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  • 251.
    Klinga, Gustaf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Evaluation of preoperative anemia in patients undergoing radical cystectomy with or without neoadjuvant chemotherapy: A retrospective single-center study2015Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 252.
    Klinga, Gustaf
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    A retrospective evaluation of preoperative anemia in patients undergoing radical cystectomy for muscle-invasive urothelial urinary bladder cancer, with or without neoadjuvant chemotherapy2016In: SpringerPlus, E-ISSN 2193-1801, Vol. 5, article id 1167Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE: Neoadjuvant chemotherapy (NAC) can be associated with anemia, which can lead to more perioperative blood transfusions (PBT). Usage of PBT is associated with worse oncological outcomes. We evaluated the prevalence of preoperative anemia (PA) and the effect on hemoglobin levels depending on surgery timing after NAC.

    METHODS: A retrospective single-center study with 240 consecutive patients undergoing radical cystectomy (RC) between 2001 and 2014 for muscle-invasive urothelial carcinoma (MIBC). Anemia was defined according to the WHO classification (male ≤ 130 g/L, female ≤ 120 g/L). Multivariable logistical regression was used to identify factors associated with PA and Pearson correlation for evaluating the change in hemoglobin levels depending on surgery timing.

    RESULTS: Overall, 128 (53.3 %) patients were anemic pre-RC and 87 (36.3 %) patients received NAC. In a multivariable analysis, age, receipt of NAC, female gender, and low BMI were independent predictors of PA. In patients receiving NAC, the time to surgery from the last NAC cycle was correlated with the change in hemoglobin levels between the initiation of NAC and surgery.

    CONCLUSIONS: PA was common in patients undergoing RC for MIBC. Receipt of NAC was found to be a strong predictor of PA.

    CLINICAL MESSAGE: The emerging treatment of cisplatin based neoadjuvant chemotherapy for muscle-invasive bladder cancer, confers an increased risk for preoperative anemia. In the management of this malignancy, preoperative anemia renders further attention and focus.

  • 253. Korodi, Zoltan
    et al.
    Dillner, Joakim
    Jellum, Egil
    Lumme, Sonja
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Thoresen, Steinar
    Hakulinen, Timo
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Luostarinen, Tapio
    Lehtinen, Matti
    Hakama, Matti
    Human papillomavirus 16, 18, and 33 infections and risk of prostate cancer: a Nordic nested case-control study.2005In: Cancer Epidemiology Biomarkers & Prevention, ISSN 1055-9965, Vol. 14, no 12, p. 2952-5Article in journal (Refereed)
  • 254. Krantz, David
    et al.
    Hartana, Ciputra Adijaya
    Winerdal, Malin E
    Johansson, Markus
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Sundsvall Hospital, Sundsvall, Sweden.
    Alamdari, Farhood
    Jakubczyk, Tomasz
    Huge, Ylva
    Aljabery, Firas
    Palmqvist, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urology Section, Department of Surgery, Östersund County Hospital, Östersund, Sweden.
    Zirakzadeh, A Ali
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Holmström, Benny
    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. Division of Urology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Winqvist, Ola
    Neoadjuvant Chemotherapy Reinforces Antitumour T cell Response in Urothelial Urinary Bladder Cancer2018In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 74, no 6, p. 688-692Article in journal (Refereed)
    Abstract [en]

    Evidence indicates that neoadjuvant chemotherapy (NAC) may promote antitumour immune responses by activating T cells. The tumour-draining sentinel node (SN) is a key site to study tumour-specific T cell activation, being the primary immunological barrier against the tumour. In this prospective study, we set out to elucidate the effects of NAC on T cell subsets in the SNs of patients with muscle-invasive urothelial bladder cancer. We found that CD8+ effector T (Teff) cell exhaustion was reduced after NAC treatment, while cytotoxicity was increased. Additionally, in complete responders (CR patients), these cells were functionally committed effectors, as displayed by epigenetic analysis. In CD4+ Teffs, NAC treatment was associated with increased clonal expansion of tumour-specific SN-derived cells, as demonstrated by a specific cell reactivity assay. In contrast, we observed an attenuating effect of NAC on regulatory T cells (Tregs) with a dose-dependent decrease in Treg frequency and reduced effector molecule expression in the remaining Tregs. In addition, multicolour flow cytometry analysis revealed that CR patients had higher Teff to activated Treg ratio, promoting antitumoural T cell activation. These results suggest that NAC reinforces the antitumour immune response by activating the effector arm of the T cell compartment and diminishing the influence of suppressive Tregs.

    PATIENT SUMMARY: In this report, we analysed the effect of chemotherapy on immune cell subsets of 40 patients with advanced bladder cancer. We found that chemotherapy has a positive effect on immune effector T cells, whereas an opposite, diminishing effect was observed for immune-suppressive regulatory T cells. We conclude that chemotherapy reinforces the antitumour immune response in bladder cancer patients.

  • 255. Kriegmair, Maximilian C.
    et al.
    Bertolo, Riccardo
    Karakiewicz, Pierre, I
    Leibovich, Bradley C.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Mir, Maria C.
    Ouzaid, Idir
    Salagierski, Maciej
    Staehler, Michael
    van Poppel, Hendrik
    Wood, Christopher C.
    Capitanio, Umberto
    Systematic Review of the Management of Local Kidney Cancer Relapse2018In: European Urology Oncology, ISSN 2588-9311, Vol. 1, no 6, p. 512-523Article, review/survey (Refereed)
    Abstract [en]

    Context: Management of locally recurrent renal cancer is complex.

    Objective: In this systematic review we analyse the available literature on the management of local renal cancer recurrence.

    Evidence acquisition: A systematic search (PubMed, Web of Science, CINAHL, Clinical Trials, and Scopus) of English literature from 2000 to 2017 was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.

    Evidence synthesis: The search identified 1838 articles. Of those, 36 were included in the evidence synthesis. The majority of the studies identified were retrospective and not controlled. Local recurrence after thermal ablation (TA) may be managed with repeat TA. Alternatively, salvage nephrectomy is possible. However, a higher rate of complications should be expected than after primary nephrectomy. Salvage nephrectomy and TA represent treatment options for local recurrence after partial nephrectomy. Local retroperitoneal recurrence after radical nephrectomy is ideally treated with surgical resection, for which minimally invasive approaches might be applicable to select patients. For large recurrences, addition of intraoperative radiation may improve local control. Local tumour destruction appears to be more beneficial than systemic therapy alone for local recurrences.

    Conclusions: Management of local renal cancer relapse varies according to the clinical course and prior treatments. The available data are mainly limited to noncontrolled retrospective series. After nephron-sparing treatment, TA represents an effective treatment with low morbidity. For local recurrence after radical nephrectomy, the low-level evidence available suggests superiority of surgical excision relative to systemic therapy or best supportive care. As a consequence, surgery should be prioritised when feasible and applicable.

    Patient summary: In renal cell cancer, the occurrence and management of local recurrence depend on the initial treatment. This cancer is a disease with a highly variable clinical course. After initial organ-sparing treatment, thermal ablation offers good cancer control and low rates of complications. For recurrence after radical nephrectomy, surgical excision seems to provide the best long-term cancer control and it is superior to medical therapy alone.

