-1 mRNA levels and the effect of local HA treatment on tumour growth.

    Results: Tumour cell proliferation (Ki67) and the density of intra-tumoural endoglin stained blood vessels were independent prognostic markers (i.e. they added prognostic information to the conventional prognostic markers; clinical stage and GS). None of the GS 6 patients with low staining for both Ki67 and endoglin died of PC within 15 years of follow-up. High HA staining in the tumour epithelium and stroma was a negative prognostic marker of cancer specific survival but they were not independent of GS. High HA staining and high vascular density in the stroma of the surrounding morphologically normal prostate were prognostic for short cancer specific survival. Implantation of tumour cells in the normal rat prostate resulted in an increase in HA and HAS-1 mRNA levels in the prostate tissue surrounding prostate tumours. Concurrently intra-prostatic injection of HA also stimulated tumour growth.

    Conclusions: By evaluating both tumour cell proliferation (Ki67) and vascular density, it is possible to identify patients with very low risk of cancer specific death in the absence of active treatment. Prostate tumours influence the surrounding non-malignant prostate tissue, for example they cause an increased angiogenesis and synthesis of hyaluronan. Such responses can possibly be used to diagnose PC and to evaluate PC aggressiveness.

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  • 17.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Adamo, Hani
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Granfors, Torvald
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Laurent, Anna Engström
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Prostate cancer increases hyaluronan in surrounding nonmalignant stroma, and this response is associated with tumor growth and an unfavorable outcome2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 179, no 4, p. 1961-1968Article in journal (Refereed)
    Abstract [en]

    Our objective was to investigate whether the presence of a tumor increases hyaluronan (HA) levels in surrounding prostate tissues and whether this extratumoral HA influences tumor growth and outcome. From a series of 287 men diagnosed with prostate cancer at transurethral resection and followed up with watchful waiting, tissue microarrays were constructed, stained, and scored for HA. A high HA staining score in the tumor stroma or in nonmalignant prostate tissue stroma were both associated positively with higher Gleason score and larger tumor volume, and was associated with a poor outcome. HA staining score was not an independent marker for outcome (multivariate Cox, with Gleason score, tumor volume, stage, and HA variables). In an orthotopic rat prostate cancer model, hyaluronic acid synthase-1 mRNA levels and HA staining were increased in normal prostate tissue surrounding prostate cancer. Orthotopic prostate cancer growth was increased by intraprostatic injection of HA. In conclusion, cancer in the prostate apparently stimulates HA synthesis both in tumor stroma and in the surrounding normal tissue. This promoted tumor growth and was associated with an unfavorable outcome.

  • 18.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Urology, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Damber, Jan-Erik
    Welén, Karin
    AR-V7 expression in circulating tumor cells as a potential prognostic marker in metastatic hormone-sensitive prostate cancer2019In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 58, no 11, p. 1660-1664Article in journal (Refereed)
    Abstract [en]

    Treatment of patients with metastatic hormone-sensitive (mHSPC) depends on androgen deprivation therapy (ADT) to inhibit androgen receptor (AR) signaling. Although the majority of patients respond well to ADT, castration-resistant prostate cancer (CRPC) inevitably develops. Addition of docetaxel, abiraterone acetate, or enzalutamide, to ADT significantly increases cancer-specific survival (CSS) [1–3]. The drawback is that not all patients respond to the therapies equally well and biomarkers to enable personalized treatment are urgently needed. Prostate-specific antigen (PSA) is a powerful biomarker for diagnosis of PC, but there are no validated biomarkers to prognosticate prognosis, let alone prediction of therapy response, of metastatic disease prior to ADT. Mechanisms important for resistance to ADT and development of CRPC include increased AR levels, constitutively active AR variants such as AR-V7, and intratumoral steroid production to sustain AR signaling despite castrate levels of steroids [4–7]. Although these changes mainly have been reported in CRPC, inherent expression could indicate predisposition for CRPC and poor response to ADT and other therapies targeting AR signaling.

    To identify patients with optimal therapeutic benefit from drugs with conceptually different targets, their metastatic disease needs to be characterized. Given the difficulty to access metastatic tissue for analysis, circulating tumor cells (CTCs) have a potential to provide phenotypic information of the tumor, in addition to the prognostic value associated with their abundance [8]. We have demonstrated that gene expression in circulating tumor cells (CTCs) reflects the phenotype of prostate cancer metastases [9]. It has also been suggested that detection of AR-V7 mRNA and AR-V7 localization to the nucleus in CTCs predict poor response to drugs targeting the androgen signaling axis, such as abiraterone acetate and enzalutamide, in patients with CRPC [10,11]. Although the biomarker potential of CTCs mostly has been evaluated in CRPC [10,12,13], two studies have described the presence of CTCs as a prognostic marker for overall survival, progression-free survival (PFS), and time to CRPC also in mHSPC [14,15]. In addition, we previously showed that detection of EGFR mRNA in CTCs is a negative prognostic biomarker for CSS in mHSPC [16].

    The present study investigates expression of genes associated with development of CRPC [17] for their prognostic value in mHSPC response to ADT. We showed that mRNA for the steroidogenic enzymes AKR1C3 and CYP17A1 can be detected in CTCs in high volume mHSPC, and that the detection of mRNA for AR-V7 in CTCs before ADT has prognostic value.

  • 19.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Jellvert, Åsa
    Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Region Västra Götaland, NU Hospital Group, Department of Surgery, Uddevalla, Sweden; Department of Oncology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Holmberg, Erik
    Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Regional Cancer Centre West, Gothenburg, Sweden.
    Brasso, Klaus
    Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
    Meidahl Petersen, Peter
    Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
    Aaltomaa, Sirpa
    Department of Urology, Kuopio University Hospital, Kuopio, Finland.
    Luukkaa, Marjaana
    Department of Oncology, Turku University Hospital, Turku, Finland.
    Verhagen, Paul
    Department of Urology, Erasmus Medical Centre, Rotterdam, Netherlands.
    de Wit, Ronald
    Department of Medical Oncology, Erasmus University Medical Centre Cancer Institute, Rotterdam, Netherlands.
    Ahlgren, Göran
    Department of Urology, Lund University, Skåne University Hospital, Sweden.
    Andrén, Ove
    School of Medical Sciences, Örebro University, Örebro, Sweden.
    Castellanos, Enrique
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Seke, Mihalj
    Centrallasarettet Växjö, Växjö, Sweden.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Damber, Jan-Erik
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Effect of docetaxel added to bicalutamide in Hormone-Naïve non-metastatic prostate cancer with rising PSA, a randomized clinical trial (SPCG-14)2023In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 62, no 4, p. 372-380Article in journal (Refereed)
    Abstract [en]

    Background: Historically, endocrine therapy was used in a range of scenarios in patients with rising PSA, both as a treatment for locally advanced non-metastatic prostate cancer and PSA recurrence following curative intended therapy. In the present study the objective was to investigate if chemotherapy added to endocrine therapy could improve progression-free survival (PFS).

