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  • 251.
    Hammarsten, Peter
    et al.
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Josefsson, Andreas
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Urol, Gothenburg, Sweden.
    Thysell, Elin
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Lundholm, Marie
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Hagglof, Christina
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Iglesias-Gato, Diego
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Copenhagen, Denmark.
    Flores-Morales, Amilcar
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Copenhagen, Denmark.
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Egevad, Lars
    Karolinska Univ Hosp, Dept Pathol & Cytol, Stockholm, Sweden.
    Granfors, Torvald
    Cent Hosp Vasteras, Dept Urol, Vasteras, Sweden.
    Wikstrom, Pernilla
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Bergh, Anders
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Immunoreactivity for prostate specific antigen and Ki67 differentiates subgroups of prostate cancer related to outcome2019In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 32, no 9, p. 1310-1319Article in journal (Refereed)
    Abstract [en]

    Based on gene-expression profiles, prostate tumors can be subdivided into subtypes with different aggressiveness and response to treatment. We investigated if similar clinically relevant subgroups can be identified simply by the combination of two immunohistochemistry markers: one for tumor cell differentiation (prostate specific antigen, PSA) and one for proliferation (Ki67). This was analyzed in men with prostate cancer diagnosed at transurethral resection of the prostate 1975-1991 (n = 331) where the majority was managed by watchful waiting. Ki67 and PSA immunoreactivity was related to outcome and to tumor characteristics previously associated with prognosis. Increased Ki67 and decreased PSA were associated with poor outcome, and they provided independent prognostic information from Gleason score. A combinatory score for PSA and Ki67 immunoreactivity was produced using the median PSA and Ki67 levels as cut-off (for Ki67 the upper quartile was also evaluated) for differentiation into subgroups. Patients with PSA low/Ki67 high tumors showed higher Gleason score, more advanced tumor stage, and higher risk of prostate cancer death compared to other patients. Their tumor epithelial cells were often ERG positive and expressed higher levels of ErbB2, phosphorylated epidermal growth factor receptor (pEGF-R) and protein kinase B (pAkt), and their tumor stroma showed a reactive response with type 2 macrophage infiltration, high density of blood vessels and hyaluronic acid, and with reduced levels of caveolin-1, androgen receptors, and mast cells. In contrast, men with PSA high/Ki67 low tumors were characterized by low Gleason score, and the most favorable outcome amongst PSA/Ki67-defined subgroups. Men with PSA low/Ki67 low tumors showed clinical and tumor characteristics intermediate of the two groups above. A combinatory PSA/Ki67 immunoreactivity score identifies subgroups of prostate cancers with different epithelial and stroma phenotypes and highly different outcome but the clinical usefulness of this approach needs to be validated in other cohorts.

  • 252.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Department of Urology, Institute of Clinical Sciences at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Iglesias-Gato, Diego
    Flores-Morales, Amilcar
    Stattin, Pär
    Egevad, Lars
    Granfors, Torvald
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Immunoreactivity for prostate specific antigen and Ki67 differentiates subgroups of prostate cancer related to outcome2019In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 32, no 9, p. 1310-1319Article in journal (Refereed)
    Abstract [en]

    Based on gene-expression profiles, prostate tumors can be subdivided into subtypes with different aggressiveness and response to treatment. We investigated if similar clinically relevant subgroups can be identified simply by the combination of two immunohistochemistry markers: one for tumor cell differentiation (prostate specific antigen, PSA) and one for proliferation (Ki67). This was analyzed in men with prostate cancer diagnosed at transurethral resection of the prostate 1975-1991 (n = 331) where the majority was managed by watchful waiting. Ki67 and PSA immunoreactivity was related to outcome and to tumor characteristics previously associated with prognosis. Increased Ki67 and decreased PSA were associated with poor outcome, and they provided independent prognostic information from Gleason score. A combinatory score for PSA and Ki67 immunoreactivity was produced using the median PSA and Ki67 levels as cut-off (for Ki67 the upper quartile was also evaluated) for differentiation into subgroups. Patients with PSA low/Ki67 high tumors showed higher Gleason score, more advanced tumor stage, and higher risk of prostate cancer death compared to other patients. Their tumor epithelial cells were often ERG positive and expressed higher levels of ErbB2, phosphorylated epidermal growth factor receptor (pEGF-R) and protein kinase B (pAkt), and their tumor stroma showed a reactive response with type 2 macrophage infiltration, high density of blood vessels and hyaluronic acid, and with reduced levels of caveolin-1, androgen receptors, and mast cells. In contrast, men with PSA high/Ki67 low tumors were characterized by low Gleason score, and the most favorable outcome amongst PSA/Ki67-defined subgroups. Men with PSA low/Ki67 low tumors showed clinical and tumor characteristics intermediate of the two groups above. A combinatory PSA/Ki67 immunoreactivity score identifies subgroups of prostate cancers with different epithelial and stroma phenotypes and highly different outcome but the clinical usefulness of this approach needs to be validated in other cohorts.

  • 253.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Scherdin, Tove Dahl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hagglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersson, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Granfors, Torvald
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High Caveolin-1 Expression in Tumor Stroma Is Associated with a Favourable Outcome in Prostate Cancer Patients Managed by Watchful Waiting2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164016Article in journal (Refereed)
    Abstract [en]

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

  • 254.
    Hansell, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Rügheimer, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Evi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göransson, Viktoria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hyaluronan and renal ischemic damage2005Book (Refereed)
  • 255. Hartana, C. A.
    et al.
    Ahlén Bergman, E.
    Broomé, A.
    Berglund, S.
    Johansson, M.
    Alamdari, F.
    Jakubczyk, T.
    Huge, Y.
    Aljabery, F.
    Palmqvist, K.
    Holmström, B.
    Glise, H.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, O.
    Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 39-53Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

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

  • 257.
    Haya, N
    et al.
    Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia.
    Baessler, K
    Charite, Beckenbodenzentrum Charite, Berlin, Germany.
    Christmann-Schmid, C
    Hosp Lucerne, Luzern, Switzerland.
    de Tayrac, R
    Caremeau Univ Hosp, Nimes, France.
    Dietz, V
    Catharina Hosp, Eindhoven, Netherlands.
    Guldberg, R
    Odense Univ Hosp, Ctr Clin Epidemiol, DK-5000 Odense, Denmark.
    Mascarenhas, T
    Hosp Sao Joao, Oporto, Portugal.
    Nüssler, Emil
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Ballard, E
    Royal Brisbane & Womens Hosp, QIMR Berghofer RBWH Stat Unit, Brisbane, Qld, Australia.
    Ankardal, M
    Hallands Sjukhus, Kungsbacka, Sweden.
    Boudemaghe, T
    Caremeau Univ Hosp, Nimes, France.
    Maher, C
    Royal Brisbane & Womens Hosp, Brisbane, Qld, Australia.
    Prolapse and continence surgery in OECD countries2014In: International Urogynecology Journal, ISSN 0937-3462, E-ISSN 1433-3023, Vol. 25, p. S98-S100Article in journal (Other academic)
  • 258. Haynes, Richard
    et al.
    Lewis, David
    Emberson, Jonathan
    Reith, Christina
    Agodoa, Lawrence
    Cass, Alan
    Craig, Jonathan C.
    de Zeeuw, Dick
    Feldt-Rasmussen, Bo
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Levin, Adeera
    Wheeler, David C.
    Walker, Rob
    Herrington, William G.
    Baigent, Colin
    Landray, Martin J.
    Effects of Lowering LDL Cholesterol on Progression of Kidney Disease2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 8, p. 1825-1833Article in journal (Refereed)
    Abstract [en]

    Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD.