  • 256. Kristiansen, Anna
    et al.
    Drevin, Linda
    Delahunt, Brett
    Samaratunga, Hemamali
    Robinson, David
    Lissbrant, Ingela Franck
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Prognostic significance and biopsy characteristics of prostate cancer with seminal vesicle invasion on radical prostatectomy: a nationwide population-based study2017In: Pathology (Sydney), ISSN 0031-3025, E-ISSN 1465-3931, Vol. 49, no 7, p. 715-720Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to evaluate the prognostic significance of seminal vesicle invasion (SVI, pT3b) compared with extraprostatic extension (EPE) alone (pT3a) after radical prostatectomy, and to correlate pre-operative biopsy pathology with SVI and EPE. The National Prostate Cancer Register includes all prostate cancers diagnosed in Sweden. We analysed 4063 cases with stage category pT3a and 1371 cases with pT3b at radical prostatectomy between 2000 and 2012. Associations between pT3a and pT3b and progression were evaluated and adjusted for year, age, biopsy grade and s-PSA. Needle biopsy findings in these stages were compared. Patients with pT3b (n = 1371) had a higher risk of death from prostate cancer (HR 2.3, 95% CI 1.5-3.3, p < 0.001) and death from any cause (HR 1.5, 95% CI 1.2-1.8, p < 0.001) than those with pT3a (n = 4063). They were also more likely to be treated with post-operative radiotherapy (HR 1.5, 95% CI 1.4-1.7, p < 0.001) or androgen deprivation therapy (HR 3.0, 95% CI 2.5-3.7, p < 0.001), indicating clinical progression. Yet, disease-specific survival of patients with stage pT3b was 94% after 6 years. Median cancer extent in pre-operative biopsies of pT3a and pT3b was 14 and 24 mm (p < 0.001), number of positive cores was four and five, (p < 0.001) and biopsy Gleason score was 8-10 in 11.6% and 27.3%, respectively (p < 0.001). SVI of prostate cancer is associated with worse outcome after radical prostatectomy than EPE alone. However, few patients with SVI die within 6 years from surgery, suggesting that radical prostatectomy may be curative in locally advanced cancers.

  • 257.
    Köhn, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Specific Genomic Aberrations Predict Survival, But Low Mutation Rate in Cancer Hot Spots, in Clear Cell Renal Cell Carcinoma2015In: Applied immunohistochemistry & molecular morphology (Print), ISSN 1541-2016, E-ISSN 1533-4058, Vol. 23, no 5, p. 334-342Article in journal (Refereed)
    Abstract [en]

    Detailed genetic profiling of clear cell renal cell carcinoma (ccRCC) has revealed genomic regions commonly affected by structural changes and a general genetic heterogeneity. VHL and PBRM1, both located at chromosome 3p, are 2 major genes mutated at high frequency but apart from these aberrations, the mutational landscape in ccRCC is largely undefined. Potential prognostic information given by the genomic changes appears to depend on the particular cohort studied. We analyzed a Swedish ccRCC cohort of 74 patients and found common changes (loss or gain occurring in >20% of the tumors) in 12 chromosomal regions (1p, 3p, 3q, 5q, 6q, 7p, 7q 8p, 9p, 9q, 10q, and 14q). A poor outcome was associated with gain of 7q and losses on 9p, 9q, and 14q. These aberrations were more frequent in metastasized tumors, suggesting alterations of genes important for tumor progression. Sequencing of 48 genes implicated in cancer revealed that only VHL, TP53, and PTEN were mutated at a noticeable frequency (51%, 9%, and 9%, respectively). Shorter relative telomere length (RTL) has been associated with loss of specific chromosomal regions in ccRCC tumors, but we could not verify this finding. However, a significantly lower tumor/nontumor (T/N) RTL ratio was detected for tumors with losses in 4q or 9p. In conclusion, poor outcome in ccRCC was associated with gain of 7q and loss on 9p, 9q, and 14q, whereas the mutation rate overall was low in a screen of cancer-associated genes.

  • 258.
    Lalos, Othon
    et al.
    Umeå University, Faculty of Medicine, Clinical Sciences.
    Lundqvist, Stefan
    Umeå University, Faculty of Medicine, Radiation Sciences, Diagnostic Radiology.
    Sjödin, Jan-Gunnar
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Stenbildning i kvinnlig uretradivertikel. Ytterst sällsynt men kan orsaka recidiverande urinvägsinfektion2004In: Läkartidningen, ISSN 0023-7205, Vol. 101, no 14, p. 1290-1291Article in journal (Refereed)
  • 259. Lardas, Michael
    et al.
    Stewart, Fiona
    Scrimgeour, Duncan
    Hofmann, Fabian
    Marconi, Lorenzo
    Dabestani, Saeed
    Bex, Axel
    Volpe, Alessandro
    Canfield, Steven E
    Staehler, Michael
    Hora, Milan
    Powles, Thomas
    Merseburger, Axel S
    Kuczyk, Markus A
    Bensalah, Karim
    Mulders, Peter F A
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lam, Thomas B L
    Systematic Review of Surgical Management of Nonmetastatic Renal Cell Carcinoma with Vena Caval Thrombus2016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 70, no 2, p. 265-280Article, review/survey (Refereed)
    Abstract [en]

    CONTEXT: Overall, 4-10% of patients with renal cell carcinoma (RCC) present with venous tumour thrombus. It is uncertain which surgical technique is best for these patients. Appraisal of outcomes with differing techniques would guide practice.

    OBJECTIVE: To systematically review relevant literature comparing the outcomes of different surgical therapies and approaches in treating vena caval thrombus (VCT) from nonmetastatic RCC.

    EVIDENCE ACQUISITION: Relevant databases (Medline, Embase, and the Cochrane Library) were searched to identify relevant comparative studies. Risk of bias and confounding assessments were performed. A narrative synthesis of the evidence was presented.

    EVIDENCE SYNTHESIS: The literature search identified 824 articles. Fourteen studies reporting on 2262 patients were included. No distinct surgical method was superior for the excision of VCT, although the method appeared to be dependent on tumour thrombus level. Minimal access techniques appeared to have better perioperative and recovery outcomes than traditional median sternotomy, but the impact on oncologic outcomes is unknown. Preoperative renal artery embolisation did not offer any oncologic benefits and instead resulted in significantly worse perioperative and recovery outcomes, including possibly higher perioperative mortality. The comparison of cardiopulmonary bypass versus no cardiopulmonary bypass showed no differences in oncologic outcomes. Overall, there were high risks of bias and confounding.

    CONCLUSIONS: The evidence base, although derived from retrospective case series and complemented by expert opinion, suggests that patients with nonmetastatic RCC and VCT and acceptable performance status should be considered for surgical intervention. Despite a robust review, the findings were associated with uncertainty due to the poor quality of primary studies available. The most efficacious surgical technique remains unclear.

    PATIENT SUMMARY: We examined the literature on the benefits of surgery to remove kidney cancers that have spread to neighbouring veins. The results suggest such surgery, although challenging and associated with high risk of complications, appears to be feasible and effective and should be contemplated for suitable patients if possible; however, many uncertainties remain due to the poor quality of the data.

  • 260. Laskar, Ruhina S
    et al.
    Muller, David C
    Li, Peng
    Machiela, Mitchell J
    Ye, Yuanqing
    Gaborieau, Valerie
    Foll, Matthieu
    Hofmann, Jonathan N
    Colli, Leandro
    Sampson, Joshua N
    Wang, Zhaoming
    Bacq-Daian, Delphine
    Boland, Anne
    Abedi-Ardekani, Behnoush
    Durand, Geoffroy
    Le Calvez-Kelm, Florence
    Robinot, Nivonirina
    Blanche, Helene
    Prokhortchouk, Egor
    Skryabin, Konstantin G
    Burdett, Laurie
    Yeager, Meredith
    Radojevic-Skodric, Sanja
    Savic, Slavisa
    Foretova, Lenka
    Holcatova, Ivana
    Janout, Vladimir
    Mates, Dana
    Rascu, Stefan
    Mukeria, Anush
    Zaridze, David
    Bencko, Vladimir
    Cybulski, Cezary
    Fabianova, Eleonora
    Jinga, Viorel
    Lissowska, Jolanta
    Lubinski, Jan
    Navratilova, Marie
    Rudnai, Peter
    Świątkowska, Beata
    Benhamou, Simone
    Cancel-Tassin, Geraldine
    Cussenot, Olivier
    Trichopoulou, Antonia
    Riboli, Elio
    Overvad, Kim
    Panico, Salvatore
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tumkur Sitaram, Raviprakash
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Giles, Graham G
    Milne, Roger L
    Severi, Gianluca
    Bruinsma, Fiona
    Fletcher, Tony
    Koppova, Kvetoslava
    Larsson, Susanna C
    Wolk, Alicja
    Banks, Rosamonde E
    Selby, Peter J
    Easton, Douglas F
    Pharoah, Paul
    Andreotti, Gabriella
    Beane Freeman, Laura E
    Koutros, Stella
    Albanes, Demetrius
    Männistö, Satu
    Weinstein, Stephanie
    Clark, Peter E
    Edwards, Todd L
    Lipworth, Loren
    Carol, Hallie
    Freedman, Matthew L
    Pomerantz, Mark M
    Cho, Eunyoung
    Kraft, Peter
    Preston, Mark A
    Wilson, Kathryn M
    Michael Gaziano, J
    Sesso, Howard D
    Black, Amanda
    Freedman, Neal D
    Huang, Wen-Yi
    Anema, John G
    Kahnoski, Richard J
    Lane, Brian R
    Noyes, Sabrina L
    Petillo, David
    Teh, Bin Tean
    Peters, Ulrike
    White, Emily
    Anderson, Garnet L
    Johnson, Lisa
    Luo, Juhua
    Chow, Wong-Ho
    Moore, Lee E
    Choueiri, Toni K
    Wood, Christopher
    Johansson, Mattias
    McKay, James D
    Brown, Kevin M
    Rothman, Nathaniel
    Lathrop, Mark G
    Deleuze, Jean-Francois
    Wu, Xifeng
    Brennan, Paul
    Chanock, Stephen J
    Purdue, Mark P
    Scelo, Ghislaine
    Sex specific associations in genome wide association analysis of renal cell carcinoma2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438Article in journal (Refereed)
    Abstract [en]

    Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

  • 261.
    Li, Xingru
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersson-Evelönn, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Wang, Sihan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Raviprakash, Tumkur Sitaram
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ottosson, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersson, Charlotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nilsson, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Li, Aihong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Prognostic Significance of Hypermethylation in the Promoter Region of the Wilms’ Tumour Gene 1 in Clear Cell Renal Cell CarcinomaManuscript (preprint) (Other academic)
  • 262.
    Li, Xingru
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Wang, Sihan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Sitaram, Raviprakash Tumkur
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Andersson, Charlotta
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Li, Ai-Hong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Single Nucleotide Polymorphisms in the Wilms' Tumour Gene 1 in Clear Cell Renal Cell Carcinoma2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, article id e58396Article in journal (Refereed)
    Abstract [en]

    The Wilms' tumour gene 1 (WT1) single nucleotide polymorphism (SNP) rs16754 has recently been described as an independent prognostic factor in acute myeloid leukaemia (AML) patients. It is of great interest to test whether WT1 SNPs can be used as a molecular marker in other cancer types in order to improve risk and treatment stratification. We performed sequencing analysis on all 10 exons of the WT1 gene in a total of 182 patients with clear cell renal cell carcinoma (ccRCC). Six different SNPs were identified, in descending order for minor allele frequency: rs2234582, rs16754, rs1799925, rs5030315, rs2234583, and rs2234581. At least one minor allele for WT1 SNP was identified in 61% of ccRCC patients. In the entire study population, only 6% carried two copies of the minor allele. The genotypes of WT1 SNPs in 78 tumour-free kidney tissue specimens were found to be in 95% concordance with corresponding tumour samples. No correlation was observed between WT1 SNP genotypes and RNA expression level. WT1 SNP genotypes did not associate with clinical and pathological characteristics. We found favourable outcomes associated with the homozygous minor allele for WT1 SNP. However, SNP genotypes did not show to be of prognostic significance when comparing wild-type versus homozygous or heterozygous for the minor allele in the entire cohort. None of the previously reported WT1 mutations in AML was found in the present study. A novel WT1 missense mutation was identified in only one patient. Our data suggest that common WT1 mutations are not involved in ccRCC. Due to too few cases harbouring the homozygous minor allele, the prognostic impact needs to be verified in larger study populations.

  • 263. Licciardello, Marco P.
    et al.
    Ringler, Anna
    Markt, Patrick
    Klepsch, Freya
    Lardeau, Charles-Hugues
    Sdelci, Sara
    Schirghuber, Erika
    Mueller, Andre C.
    Caldera, Michael
    Wagner, Anja
    Herzog, Rebecca
    Penz, Thomas
    Schuster, Michael
    Boidol, Bernd
    Duernberger, Gerhard
    Folkvaljon, Yasin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Ivanov, Vladimir
    Colinge, Jacques
    Bock, Christoph
    Kratochwill, Klaus
    Menche, Joerg
    Bennett, Keiryn L.
    Kubicek, Stefan
    A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor2017In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 13, no 7, p. 771-778Article in journal (Refereed)
    Abstract [en]

    Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for gamma-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.

  • 264.
    Lidgren, Anders
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Lindh, Gudrun
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Hypoxia-inducible factor-1alfa mRNA and protein levels in renal cell carcinoma2008In: Journal of Cancer Molecules, ISSN Print ISSN 1816-0735; Online ISSN 1817-4256, Vol. 4, no 5, p. 153-157Article in journal (Refereed)
  • 265.
    Lidgren, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Glucose transporter-1 expression in renal cell carcinoma and its correlation with hypoxia inducible factor-1 alpha2008In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 101, no 4, p. 480-484Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate transcription factor hypoxia inducible factor-1 alpha (HIF-1 alpha) activity, by analysing a target gene for HIF-1 alpha, glucose transporter-1 (GLUT-1), using a tissue microarray (TMA) in different types of renal cell carcinoma (RCC, a tumour with a variable clinical course, partly due to angiogenic activity), as angiogenesis is important for tumour progression and metastatic spread, and is activated by hypoxia.

    PATIENTS AND METHODS: GLUT-1 and HIF-1 alpha expressions were semiquantitatively analysed using immunohistological staining of a prepared TMA, using samples from 187 patients, including 148 with conventional, 26 with papillary and 13 with chromophobe RCC.

    RESULTS: GLUT-1 staining was found mainly in the cytoplasm. The tumours were subdivided into GLUT -1(LOW) and GLUT-1(HIGH), based on staining intensity. There was a significant difference in GLUT-1 expression between RCC types (P < 0.05). In conventional RCC, GLUT-1 had no correlation with clinicopathological variables. By contrast there was a correlation with tumour stage in papillary RCC. There was an insignificant trend to better survival of patients with GLUT-1(LOW) expression in both conventional and papillary RCC. GLUT-1 correlated significantly (P = 0.008) with HIF-1 alpha.

    CONCLUSIONS: Most patients with conventional RCC had GLUT-1(HIGH) staining and there was a significant correlation with HIF-1 alpha. In papillary RCC, GLUT-1 expression was associated with stage; GLUT-1 expression was significantly higher in conventional RCC than in papillary and chromophobe RCC. GLUT-1(LOW) in both papillary and conventional RCC appeared to correspond with a better prognosis.

  • 266.
    Lidgren, Anders
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Hedberg, Ylva
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Clinical Microbiology. Umeå University, Faculty of Medicine, Clinical Microbiology, Biomedical Laboratory Science.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology. Onkologi.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Hypoxia-inducible factor 1alpha expression in renal cell carcinoma analyzed by tissue microarray2006In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 50, no 6, p. 1272-1277Article in journal (Refereed)
  • 267.
    Lidgren, Anders
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Hedberg, Ylva
    Umeå University, Faculty of Medicine, Medical Biosciences. Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Clinical Microbiology. Umeå University, Faculty of Medicine, Clinical Microbiology, Biomedical Laboratory Science.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry. Klinisk kemi.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology. Onkologi.
    Vasko, Janos
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    The expression of hypoxia-inducible factor 1alpha is a favorable independent prognostic factor in renal cell carcinoma2005In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 11, no 3, p. 1129-1135Article in journal (Refereed)
  • 268. Liedberg, Fredrik
    et al.
    Hagberg, Oskar
    Aljabery, Firas
    Gårdmark, Truls
    Hosseini, Abolfazl
    Jahnson, Staffan
    Jancke, Georg
    Jerlström, Tomas
    Malmström, Per-Uno
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ströck, Viveka
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala.
    Holmberg, Lars
    Period-specific mean annual hospital volume of radical cystectomy is associated with outcome and perioperative quality of care: a nationwide population-based study2019In: BJU International, ISSN 1464-4096, E-ISSN 1464-410XArticle in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the association between hospital volume and overall survival (OS), cancer-specific survival (CSS), and quality of care of patients with bladder cancer who undergo radical cystectomy (RC), defined as the use of extended lymphadenectomy (eLND), continent reconstruction, neoadjuvant chemotherapy (NAC), and treatment delay of <3 months.