    Materials and Methods: Patients with hormone-naïve, non-metastatic prostate cancer and rising prostate-specific antigen (PSA), enrolled from Sweden, Denmark, the Netherlands, and Finland, were randomized to long-term bicalutamide (150 mg daily) or plus docetaxel (75 mg/m2, q3w, 8–10 cycles) without prednisone, after stratification for the site, prior local therapy or not, and PSA doubling time. The primary endpoint was 5-year PFS analyzed with a stratified Cox proportional hazards regression model on intention to treat basis.

    Results: Between 2009 and 2018, a total of 348 patients were randomized; 315 patients had PSA relapse after radical treatment, 33 patients had no prior local therapy. Median follow-up was 4.9 years (IQR 4.0–5.1). Adding docetaxel improved PFS (HR 0.68, 95% CI 0.50–0.93; p = 0.015). Docetaxel showed an advantage for patients with PSA relapse after prior local therapy (HR 0.67, 95% CI 0.49–0.94; p = 0.019). One event of neutropenic infection/fever occurred in 27% of the patients receiving docetaxel. Limitations were slow recruitment, lack of enrolling patients without radical local treatment, and too short follow-up for evaluation of overall survival in patients with PSA relapse.

    Conclusion: Docetaxel improved PFS in patients starting bicalutamide due to PSA relapse after local therapy or localized disease without local therapy. Confirmatory studies of the efficacy of docetaxel in the setting of PSA-only relapse in addition to endocrine therapies may be justified if longer follow-up will show increased metastatic-free survival.

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  • 20.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Urology, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Larsson, Karin
    Freyhult, Eva
    Damber, Jan-Erik
    Welén, Karin
    Gene Expression Alterations during Development of Castration-Resistant Prostate Cancer Are Detected in Circulating Tumor Cells2020In: Cancers, ISSN 2072-6694, Vol. 12, no 1, article id 39Article in journal (Refereed)
    Abstract [en]

    Development of castration-resistant prostate cancer (CRPC) is associated with alterations in gene expression involved in steroidogenesis and androgen signaling. This study investigates whether gene expression changes related to CRPC development can be identified in circulating tumor cells (CTCs). Gene expression in paired CTC samples from 29 patients, before androgen deprivation therapy (ADT) and at CRPC relapse, was compared using a panel including 47 genes related to prostate cancer progression on a qPCR platform. Fourteen genes displayed significantly changed gene expression in CTCs at CRPC relapse compared to before start of ADT. The genes with increased expression at CRPC relapse were related to steroidogenesis, AR-signaling, and anti-apoptosis. In contrast, expression of prostate markers was downregulated at CRPC. We also show that midkine (MDK) expression in CTCs from metastatic hormone-sensitive prostate cancer (mHSPC) was associated to short cancer-specific survival (CSS). In conclusion, this study shows that gene expression patterns in CTCs reflect the development of CRPC, and that MDK expression levels in CTCs are prognostic for cancer-specific survival in mHSPC. This study emphasizes the role of CTCs in exploring mechanisms of therapy resistance, as well as a promising biomarker for prognostic and treatment-predictive purposes in advanced mHSPC.

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  • 21.
    Josefsson, Andreas
    et al.
    Sahlgrenska Cancer Center, Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Larsson, Karin
    Månsson, Marianne
    Björkman, Jens
    Rohlova, Eva
    Åhs, Daniel
    Brisby, Helena
    Damber, Jan-Erik
    Welén, Karin
    Circulating tumor cells mirror bone metastatic phenotype in prostate cancer2018In: Oncotarget, E-ISSN 1949-2553, Vol. 9, no 50, p. 29403-29413Article in journal (Refereed)
    Abstract [en]

    Circulating tumor cells (CTCs) are promising biomarkers in prostate cancer (PC) because they derive from primary tumor and metastatic tissues. In this study, we used quantitative real-time PCR (qPCR) to compare the expression profiles of 41 PC-related genes between paired CTC and spinal column metastasis samples from 22 PC patients that underwent surgery for spinal cord compression. We observed good concordance between the gene expression profiles in the CTC and metastasis samples in most of the PC patients. Expression of nine genes (AGR2, AKR1C3, AR, CDH1, FOLH1, HER2, KRT19, MDK, and SPINK1) showed a significant correlation between the CTC and metastasis samples. Hierarchical clustering analysis showed a similar grouping of PC patients based on the expression of these nine genes in both CTC and metastasis samples. Our findings demonstrate that CTCs mirror gene expression patterns in tissue metastasis samples from PC patients. Although low detection frequency of certain genes is a limitation in CTCs, our results indicate the potential for CTC phenotyping as a tool to improve individualized therapy in metastatic prostate cancer.

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  • 22.
    Josefsson, Andreas
    et al.
    Sahlgrenska Cancer Center, Department of Urology, Institute of Clinical Sciences at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Linder, Anna
    Flondell Site, Despina
    Canesin, Giacomo
    Stiehm, Anna
    Anand, Aseem
    Bjartell, Anders
    Damber, Jan-Erik
    Welén, Karin
    Circulating Tumor Cells as a Marker for Progression-free Survival in Metastatic Castration-naïve Prostate Cancer2017In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, no 8, p. 849-858Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Analysis of circulating tumor cells (CTC) is a promising prognostic marker in castration-resistant prostate cancer (CRPC). The aim of this study was to investigate CTC detection and phenotyping as prognostic biomarkers for response to primary androgen deprivation therapy (ADT) of metastatic prostate cancer (PC).

    METHODS: PC patients presenting with a prostate specific antigen (PSA) >80 ng/ml and/or metastatic disease, intended for ADT were enrolled in the study. CTCs were analysed for expression of PSA prostate specific membrane antigen (PSMA) and epidermal growth factor receptor (EGFR) before and three months after ADT and related to progression.

    RESULTS: At inclusion, 46 out of 53 patients (87%) were CTC-positive with a sensitivity and specificity for distant metastases (M1) of 98% and 75%, respectively. In patients with M1-disease, EGFR-detection in CTC was an independent prognostic marker for progression-free survival, whereas PSA and alkaline phosphatase serum levels, Gleason score, or T-stage were not. EGFR-positive patients had significantly shorter time to progression (5 months) compared to EGFR-negative patients (11 months) (P < 0.05).

    CONCLUSIONS: In this explorative study, CTCs were detected in 98% of M1 patients and detection of EGFR in CTCs was strongly associated with poor outcome, which indicated that phenotypical analysis of CTC could be a promising prognostic marker of ADT-response in castration-naïve metastatic PC patients. Prostate 77:849-858, 2017. © 2017 Wiley Periodicals, Inc.