  • 259. He, Bing
    et al.
    Ebarasi, Lwaki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Zhao, Zhe
    Guo, Jing
    Ojala, Juha R. M.
    Hultenby, Kjell
    De Val, Sarah
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tryggvason, Karl
    Lmx1b and FoxC Combinatorially Regulate Podocin Expression in Podocytes2014In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 25, no 12, p. 2764-2777Article in journal (Refereed)
    Abstract [en]

    Podocin is a key protein of the kidney podocyte slit diaphragm protein complex, an important part of the glomerular filtration barrier. Mutations in the human podocin gene NPHS2 cause familial or sporadic forms of renal disease owing to the disruption of filtration barrier integrity. The exclusive expression of NPHS2 in podocytes reflects its unique function and raises interesting questions about its transcriptional regulation. Here, we further define a 2.5-kb zebrafish nphs2 promoter fragment previously described and identify a 49-bp podocyte-specific transcriptional enhancer using Tol2-mediated G(0) transgenesis in zebrafish. Within this enhancer, we identified a cis-acting element composed of two adjacent DNA-binding sites (FLAT-E and forkhead) bound by transcription factors Lnnx1b and FoxC. In zebrafish, double knockdown of Lmx1b and FoxC orthologs using morpholino doses that caused no or minimal phenotypic changes upon individual knockdown completely disrupted podocyte development in 40% of injected embryos. Co-overexpression of the two genes potently induced endogenous nphs2 expression in zebrafish podocytes. We found that the NPHS2 promoter also contains a cis-acting Lmx1b-FoxC motif that binds LMX1B and FoxC2. Furthermore, a genome-wide search identified several genes that carry the Lmx1b-FoxC motif in their promoter regions. Among these candidates, motif-driven podocyte enhancer activity of CCNC and MEIS2 was functionally analyzed in vivo. Our results show that podocyte expression of some genes is combinatorially regulated by two transcription factors interacting synergistically with a common enhancer. This finding provides insights into transcriptional mechanisms required for normal and pathologic podocyte functions.

  • 260.
    Heddini, Ulrika
    et al.
    Karolinska Institutet.
    Bohm-Starke, Nina
    Karolinska Institutet.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Kent W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Johannesson, Ulrika
    Karolinska Institutet.
    Serotonin receptor gene (5HT-2A) polymorphism is associated with provoked vestibulodynia and comorbid symptoms of pain2014In: Journal of Sexual Medicine, ISSN 1743-6095, E-ISSN 1743-6109, Vol. 11, no 12, p. 3064-3071Article in journal (Refereed)
    Abstract [en]

    IntroductionProvoked vestibulodynia (PVD) is a common type of dyspareunia among young women. The patho-physiology remains largely unclear. Women with PVD have general pain hypersensitivity and often report additional pain symptoms. Signs point towards PVD being a chronic pain disorder similar to other syndromes of longstanding pain, including a common comorbidity of anxiety and depression. Polymorphism in the serotonin receptor gene, 5HT-2A, has been associated with other chronic pain disorders such as fibromyalgia but has not been investigated in PVD patients. AimWe aimed to investigate a possible contribution of polymorphism in the 5HT-2A gene to the etiology of PVD as well as a potential influence on pain sensitivity. MethodsIn this case-control study 98 women with PVD and 103 healthy controls between 18 and 44 years and in the same menstrual cycle phase completed questionnaires and underwent quantitative sensory testing. Venous blood samples were collected for DNA isolation. Main Outcome MeasuresConcomitant pain was reported, a bodily pain score was created and pressure pain thresholds (PPTs) on the arm, leg, and in the vestibule were measured. Intensity of coital pain was rated on a visual analog scale, range 0-100. The T102C (rs6313) and A-1438G (rs6311) single nucleotide polymorphisms (SNPs) in the 5HT-2A gene were analyzed. ResultsThe probability of PVD was elevated in participants carrying the 1438G- and 102C-alleles of the 5HT-2A gene (OR 2.9). The G-/C- genotypes were also associated with more concomitant bodily pain in addition to the dyspareunia, but not with experimental PPTs or coital pain ratings. PVD patients reported more concomitant bodily pain and had lower PPTs compared with controls. ConclusionThe results indicate a contribution of alterations in the serotonergic system to the patho-genesis of PVD and gives further evidence of PVD being a general pain disorder similar to other chronic pain disorders. Heddini U, Bohm-Starke N, Gronbladh A, Nyberg F, Nilsson KW, and Johannesson U. Serotonin receptor gene (5HT-2A) polymorphism is associated with provoked vestibulodynia and comorbid symptoms of pain.

  • 261.
    Hedegaard, Jakob
    et al.
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Lamy, Philippe
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Nordentoft, Iver
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Algaba, Ferran
    Univ Autonoma Barcelona, Fundacio Puigvert, Sect Pathol, Barcelona 08025, Spain..
    Hoyer, Soren
    Aarhus Univ Hosp, Dept Pathol, DK-8000 Aarhus, Denmark..
    Ulhoi, Benedicte Parm
    Aarhus Univ Hosp, Dept Pathol, DK-8000 Aarhus, Denmark..
    Vang, Soren
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Reinert, Thomas
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Hermann, Gregers G.
    Frederiksberg Univ Hosp, Dept Urol, DK-2000 Frederiksberg, Denmark..
    Mogensen, Karin
    Frederiksberg Univ Hosp, Dept Urol, DK-2000 Frederiksberg, Denmark..
    Thomsen, Mathilde Borg Houlberg
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Nielsen, Morten Muhlig
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Marquez, Mirari
    Spanish Natl Canc Res Ctr CNIO, Madrid 28029, Spain..
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Aine, Mattias
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, S-22100 Lund, Sweden..
    Hoglund, Mattias
    Lund Univ, Dept Clin Sci Lund, Div Oncol & Pathol, S-22100 Lund, Sweden..
    Birkenkamp-Demtroder, Karin
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Fristrup, Niels
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Borre, Michael
    Aarhus Univ Hosp, Dept Urol, DK-8200 Aarhus, Denmark..
    Hartmann, Arndt
    Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Pathol, D-91054 Erlangen, Germany..
    Stoehr, Robert
    Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Pathol, D-91054 Erlangen, Germany..
    Wach, Sven
    Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Urol, D-91054 Erlangen, Germany..
    Keck, Bastian
    Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Urol, D-91054 Erlangen, Germany..
    Seitz, Anna Katharina
    Tech Univ Munich, Klinikum Rechts Isar, Dept Urol, D-81675 Munich, Germany..
    Nawroth, Roman
    Tech Univ Munich, Klinikum Rechts Isar, Dept Urol, D-81675 Munich, Germany..
    Maurer, Tobias
    Tech Univ Munich, Klinikum Rechts Isar, Dept Urol, D-81675 Munich, Germany..
    Tulic, Cane
    Univ Belgrade, Clin Ctr Serbia, Clin Urol, Fac Med, Belgrade 11000, Serbia..
    Simic, Tatjana
    Univ Belgrade, Fac Med, Inst Med & Clin Biochem, Belgrade 11000, Serbia..
    Junker, Kerstin
    Univ Saarland, Dept Urol, D-66421 Homburg, Germany..
    Horstmann, Marcus
    Univ Jena, Dept Urol, D-07737 Jena, Germany..
    Harving, Niels
    Aalborg Univ Hosp, Dept Urol, DK-9000 Aalborg, Denmark..
    Petersen, Astrid Christine
    Aalborg Univ Hosp, Dept Pathol, DK-9000 Aalborg, Denmark..
    Luz Calle, M.
    Univ Vic, Dept Syst Biol, Barcelona 08500, Spain..
    Steyerberg, Ewout W.
    Erasmus MC, Dept Publ Hlth, NL-3015 CE Rotterdam, Netherlands..
    Beukers, Willemien
    Erasmus MC, Dept Pathol, NL-3015 CE Rotterdam, Netherlands..
    van Kessel, Kim E. M.
    Erasmus MC, Dept Pathol, NL-3015 CE Rotterdam, Netherlands..
    Jensen, Jorgen Bjerggaard
    Aarhus Univ Hosp, Dept Urol, DK-8200 Aarhus, Denmark..
    Pedersen, Jakob Skou
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Malats, Nuria
    Spanish Natl Canc Res Ctr CNIO, Madrid 28029, Spain..
    Real, Francisco X.
    Spanish Natl Canc Res Ctr CNIO, Madrid 28029, Spain.;Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona 08003, Spain..
    Zwarthoff, Ellen C.
    Erasmus MC, Dept Pathol, NL-3015 CE Rotterdam, Netherlands..
    Orntoft, Torben Falck
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Dyrskjot, Lars
    Aarhus Univ Hosp, Dept Mol Med, DK-8200 Aarhus, Denmark..
    Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma2016In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 30, no 1, p. 27-42Article in journal (Refereed)
    Abstract [en]

    Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal-and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.