    PATIENTS AND METHODS: We used the Bladder Cancer Data Base Sweden (BladderBaSe) to study survival and indicators of perioperative quality of care in all 3172 patients who underwent RC for primary invasive bladder cancer stage T1-T3 in Sweden between 1997 and 2014. The period-specific mean annual hospital volume (PSMAV) during the 3 years preceding surgery was applied as an exposure and analysed using univariate and multivariate mixed models, adjusting for tumour and nodal stage, age, gender, comorbidity, educational level, and NAC. PSMAV was either categorised in tertiles, dichotomised (at ≥25 RCs annually), or used as a continuous variable for every increase of 10 RCs annually.

    RESULTS: PSMAV in the highest tertile (≥25 RCs annually) was associated with improved OS (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.75-1.0), whereas the corresponding HR for CSS was 0.87 (95% CI 0.73-1.04). With PSMAV as a continuous variable, OS was improved for every increase of 10 RCs annually (HR 0.95, 95% CI 0.90-0.99). Moreover, higher PSMAV was associated with increased use of eLND, continent reconstruction and NAC, but also more frequently with a treatment delay of >3 months after diagnosis.

    CONCLUSIONS: The current study supports centralisation of RC for bladder cancer, but also underpins the need for monitoring treatment delays associated with referral.

  • 269. Lin, Crystal
    et al.
    Travis, Ruth C.
    Appleby, Paul N.
    Tipper, Sarah
    Weiderpass, Elisabete
    Chang-Claude, Jenny
    Gram, Inger T.
    Kaaks, Rudolf
    Kiemeney, Lambertus A.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tumino, Rosario
    Tjonneland, Anne
    Roswall, Nina
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Manciniveri, Francesca Romana
    Severi, Gianluca
    Trichopoulou, Antonia
    Masala, Giovanna
    Sacerdote, Carlotta
    Agnoli, Claudia
    Panico, Salvatore
    Bueno-de-Mesquita, Bas
    Peeters, Petra H.
    Salamanca-Fernandez, Elena
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Dorronsoro, Miren
    Menendez, Virginia
    Lujan-Barroso, Leila
    Liedberg, Fredrik
    Freisling, Heinz
    Gunter, Marc
    Aune, Dagfinn
    Cross, Amanda J.
    Riboli, Elio
    Key, Timothy J.
    Perez-Cornago, Aurora
    Pre-diagnostic circulating insulin-like growth factor-I and bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 10, p. 2351-2358Article in journal (Refereed)
    Abstract [en]

    Previous in vitro and case–control studies have found an association between the insulin‐like growth factor (IGF)‐axis and bladder cancer risk. Circulating concentrations of IGF‐I have also been found to be associated with an increased risk of several cancer types; however, the relationship between pre‐diagnostic circulating IGF‐I concentrations and bladder cancer has never been studied prospectively. We investigated the association of pre‐diagnostic plasma concentrations of IGF‐I with risk of overall bladder cancer and urothelial cell carcinoma (UCC) in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 843 men and women diagnosed with bladder cancer between 1992 and 2005 were matched with 843 controls by recruitment centre, sex, age at recruitment, date of blood collection, duration of follow‐up, time of day and fasting status at blood collection using an incidence density sampling protocol. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression with adjustment for smoking status. No association was found between pre‐diagnostic circulating IGF‐I concentration and overall bladder cancer risk (adjusted OR for highest versus lowest fourth: 0.91, 95% CI: 0.66–1.24, ptrend = 0.40) or UCC (n of cases = 776; 0.91, 0.65–1.26, ptrend = 0.40). There was no significant evidence of heterogeneity in the association of IGF‐I with bladder cancer risk by tumour aggressiveness, sex, smoking status, or by time between blood collection and diagnosis (pheterogeneity > 0.05 for all). This first prospective study indicates no evidence of an association between plasma IGF‐I concentrations and bladder cancer risk.

  • 270.
    Lind, Anna Johansson
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Granfors, Torvald
    Egevad, Lars
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Angiopoietin 2 expression is related to histological grade, vascular density, metastases, and outcome in prostate cancer.2005In: Prostate, ISSN 0270-4137, Vol. 62, no 4, p. 394-399Article in journal (Refereed)
  • 271.
    Lindahl, Olof A
    et al.
    Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF). Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ramser, K.
    Bäcklund, Tomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Prostate cancer detection ex vivo combining Raman spectroscopy and tactile resonance technology2018In: EMBEC & NBC 2017 / [ed] Eskola, H Vaisanen, O Viik, J Hyttinen, J, SPRINGER-VERLAG SINGAPORE PTE LTD , 2018, p. 193-196Conference paper (Refereed)
    Abstract [en]

    Prostate cancer is the most common cancer for men in the western world. The most prevalent curative treatment is radical prostatectomy. However, prostate surgery can give unwanted side effects and there is a need for an instrument that can provide decision support to the surgeon during surgery on the presence of cancer cells in the surgical margin. A dual modality probe, combining Raman spectroscopy and tactile resonance technology, has been used for detecting cancer in fresh human prostate tissue. The tactile resonance modality measures the tissue stiffness and Raman spectroscopy depicts the molecular content in tissue, both related to cancer. After ethical approval, the study investigated the potential of the dual-modality probe by testing its ability to differentiate between normal and cancerous prostate tissue ex vivo. It also investigated the minimal amount of measurement points needed to securely detect cancer on the surface of prostate tissue. Measurements on three prostate tissue slices show that the tactile resonance modality measuring stiffness was able to detect differences between normal and cancerous tissue on a significant level of 90%, but the sample size was too low to draw any firm conclusions. It was also suggested from the study results that the high wavenumber region in the Raman spectrum can give valuable information about cancer in prostate tissue. A number of 24 measurement points were enough for detecting cancer in prostate slices in this study. It can be suggested from this study that combining these two sensor modalities is promising for accurate detection of prostate cancer that is needed during prostate surgery, but more measurements including more prostates must be performed before the full value of the study result can be established.

  • 272. Lindberg, Peter
    et al.
    Andersson, Britt
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Lindahl, Olof
    Prostate cancer detection with an improved resonance sensor system: parameter evaluation in a silicone model and on human prostate tissue in vitro.2006In: Med Biol Eng Comput, ISSN 0140-0118, Vol. 44, no 12, p. 1053-9Article in journal (Refereed)
  • 273.
    Lindberg, Peter L
    et al.
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Andersson, Britt M
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lindahl, Olof A
    Luleå tekniska Universitet.
    An image analysis method for prostate tissue classification: preliminary validation with resonance sensor data2009In: Journal of Medical Engineering & Technology, ISSN 0309-1902, E-ISSN 1464-522X, Vol. 33, no 1, p. 18-24Article in journal (Refereed)
    Abstract [en]

    Resonance sensor systems have been shown to be able to distinguish between cancerous and normal prostate tissue, in vitro. The aim of this study was to improve the accuracy of the tissue determination, to simplify the tissue classification process with computerized morphometrical analysis, to decrease the risk of human errors, and to reduce the processing time. In this article we present our newly developed computerized classification method based on image analysis. In relation to earlier resonance sensor studies we increased the number of normal prostate tissue classes into stroma, epithelial tissue, lumen and stones. The linearity between the impression depth and tissue classes was calculated using multiple linear regression (R(2) = 0.68, n = 109, p < 0.001) and partial least squares (R(2) = 0.55, n = 109, p < 0.001). Thus it can be concluded that there existed a linear relationship between the impression depth and the tissue classes. The new image analysis method was easy to handle and decreased the classification time by 80%.