  • 23.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Månsson, Marianne
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Kohestani, Kimia
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Spyratou, Vasiliki
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Wallström, Jonas
    Department of Radiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Hellström, Mikael
    Department of Radiology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Radiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lilja, Hans
    Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, NY, New York, United States; Department of Surgery, Memorial Sloan Kettering Cancer Center, NY, New York, United States; Department of Medicine, Memorial Sloan Kettering Cancer Center, NY, New York, United States; Department of Translational Medicine, Lund University, Malmö, Sweden.
    Vickers, Andrew
    Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, NY, New York, United States.
    Carlsson, Sigrid V.
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Surgery, Memorial Sloan Kettering Cancer Center, NY, New York, United States; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, NY, New York, United States; Department of Translational Medicine, Division of Urological Cancers, Medical Faculty, Lund University, Skåne University Hospital, Malmö, Sweden.
    Godtman, Rebecka
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Hugosson, Jonas
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Performance of 4Kscore as a reflex test to prostate-specific antigen in the GÖTEBORG-2 prostate cancer screening trial2024In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560Article in journal (Refereed)
    Abstract [en]

    Background and objective: We investigated whether adding 4Kscore as a reflex test to prostate-specific antigen (PSA) could improve the screening algorithm for prostate cancer (PC).

    Methods: In the GÖTEBORG-2 PC screening trial, 38 000men (50–60 yr) were invited to PSA testing and, if elevated, followed by magnetic resonance imaging (MRI). For 571 men with PSA ≥3.0 ng/ml and evaluable outcomes, 4Kscore was calculated. The performance using a prespecified 4Kscore cutoff of 7.5% was evaluated.

    Key findings and limitations: The area under the curve for 4Kscore to identify intermediate- and high-risk PC was 0.84 (95% confidence interval 0.79–0.89), and the positive predictive value, and negative predictive value were 15% (0.12–0.20) and 99% (97–100%), respectively. Of the 54 men diagnosed with intermediate- or high-grade PC, two had a 4Kscore cutoff below 7.5%, both with organ-confined intermediate-risk PC. Per 1000 men with elevated PSA, adding 4Kscore would have resulted in avoidance of MRI for 408 (41%) men, biopsies for 95 (28% reduction) men, and diagnosis of 23 low-grade cancers (23% reduction) while delaying the diagnosis of four men with intermediate-grade cancers (4%).

    Conclusions and clinical implications: Including 4Kscore as a reflex test for men with elevated PSA reduces the need for MRI and biopsy markedly, and results in less overdiagnosis of low-grade PC at the cost of delaying the diagnosis of intermediate-grade PC in a few men. These results add further evidence for including new blood-based biomarkers in addition to PSA to improve the harm and benefit ratio of PC screening and reduce the need for resource-demanding MRI and biopsies.

    Patient summary: In this study, 4Kscore, a blood-based biomarker, as a reflex test for men with elevated prostate-specific antigen (PSA), reduces the need for magnetic resonance imaging and biopsy. These results support the inclusion of new blood-based biomarkers in addition to PSA.

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  • 24.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Egevad, Lars
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Granfors, Torvald
    Department of Urology, Central Hospital Västerås, Västerås, Sweden.
    Karlberg, Lars
    Department of Urology, Central Hospital Västerås, Västerås, Sweden.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Low endoglin vascular density and Ki67 index in Gleason score 6 tumours may identify prostate cancer patients suitable for surveillance2012In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, no 4, p. 247-257Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to explore whether vascular density and tumour cell proliferation are related to the risk of prostate cancer death in patients managed by watchful waiting. Material and methods. From a consecutive series of men diagnosed with prostate cancer at transurethral resection in 1975-1990, tissue microarrays (TMAs) were constructed. A majority of men had no metastases at diagnosis and were followed by watchful waiting (n = 295). The TMAs were stained for Ki67, endoglin and factor VIII-related antigen (vWf).

    Results: In univariate Cox analyses, increased Ki67 index, endoglin vascular density and vWf vascular density were associated with shorter cancer-specific survival. Ki67 index and endoglin vascular density added independent prognostic information to clinical stage, estimated tumour size and Gleason score (GS) in multivariate Cox analysis. In GS 6 tumours, high Ki67 index and high endoglin vascular density identified patients with poor outcome. After 15 years of follow-up not a single man out of 34 men with low staining for both markers (35% of all GS 6 tumours) had died of prostate cancer, in contrast to 15 prostate cancer deaths among the remaining 63 men with GS 6 tumours (65% cumulative risk of prostate cancer death). vWf vascular density in benign areas was a prognostic marker in GS 6 and 7 tumours.

    Conclusions: Men with GS 6 tumours with both low Ki67 index and endoglin vascular density staining scores have a low risk of progression. Additional studies are needed to test whether these two markers can be applied to core biopsies to select patients suitable for surveillance.

  • 25.
    Josefsson, Andreas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Granfors, Torvald
    Egevad, Lars
    Karlberg, Lars
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tumor size, vascular density and proliferation as prognostic markers in GS 6 and GS 7 prostate tumors in patients with long follow-up and non-curative treatment2005In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 48, no 4, p. 577-583Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate the prognostic value of potential markers in localized, Gleason score 6 and 7 prostate cancer (PC).

    Methods: From a consecutive series of men with PC diagnosed at transurethral resection (1975-1990),. specimens from 132 patients without metastases, with Gleason score (GS) 6 (n = 80) or 7 (n = 52) tumors followed with watchful waiting were examined. The fraction of resected prostate tissue containing cancer, the micro-vessel density (v.d.) when stained for endoglin or von Willebrand factor (vWf), and the percentage of Ki-67 labeled tumor cells were measured using immunohistochemistry.

    Results: High levels of vWf v.d., endoglin v.d., and percent cancer of the TURP specimen were significantly associated with short cancer-specific survival in Kaplan-Meier analysis of all patients with GS 6 and 7 tumors. Interestingly, a combined estimate of percent cancer and vWF v.d. could be used to identify a large subset (50%) of GS 6 tumors with only a 2.5% risk of PC death within 15 years. None of the tested markers gave independent prognostic information for the GS 7 tumors.

    Conclusions: Estimates of tumor size and vascular density may identify a large proportion of non-aggressive GS 6, but not GS 7, tumors.