  • 262.
    Hedelin, Hans
    et al.
    Department of Research and Development, Skaraborgs Sjukhus, Skövde, Sweden.
    Jonsson, Karin
    Department of Research and Development, Skaraborgs Sjukhus, Skövde, Sweden.
    Lundh, Dan
    Department of Research and Development, Skaraborgs Sjukhus, Skövde, Sweden.
    Pain associated with the chronic pelvic pain syndrome is strongly related to the ambient temperature2012In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, no 4, p. 279-283Article in journal (Refereed)
    Abstract [en]

    Objective. There are indications suggesting that the pain associated with the chronic pelvic pain syndrome (CPPS) may be related to cold. The purpose of the present study was to evaluate how the symptom intensity reported by the patient relates to the time of the year in a temperate climate, i.e. to the ambient temperature and to weather changes.

    Material and methods. Thirty-one patients, mean age 51 years (range 35-66 years), with CPPS for 17 +/- 10 years (3-42 years) were asked to complete a set of questionnaires including questions concerning how they experienced their symptom intensity during the different seasons using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) questionnaire.

    Results. The total NIH-CPSI score was 22.2 +/- 8.2. There was a highly marked relationship between season and pain intensity as reported by the informants: it was experienced to be three times more intense during the winter months. All subjects reported that a temperature drop was associated with deterioration.

    Conclusion. The strong relationship between the ambient temperature, a drop in temperature and the pain experienced by men with CPPS confirms the association between cold and symptom intensity in the Scandinavian countries, where the seasonal temperature variation spans a long range and the winters are long. The cause of this relationship is still to be established. Muscular spasm/stiffness is a possibility that remains to be explored.

  • 263. Hedlund, Per Olov
    et al.
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Damber, Jan Erik
    Hagerman, Inger
    Henriksson, Peter
    Iversen, Peter
    Klarskov, Peter
    Mogensen, Peter
    Rasmussen, Finn
    Varenhorst, Eberhard
    Significance of pretreatment cardiovascular morbidity as a risk factor during treatment with parenteral oestrogen or combined androgen deprivation of 915 patients with metastasized prostate cancer: Evaluation of cardiovascular events in a randomized trial2011In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 45, no 5, p. 346-353Article in journal (Refereed)
    Abstract [en]

    Objective. This study aimed to evaluate prognostic risk factors for cardiovascular events during treatment of metastatic prostate cancer patients with high-dose parenteral polyoestradiol phosphate (PEP, Estradurin (R)) or combined androgen deprivation (CAD) with special emphasis on pretreatment cardiovascular disease. Material and methods. Nine-hundred and fifteen patients with T0-4, Nx, M1, G1-3, hormone- naive prostate cancer were randomized to treatment with PEP 240 mg i.m. twice a month for 2 months and thereafter monthly, or to flutamide (Eulexin (R)) 250 mg per os three times daily in combination with either triptorelin (Decapeptyl (R)) 3.75 mg i.m. per month or on an optional basis with bilateral orchidectomy. Pretreatment cardiovascular morbidity was recorded and cardiovascular events during treatment were assessed by an experienced cardiologist. A multivariate analysis was done using logistic regression. Results. There was a significant increase in cardiovascular events during treatment with PEP in patients with previous ischaemic heart disease (p = 0.008), ischaemic cerebral disease (p = 0.002), intermittent claudication (p = 0.031) and especially when the whole group of patients with pretreatment cardiovascular diseases was analysed together (p < 0.001). In this group 33% of the patients had a cardiovascular event during PEP treatment. In the multivariate analysis PEP stood out as the most important risk factor for cardiac complications (p = 0.029). Even in the CAD group there was a significant increase in cardiovascular events in the group with all previous cardiovascular diseases taken together (p = 0.036). Conclusions. Patients with previous cardiovascular disease are at considerable risk of cardiovascular events during treatment with high-dose PEP and even during CAD therapy. Patients without pretreatment cardiovascular morbidity have a moderate cardiovascular risk during PEP treatment and could be considered for this treatment if the advantages of this therapy, e. g. avoidance of osteopenia and hot flushes and the low price, are given priority.

  • 264.
    Hellqvist, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Heiene, Reidun
    Norwegian School of Veterinary Science.
    Croubles, Siska
    Ghent University.
    De Baere, Siegrid
    Ghent University.
    Hedeland, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Development of a capillary electrophoretic method for determination of plasma clearance of iohexol in dogs and cats2013Conference paper (Refereed)
  • 265.
    Hellqvist, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Heiene, Reidun
    Hedeland, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    A robust and reliable capillary electrophoretic method for quantitative determination of iohexol in plasma2012Conference paper (Refereed)
  • 266.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Day-to-day variation of urinary NGAL and rational for creatinine correction2013In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 46, no 1-2, p. 70-72Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Clinical studies evaluating the new tubular biomarker urinary neutrophil gelatinase-associated lipocalin (U-NGAL) in urine increase and there is no consensus whether absolute U-NGAL concentrations or urinary NGAL/creatinine (U-NGAL/Cr) ratios should be used when chronic tubular dysfunction is studied. The aim was to study the biological variation of U-NGAL in healthy subjects and the rational for urinary Creatinine (U-Cr) correction in two different study samples.

    DESIGN AND METHODS:

    To study biological variation of U-NGAL and U-NGAL/Cr ratio and the association between U-NGAL and U-Cr in healthy subjects 13 young males and females (median age 29years) collected morning urine in 10 consecutive days. Additionally, a random subsample of 400 males from a population-based cohort (aged 78years) collecting 24-hour urine during one day was studied.

    RESULTS:

    The calculated biological variation for absolute U-NGAL was 27% and for U-NGAL/Cr ratio 101%. Absolute U-NGAL increased linearly with U-Cr concentration (the theoretical basis for creatinine adjustment) in the older males (R=0.19, P<0.001) and with borderline significance in the young adults (R=0.16, P=0.08). The U-NGAL/Cr ratio was, however, negatively associated with creatinine in the older males (R=-0.14, P<0.01) and in the young adults (R=-0.16, P=0.07) indicating a slight "overadjustment".

    CONCLUSIONS:

    The study provide some support for the use of U-NGAL/Cr ratio but the rather large biological variation and risk of possible overadjustment need to be considered. Both absolute U-NGAL and U-NGAL/Cr ratios should be reported for the estimation of chronic tubular dysfunction.

  • 267. Hemdan, Tammer
    Choline Phosphate Cytidylyltransferase-α (CCT-α) a Novel Predictor of Response to Cisplatin Neoadjuvant Chemotherapy in Urothelial Cancer of the BladderManuscript (preprint) (Other academic)
  • 268.
    Hemdan, Tammer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Prognostic and Predictive Factors in Bladder Cancer2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Bladder cancer is a potentially curable malignancy; however in regards to the state of current therapy regimens, a plateau has been reached in both the non-muscle and muscle invasive types. To obtain effective treatment, and consequently a decreased mortality, it has become imperative to test and understand aspects affecting therapy response. The aim of this thesis is to illustrate a better understanding of clinical factors affecting therapy response using new drug combinations and new tumor markers alongside established risk criteria. In Paper I we reported the 5 year follow up from a multicenter, prospectively randomized study and we evaluated the 5-year outcomes of BCG alone compared to a combination of epirubicin and interferon-a2b in the treatment of patients with T1 bladder cancer. Treatment, tumor size and tumor status at second resection were independent variables associated with recurrence. Concomitant Cis was not predictive of failure of BCG therapy. Independent factor for treatment failure was remaining T1 stage at second resection. In Paper II &III we investigated the validity of emmprin, survivin and CCTα proteins as biomarkers for response and survival before neoadjuvant cisplatin chemotherapy. Bladder tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry (IHC). Patients in the chemotherapy cohort with negative emmprin and CCTα expression had significantly better overall survival (OS) than those with positive expression. In Paper IV primary end point was examining STMN1 as prognostic factor in bladder cancer.  Analysis was performed on three bladder cancer patient cohorts using IHC, western blot and a bladder cancer cell line. High levels of STMN1, expression correlated to shorter disease-specific survival and the growth and migration of the cells were significantly reduced when transfecting the cells with STMN1 siRNA. Conclusion Risk assessment and predictors of outcomes could help in individualized treatment and follow up.  Biomarkers will become more important for treatment choices in bladder cancer management.