  • 274.
    Lindgren, Pierre
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    A pilot study investigation of muscle invasive bladder cancer and the national standard of treatment2018Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 275. Lindhagen, Lars
    et al.
    Van Hemelrijck, Mieke
    Robinson, David
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Garmo, Hans
    How to model temporal changes in comorbidity for cancer patients using prospective cohort data2015In: BMC Medical Informatics and Decision Making, ISSN 1472-6947, E-ISSN 1472-6947, Vol. 15, article id 96Article in journal (Refereed)
    Abstract [en]

    Background: The presence of comorbid conditions is strongly related to survival and also affects treatment choices in cancer patients. This comorbidity is often quantified by the Charlson Comorbidity Index (CCI) using specific weights (1, 2, 3, or 6) for different comorbidities. It has been shown that the CCI increases at different times and with different sizes, so that traditional time to event analysis is not adequate to assess these temporal changes. Here, we present a method to model temporal changes in CCI in cancer patients using data from PCBaSe Sweden, a nation-wide population-based prospective cohort of men diagnosed with prostate cancer. Our proposed model is based on the assumption that a change in comorbidity, as quantified by the CCI, is an irreversible one-way process, i.e., CCI accumulates over time and cannot decrease.

    Methods: CCI was calculated based on 17 disease categories, which were defined using ICD-codes for discharge diagnoses in the National Patient Register. A state transition model in discrete time steps (i.e., four weeks) was applied to capture all changes in CCI. The transition probabilities were estimated from three modelling steps: 1) Logistic regression model for vital status, 2) Logistic regression model to define any changes in CCI, and 3) Poisson regression model to determine the size of CCI change, with an additional logistic regression model for CCI changes ≥ 6. The four models combined yielded parameter estimates to calculate changes in CCI with their confidence intervals.

    Results: These methods were applied to men with low-risk prostate cancer who received active surveillance (AS), radical prostatectomy (RP), or curative radiotherapy (RT) as primary treatment. There were large differences in CCI changes according to treatment.

    Conclusions: Our method to model temporal changes in CCI efficiently captures changes in comorbidity over time with a small number of regression analyses to perform – which would be impossible with tradition time to event analyses. However, our approach involves a simulation step that is not yet included in standard statistical software packages. In our prostate cancer example we showed that there are large differences in development of comorbidities among men receiving different treatments for prostate cancer.

  • 276. Lindkvist, Björn
    et al.
    Almquist, Martin
    Bjørge, Tone
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Institute of Preventive Medicine, Copenhagen University Hospitals, Copenhagen, Denmark.
    Borena, Wegene
    Johansen, Dorthe
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Engeland, Anders
    Nagel, Gabriele
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Selmer, Randi
    Diem, Guenter
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tretli, Steinar
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Manjer, Jonas
    Prospective cohort study of metabolic risk factors and gastric adenocarcinoma risk in the Metabolic Syndrome and Cancer Project (Me-Can)2013In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, no 1, p. 107-116Article in journal (Refereed)
    Abstract [en]

    Purpose: Little is known about the association between the metabolic syndrome (MetS) and the risk of gastric adenocarcinoma. The aim of this study was to investigate whether metabolic risk factors, together or combined, were associated with the risk of gastric adenocarcinoma. Methods: The Metabolic Syndrome and Cancer Project (Me-Can) is a pooling of prospective cohorts in Austria, Norway, and Sweden with information on blood pressure, lipids, glucose, and BMI available in 578,700 individuals. Cox proportional hazards analysis was used to calculate hazard ratio (HR) of gastric adenocarcinoma using metabolic risk factors categorized into quintiles and transformed into z-scores (with mean = 0 and SD = 1). The standardized sum of all z-scores created a composite MetS score. Results: In total, 1,210 incident cases of gastric adenocarcinoma were identified. Glucose was significantly associated with the risk of gastric adenocarcinoma [calibrated HR 1.58 (1.14-2.20) per one unit increment in z-score] in women. There was a statistically significant association between triglycerides and risk of gastric adenocarcinoma per mmol increment in triglycerides [HR 1.20 (1.06-1.36) per mmol] but not for the adjusted z-score in women. There were no significant association between any metabolic factors and gastric cancer among men. The composite MetS score was associated with the risk of gastric adenocarcinoma in women [HR 1.18 (1.00-1.38) per one unit increment in z-score] but not in men. Conclusions: Glucose and high levels of the composite MetS score were associated with an increased risk of gastric adenocarcinoma in women but not in men.

  • 277. Lindkvist, Björn
    et al.
    Johansen, Dorthe
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Concin, Hans
    Bjorge, Tone
    Almquist, Martin
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Engeland, Anders
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Nagel, Gabriele
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Selmer, Randi
    Ulmer, Hanno
    Tretli, Steinar
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Manjer, Jonas
    Metabolic risk factors for esophageal squamous cell carcinoma and adenocarcinoma: a prospective study of 580 000 subjects within the Me-Can project2014In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, p. 103-Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is associated with an increased risk of esophageal adenocarcinoma (EAC) and a decreased risk of esophageal squamous cell carcinoma (ESCC). However, little is known about the risk of EAC and ESCC related to other metabolic risk factors. We aimed to examine the risk of EAC and ESCC in relation to metabolic risk factors, separately and combined in a prospective cohort study. Methods: The Metabolic Syndrome and Cancer cohort includes prospective cohorts in Austria, Norway and Sweden, with blood pressure, lipids, glucose and BMI available from 578 700 individuals. Relative risk (RR) for EAC and ESCC was calculated using Cox's proportional hazards analysis for metabolic risk factors categorized into quintiles and transformed into z-scores. The standardized sum of all z-scores was used as a composite score for the metabolic syndrome (MetS). Results: In total, 324 histologically verified cases of esophageal cancer were identified (114 EAC, 184 ESCC and 26 with other histology). BMI was associated with an increased risk of EAC (RR 7.34 (95% confidence interval, 2.88-18.7) top versus bottom quintile) and negatively associated with the risk of ESCC (RR 0.38 (0.23-0.62)). The mean value of systolic and diastolic blood pressure (mid blood pressure) was associated with the risk of ESCC (RR 1.77 (1.37-2.29)). The composite MetS score was associated with the risk of EAC (RR 1.56 (1.19-2.05) per one unit increase of z-score) but not ESCC. Conclusions: In accordance with previous studies, high BMI was associated with an increased risk of EAC and a decreased risk of ESCC. An association between high blood pressure and risk of ESCC was observed but alcohol consumption is a potential confounding factor that we were not able to adjust for in the analysis. The MetS was associated with EAC but not ESCC. However this association was largely driven by the strong association between BMI and EAC. We hypothesize that this association is more likely to be explained by factors directly related to obesity than the metabolic state of the MetS, considering that no other metabolic factor than BMI was associated with EAC.

  • 278.
    Lindmark, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Zheng, S Lilly
    Meyers, Deborah A
    Xu, Jianfeng
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Analysis of the macrophage scavenger receptor 1 gene in Swedish hereditary and sporadic prostate cancer.2004In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 59, no 2, p. 132-140Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The macrophage scavenger receptor 1 (MSR1) gene on chromosome 8p22 was recently reported as a candidate gene for hereditary prostate cancer (HPC). Here, we further elucidate the role of MSR1 in both Swedish families with HPC and in a cohort of unselected prostate cancer. METHODS: DNA samples from 83 Swedish HPC families and 215 unselected population based cases of prostate cancer as well as 425 age-matched controls were genotyped. RESULTS: A total of 18 variants were identified, including 2 exonic, 7 intronic changes, and 9 changes in the 5'- or 3'-uncoding region. Of the two exonic changes, one previously reported truncation mutation was identified, a R293X nonsense mutation. This mutation was found in 2 of the 83 (2.4%) HPC families. The R293X mutation was found more frequently in men with PC (4.9%) than in unaffected men (2.7%), consistent with previous published results, however our results were not significant (P = 0.16). To additionally test for potential association of common sequence variants and increased risk for the disease, five common polymorphisms (PRO3, INDEL1, IVS5-57, P275A, INDEL7) were genotyped in the group of 215 prostate cancer cases and 425 age-matched controls. No association between any of the five common sequence variants and prostate cancer were found. CONCLUSION: Our results suggest that mutations in MSR1 gene might play a role in prostate cancer susceptibility, particularly the R293X mutation. This study warrants further investigations of the role of MSR1 in prostate cancer etiology.