  • 26.
    Järemo, Helena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Semenas, Julius
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Halin Bergström, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Freyhult, Eva
    Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Urology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Welén, Karin
    Department of Urology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Thellenberg-Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The microRNA landscape of prostate cancer bone metastases and the role of miRNA-375 in modulating phenotypic characteristics of metastatic cellsManuscript (preprint) (Other academic)
  • 27. Kohestani, Kimia
    et al.
    Wallström, Jonas
    Dehlfors, Niclas
    Sponga, Ole Martin
    Månsson, Marianne
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Urology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Carlsson, Sigrid
    Hellström, Mikael
    Hugosson, Jonas
    Performance and inter-observer variability of prostate MRI (PI-RADS version 2) outside high-volume centres2019In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 53, no 5, p. 304-311Article in journal (Refereed)
    Abstract [en]

    Objective: Despite the growing trend to embrace pre-biopsy MRI in the diagnostic pathway for prostate cancer (PC), its performance and inter-observer variability outside high-volume centres remains unknown. This study aims to evaluate sensitivity of and variability between readers of prostate MRI outside specialized units with radical prostatectomy (RP) specimen as the reference standard.

    Materials and methods: Retrospective study comprising a consecutive cohort of all 97 men who underwent MRI and subsequent RP between January 2012 and December 2014 at a private hospital in Sweden. Three readers, blinded to clinical data, reviewed all images (including 11 extra prostate MRI to reduce bias). A tumour was considered detected if the overall PI-RADS v2 score was 3-5 and there was an approximate match (same or neighbouring sector) of tumour sector according to a 24 sector system used for both MRI and whole mount sections.

    Results: Detection rate for the index tumour ranged from 67 to 76%, if PI-RADS 3-5 lesions were considered positive and 54-66% if only PI-RADS score 4-5 tumours were included. Detection rate for aggressive tumours (GS >= 4 + 3) was higher; 83.1% for PI-RADS 3-5 and 79.2% for PI-RADS 4-5. The agreement between readers showed average values of 0.41 for PI-RADS score 3-5 and 0.51 for PI-RADS score 4-5.

    Conclusions: Prostate MRI evidenced a moderate detection rate for clinically significant PC with a rather large variability between readers. Clinics outside specialized units must have knowledge of their performance of prostate MRI before considering omitting biopsies in men with negative MRI.

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  • 28.
    Magnusson, Cecilia
    et al.
    Department of Translational Medicine, Lund University, Lund, Sweden.
    Augustsson, Per
    Department of Biomedical Engineering, Lund University, Lund, Sweden.
    Undvall Anand, Eva
    Department of Biomedical Engineering, Lund University, Lund, Sweden.
    Lenshof, Andreas
    Department of Biomedical Engineering, Lund University, Lund, Sweden.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Institute of Clinical Sciences, Department of Urology, Gothenburg University, Gothenburg, Sweden.
    Welén, Karin
    Institute of Clinical Sciences, Department of Urology, Gothenburg University, Gothenburg, Sweden.
    Bjartell, Anders
    Department of Translational Cancer Research, Lund University, Lund, Sweden.
    Ceder, Yvonne
    Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Lilja, Hans
    Department of Translational Medicine, Lund University, Lund, Sweden; Department of Pathology and Laboratory Medicine, Surgery (Urology), and Medicine (GU Oncology), Memorial Sloan-Kettering Cancer Center, NY, New York, United States.
    Laurell, Thomas
    Department of Biomedical Engineering, Lund University, Lund, Sweden.
    Acoustic enrichment of heterogeneous circulating tumor cells and clusters from metastatic prostate cancer patients2024In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 96, no 18, p. 6914-6921Article in journal (Refereed)
    Abstract [en]

    Background: There are important unmet clinical needs to develop cell enrichment technologies to enable unbiased label-free isolation of both single cell and clusters of circulating tumor cells (CTCs) manifesting heterogeneous lineage specificity. Here, we report a pilot study based on the microfluidic acoustophoresis enrichment of CTCs using the CellSearch CTC assay as a reference modality.

    Methods: Acoustophoresis uses an ultrasonic standing wave field to separate cells based on biomechanical properties (size, density, and compressibility), resulting in inherently label-free and epitope-independent cell enrichment. Following red blood cell lysis and paraformaldehyde fixation, 6 mL of whole blood from 12 patients with metastatic prostate cancer and 20 healthy controls were processed with acoustophoresis and subsequent image cytometry.

    Results: Acoustophoresis enabled enrichment and characterization of phenotypic CTCs (EpCAM+, Cytokeratin+, DAPI+, CD45-/CD66b-) in all patients with metastatic prostate cancer and detected CTC-clusters composed of only CTCs or heterogeneous aggregates of CTCs clustered with various types of white blood cells in 9 out of 12 patients. By contrast, CellSearch did not detect any CTC clusters, but detected comparable numbers of phenotypic CTCs as acoustophoresis, with trends of finding a higher number of CTCs using acoustophoresis.

    Conclusion: Our preliminary data indicate that acoustophoresis provides excellent possibilities to detect and characterize CTC clusters as a putative marker of metastatic disease and outcomes. Moreover, acoustophoresis enables the sensitive label-free enrichment of cells with epithelial phenotypes in blood and offers opportunities to detect and characterize CTCs undergoing epithelial-to-mesenchymal transitioning and lineage plasticity.

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  • 29. Mirtti, Tuomas
    et al.
    Leiby, Benjamin E.
    Abdulghani, Junaid
    Aaltonen, Elina
    Pavela, Miia
    Mamtani, Anita
    Alanen, Kalle
    Egevad, Lars
    Granfors, Torvald
    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.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nevalainen, Marja T.
    Nuclear Stat5a/b predicts early recurrence and prostate cancer-specific death in patients treated by radical prostatectomy2013In: Human Pathology, ISSN 0046-8177, E-ISSN 1532-8392, Vol. 44, no 3, p. 310-319Article in journal (Refereed)
    Abstract [en]

    There is an urgent need for reliable markers to identify patients whose prostate cancer (PCa) will recur after initial therapy and progress to lethal disease. Gleason score (GS) is considered the most accurate predictive marker for disease-specific mortality after primary treatment of localized PCa. Most PCas cluster into groups of GS 6 and 7 with considerable variation in the disease recurrence and disease-specific death. In preclinical PCa models, Stat5a/b promotes PCa growth and progression. Stat5a/b is critical for PCa cell viability in vitro and for tumor growth in vivo and promotes metastatic dissemination of cancer in nude mice. Here, we analyzed the predictive value of high nuclear Stat5a/b protein levels in 2 cohorts of PCas: Material I (n = 562) PCas treated by radical prostatectomy (RP), and Material II (n = 106) PCas treated by deferred palliative therapy. In intermediate GS PCas treated by radical prostatectomy, high levels of nuclear Stat5a/b predicted both early recurrence (univariable analysis; P < .0001, multivariable analysis; HR = 1.82, P = .017) and early PCa-specific death (univariable analysis; P = .028). In addition, high nuclear Stat5a/b predicted early disease recurrence in both univariable (P < .0001) and multivariable (HR = 1.61; P = .012) analysis in the entire cohort of patients treated by RP regardless of the GS. Patients treated by deferred palliative therapy, elevated nuclear Stat5a/b expression was associated with early PCa-specific death by univariable Cox regression analysis (HR. = 1.59; 95% CI = [1.04, 2.44]; P = .034). If confirmed in future prospective studies, nuclear Stat5a/b may become a useful independent predictive marker of recurrence of lethal PCa after RP for intermediate GS PCas. (c) 2013 Elsevier Inc. All rights reserved.