  • 269. Hemdan, Tammer
    et al.
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jahnson, Staffan
    Hellstrom, Pekka
    Tasdemir, Ilker
    Malmstrom, Per-Uno
    Five-year results of nordic T1G2-3, a randomized trial comparing bcg with epirubicin and interferon alpha 2b2013In: Scandinavian journal of urology, ISSN 2168-1805, Vol. 47, no Suppl. 219, p. 19-20Article in journal (Other academic)
  • 270.
    Hemdan, Tammer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Johansson, Robert
    Jahnson, Staffan
    Hellström, Pekka
    Tasdemir, Ilker
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Five year outcome of a randomized prospective study comparing bacillus Calmette-Guerin with epirubicin and interferon α 2b in patients with T1 bladder cancer2014In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 191, no 5, p. 1244-1249Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    In a multicenter, prospectively randomized study we evaluated the five-year outcome of bacillus Calmette-Guérin (BCG) alone compared to a combination of epirubicin and interferon α 2b in the treatment of patients with T1 bladder cancer.

    MATERIAL AND METHODS:

    The transurethral resection was followed by a second resection and bladder mapping. Stratification was for grade and cancer in situ. Follow-up entailed regular cystoscopy and cytology during the first 5 years. The end points assessed in this analysis were recurrence-free survival, time to failure of the treatment and progression, cancer-specific survival, and prognostic factors.

    RESULTS:

    The study recruited 250 eligible patients.The five years recurrence-free survival were 38% in the combination arm and 59% in the BCG arm (p=0.001). The corresponding rates for the other endpoints were not significantly different; free of - progression 78 and 77%, - treatment failure 75 and 75% and cancer-specific survival 90 and 92%. The type of treatment, size and tumour status at second resection were independent variables associated with recurrence. Concomitant carcinoma in situ was not predictive of failure of BCG therapy. Independent factor for treatment failure was remaining T1 stage at second resection.

    CONCLUSIONS:

    BCG therapy was more effective than the tested combination. Presently recommended management with second resection and three week maintenance BCG entails a low risk of cancer specific death. More aggressive treatment in patients with infiltrative tumours at second resection might improve these results. In particular, concomitant carcinoma in situ was not a predictive factor for poor outcome after BCG therapy.

  • 271.
    Hemdan, Tammer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Jahnson, Staffan
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Emmprin Expression Predicts Response and Survival following Cisplatin Containing Chemotherapy for Bladder Cancer: A Validation Study.2015In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 194, no 6, p. 1575-1581Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Neoadjuvant chemotherapy before cystectomy is recommended. To our knowledge the subset of patients likely to benefit has not been identified. We validate emmprin and survivin as markers of chemotherapy response.

    MATERIALS AND METHODS: Tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry.

    RESULTS: Expression was categorized according to predefined cutoffs reported in the literature. Data were analyzed with the Kaplan-Meier method and Cox models. Patients in the chemotherapy cohort with negative emmprin expression had significantly higher down staging overall survival than those with positive expression (71% vs 38%, p <0.001). The values for cancer specific survival were 76% and 56%, respectively (p <0.027). In the cystectomy only cohort emmprin expression was not associated with overall survival (46% vs 35%, p = 0.23) or cancer specific survival (55% vs 51%, p = 0.64). Emmprin negative patients had an absolute risk reduction of 25% in overall survival (95% CI 11-40) and a number needed to treat of 4 (95% CI 2.5-9.3). Survivin expression was not useful as a biomarker in this study. Limitations were the retrospective design and heterogeneity coupled with the time difference between the trials.

    CONCLUSIONS: Patients with emmprin negative tumors have a better response to neoadjuvant chemotherapy before cystectomy than those with positive expression.

  • 272.
    Hemdan, Tammer
    et al.
    Department of Surgical Sciences, Uppsala University, Uppsala.
    Malmström, Per-Uno
    Department of Surgical Sciences, Uppsala University, Uppsala.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland. Department of Surgical Sciences, Uppsala University, Uppsala.
    Segersten, Ulrika
    Department of Surgical Sciences, Uppsala University, Uppsala.
    Emmprin expression predicts response and survival following cisplatin containing chemotherapy for bladder cancer: A validation study2015In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 194, no 6, p. 1575-1581Article in journal (Refereed)
    Abstract [en]

    Purpose Neoadjuvant chemotherapy before cystectomy is recommended. To our knowledge the subset of patients likely to benefit has not been identified. We validate emmprin and survivin as markers of chemotherapy response. Materials and Methods Tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry. Results Expression was categorized according to predefined cutoffs reported in the literature. Data were analyzed with the Kaplan-Meier method and Cox models. Patients in the chemotherapy cohort with negative emmprin expression had significantly higher down staging overall survival than those with positive expression (71% vs 38%, p <0.001). The values for cancer specific survival were 76% and 56%, respectively (p <0.027). In the cystectomy only cohort emmprin expression was not associated with overall survival (46% vs 35%, p = 0.23) or cancer specific survival (55% vs 51%, p = 0.64). Emmprin negative patients had an absolute risk reduction of 25% in overall survival (95% CI 11-40) and a number needed to treat of 4 (95% CI 2.5-9.3). Survivin expression was not useful as a biomarker in this study. Limitations were the retrospective design and heterogeneity coupled with the time difference between the trials. Conclusions Patients with emmprin negative tumors have a better response to neoadjuvant chemotherapy before cystectomy than those with positive expression. © 2015 American Urological Association Education and Research, Inc.

  • 273.
    Hemdan, Tammer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Turker, Polat
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Choline-phosphate cytidylyltransferase-alpha as a possible predictor of survival and response to cisplatin neoadjuvant chemotherapy in urothelial cancer of the bladder2018In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 52, no 3, p. 200-205Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to test choline-phosphate cytidylyltransferase-alpha (CCT-alpha) protein as a biomarker for neoadjuvant cisplatin chemotherapy response in a bladder tumor setting. Materials and methods: A total of 238 patients with T2-T4 bladder cancer enrolled into two prior randomized trials comparing neoadjuvant cisplatin-based chemotherapy (NAC) plus cystectomy with cystectomy only (no-NAC) were used as discovery and validation cohorts. Protein expression was determined with immunohistochemistry and assessed with Histo (H)-scoring. Results: In the discovery cohort, comprising 61 patients, the survival ratio after NAC treatment for CCT-alpha-negative patients was significantly increased (p = 0.001) while there was no survival advantage in the CCT-alpha-positive patient group. Similarly, in the validation cohort with 177 patients, NAC treatment improved survival only in the CCT-alpha-negative group (p = 0.006). Although there was a tendency for a good NAC response with negative CCT-alpha status, the interaction variable between biomarker and treatment was not significant (p = 0.24). In the cystectomy-only group, patients with positive CCT-alpha expression had a better survival than CCT-alpha-negative patients. This prognostic effect of CCT-alpha expression remained significant after adjusting for well-known prognostic factors in a multivariate analysis. In a pooled database of both patient data sets, multivariate analyses showed CCT-alpha status as an independent factor for overall survival (p = 0.018; hazard ratio = 1.80, 95% confidence interval 1.11-2.93). Conclusion: CCT-alpha status was not predictive of outcome of NAC response; however, in the control group with cystectomy only it was found to have prognostic value.

  • 274.
    Henriksson, Tobias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Impact of home adress and distance to nearest urological unit on survival in invasive urinary bladder cancer2017Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 275. Herbert, Annie
    et al.
    Cruickshank, John Kennedy
    Laurent, Stéphane
    Boutouyrie, Pierre
    Establishing reference values for central blood pressure and its amplification in a general healthy population and according to cardiovascular risk factors.2014In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 35, no 44, p. 3122-33Article in journal (Refereed)
    Abstract [en]

    AIMS: Estimated central systolic blood pressure (cSBP) and amplification (Brachial SBP-cSBP) are non-invasive measures potentially prognostic of cardiovascular (CV) disease. No worldwide, multiple-device reference values are available. We aimed to establish reference values for a worldwide general population standardizing between the different available methods of measurement. How these values were significantly altered by cardiovascular risk factors (CVRFs) was then investigated.

    METHODS AND RESULTS: Existing data from population surveys and clinical trials were combined, whether published or not. Reference values of cSBP and amplification were calculated as percentiles for 'Normal' (no CVRFs) and 'Reference' (any CVRFs) populations. We included 45,436 subjects out of 82,930 that were gathered from 77 studies of 53 centres. Included subjects were apparently healthy, not treated for hypertension or dyslipidaemia, and free from overt CV disease and diabetes. Values of cSBP and amplification were stratified by brachial blood pressure categories and age decade in turn, both being stratified by sex. Amplification decreased with age and more so in males than in females. Sex was the most powerful factor associated with amplification with 6.6 mmHg (5.8-7.4) higher amplification in males than in females. Amplification was marginally but significantly influenced by CVRFs, with smoking and dyslipidaemia decreasing amplification, but increased with increasing levels of blood glucose.