  • 279.
    Lindmark, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Zheng, S Lilly
    Wiklund, Fredrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Bensen, Jeannette
    Augustsson Bälter, Katarina
    Chang, Baoli
    Hedelin, Maria
    Clark, Jonathan
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Meyers, Deborah A
    Adami, Hans-Olov
    Isaacs, William
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Xu, Jianfeng
    H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer2004In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 96, no 16, p. 1248-1254Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Accumulating epidemiologic and molecular evidence suggest that inflammation is an important component in the etiology of prostate cancer. Macrophage-inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor beta superfamily, is thought to play an important role in inflammation by regulating macrophage activity. We examined whether sequence variants in the MIC-1 gene are associated with the risk of prostate cancer. METHODS: The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 780 control subjects. From 94 of the control subjects, we constructed gene-specific haplotypes of MIC-1 and identified four haplotype-tagging single-nucleotide polymorphisms (SNPs): Exon1+25 (V9L), Exon1+142 (S48T), IVS1+1809, and Exon2+2423 (H6D). All study subjects were genotyped for the four SNPs, and conditional logistic regression analysis was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A statistically significant difference (P =.006) in genotype frequency was observed for the nonsynonymous change H6D (histidine to aspartic acid at position 6) between prostate cancer patients and control subjects. Carriers of the GC genotype, which results in the H6D change, experienced a lower risk of sporadic prostate cancer (OR = 0.80, 95% CI = 0.66 to 0.97) and of familial prostate cancer (OR = 0.61, 95% CI = 0.42 to 0.89) than the CC genotype carriers. In the study population, the proportion of prostate cancer cases attributable to the CC genotype was 7.2% for sporadic cancer and 19.2% for familial cancer. None of the other SNPs or haplotypes was associated with prostate cancer. CONCLUSION: This study shows an association between a nonsynonymous change (H6D) in the MIC-1 gene and prostate cancer. This finding supports the hypothesis that genetic variation in the inflammatory process contributes to prostate cancer susceptibility.

  • 280. Lindskog, Magnus
    et al.
    Wahlgren, Thomas
    Sandin, Rickard
    Kowalski, Jan
    Jakobsson, Maria
    Lundstam, Sven
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Harmenberg, Ulrika
    Overall survival in Swedish patients with renal cell carcinoma treated in the period 2002 to 2012: Update of the RENCOMP study with subgroup analysis of the synchronous metastatic and elderly populations2017In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 35, no 9, p. 541.e15-541.e22Article in journal (Refereed)
    Abstract [en]

    Background: This retrospective study investigated overall survival (OS) and factors influencing OS in Swedish patients with metastatic renal cell carcinoma (mRCC) during the pre- (2002-2005), early (2006-2008), and late (2009-2012) targeted therapy (TT) era. Methods: Three national Swedish registries identified patients with mRCC. Median OS was estimated using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards regression. Subgroup analysis was conducted for patients with synchronous metastases (Ml) and the elderly (aged >= 75 y). Results: A total of 4,217 patients with mRCC were identified, including 1,533 patients with Ml and 1,275 elderly patients. For patients with mRCC diagnosed in 2002 to 2005, 2006 to 2008, and 2009 to 2012, median OS was 10.0, 13.0, and 18.0 months. Similarly, median OS improved in the M1 and elderly populations. Elderly patients were less likely to be prescribed TT (>= 75 vs. <75 y): 18.3 vs. 63.5% (in 2006-2008) and 28.6% vs. 55.9% (in 2009-2012). Diagnosis of mRCC in 2009 to 2012, nephrectomy and TT prescription were associated with improved OS in the total mRCC, Ml, and elderly populations. Conclusion: This real-world study showed continued significant improvement in mRCC OS during the late TT era, including in Ml and elderly populations. TT should be considered for all patients with mRCC based on tolerability, regardless of age. 

  • 281. Lindstroem, Sara
    et al.
    Schumacher, Fredrick R
    Cox, David
    Travis, Ruth C
    Albanes, Demetrius
    Allen, Naomi E.
    Andriole, Gerald
    Berndt, Sonja I
    Boeing, Heiner
    Bueno-de-Mesquita, H Bas
    Crawford, E David
    Diver, W Ryan
    Gaziano, J Michael
    Giles, Graham G
    Giovannucci, Edward
    Gonzalez, Carlos A
    Henderson, Brian
    Hunter, David J
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer, Lyon, France.
    Kolonel, Laurence N
    Ma, Jing
    Le Marchand, Loic
    Pala, Valeria
    Stampfer, Meir
    Stram, Daniel O
    Thun, Michael J
    Tjonneland, Anne
    Trichopoulos, Dimitrios
    Virtamo, Jarmo
    Weinstein, Stephanie J
    Willett, Walter C
    Yeager, Meredith
    Hayes, Richard B
    Severi, Gianluca
    Haiman, Christopher A
    Chanock, Stephen J
    Kraft, Peter
    Common genetic variants in prostate cancer risk prediction-results from the NCI breast and prostate cancer cohort consortium (BPC3)2012In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, no 3, p. 437-444Article in journal (Refereed)
    Abstract [en]

    Background: One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent single-nucleotide polymorphism markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer, and age.

    Methods: We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data.

    Results: The best risk model (C-statistic = 0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P = 0.009), with highest accuracy in men younger than 60 years (C-statistic = 0.679). The absolute ten-year risk for 50-year-old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile).

    Conclusions: Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from prostate-specific antigen screening.

    Impact: Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited.

  • 282. Lindstrom, Sara
    et al.
    Schumacher, Fredrick
    Siddiq, Afshan
    Travis, Ruth C.
    Campa, Daniele
    Berndt, Sonja I.
    Diver, W. Ryan
    Severi, Gianluca
    Allen, Naomi
    Andriole, Gerald
    Bueno-de-Mesquita, Bas
    Chanock, Stephen J.
    Crawford, David
    Gaziano, J. Michael
    Giles, Graham G.
    Giovannucci, Edward
    Guo, Carolyn
    Haiman, Christopher A.
    Hayes, Richard B.
    Halkjaer, Jytte
    Hunter, David J.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer, Lyon, France .
    Kaaks, Rudolf
    Kolonel, Laurence N.
    Navarro, Carmen
    Riboli, Elio
    Sacerdote, Carlotta
    Stampfer, Meir
    Stram, Daniel O.
    Thun, Michael J.
    Trichopoulos, Dimitrios
    Virtamo, Jarmo
    Weinstein, Stephanie J.
    Yeager, Meredith
    Henderson, Brian
    Ma, Jing
    Le Marchand, Loic
    Albanes, Demetrius
    Kraft, Peter
    Characterizing Associations and SNP-Environment Interactions for GWAS-Identified Prostate Cancer Risk Markers-Results from BPC32011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, article id e17142Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10(-28)). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade,8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined.

  • 283.
    Lindström, Sara
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Adami, Hans-Olov
    Bälter, Katarina
    Xu, Jianfeng
    Zheng, Lilly S
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Grönberg, Henrik
    Wiklund, Fredrik
    Inherited genetic variation in hormone regulating genes and prostate cancer survival2007In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, no 17, p. 5156-5161Article in journal (Refereed)
  • 284.
    Lindström, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Adami, Hans-Olov
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bälter, Katarina
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Xu, Jianfeng
    Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
    Zheng, S Lilly
    Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
    Sun, Jielin
    Center for Human Genomics, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Grönberg, Henrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Wiklund, Fredrik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Genetic variation in the upstream region of ERG and prostate cancer.2009In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 20, no 7, p. 1173-1180Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: A considerable fraction of prostate cancers harbor a gene fusion between the androgen-regulated TMPRSS2 and ERG, one of the most frequently over-expressed proto-oncogenes in prostate cancer. Here, we investigated if inherited genetic variation upstream of ERG alters prostate cancer risk and survival. METHODS: We genotyped 21 haplotype tagging SNPs (htSNPs) covering 123 kb of 5'UTR DNA including exon 3 of ERG in 2,760 incident prostate cancer cases and 1,647 controls from a population-based Swedish case-control study (CAPS). Individual SNPs and haplotypes were tested for association with prostate cancer risk and survival. RESULTS: One haplotype-'CTCGTATG' located 100 kb upstream of ERG-was associated with lethal prostate cancer (HR, 1.36; 95% CI, 1.2-1.9, p = 0.006). Carriers of the variant 'T' allele of rs2836626 were diagnosed with higher TNM-stage (p = 0.009) and had an increased risk of prostate cancer-specific death (HR = 1.3; 95% CI, 1.1-1.7, p = 0.009). However, this association did not remain statistically significant after adjusting for multiple testing. We found overall no association between ERG variation and prostate cancer risk. CONCLUSIONS: Genetic variation upstream of ERG may alter prostate cancer stage and ultimately prostate cancer-specific death but it is unlikely that it plays a role in prostate cancer development.