  • 30.
    Rajwa, Pawel
    et al.
    Department of Urology, Medical University of Silesia, Zabrze, Poland; Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    Borkowetz, Angelika
    Department of Urology, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
    Abbott, Thomas
    European Association of Urology, Nijmegen, Netherlands.
    Alberti, Andrea
    Unit of Urological Robotic Surgery and Renal Transplantation, University of Florence, Careggi Hospital, Florence, Italy.
    Bjartell, Anders
    Department of Translational Medicine, Lund University, Lund, Sweden.
    Brash, James T.
    IQVIA, Real World Solutions, Brighton, United Kingdom.
    Campi, Riccardo
    Unit of Urological Robotic Surgery and Renal Transplantation, University of Florence, Careggi Hospital, Florence, Italy.
    Chilelli, Andrew
    Astellas Pharma Europe Ltd, Surrey, United Kingdom.
    Conover, Mitchell
    Janssen Research & Development, NJ, Titusville, United States.
    Constantinovici, Niculae
    Bayer AG, Berlin, Germany.
    Davies, Eleanor
    IQVIA, Real World Solutions, Brighton, United Kingdom.
    De Meulder, Bertrand
    Association EISBM, Vourles, France.
    Eid, Sherrine
    SAS Institute, NC, Cary, United States.
    Gacci, Mauro
    Unit of Urological Robotic Surgery and Renal Transplantation, University of Florence, Careggi Hospital, Florence, Italy.
    Golozar, Asieh
    Odysseus Data Services, NY, New York, United States; OHDSI Center, Northeastern University, MA, Boston, United States.
    Hafeez, Haroon
    Shaukat Khanum Memorial Cancer Hospital & Research Centre, Peshawar, Pakistan.
    Haque, Samiul
    SAS Institute, NC, Cary, United States.
    Hijazy, Ayman
    Association EISBM, Vourles, France.
    Hulsen, Tim
    Department of Hospital Services & Informatics, Philips Research, Eindhoven, Netherlands.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Diagnostics and Intervention. Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Khalid, Sara
    University of Oxford, Oxford, United Kingdom.
    Kolde, Raivo
    Institute of Computer Science, University of Tartu, Estonia, Tartu, Estonia.
    Kotik, Daniel
    Center for Advanced Systems Understanding, Görlitz, Germany; Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.
    Kurki, Samu
    Bayer OY, Turku, Finland.
    Lambrecht, Mark
    SAS Institute, NC, Cary, United States.
    Leung, Chi-Ho
    S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, Hong Kong.
    Moreno, Julia
    SAS Institute, NC, Cary, United States.
    Nicoletti, Rossella
    Unit of Urological Robotic Surgery and Renal Transplantation, University of Florence, Careggi Hospital, Florence, Italy.
    Nieboer, Daan
    Erasmus MC University Medical Center, Rotterdam, Netherlands.
    Oja, Marek
    Institute of Computer Science, University of Tartu, Estonia, Tartu, Estonia.
    Palanisamy, Soundarya
    SAS Institute, NC, Cary, United States.
    Prinsen, Peter
    Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, Netherlands.
    Reich, Christian
    Odysseus Data Services, NY, New York, United States; OHDSI Center, Northeastern University, MA, Boston, United States.
    Raffaele Resta, Giulio
    Unit of Urological Robotic Surgery and Renal Transplantation, University of Florence, Careggi Hospital, Florence, Italy.
    Ribal, Maria J.
    Uro-Oncology Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain.
    Gómez Rivas, Juan
    Department of Urology, Hospital Clinico San Carlos, Madrid, Spain.
    Smith, Emma
    Guidelines Office, European Association of Urology, Arnhem, Netherlands.
    Snijder, Robert
    Janssen Research & Development, NJ, Titusville, United States.
    Steinbeisser, Carl
    Collaborate Project Management, Munich, Germany.
    Vandenberghe, Frederik
    SAS Institute, NC, Cary, United States.
    Cornford, Philip
    Liverpool University Hospitals NHS Trust, Liverpool, United Kingdom.
    Evans-Axelsson, Susan
    Bayer AG, Berlin, Germany.
    N'Dow, James
    Academic Urology Unit, University of Aberdeen, Aberdeen, United Kingdom.
    Willemse, Peter-Paul M.
    Department of Urology, Cancer Center, University Medical Center Utrecht, Utrecht, Netherlands.
    Research protocol for an observational health data analysis on the adverse events of systemic treatment in patients with metastatic hormone-sensitive prostate cancer: big data analytics using the PIONEER platform2024In: European Urology Open Science, ISSN 2666-1691, E-ISSN 2666-1683, Vol. 63, p. 81-88Article in journal (Refereed)
    Abstract [en]

    Combination therapies in metastatic hormone-sensitive prostate cancer (mHSPC), which include the addition of an androgen receptor signaling inhibitor and/or docetaxel to androgen deprivation therapy, have been a game changer in the management of this disease stage. However, these therapies come with their fair share of toxicities and side effects. The goal of this observational study is to report drug-related adverse events (AEs), which are correlated with systemic combination therapies for mHSPC. Determining the optimal treatment option requires large cohorts to estimate the tolerability and AEs of these combination therapies in “real-life” patients with mHSPC, as provided in this study. We use a network of databases that includes population-based registries, electronic health records, and insurance claims, containing the overall target population and subgroups of patients defined by unique certain characteristics, demographics, and comorbidities, to compute the incidence of common AEs associated with systemic therapies in the setting of mHSPC. These data sources are standardised using the Observational Medical Outcomes Partnership Common Data Model. We perform the descriptive statistics as well as calculate the AE incidence rate separately for each treatment group, stratified by age groups and index year. The time until the first event is estimated using the Kaplan-Meier method within each age group. In the case of episodic events, the anticipated mean cumulative counts of events are calculated. Our study will allow clinicians to tailor optimal therapies for mHSPC patients, and they will serve as a basis for comparative method studies.