    CONCLUSION: Typical values of cSBP and amplification in a healthy population and a population free of traditional CVRFs are now available according to age, sex, and brachial BP, providing values included from different devices with a wide geographical representation. Amplification is significantly influenced by CVRFs, but differently in men and women.

  • 276. Herrington, William
    et al.
    Emberson, Jonathan
    Mihaylova, Borislava
    Blackwell, Lisa
    Reith, Christina
    Solbu, Marit
    Mark, Patrick
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Jardine, Alan
    Wanner, Christoph
    Holdaas, Hallvard
    Fulcher, Jordan
    Haynes, Richard
    Landray, Martin
    Keech, Anthony
    Simes, John
    Collins, Rory
    Baigent, Colin
    Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials2016In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 4, no 10, p. 829-839, article id S2213-8587(16)30156-5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Statin therapy is effective for the prevention of coronary heart disease and stroke in patients with mild-to-moderate chronic kidney disease, but its effects in individuals with more advanced disease, particularly those undergoing dialysis, are uncertain.

    METHODS: We did a meta-analysis of individual participant data from 28 trials (n=183 419), examining effects of statin-based therapy on major vascular events (major coronary event [non-fatal myocardial infarction or coronary death], stroke, or coronary revascularisation) and cause-specific mortality. Participants were subdivided into categories of estimated glomerular filtration rate (eGFR) at baseline. Treatment effects were estimated with rate ratio (RR) per mmol/L reduction in LDL cholesterol.

    FINDINGS: Overall, statin-based therapy reduced the risk of a first major vascular event by 21% (RR 0·79, 95% CI 0·77-0·81; p<0·0001) per mmol/L reduction in LDL cholesterol. Smaller relative effects on major vascular events were observed as eGFR declined (p=0·008 for trend; RR 0·78, 99% CI 0·75-0·82 for eGFR ≥60 mL/min per 1·73 m(2); 0·76, 0·70-0·81 for eGFR 45 to <60 mL/min per 1·73 m(2); 0·85, 0·75-0·96 for eGFR 30 to <45 mL/min per 1·73 m(2); 0·85, 0·71-1·02 for eGFR <30 mL/min per 1·73 m(2) and not on dialysis; and 0·94, 0·79-1·11 for patients on dialysis). Analogous trends by baseline renal function were seen for major coronary events (p=0·01 for trend) and vascular mortality (p=0·03 for trend), but there was no significant trend for coronary revascularisation (p=0·90). Reducing LDL cholesterol with statin-based therapy had no effect on non-vascular mortality, irrespective of eGFR.

    INTERPRETATION: Even after allowing for the smaller reductions in LDL cholesterol achieved by patients with more advanced chronic kidney disease, and for differences in outcome definitions between dialysis trials, the relative reductions in major vascular events observed with statin-based treatment became smaller as eGFR declined, with little evidence of benefit in patients on dialysis. In patients with chronic kidney disease, statin-based regimens should be chosen to maximise the absolute reduction in LDL cholesterol to achieve the largest treatment benefits.

    FUNDING: UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Community Biomed Programme, Australian National Health and Medical Research Council, Australian National Heart Foundation.

  • 277.
    Hijazi, Ziad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hohnloser, Stefan H
    Goethe Univ Frankfurt, Frankfurt, Germany.
    Andersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Alexander, John H
    Duke Med, Duke Clin Res Inst, Durham, NC USA.
    Hanna, Michael
    Bristol Myers Squibb, Princeton, NJ USA.
    Keltai, Matyas
    Semmelweis Univ, Hungarian Inst Cardiol, Budapest, Hungary.
    Parkhomenko, Alexander
    Inst Cardiol, Kiev, Ukraine.
    López-Sendón, José L
    Hosp Univ La Paz, IdiPaz, Madrid, Spain.
    Lopes, Renato D
    Duke Med, Duke Clin Res Inst, Durham, NC USA.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Granger, Christopher B
    Duke Med, Duke Clin Res Inst, Durham, NC USA.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation in Relation to Renal Function Over Time: Insights From the ARISTOTLE Randomized Clinical Trial2016In: JAMA cardiology, ISSN 2380-6591, Vol. 1, no 4, p. 451-460Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE: Renal impairment confers an increased risk of stroke, bleeding, and death in patients with atrial fibrillation. Little is known about the efficacy and safety of apixaban in relation to renal function changes over time.

    OBJECTIVES: To evaluate changes of renal function over time and their interactions with outcomes during a median of 1.8 years of follow-up in patients with atrial fibrillation randomized to apixaban vs warfarin treatment.

    DESIGN, SETTING, AND PARTICIPANTS: The prospective, randomized, double-blind Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) clinical trial randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Serial creatinine measurements were available in 16 869 patients. Worsening of renal function was defined as an annual decrease in estimated glomerular filtration more than 20%. The relations between treatment, outcomes, and renal function were investigated using Cox regression models, with renal function as a time-dependent covariate.

    MAIN OUTCOMES AND MEASURES: Stroke or systemic embolism (primary outcome), major bleeding (safety outcome), and mortality were examined in relation to renal function over time estimated with both the Cockcroft-Gault and Chronic Kidney Disease Epidemiology Collaboration equations.

    RESULTS: Among 16 869 patients, the median age was 70 years and 65.2% of patients were men. Worsening in estimated glomerular filtration more than 20% was observed in 2294 patients (13.6%) and was associated with older age and more cardiovascular comorbidities. The risks of stroke or systemic embolism, major bleeding, and mortality were higher in patients with worsening renal function (HR, 1.53; 95% CI, 1.17-2.01 for stroke or systemic embolism; HR, 1.56; 95% CI, 1.27-1.93 for major bleeding; and HR, 2.31; 95% CI, 1.98-2.68 for mortality). The beneficial effects of apixaban vs warfarin on rates of stroke or systemic embolism and major bleeding were consistent in patients with normal or poor renal function over time and also in those with worsening renal function.

    CONCLUSIONS AND RELEVANCE: In patients with atrial fibrillation, declining renal function was more common in elderly patients and those with cardiovascular comorbidities. Worsening renal function was associated with a higher risk of subsequent cardiovascular events and bleeding. The superior efficacy and safety of apixaban as compared with warfarin were similar in patients with normal, poor, and worsening renal function.

    TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00412984.

  • 278. Hilderman, Marie
    et al.
    Qureshi, Abdul R
    Al-Abed, Yousef
    Abtahi, Farhad
    KTH, School of Technology and Health (STH), Medical Engineering, Medical sensors, signals and systems.
    Lindecrantz, Kaj
    Anderstam, Björn
    Bruchfeld, Annette
    Cholinergic anti-inflammatory pathway activity in dialysis patients: a role for neuroimmunomodulation?2015In: Clinical Kidney Journal, ISSN 2048-8505, E-ISSN 2048-8513, Vol. 8, no 5Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The cholinergic anti-inflammatory pathway (CAP) modulates inflammatory responses through the vagus nerve and the α-7-nicotinic acetylcholine receptor (α7nAChR) on macrophages and immune cells. Sympathetic/parasympathetic imbalance and chronic inflammation are both linked to poor outcome in dialysis patients. The aim of this study was to investigate CAP activity in these patients.

    METHODS: Twenty dialysis patients, 12 hemodialysis (HD) and 8 peritoneal dialysis (PD) patients (12 male, 8 female; age range 47-83 years) and 8 controls (5 male, 3 female; age range 31-52 years) were analyzed for C-reactive protein (CRP), tumor necrosis factor (TNF), interleukin-1b (IL-1b), IL-6 and IL-10 at baseline. The cytokines were then assessed after whole blood stimulation ex vivo with lipopolysaccharide (LPS) (10 and 100 ng/mL) and again in the presence of 45 and 90 μmol/L GTS-21, a cholinergic α7nAChR agonist.