  • 285. Lindström, Sara
    et al.
    Hunter, David J
    Grönberg, Henrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Wiklund, Fredrik
    Xu, Jianfeng
    Chanock, Stephen J
    Hayes, Richard
    Kraft, Peter
    Sequence variants in the TLR4 and TLR6-1-10 genes and prostate cancer risk. Results based on pooled analysis from three independent studies.2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 3, p. 873-876Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Genetic variation in two members of the Toll-like receptor family, TLR4 and the gene cluster TLR6-1-10, has been implicated in prostate cancer in several studies but the associated alleles have not been consistent across reports. METHODS: We did a pooled analysis combining genotype data from three case-control studies, Cancer of the Prostate in Sweden, the Health Professionals Follow-up Study, and the Prostate, Lung, Colon and Ovarian Cancer Screening Trial, with data from 3,101 prostate cancer cases and 2,523 controls. We did imputation to obtain dense coverage of the genes and comparable genotype data for all cohorts. In total, 58 single nucleotide polymorphisms in TLR4 and 96 single nucleotide polymorphisms in TLR6-1-10 were genotyped or imputed and analyzed in the entire data set. We did a cohort-specific analysis as well as meta-analysis and pooled analysis. We also evaluated whether the analyses differed by age or disease severity. RESULTS: We observed no overall association between genetic variation at the TLR4 and TLR6-1-10 loci and risk of prostate cancer. CONCLUSIONS: Common germ line genetic variation in TLR4 and TLR6-1-10 did not seem to have a strong association with risk of prostate cancer. IMPACT: This study suggests that earlier associations between prostate cancer risk and TLR4 and TLR6-1-10 sequence variants were chance findings. To definitely assess the causal relationship between TLR sequence variants and prostate cancer risk, very large sample sizes are needed.

  • 286. Lindström, Sara
    et al.
    Ma, Jing
    Altshuler, David
    Giovannucci, Edward
    Riboli, Elio
    Albanes, Demetrius
    Allen, Naomi E
    Berndt, Sonja I
    Boeing, Heiner
    Bueno-de-Mesquita, H Bas
    Chanock, Stephen J
    Dunning, Alison M
    Feigelson, Heather Spencer
    Gaziano, J Michael
    Haiman, Christopher A
    Hayes, Richard B
    Henderson, Brian E
    Hunter, David J
    Kaaks, Rudolf
    Kolonel, Laurence N
    Le Marchand, Loic
    Martínez, Carmen
    Overvad, Kim
    Siddiq, Afshan
    Stampfer, Meir
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stram, Daniel O
    Thun, Michael J
    Trichopoulos, Dimitrios
    Tumino, Rosario
    Virtamo, Jarmo
    Weinstein, Stephanie J
    Yeager, Meredith
    Kraft, Peter
    Freedman, Matthew L
    A large study of androgen receptor germline variants and their relation to sex hormone levels and prostate cancer risk: Results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium2010In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, no 9, p. E121-E127Article in journal (Refereed)
    Abstract [en]

    Background: Androgens are key regulators of prostate gland maintenance and prostate cancer growth, and androgen deprivation therapy has been the mainstay of treatment for advanced prostate cancer for many years. A long-standing hypothesis has been that inherited variation in the androgen receptor (AR) gene plays a role in prostate cancer initiation. However, studies to date have been inconclusive and often suffered from small sample sizes.

    Objective and Methods: We investigated the association of AR sequence variants with circulating sex hormone levels and prostate cancer risk in 6058 prostate cancer cases and 6725 controls of Caucasian origin within the Breast and Prostate Cancer Cohort Consortium. We genotyped a highly polymorphic CAG microsatellite in exon 1 and six haplotype tagging single nucleotide polymorphisms and tested each genetic variant for association with prostate cancer risk and with sex steroid levels.

    Results: We observed no association between AR genetic variants and prostate cancer risk. However, there was a strong association between longer CAG repeats and higher levels of testosterone (P = 4.73 × 10−5) and estradiol (P = 0.0002), although the amount of variance explained was small (0.4 and 0.7%, respectively).

    Conclusions: This study is the largest to date investigating AR sequence variants, sex steroid levels, and prostate cancer risk. Although we observed no association between AR sequence variants and prostate cancer risk, our results support earlier findings of a relation between the number of CAG repeats and circulating levels of testosterone and estradiol.

  • 287. Lissbrant, Ingela Franck
    et al.
    Garmo, Hans
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Population-based study on use of chemotherapy in men with castration resistant prostate cancer2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 8, p. 1593-1601Article in journal (Refereed)
    Abstract [en]

    Background. Chemotherapy prolongs life and relieves symptoms in men with castration resistant prostate cancer (CRPC). There is limited information on a population level on the use of chemotherapy for CRPC. Material and methods. To assess the use of chemotherapy in men with CRPC we conducted a register-based nationwide population-based study in Prostate Cancer data Base Sweden (PCBaSe) and a nationwide in-patient drug register (SALT database) between May 2009 and December 2010. We assumed that men who died of prostate cancer (PCa) underwent a period of CRPC before they died. Results. Among the 2677 men who died from PCa during the study inclusion period, 556 (21%) had received chemotherapy (intravenous or per oral) detectable within the observation period in SALT database. Specifically, 239 (61%) of men <70 years had received chemotherapy, 246 (30%) of men between 70 and 79 years and 71 (5%) men older than 80 years. The majority of men 465/556 (84%) had received a docetaxel-containing regimen. Among chemotherapy treated men, 283/556 (51%) received their last dose of chemotherapy during the last six months prior to death. Treatment with chemotherapy was more common among men with little comorbidity and high educational level, as well as in men who had received curatively intended primary treatment. Conclusion. A majority of men younger than 70 years with CRPC were treated with chemotherapy in contrast to men between 70 and 79 years of whom half as many received chemotherapy. Chemotherapy treatment was often administered shortly prior to death. The low uptake of chemotherapy in older men with CRPC may be caused by concerns about tolerability of treatment, as well as treatment decisions based on chronological age rather than global health status.

  • 288.
    Lissbrant, Ingela Franck
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Lissbrant, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ferrara, Napoleone
    Rudolfsson, Stina Häggström
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Neutralizing VEGF bioactivity with a soluble chimeric VEGF-receptor protein flt(1-3)IgG inhibits testosterone-stimulated prostate growth in castrated mice.2004In: Prostate, ISSN 0270-4137, Vol. 58, no 1, p. 57-65Article in journal (Refereed)
  • 289. Liu, Wennuan
    et al.
    Sun, Jishan
    Li, Ge
    Zhu, Yi
    Zhang, Scott
    Kim, Seong-Tae
    Sun, Jielin
    Wiklund, Fredrik
    Wiley, Kathleen
    Isaacs, Sarah D
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Xu, Jianfeng
    Duggan, David
    Carpten, John D
    Isaacs, William B
    Grönberg, Henrik
    Zheng, S Lilly
    Chang, Bao-Li
    Association of a germ-line copy number variation at 2p24.3 and risk for aggressive prostate cancer.2009In: Cancer research, ISSN 1538-7445, Vol. 69, no 6, p. 2176-9Article in journal (Refereed)
    Abstract [en]

    We searched for deletions in the germ-line genome among 498 aggressive prostate cancer cases and 494 controls from a population-based study in Sweden [CAncer of the Prostate in Sweden (CAPS)] using Affymetrix SNP arrays. By comparing allele intensities of approximately 500,000 SNP probes across the genome, a germ-line deletion at 2p24.3 was observed to be significantly more common in cases (12.63%) than in controls (8.28%); P = 0.028. To confirm the association, we genotyped this germ-line copy number variation (CNV) in additional subjects from CAPS and from Johns Hopkins Hospital (JHH). Overall, among 4,314 cases and 2,176 controls examined, the CNV was significantly associated with prostate cancer risk [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.06-1.48; P = 0.009]. More importantly, the association was stronger for aggressive prostate cancer (OR, 1.31; 95% CI, 1.08-1.58; P = 0.006) than for nonaggressive prostate cancer (OR, 1.19; 95% CI, 0.98-1.45; P = 0.08). The biological effect of this germ-line CNV is unknown because no known gene resides in the deletion. Results from this study represent the first novel germ-line CNV that was identified from a genome-wide search and was significantly, but moderately, associated with prostate cancer risk. Additional confirmation of this association and functional studies are warranted.