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  • 31.
    Spyratou, Vasiliki
    et al.
    Department of Urology, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden.
    Freyhult, Eva
    Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thellenberg-Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Welén, Karin
    Department of Urology, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden; Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Institute of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden.
    Ki67 and prostate specific antigen are prognostic in metastatic hormone naïve prostate cancer2023In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 6212, p. 1698-1706Article in journal (Refereed)
    Abstract [en]

    Background: For metastatic hormone naïve prostate cancer patients, androgen deprivation therapy (ADT) with escalation therapy including docetaxel and/or androgen targeting drugs is the standard therapy. However, de-escalation is preferable to avoid unnecessary side effects, especially from docetaxel, but markers to identify these patients are lacking. The purpose of the present study was to investigate the potential of PSA and Ki67 immunoreactive scores as prognostic and treatment-predictive markers.

    Material and methods: Prostate biopsies from 92 patients with metastatic hormone naïve PC (PSA > 80 ng/mL or clinical metastases) were immunohistochemically evaluated for PSA and Ki67. Gene expression analysis was performed with Clariom D microarrays to identify the phenotypic profile associated with the immunohistochemistry scores of biopsies. Cox regression analysis for progression free survival after ADT adjustment for age, ISUP, and serum PSA and Kaplan-Meier analyses were performed to assess prognostic values of Ki67, PSA, and the Ki67/PSA ratio.

    Results: The immunohistochemical score for PSA was the strongest prognostic factor for progression-free and overall survival after ADT. Consequently, the ratio between Ki67 and PSA displayed a stronger prognostic value than Ki67 itself. Further, mRNA expression data analysis showed an association between high Ki67/PSA ratio, cell-cycle regulation, and DNA damage repair. In an exploratory sub-analysis of 12 patients treated with early docetaxel as addition to ADT and matched controls, a high Ki67/PSA ratio showed potential to identify those who benefit from docetaxel.

    Conclusion: PSA and Ki67 immunoreactive scores are prognostic in the metastatic hormone-sensitive setting, with PSA being superior. The combination of Ki67 and PSA did not give additional prognostic value. The results suggest immunohistochemical scoring of PSA to have potential to improve identification of patients responding well to ADT alone.

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  • 32.
    Stinesen Kollberg, K.
    et al.
    Department of Urology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Social Work, Faculty of Social Sciences, University of Gothenburg, Gothenburg, Sweden.
    Holmberg, E.
    Sahlgrenska University Hospital, Department of Urology, Region Västra Götaland, Sweden; Regional Cancer Center West, Western Sweden Healthcare Region, Gothenburg, Sweden.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Hugosson, J.
    Department of Urology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Arnsrud Godtman, R.
    Department of Urology, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Sahlgrenska University Hospital, Department of Urology, Region Västra Götaland, Sweden.
    Prostate specific antigen and biopsy contamination in the Göteborg-1 randomized, population-based, prostate cancer screening trial2022In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 208, no 5, p. 1018-1027Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Even when a screening study has demonstrated a mortality reduction, the degree of pre-testing and contamination is of importance as it can dilute the "true" effect of screening. Our object was to describe the level of pre-testing and contamination in the Göteborg-1 prostate cancer screening trial.

    MATERIALS AND METHODS: A total of 20,000 men, 50-64 years old, were invited in 1994 and randomized to either a screening group (offered prostate specific antigen testing every 2 years) or to a control group. Follow-up was through December 31, 2014. Outcome measurement was overall testing in the screening group and control group. A positive prostate specific antigen test was defined as a prostate specific antigen ≥3 ng/ml.

    RESULTS: In the study, 4.2% in the screening group and 4.6% men in the control group were tested before study start. During follow-up, 72% in the control group took at least 1 prostate specific antigen test (contamination) compared to 87% of men in the screening group. Of all prostate specific antigens, 24% in the screening group and 39% in the control group were above threshold. In total, 66% of the men underwent prostate biopsy within 12 months from a raised prostate specific antigen in the screening group and 28% in the control group.

    CONCLUSIONS: Similar proportions of men were prostate specific antigen-tested in both the screening group and control group, yet only a minority of contamination prostate specific antigens led to biopsy. Also, men in the screening group started screening at a younger age. These could both be explanations for our result that organized screening is more effective in reducing prostate cancer mortality than non-organized testing. When carried out properly and compared to an unscreened population, the effects of organized screening are likely even greater than previously shown in the Göteborg screening trial.

  • 33.
    Sund, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Department of Surgery, Univerisity of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    Fonseca-Rodríguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, University of Gothenburg, Gothenburg, Sweden.
    Welen, Karin
    Department of Urology, University of Gothenburg, Gothenburg, Sweden.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Association between pharmaceutical modulation of oestrogen in postmenopausal women in Sweden and death due to COVID-19: a cohort study2022In: BMJ Open, E-ISSN 2044-6055, Vol. 12, no 2, article id e053032Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Determine whether augmentation of oestrogen in postmenopausal women decreases the risk of death following COVID-19.

    DESIGN: Nationwide registry-based study in Sweden based on registries from the Swedish Public Health Agency (all individuals who tested positive for SARS-CoV-2); Statistics Sweden (socioeconomical variables) and the National Board of Health and Welfare (causes of death).

    PARTICIPANTS: Postmenopausal women between 50 and 80 years of age with verified COVID-19.

    INTERVENTIONS: Pharmaceutical modulation of oestrogen as defined by (1) women with previously diagnosed breast cancer and receiving endocrine therapy (decreased systemic oestrogen levels); (2) women receiving hormone replacement therapy (increased systemic oestrogen levels) and (3) a control group not fulfilling requirements for group 1 or 2 (postmenopausal oestrogen levels). Adjustments were made for potential confounders such as age, annual disposable income (richest group as the reference category), highest level of education (primary, secondary and tertiary (reference)) and the weighted Charlson Comorbidity Index (wCCI). PRIMARY OUTCOME MEASURE: Death following COVID-19.

    RESULTS: From a nationwide cohort consisting of 49 853 women diagnosed with COVID-19 between 4 February and 14 September 2020 in Sweden, 16 693 were between 50 and 80 years of age. We included 14 685 women in the study with 11 923 (81%) in the control group, 227 (2%) women in group 1 and 2535 (17%) women in group 2. The unadjusted ORs for death following COVID-19 were 2.35 (95% CI 1.51 to 3.65) for group 1 and 0.45 (0.34 to 0.6) for group 2. Only the adjusted OR for death remained significant for group 2 with OR 0.47 (0.34 to 0.63). Absolute risk of death was 4.6% for the control group vs 10.1% and 2.1%, for the decreased and increased oestrogen groups, respectively. The risk of death due to COVID-19 was significantly associated with: age, OR 1.15 (1.14 to 1.17); annual income, poorest 2.79 (1.96 to 3.97), poor 2.43 (91.71 to 3.46) and middle 1.64 (1.11 to 2.41); and education (primary 1.4 (1.07 to 1.81)) and wCCI 1.13 (1.1 to 1.16).