    RESULTS: CRP, TNF, IL-1 and IL-6 were significantly higher, whereas IL-10 was significantly lower at baseline in patients compared with controls. After LPS stimulation, TNF increased significantly more in patients than in controls but decreased to similar levels in both groups after addition of GTS-21. IL-6 attenuation was comparable with TNF and the IL-1b pattern was similar but remained significantly higher in patients. Interestingly, IL-10 increased after GTS-21 in a dose-dependent manner, but only in patients. Results in HD and PD patients did not differ.

    CONCLUSIONS: The response of immune cells after LPS exposure and cholinergic stimulation suggests a functional CAP in dialysis patients. It may thus be possible to target the α7nAChR control of cytokine release as an anti-inflammatory strategy and thereby improve outcome in these patients.

  • 279. Holdaas, H
    et al.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan
    Lipid abnormalities in solid organ transplant recipients. Ballantyne et al2008In: Clinical Lipidology, ISSN 1758-4302, p. 486-499Article, book review (Other academic)
  • 280. Holdaas, Hallvard
    et al.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan G.
    Clinical practice guidelines for managing dyslipidemias in kidney transplant patients: lessons to be learnt from the assessment of Lescol in renal transplantation (ALERT) trial2005In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 5, no 6, p. 1574-1575Article in journal (Refereed)
  • 281. Holdaas, Hallvard
    et al.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan G.
    Nyberg, Gudrun
    Grönhagen-Riska, Carola
    Madsen, Sören
    Heumayer, Hans-Hellmut
    Cole, Edward
    Maes, Bart
    Ambühl, Patrice
    Logan, John O.
    Staffler, Beatrix
    Gimpelewicz, Claudio
    Beneficial effect of early initiation of lipid-lowering therapy following renal transplantation2005In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 20, no 5, p. 974-980Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Renal transplant recipients have a significantly reduced life expectancy, largely due to premature cardiovascular disease. The aim of the current analysis was to investigate the importance of time of initiation of therapy after transplantation, on the benefits of statin therapy. METHODS: 2102 renal transplant recipients with total cholesterol levels of 4.0-9.0 mmol/l were randomly assigned to treatment with fluvastatin (n = 1050) or placebo (n = 1052) and followed for a mean time of 5.1 years. The end-points were major cardiac events. The average median time from transplantation to randomization was 4.5 years (range: 0.5-29 years). RESULTS: In patients starting treatment with fluvastatin <4.5 years after renal transplantation, the incidence of cardiac events was 4.6% over 5.1 years vs 9.2% in those on placebo (P = 0.007). Fluvastatin significantly reduced the risk of cardiac death and non-fatal myocardial infarction by 56% [risk ratio (RR): 0.44; 95% confidence interval (95% CI): 0.26-0.74; P = 0.002]. In a more detailed analysis patients were grouped into 2-year intervals (since the last transplantation). The frequency of cardiac death and non-fatal myocardial infarction was reduced by 3.2%, 5.1%, 9.6% and 8.2% with fluvastatin treatment as compared to 6%, 10.4%, 13.4% and 9.6% with placebo when treatment was initiated at 0-2, 2-4, 4-6 and >6 years, respectively. The risk reduction for patients initiating therapy with fluvastatin at years 0-2 (compared with >6 years) following transplantation was 59% (RR: 0.41; 95% CI: 0.18-0.92; P = 0.0328). This is also reflected in total time on renal replacement therapy: in patients in the first quartile (<47 months) fluvastatin use was associated with a risk reduction of 64% compared with 19% for patients in the fourth quartile (>120 months) (P = 0.033). CONCLUSIONS: Our data support an early introduction of fluvastatin therapy in a population of transplant recipients at high risk of premature coronary heart disease.

  • 282. Holdaas, Halvard
    et al.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan
    Lipid abnormalities in solid organ transplant recipients2009In: Clinical lipidology: a companion to Braunwald's heart disease / [ed] Christie M. Ballantyne, Philadelphia: Saunders/Elsevier , 2009, , p. 486-499p. 486-499Chapter in book (Other academic)
  • 283. Holdaas, Halvard
    et al.
    Jardine, G Alan
    Schmieder, Roland
    Zannad, Faiez
    Gottlow, Mattis
    Johansson, Eva
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rosuvastatin lowers cardiac events in diabetic patients receiving hemodialysis:a subgroup analyses from the AURORA trial (2009)Manuscript (preprint) (Other academic)
  • 284. Holdaas, Halvard
    et al.
    Rostaing, Lionel
    Serón, Daniel
    Cole, Edward
    Chapman, Jeremy
    Fellström, Bengt
    Heyerdahl-Strom, Erik
    Jardine, Alan
    Midtvedt, Karsten
    Machein, Uwe
    Ulbricht, Bettina
    Karpov, Alexander
    O’Connell, Phil
    COnversation of long-term of kidney transplant recipients from calcineurine inhibitor therapy to everolimus: A randomized, multicenter 24 month study2011In: TransplantationArticle in journal (Refereed)
  • 285.
    Holm, Alexander
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Patients’ perspective on prostate artery embolization2017Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 286.
    Holmar, Jana
    et al.
    1Tallinn University of Technology, Department of Biomedical Engineering, Tallinn, Estonia.
    Uhlin, Fredrik
    Linköping University, Department of Medical and Health Sciences.
    Fernström, Anders
    Linköping University, Department of Medical and Health Sciences.
    Luman, Merike
    North Estonia, Medical Centre, Centre of Nephrology,Tallinn, Estonia.
    Jankowski, Joachim
    RWTH Aachen University, Institute for Molecular Cardiovascular.
    Fridolin, Ivo
    1Tallinn University of Technology, Department of Biomedical Engineering, Tallinn, Estonia.
    Optical assesment of calcification markers during hemodialysis2015Conference paper (Other academic)
  • 287.
    Holmberg, Benny
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Andersson, Christer
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Stegmayr, Bernd G
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    There is no benefit of atorvastatin for patients with severe renal impairment independent if they have DM or notArticle in journal (Other academic)
  • 288.
    Holmberg, Benny
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Brännström, M
    Bucht, B
    Crougneau, V
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Dimeny, E
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ekspong, A
    Granroth, B
    Gröntoft, KC
    Hadimeri, H
    Ingman, B
    Isaksson, B
    Johansson, G
    Lindberger, K
    Lundberg, Lennart
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mikaelsson, L
    Olausson, E
    Persson, B
    Welin, D
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wikdahl, AM
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Safety and efficacy of atorvastatin in patients with severe renal dysfunction2005In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 39, no 6, p. 503-510Article in journal (Refereed)
  • 289.
    Holmberg, Benny
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stegmayr, Bernd G
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Cardiovascular conditions in hemodialysis patients may be worsened by extensive interdialytic weight gain2009In: Hemodialysis International, ISSN 1492-7535, E-ISSN 1542-4758, Vol. 13, no 1, p. 27-31Article in journal (Refereed)
    Abstract [en]

    The risk of death is increased for hemodialysis (HD) patients compared with age-matched healthy subjects, the main reason for this being cardiovascular conditions. This prospective study investigated whether the burden of interdialytic weight gain (IDWG) was of importance for cardiovascular end points and survival. A total of 97 HD patients were studied. The end points included death (reasons given), acute myocardial infarction, or coronary vascular intervention. The extent of ultrafiltration was measured at predefined follow-up points. The IDWG was calculated as ultrafiltration/body weight given in weight%. The burden of IDWG was analyzed. End points occurred in 77 (79%) of the patients during the 5-year study period. The extent of IDWG was higher in those with end points due to cardiovascular reasons (3.77 weight% vs. 3.19 P<0.001), cardiac reasons (P<0.001), congestive heart failure (P<0.01), aortic aneurysm, and intracerebral bleeding (P<0.024). To reduce the risk for cardiovascular events, it is important to avoid too extensive IDWG in HD patients.