  • 290.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Contemporary status of open nephron-sparing surgery in renal cell carcinoma.2009In: Archivio italiano di urologia, andrologia : organo ufficiale [di] Società italiana di ecografia urologica e nefrologica / Associazione ricerche in urologia, ISSN 1124-3562, Vol. 81, no 2, p. 61-4Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The contemporary management of renal cell carcinoma (RCC) has changed significantly over the last decade. There has been a paradigm shift in the surgical strategy, especially for the treatment of small renal tumors using partial nephrectomy and minimal invasive techniques instead of radical neprectomy. The backgrounds are an enhanced awareness of the overall health as co-morbid conditions and overall morbidity. One such mechanism by which radical surgery of renal tumors might adversely influence overall health of the patients is by development or worsening of chronic kidney disease, a condition associated with cardiovascular disease and pre-mature death. MATERIAL AND METHODS: Previously nephron-sparing surgery was mostly used in imperative cases. An increased number of incidentally detected renal cell carcinomas are diagnosed due to the development and increased use of imaging techniques. These incidentally detected tumors generally tend to be smaller and having a lower stage. RESULTS: The excellent results of partial nephrectomy in RCC with low operative morbidity and a good oncologic control, have promoted the use of nephron-sparing approach also in patients with a normal contralateral kidney and having tumors smaller than 4 and up to 7 cm. CONCLUSION: Open partial nephrectomy has become the recommended technique in the treatment of properly selected patients.

  • 291.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Kidney cancer: a new nomogram predicting survival in renal cell carcinoma2010In: Nature reviews. Urology, ISSN 1759-4820, Vol. 7, no 8, p. 423-424Article in journal (Refereed)
  • 292.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Nephron-sparing surgery--strategies for partial nephrectomy in renal cell carcinoma.2004In: Scand J Surg, ISSN 1457-4969, Vol. 93, no 2, p. 126-31Article in journal (Refereed)
  • 293.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prognostic factors in renal cell carcinoma2004In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 93, no 2, p. 118-125Article in journal (Refereed)
  • 294.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prognostic factors in renal cell carcinoma2004In: Der Urologe (Ausg. A), ISSN 0340-2592, E-ISSN 1433-0563, Vol. 43, no Suppl 3, p. 119-120Article in journal (Refereed)
  • 295.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Prognostic markers in renal cell carcinoma.2007In: Curr Opin Urol, ISSN 0963-0643, Vol. 17, no 5, p. 303-8Article, review/survey (Other (popular science, discussion, etc.))
  • 296.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Re: can partial nephrectomy preserve renal function and modify survival in comparison with radical nephrectomy?2011In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 60, no 3, p. 595-596Article in journal (Refereed)
  • 297.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Should patients with pathologic stage pT3 and pT4 RCC be reclassified to improve prognostic accuracy?2006In: Nature Clinical Practice Urology, ISSN 1743-4270, Vol. 3, no 3, p. 136-137Article, book review (Refereed)
  • 298.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    The role of metastasectomy in renal cell carcinoma in the era of targeted therapy2013In: Current Urology Reports, ISSN 1527-2737, Vol. 14, no 1, p. 19-25Article in journal (Refereed)
    Abstract [en]

    Despite contemporary innovations in systemic therapy and surgical treatment, renal cell carcinoma (RCC) remains the most lethal urologic malignancy. Still, around 20 % of patients with RCC present with metastases at diagnosis, and 40-50 % of those with localized advanced disease will ultimately progress to metastatic disease. Although the new, targeted therapy paradigms have changed the treatment of patients with advanced RCC and offer prolonged survival, cure is extremely uncommon in the absence of surgical resections. In this paper, the current role of metastasectomy is reviewed. Searches were carried out in the PubMed database and the Cochrane Library of Controlled Clinical Trials. While there is no randomized study available, recent large observational studies have better defined the prognosis of patients with metastatic RCC with or without metastasectomy. In multivariate analysis, independent predictive factors included male gender, disease-free interval > 1 year, single metastatic site and complete metastasectomy. Other reports from selected patient materials show 29-31 % 5-year overall survival rates. In patients with recurrent disease after resection of a lung metastasis, 60 % were able to undergo a subsequent resection, compared with 25 % with recurrent bone metastasis. Also, metastasectomy after initial systemic therapy gave partial or complete response in a majority of patients. In these patients, the median survival was 4.7 years and 21 % remained free of disease at last follow-up. Patients with metastatic renal cell carcinoma should be considered for multimodal therapy, including surgery of metastatic lesions. A proportion of patients will achieve long-term survival with aggressive surgical resection.

  • 299.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Words of wisdom. Re: Radical nephrectomy with and without lymph-node dissection2009In: European urology, ISSN 1873-7560, Vol. 55, no 6, p. 1486-7Article in journal (Refereed)
  • 300.
    Ljungberg, Börje
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Albiges, Laurance
    Abu-Ghanem, Yasmin
    Bensalan, Karim
    Dabestani, Saeed
    Montes, Sergio Fernandez-Pello
    Giles, Rachel H.
    Hofmann, Fabian
    Hora, Milan
    Kuczyk, Markus A.
    Kuusk, Teele
    Lam, Thomas B.
    Marconi, Lorenzo
    Merseburger, Axel S.
    Powles, Thomas
    Staehler, Michael
    Tahbaz, Rana
    Volpe, Alessandro
    Bex, Axel
    European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update2019In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 75, no 5, p. 799-810Article in journal (Refereed)
    Abstract [en]

    Context: The European Association of Urology Renal Cell Carcinoma (RCC) Guideline Panel has prepared evidence-based guidelines and recommendations for the management of RCC.

    Objective: To provide an updated RCC guideline based on standardised methodology including systematic reviews, which is robust, transparent, reproducible, and reliable.

    Evidence acquisition: For the 2019 update, evidence synthesis was undertaken based on a comprehensive and structured literature assessment for new and relevant data. Where necessary, formal systematic reviews adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were undertaken. Relevant databases (Medline, Cochrane Libraries, trial registries, conference proceedings) were searched until June 2018, including randomised controlled trials (RCTs) and retrospective or controlled studies with a comparator arm, systematic reviews, and meta-analyses. Where relevant, risk of bias (RoB) assessment, and qualitative and quantitative syntheses of the evidence were performed. The remaining sections of the document were updated following a structured literature assessment. Clinical practice recommendations were developed and issued based on the modified GRADE framework.

    Evidence synthesis: All chapters of the RCC guidelines were updated based on a structured literature assessment, for prioritised topics based on the availability of robust data. For RCTs, RoB was low across studies. For most non-RCTs, clinical and methodological heterogeneity prevented pooling of data. The majority of included studies were retrospective with matched or unmatched cohorts, based on single- or multi-institutional data or national registries. The exception was for the treatment of metastatic RCC, for which there were several large RCTs, resulting in recommendations based on higher levels of evidence.

    Conclusions: The 2019 RCC guidelines have been updated by the multidisciplinary panel using the highest methodological standards. These guidelines provide the most reliable contemporary evidence base for the management of RCC in 2019.

    Patient summary: The European Association of Urology Renal Cell Carcinoma Guideline Panel has thoroughly evaluated the available research data on kidney cancer to establish international standards for the care of kidney cancer patients.

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