    CONCLUSIONS: Oestrogen supplementation in postmenopausal women is associated with a decreased risk of dying from COVID-19 in this nationwide cohort study. These findings are limited by the retrospective and non-randomised design. Further randomised intervention trials are warranted.

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  • 34.
    Thomasson, Marcus
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wang, Baofeng
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlman, Anna
    Persson, Jenny Liao
    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.
    Granfors, Torvald
    Egevad, Lars
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    LRIG1 and the liar paradox in prostate cancer: A study of the expression and clinical significance of LRIG1 in prostate cancer.2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 128, no 12, p. 2843-2852Article in journal (Refereed)
    Abstract [en]

    The course of prostate cancer varies greatly, and additional prognostic markers are needed. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) is an endogenous inhibitor of growth factor signalling and a proposed tumour suppressor. Publicly available gene expression datasets indicate that LRIG1 may be overexpressed in prostate cancer. In the present study, the expression of LRIG1 protein in prostate cancer was evaluated for the first time. Immunohistochemistry was performed on tissue microarrays from two different patient series: 355 Swedish patients diagnosed by transurethral resection and 293 American patients who underwent radical prostatectomy. In the Swedish series, high expression of LRIG1 correlated with Gleason score, T-stage, tumour cell proliferation, vascular density, and epidermal growth factor receptor (EGFR) phosphorylation. Among the 256 Swedish patients, followed by watchful waiting, high LRIG1 expression was significantly associated with short overall and prostate cancer-specific survival. In contrast, in the U.S. series, high LRIG1 expression was significantly associated with longer overall survival. In vitro cell experiments showed that LRIG1 was induced by androgen stimulation, and its expression inhibited prostate cancer cell proliferation. Thus, LRIG1 expression was an independent marker for poor survival in the untreated patient series, perhaps as a secondary marker of androgen receptor and/or EGFR activation. On the contrary, LRIG1 was a marker for good prognosis after prostatectomy, which might be due to its growth inhibiting properties. We propose that LRIG1 is an important determinant of prostate cancer growth, and the implications of its expression on patient outcome depend upon the clinical and biological circumstances.

  • 35.
    Thysell, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Köhn, Linda
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Semenas, Julius
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Järemo, Helena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Freyhult, Eva
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thellenberg-Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Damber, Jan-Erik
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Urology, Sahlgrenska.
    Welén, Karin
    Nilsson, R. Jonas A.
    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.
    Clinical and biological relevance of the transcriptomic-based prostate cancer metastasis subtypes MetA-C2022In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, no 4Article in journal (Refereed)
    Abstract [en]

    To improve treatment of metastatic prostate cancer, the biology of metastases needs to be understood. We recently described three subtypes of prostate cancer bone metastases (MetA-C), based on differential gene expression. The aim of this study was to verify the clinical relevance of these subtypes, and to explore their biology and relations to genetic drivers. Freshly-frozen metastasis samples were obtained as hormone-naive (n=17), short-term castrated (n=21) or castration resistant (n=65) from a total of 67 patients. Previously published sequencing data from 573 metastasis samples was also analyzed. Through transcriptome profiling and sample classification based on a set of predefined MetA-C-differentiating genes, we found that most metastases were heterogeneous for the MetA-C subtypes. Overall, MetA was the most common subtype, while MetB was significantly enriched in castration-resistant samples and in liver metastases, and consistently associated with poor prognosis. By gene set enrichment analysis, the phenotype of MetA was described by high androgen response, protein secretion and adipogenesis, MetB by high cell cycle activity and DNA repair, and MetC by epithelial-to-mesenchymal transition and inflammation. The MetB subtype demonstrated single-nucleotide variants of RB transcriptional corepressor 1 (RB1) and loss of 21 genes at chromosome 13, including RB1, but provided independent prognostic value to those genetic aberrations. In conclusion, a distinct set of gene transcripts can be used to classify prostate cancer metastases into the subtypes MetA-C. The MetA-C subtypes show diverse biology, organ tropism and prognosis. The MetA-C classification may be used independently, or in combination with genetic markers, primarily to identify MetB patients in need of complementary therapy to conventional androgen-receptor-targeting treatments.

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  • 36.
    Tidehag, Viktor
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Egevad, Lars
    Grantors, Torvald
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Leanderson, Tomas
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High density of S100A9 positive inflammatory cells in prostate cancer stroma is associated with poor outcome2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 10, p. 1829-1835Article in journal (Refereed)
    Abstract [en]

    Purpose: To elucidate if the density of inflammatory cells expressing S100A9 in malignant and surrounding non-malignant prostate tissues is a prognostic marker for outcome in prostate cancer patients. Experimental design: Tissue was obtained from 358 men diagnosed with prostate cancer at transurethral resection of the prostate due to obstructive voiding problems, of which 260 were then followed with watchful waiting. Tissue microarrays of both malignant and non-malignant tissues were stained with an antibody against S100A9. The number of stained inflammatory cells was scored and related to clinical outcome and histopathological parameters of known prognostic value. Results: A high number of inflammatory cells expressing S100A9 in both malignant and surrounding non-malignant tissues were associated with significantly shorter cancer-specific survival. This association remained significant when Gleason score and local tumour stage were analysed together with S100A9 in a Cox regression model. Low number of S100A9 positive cells in non-malignant stroma was correlated to significantly longer cancer-specific survival also in patients with Gleason score 8-10 tumours. S100A9 positive cells in tumour stroma were correlated with Gleason score, hyaluronan, platelet-derived growth factor receptor beta (PDGFR-beta), and androgen receptor (inverse correlation) in tumour stroma. S100A9 positive cells in non-malignant stroma correlated with androgen receptor in this tissue compartment (inverse correlation). Conclusions: A high number of S100A9 positive inflammatory cells in tumour stroma and in non-malignant stroma were associated with shorter cancer-specific survival in prostate cancer patients.