  • 290.
    Holmberg, Lars
    et al.
    Regional Cancer Center Uppsala/Örebro, Uppsala, Sweden; Division of Cancer Studies, Medical School, King’s College London, London, UK; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden .
    Bill-Axelsson, Anna
    Division of Clinical Cancer Epidemiology, Department of Oncology and Pathology Karolinska Institute, Stockholm, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden .
    Steineck, Gunnar
    Division of Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden; Division of Clinical Cancer Epidemiology, Sahlgrenska Academy, Gothenburg, Sweden .
    Garmo, Hans
    Regional Cancer Center Uppsala/Örebro, Uppsala, Sweden; Division of Cancer Studies, Medical School, King’s College London, London, UK .
    Palmgren, Juni
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
    Johansson, Eva
    Division of Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden .
    Adami, Hans-Olov
    Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Epidemiology, Harvard School of Public Health, Boston, USA.
    Johansson, Jan-Erik
    Center for Assessment of Medical Technology, Örebro, Sweden .
    Results from the scandinavian prostate cancer group trial number 4: a randomized controlled trial of radical prostatectomy versus watchful waiting2012In: Journal of the National Cancer Institute. Monographs, ISSN 1052-6773, E-ISSN 1745-6614, Vol. 2012, no 45, p. 230-233Article in journal (Refereed)
    Abstract [en]

    In the Scandinavian Prostate Cancer Group Trial Number 4 (SPCG-4), 347 men were randomly assigned to radical prostatectomy and 348 to watchful waiting. In the most recent analysis (median follow-up time = 12.8 years), the cumulative mortality curves had been stable over the follow-up. At 15 years, the absolute risk reduction of dying from prostate cancer was 6.1% following randomization to radical prostatectomy, compared with watchful waiting. Hence, 17 need to be randomized to operation to avert one death. Data on self-reported symptoms, stress from symptoms, and quality of life were collected at 4 and 12.2 years of median follow-up. These questionnaire studies show an intricate pattern of symptoms evolving after surgery, hormonal treatments, signs of tumor progression, and also from natural aging. This article discusses some of the main findings of the SPCG-4 study. The Scandinavian Prostate Cancer Group Trial Number 4 (SPCG-4) started in 1989 when radical prostatectomy was newly introduced in Scandinavia and when there was essentially no prostate-specific antigen (PSA) testing in asymptomatic men; such testing only became common at the end of the inclusion of the trial a decade later. However, the trial data continue to be important for several reasons. In many parts of the world, the clinical panorama of prostate cancer still resembles that in Sweden in the early 1990s. The trial results point to many of the issues that modern diagnosis and treatment have to solve. SPCG-4 is to date the only trial to inform about both forces of mortality and self-reported symptoms and quality of life in men after radical prostatectomy or watchful waiting two decades and more out after a primary diagnosis of prostate cancer. According to the protocol (http://www.roc.se/prostata/SPCG-4.pdf), the main trial data have been updated every 3 years since 2002 (1–6). In this presentation, we highlight some of the main findings with bearing on the topic of this conference and discuss some issues that have been raised when the trial results have been presented.

  • 291. Holme, Ingar
    et al.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan
    Holdaas, Halvard
    Comparison of predictive ability of lipoprotein components to that of traditional risk factors of coronary events in renal transplant recipients2010In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 208, no 1, p. 234-239Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Risk factors for major adverse coronary events (MACE) in renal transplant recipients are often different from those of non-transplanted populations. We compared the predictive power of lipoprotein components (LC) to that of more traditional risk factors such as serum creatinine, diabetes and inflammation measured by C-reactive protein (CRP) in the assessment of lescol in renal transplantation (ALERT) trial population. METHODS: From the 2102 randomized patients in ALERT we selected 1734 patients with a complete set of risk and adjustment factors used in the study. Cox regression analysis was used to estimate relationships between baseline values of risk factors and first occurrence of MACE. Chi square statistics, receiver operating characteristics (ROC) and net reclassification improvement (NRI) were used to compare the information value of different risk factors. RESULTS: Atherogenic LC and especially non-high density cholesterol (nHDL-C) were as predictive as creatinine and nHDL-C was about as predictive as diabetes. CRP, body mass index, hypertension and glucose had less prediction ability than nHDL-C. The rank order of prediction was the same in the two treatment groups. By regression modelling the actual MACE risk reduction from 6 weeks onwards was well predicted from the difference in LC at 6 week. CONCLUSION: LC and especially nHDL-C predicted MACE at least as good as creatinine. Diabetes was about equally good as nHDL-C to predict MACE occurrence. Inflammation had less prediction ability than the other factors. Treated levels of atherogenic LC predicted MACE risk reduction well.

  • 292.
    Holmlund, Dan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    On medical treatment for ureteral stone expulsion2018In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 52, no 2, p. 94-100Article in journal (Refereed)
    Abstract [en]

    There is evidence that α-adrenoceptor (α-AR) antagonists facilitate the passage of ureteric stones, but the mechanism behind this effect has not been established. If one accepts that it is the friction between a ureteral stone and the mucosa that hampers the passage of the stone, and that the passage traumatizes the mucosa, the aim of treatment must be to reduce this friction. Elevated pressure above an obstructing stone results in an increase in tension in the wall of the upper urinary tract, including the tension at stone level, which causes an increase in friction and ureteric colic. Reducing pressure, by low but adequate fluid intake, non-steroidal anti-inflammatory drugs (NSAIDs), or α-AR antagonists that reduce the friction and give pain relief, seems to be rational. When the stone is pressed downwards by a high pressure the mucosa forms a bar ahead of the stone. These factors reduce the ureteral lumen and hamper the passage of both urine and the stone. The swelling can be reduced by NSAIDs. Filling of the ureter ahead of the stone reduces the friction between the stone and the ureteral mucosa. Evacuation of the urine ahead of the stone by effective peristaltic activity increases this friction. α-AR antagonists that reduce peristalsis may therefore be used to reduce the friction and consequently allow the stones to pass more often and earlier. For very early stone expulsion, a combination of NSAIDs and α-AR antagonists may be useful. There is no evidence that spasm influences the passage of ureteral stones.

  • 293.
    Holmlund, Dan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ureteral stones: an experimental and clinical study of the mechanism of the passage and arrest of ureteral stones1968Doctoral thesis, monograph (Other academic)
  • 294.
    Holmström, Benny
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Early diagnosis and treatment of prostate cancer: observational studies in the National Prostate Cancer Register of Sweden and the Västerbotten Intervention Project2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

  • 295.
    Holmström, Benny
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Holmberg, Erik
    Egevad, Lars
    Adolfsson, Jan
    Johansson, Jan-Erik
    Hugosson, Jonas
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Outcome of primary versus deferred radical prostatectomy in the National Prostate Cancer Register of Sweden follow-up study2010In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 184, no 4, p. 1322-1327Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 296.
    Holmström, Benny
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC), Lyon, France.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenman, Ulf-Håkan
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prostate specific antigen for early detection of prostate cancer: longitudinal study2009In: BMJ (Clinical research ed.), ISSN 1468-5833, Vol. 339, p. b3537-Article in journal (Refereed)
    Abstract [en]

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

    DESIGN: Case-control study nested in longitudinal cohort.

    SETTING: Västerbotten Intervention Project cohort, Umeå, Sweden.

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

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

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

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

  • 297.
    Holzmann, Martin J.
    et al.
    Karolinska Univ Hosp, Dept Emergency Med, Huddinge, Sweden.;Karolinska Inst, Dept Internal Med, Huddinge, Sweden..
    Carlsson, Axel C.
    Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.;Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Huddinge, Sweden..
    Hammar, Niklas
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Huddinge, Sweden..
    Ivert, Torbjorn
    Karolinska Univ Hosp, Dept Cardiothorac Surg & Anesthesiol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Huddinge, Sweden..
    Walldius, Goran
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Huddinge, Sweden..
    Jungner, Ingmar
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Huddinge, Sweden..
    Wandell, Per
    Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden..
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    Chronic kidney disease and 10-year risk of cardiovascular death2016In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 23, no 11, p. 1187-1194Article in journal (Refereed)
    Abstract [en]

    Background In recent clinical guidelines, individuals with chronic kidney disease are considered to have a similar 10-year absolute risk of cardiovascular death as individuals with diabetes or established cardiovascular disease. There is limited evidence to support this claim. Methods We investigated the 10-year risk for cardiovascular death in individuals with moderate or severe chronic kidney disease (glomerular filtration rate of 30-60 or <30mL/min/1.73m(2), respectively) in a cohort of primary care health check-ups in Stockholm, Sweden (n=295,191, 46% women, 4290 cardiovascular deaths during 10 years follow-up). We also assessed the risk associated with diabetes or cardiovascular disease. The inclusion criteria, exposure, study outcome and follow-up period adhered strictly to the definitions of the European Society of Cardiology guidelines. Results The absolute 10-year risk of cardiovascular death was 3.9% and 14.0% in individuals with moderate and severe chronic kidney disease, respectively, but was substantially lower in women and in younger individuals. The risk in individuals with prevalent diabetes and cardiovascular disease was approximately two and three times higher compared to the risk estimate for moderate chronic kidney disease (hazard ratio (HR) 4.1, 95% confidence interval (CI) 3.8-4.5 and HR 6.2, 95% CI 5.7-6.7 vs. HR 2.3 95% CI 2.0-2.6, respectively) while the risk for individuals with severe chronic kidney disease appeared more congruent to that of diabetes and cardiovascular disease (HR 5.5, 95% CI 3.3-8.9). Conclusions Although moderate chronic kidney disease is an independent predictor for an increased 10-year risk of cardiovascular death, only those with severe chronic kidney disease had similar risk to those with diabetes or cardiovascular disease.

  • 298.
    Horning, Aaron M.
    et al.
    University of Texas Health Science Center, San Antonio, USA.
    Awe, Julius Adebayo
    University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada / Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Wang, Chiou-Miin
    University of Texas Health Science Center, San Antonio, USA.
    Liu, Joseph
    University of Texas Health Science Center, San Antonio, USA.
    Lai, Zhao
    University of Texas Health Science Center, San Antonio, USA.
    Wang, Vickie Yao
    University of Texas Health Science Center, San Antonio, USA.
    Jadhav, Rohit R.
    University of Texas Health Science Center, San Antonio, USA.
    Louie, Anna D.
    University of Texas Health Science Center, San Antonio, USA.
    Lin, Chun-Lin
    University of Texas Health Science Center, San Antonio, USA.
    Kroczak, Tad
    University of Manitoba, Winnipeg, Manitoba, Canada.
    Chen, Yidong
    University of Texas Health Science Center, San Antonio, USA.
    Jin, Victor X.
    University of Texas Health Science Center, San Antonio, USA.
    Abboud-Werner, Sherry L.
    University of Texas Health Science Center, San Antonio, USA.
    Leach, Robin J.
    University of Texas Health Science Center, San Antonio, USA.
    Hernandez, Javior
    University of Texas Health Science Center, San Antonio, USA.
    Thompson, Ian M.
    University of Texas Health Science Center, San Antonio, USA.
    Saranchuk, Jeff
    University of Manitoba, Winnipeg, Canada.
    Drachenberg, Darrel
    University of Manitoba, Winnipeg, Canada.
    Chen, Chun-Liang
    University of Texas Health Science Center, San Antonio, USA.
    Mai, Sabine
    University of Manitoba, Winnipeg, Canada.
    Huang, Tim Hui-Ming
    University of Texas Health Science Center, San Antonio, USA.
    DNA Methylation Screening of Primary Prostate Tumors Identifies SRD5A2 and CYP11A1 as Candidate Markers for Assessing Risk of Biochemical Recurrence2015In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 75, no 15, p. 1790-1801Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Altered DNA methylation in CpG islands of gene promoters has been implicated in prostate cancer (PCa) progression and can be used to predict disease outcome. In this study, we determine whether methylation changes of androgen biosynthesis pathway (ABP)-related genes in patients' plasma cell-free DNA (cfDNA) can serve as prognostic markers for biochemical recurrence (BCR). METHODS. Methyl-binding domain capture sequencing (MBDCap-seq) was used to identify differentially methylated regions (DMRs) in primary tumors of patients who subsequently developed BCR or not, respectively. Methylation pyrosequencing of candidate loci was validated in cfDNA samples of 86 PCa patients taken at and/or post-radical prostatectomy (RP) using univariate and multivariate prediction analyses. RESULTS. Putative DMRs in 13 of 30 ABP-related genes were found between tumors of BCR (n = 12) versus no evidence of disease (NED) (n = 15). In silico analysis of The Cancer Genome Atlas data confirmed increased DNA methylation of two loci-SRD5A2 and CYP11A1, which also correlated with their decreased expression, in tumors with subsequent BCR development. Their aberrant cfDNA methylation was also associated with detectable levels of PSA taken after patients' post-RP. Multivariate analysis of the change in cfDNA methylation at all of CpG sites measured along with patient's treatment history predicted if a patient will develop BCR with 77.5% overall accuracy. CONCLUSIONS. Overall, increased DNA methylation of SRD5A2 and CYP11A1 related to androgen biosynthesis functions may play a role in BCR after patients' RP. The correlation between aberrant cfDNA methylation and detectable PSA in post-RP further suggests their utility as predictive markers for PCa recurrence. (C) 2015 Wiley Periodicals, Inc.

  • 299.
    Huang, Shan
    et al.
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Sandholm, Kerstin
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.
    Jonsson, Nina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Nilsson, Anders
    Gambro Lundia AB.
    Wieslander, Anders
    Gambro Lundia AB.
    Grundström, Gunilla
    Gambro Lundia AB.
    Hancock, Viktoria
    Gambro Lundia AB.
    Nilsson Ekdahl, Kristina
    Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Uppsala University.
    Low concentrations of citrate reduce complement and granulocyte activation in vitro in human blood2015In: Clinical Kidney Journal, ISSN 2048-8505, E-ISSN 2048-8513, Vol. 8, no 1, p. 31-37Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:The use of acetate in haemodialysis fluids may induce negative effects in patients including nausea and increased inflammation. Therefore, haemodialysis fluids where acetate is substituted with citrate have recently been developed. In this study, we investigated the biocompatibility of citrate employing concentrations used in haemodialysis.

    METHODS:The effects of citrate and acetate were investigated in human whole blood in vitro under conditions promoting biomaterial-induced activation. Complement activation was measured as generation of C3a, C5a and the sC5b-9 complex, and granulocyte activation as up-regulation of CD11b expression. For the experimental set-up, a mathematical model was created to calculate the concentrations of acetate and citrate attained during haemodialysis.

    RESULTS:Citrate reduced granulocyte activation and did not induce higher complement activation compared with acetate at concentrations attained during haemodialysis. Investigating different citrate concentrations clearly showed that citrate is a potent complement inhibitor already at low concentrations, i.e. 0.25 mM, which is comparable with concentrations detected in the blood of patients during dialysis with citrate-containing fluids. Increased citrate concentration up to 6 mM further reduced the activation of C3a, C5a and sC5b-9, as well as the expression of CD11b.

    CONCLUSIONS:Our results suggest that citrate is a promising substitute for acetate for a more biocompatible dialysis, most likely resulting in less adverse effects for the patients.

  • 300. Huang, Xiaoyan
    et al.
    Sjögren, Per
    Cederholm, Tommy
    Ärnlöv, Johan
    Dalarna University, School of Education, Health and Social Studies, Medical Science.
    Lindholm, Bengt
    Risérus, Ulf
    Carrero, Juan Jesús
    Serum and adipose tissue fatty acid composition as biomarkers of habitual dietary fat intake in elderly men with chronic kidney disease2014In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 29, no 1, p. 128-136Article in journal (Refereed)
    Abstract [en]

    Background Fatty acid (FA) composition in serum cholesterol esters (CE) and adipose tissue (AT) reflect the long-term FA intake in the general population. Because both dietary intake and FA biomarkers associate with renal function, our aim was to identify which CE and AT FAs are useful biomarkers of habitual FA intake in individuals with chronic kidney disease (CKD).

    Methods Cross-sectional analysis was performed in 506 men (aged 70 years) with a glomerular filtration rate (GFR) of <60 mL/min per 1.73 m(2) from the Uppsala Longitudinal Study of Adult Men cohort. Dietary habits were evaluated with a 7-day dietary record. FA compositions in CE and AT were analyzed by gas-liquid chromatography in two random subsamples of 248 and 318 individuals, respectively.

    Results Both CE and AT linoleic acid and docosahexaenoic acid (DHA) were strongly associated with their corresponding intake, after adjustments for non-dietary factors. The proportions of eicosapentaenoic acid (EPA) and palmitic acid in CE and AT moderately correlated with dietary intake, whereas correlations of other FAs were weaker or absent. Proportions of EPA and DHA in CE and AT were positively associated with the total energy-adjusted fish intake. Results were confirmed in adequate reporters as identified by the Goldberg cutoff method. These relationships held constant, regardless of a GFR above or below 45 mL/min per 1.73 m(2) or the prevalence of microalbuminuria.

    Conclusions Proportions of EPA, DHA, palmitic and linoleic acid in serum CE and AT are good indicators of their dietary intake in men with CKD. They can be considered valid biomarkers for epidemiological studies and assessment of compliance.

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