  • 37.
    Welen, Karin
    et al.
    Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Freyhult, Eva
    Department of Medical Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). The Laboratory for Molecular Infection Medicine Sweden, Umeå, Sweden.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). The Laboratory for Molecular Infection Medicine Sweden, Umeå, Sweden.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Re: Chen Dong, Sung-Lang Chen, and Wen-Wei Sung's Letter to the Editor re: Karin Welén, Ebba Rosendal, Magnus Gisslén, et al. A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data. Eur Urol. 2022;81:285–93.2022In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 81, no 5, p. e124-e125Article in journal (Other academic)
  • 38.
    Welén, Karin
    et al.
    Institute of Clinical Sciences, Department of Urology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Freyhult, Eva
    Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Oh, William K.
    Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY, New York, United States.
    Gisslén, Magnus
    Institute of Biomedicine, Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Institute of Clinical Sciences, Department of Urology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Reply to Carlos G. Wambier and Gerard J. Nau's Letter to the Editor re: Karin Welén, Ebba Rosendal, Magnus Gisslén, et al. A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data. Eur Urol. 2022;81:285–93. Positive Effects of Enzalutamide for Hospitalized COVID-19 Patients: Still No Positive Effect of Enzalutamide for Hospitalized COVID-19 Patients2022In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 81, no 6, p. e143-e144Article in journal (Other academic)
  • 39. Welén, Karin
    et al.
    Rosendal, Ebba
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Gisslén, Magnus
    Lenman, Annasara
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Freyhult, Eva
    Fonseca Rodriguez, Osvaldo
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Bremell, Daniel
    Stranne, Johan
    Östholm Balkhed, Åse
    Niward, Katarina
    Repo, Johanna
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Robinsson, David
    Henningsson, Anna J.
    Styrke, Johan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Angelin, Martin
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindquist, Elisabeth
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Becker, Miriam
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Section of Virology.
    Rudolfsson, Stina H.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Buckland, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Thellenberg Carlsson, Camilla
    Bjartell, Anders
    Nilsson, Anna C.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Fors Connolly, Anne-Marie
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Överby, Anna K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    A Phase 2 Trial of the Effect of Antiandrogen Therapy on COVID-19 Outcome: No Evidence of Benefit, Supported by Epidemiology and In Vitro Data2022In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 81, no 3, p. 285-293Article in journal (Refereed)
    Abstract [en]

    Background: Men are more severely affected by COVID-19. Testosterone may influence SARS-CoV-2 infection and the immune response.

    Objective: To clinically, epidemiologically, and experimentally evaluate the effect of antiandrogens on SARS-CoV-2 infection.

    Designs, settings, and participants: A randomized phase 2 clinical trial (COVIDENZA) enrolled 42 hospitalized COVID-19 patients before safety evaluation. We also conducted a population-based retrospective study of 7894 SARS-CoV-2–positive prostate cancer patients and an experimental study using an air-liquid interface three-dimensional culture model of primary lung cells.

    Intervention: In COVIDENZA, patients were randomized 2:1 to 5 d of enzalutamide or standard of care.

    Outcome measurements: The primary outcomes in COVIDENZA were the time to mechanical ventilation or discharge from hospital. The population-based study investigated risk of hospitalization, intensive care, and death from COVID-19 after androgen inhibition.

    Results and limitations: Enzalutamide-treated patients required longer hospitalization (hazard ratio [HR] for discharge from hospital 0.43, 95% confidence interval [CI] 0.20–0.93) and the trial was terminated early. In the epidemiological study, no preventive effects were observed. The frail population of patients treated with androgen deprivation therapy (ADT) in combination with abiraterone acetate or enzalutamide had a higher risk of dying from COVID-19 (HR 2.51, 95% CI 1.52–4.16). In vitro data showed no effect of enzalutamide on virus replication. The epidemiological study has limitations that include residual confounders.

    Conclusions: The results do not support a therapeutic effect of enzalutamide or preventive effects of bicalutamide or ADT in COVID-19. Thus, these antiandrogens should not be used for hospitalized COVID-19 patients or as prevention for COVID-19. Further research on these therapeutics in this setting are not warranted.

    Patient summary: We studied whether inhibition of testosterone could diminish COVID-19 symptoms. We found no evidence of an effect in a clinical study or in epidemiological or experimental investigations. We conclude that androgen inhibition should not be used for prevention or treatment of COVID-19.

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  • 40.
    Wikström, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Welén, Karin
    Sahlgrenska Centrum för cancerforskning, institutionen för kliniska vetenskaper, Göteborgs universitet, Göteborg, Sweden.
    Molekylära subtyper och avancerad prostatacancer: nya möjligheter för anpassad behandling: [Molecular subtypes provide possibilities for precision medicine in a advanced prostate cancer]2024In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 121, article id 23179Article, review/survey (Refereed)
    Abstract [en]

    Increased molecular knowledge makes it possible to consider not only genetic defects but also expression profiles for precision medicine in advanced prostate cancer. Several prognostic and treatment-predictive classifiers for prostate cancer have been described, such as Prolaris, OncotypeDx, Decipher, Prostatype, PAM50, PCS1-2, and MetA-C, which all build upon transcript profiles. In research studies, the MetA-C classifier has shown clear prognostic information for patients with metastatic disease, in relation to outcome after androgen receptor targeting therapies, and so has immunohistochemical evaluation of tumor cell proliferation (Ki67) and PSA expression. Unfortunately, methods within clinical routine today do not allow molecular subclassification of prostate cancer. To enable comparison of the most promising treatment-predictive biomarkers and to evaluate the health economic value of implementing such precision medicine for prostate cancer, a prospective study is being planned as a joint initiative in Sweden that aims to evaluate and validate biomarkers and to establish a study platform for adaptive biomarker-driven clinical trials (sprintr.se).

  • 41.
    Wikström, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Halin Bergström, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Semenas, Julius
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nordstrand, Annika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics. 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.
    Thellenberg Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Epithelial and stromal characteristics of primary tumors predict the bone metastatic subtype of prostate cancer and patient survival after androgen-deprivation therapy2022In: Cancers, ISSN 2072-6694, Vol. 14, no 21, article id 5195Article in journal (Refereed)
    Abstract [en]

    Prostate cancer (PC) bone metastases can be divided into transcriptomic subtypes, by us termed MetA-C. The MetB subtype, constituting about 20% of the cases, is characterized by high cell cycle activity, low androgen receptor (AR) activity, and a limited response to standard androgen deprivation therapy (ADT). Complementary treatments should preferably be introduced early on if the risk of developing metastases of the MetB subtype is predicted to behigh. In this study, we therefore examined if the bone metastatic subtype and patient outcome after ADT could be predicted by immunohistochemical analysis of epithelial and stromal cell markers in primary tumor biopsies obtained at diagnosis (n = 98). In this advanced patient group, primary tumor International Society of Urological Pathology (ISUP) grade was not associated with outcome or metastasis subtype. In contrast, high tumor cell Ki67 labeling (proliferation) in combination with low tumor cell immunoreactivity for PSA, and a low fraction of AR positive stroma cells in the primary tumors were prognostic for poor survival after ADT. Accordingly, the same tissue markers were associated with developing metastases enriched for the aggressive MetB subtype. The development of the contrasting MetA subtype, showing the best response to ADT, could be predicted by the opposite staining pattern. We conclude that outcome after ADT and metastasis subtype can, at least to some extent, be predicted by analysis of primary tumor characteristics, such as tumor cell proliferation and PSA expression, and AR expression in stromal cells.

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