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  • 101.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tumkur Sitaram, Raviprakash
    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.
    The NBS1 gene is overexpressed and regulated by DJ-1 in clear cell renal cell carcinomaManuscript (preprint) (Other academic)
  • 102.
    Duchek, Milos
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jahnson, Staffan
    Mestad, Oddvar
    Hellström, Pekka
    Hellsten, Sverker
    Malmström, Per-Uno
    Bacillus Calmette-Guérin is superior to a combination of epirubicin and interferon-alpha2b in the intravesical treatment of patients with stage T1 urinary bladder cancer. A prospective, randomized, Nordic study.2010In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 57, no 1, p. 25-31Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bacillus Calmette-Guérin (BCG) instillation is regarded as the most effective bladder-sparing treatment for patients with high-grade T1 tumours and carcinoma in situ (CIS). The major problem with this therapy is the side-effects, making maintenance therapy difficult, even impossible, in a proportion of patients. Thus, alternative schedules and drugs have been proposed.

    OBJECTIVE: To compare BCG to the combination of epirubicin and interferon-alpha2b as adjuvant therapy of T1 tumours.

    DESIGN, SETTING, AND PARTICIPANTS: This is a Nordic multicenter, prospective, randomised trial in patients with primary T1 G2-G3 bladder cancer. Initial transurethral resection (TUR) was followed by a second-look resection. Patients were randomised to receive either regimen, given as induction for 6 wk followed by maintenance therapy for 2 yr.

    MEASUREMENTS: The drugs were compared with respect to time to recurrence and progression. Also, side-effects were documented.

    RESULTS AND LIMITATIONS: A total of 250 patients were randomised. At the primary end point, 62% were disease free in the combination arm as opposed to 73% in the BCG arm (p=0.065). At 24 mo, there was a significant difference in favour of the BCG-treated patients (p=0.012) regarding recurrence, although there was no difference regarding progression. The subgroup analysis showed that the superiority of BCG was mainly in those with concomitant CIS. In a multivariate analysis of association with recurrence/progression status, significant variables for outcome were type of drug, tumour size, multiplicity, status at second-look resection, and grade. A corresponding analysis was performed separately in the two treatment arms. Tumour size was the only significant variable for BCG-treated patients, while multiplicity, status at second-look resection, and grade were significant for patients treated with the combination.

    CONCLUSIONS: For prophylaxis of recurrence, BCG was more effective than the combination. There were no differences regarding progression and adverse events between the two treatments.

  • 103. Duggan, David
    et al.
    Zheng, Siqun L
    Knowlton, Michele
    Benitez, Debbie
    Dimitrov, Latchezar
    Wiklund, Fredrik
    Robbins, Christiane
    Isaacs, Sarah D
    Cheng, Yu
    Li, Ge
    Sun, Jielin
    Chang, Bao-Li
    Marovich, Leslie
    Wiley, Kathleen E
    Bälter, Katarina
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Adami, Hans-Olov
    Gielzak, Marta
    Yan, Guifang
    Sauvageot, Jurga
    Liu, Wennuan
    Kim, Jin Woo
    Bleecker, Eugene R
    Meyers, Deborah A
    Trock, Bruce J
    Partin, Alan W
    Walsh, Patrick C
    Isaacs, William B
    Grönberg, Henrik
    Xu, Jianfeng
    Carpten, John D
    Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP.2007In: J Natl Cancer Inst, ISSN 1460-2105, Vol. 99, no 24, p. 1836-44Article in journal (Refereed)
  • 104. Edlinger, Michael
    et al.
    Strohmaier, Susanne
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bjørge, Tone
    Manjer, Jonas
    Borena, Wegene T
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Engeland, Anders
    Tretli, Steinar
    Concin, Hans
    Nagel, Gabriele
    Selmer, Randi
    Johansen, Dorthe
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    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.
    Ulmer, Hanno
    Blood pressure and other metabolic syndrome factors and risk of brain tumour in the large population-based Me-Can cohort study2012In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 30, no 2, p. 290-296Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:: Brain tumour has few established determinants. We assessed to which extent risk of brain tumour was related to metabolic syndrome factors in adults. METHODS:: In the Me-Can project, 580 000 individuals from Sweden, Austria, and Norway were followed for a median of 10 years after baseline measurement. Data on brain tumours were obtained from national cancer registries. The factors of metabolic syndrome (BMI, SBP and DBP, and blood levels of glucose, cholesterol, and triglycerides), separately and combined, were analysed in quintiles and for transformed z-scores (mean transformed to 0 and standard deviation to 1). Cox proportional hazards multivariate regression models were used, with corrections for measurement error. RESULTS:: During follow-up, 1312 primary brain tumours were diagnosed, predominantly meningioma (n = 348) and high-grade glioma (n = 436). For meningioma, the hazard ratio was increased for z-scores of SBP [hazard ratio = 1.27 per unit standard deviation, 95% confidence interval (CI) 1.03-1.57], of DBP (hazard ratio = 1.29, 95% CI 1.04-1.58), and of the combined metabolic syndrome score (hazard ratio = 1.31, 95% CI 1.11-1.54). An increased risk of high-grade glioma was found for DBP (hazard ratio = 1.23, 95% CI 1.01-1.50) and triglycerides (hazard ratio = 1.35, 95% CI 1.05-1.72). For both meningioma and high-grade glioma, the risk was more than double in the fifth quintiles of DBP compared to the lowest quintile. For meningioma this risk was even larger for SBP. CONCLUSION:: Increased blood pressure was associated with risk of brain tumours, especially of meningiomas.

  • 105. Eichelberg, Christian
    et al.
    Junker, Kerstin
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Moch, Holger
    Diagnostic and prognostic molecular markers for renal cell carcinoma: a critical appraisal of the current state of research and clinical applicability.2009In: European urology, ISSN 1873-7560, Vol. 55, no 4, p. 851-63Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Earlier detection of renal cell carcinoma (RCC) and the recent expansion of treatment possibilities have positively influenced the outlook for patients with this disease. However, progression and treatment response are still not sufficiently predictable. Molecular markers could help to refine individual risk stratification and treatment planning, although they have not yet become clinically routine. OBJECTIVE: This review presents an overview of diagnostic and prognostic molecular markers for RCC and a subgrouping of these markers for different clinical issues. EVIDENCE ACQUISITION: Literature and recent meeting abstracts were searched using these terms: renal (cell) carcinoma, molecular/tumor markers, biopsy, blood, urine, disease progression/prognosis, immunohistochemistry, risk factors, and survival. Due to the resulting large number of articles, studies were subjectively selected according to the importance of a study on the field, number of investigated patients, originality, multivariate analyses performed, contrast with previously published data, actuality, and assumed clinical applicability of the described results. More then 90% of the selected studies originated from the past 10 yr; >50% of the articles were written in 2006 or later. EVIDENCE SYNTHESIS: These data were predominantly obtained via nonrandomized, retrospective, but often controlled studies. Thereby, the resulting level of evidence is 2A/2B. The broad spectrum of described molecular markers (MMs) for RCC consists of markers already extensively studied in other malignancies (eg, p53), as well as MMs typically associated with specific RCC-altered gene functions and pathways (eg, von Hippel-Lindau [VHL]). The main goal of using MMs is to refine the prediction of clinical end points like tumor progression, treatment response, and cancer-specific and/or overall survival. Further, MMs might facilitate the clinical work-up of undefined renal masses and prove to be more convenient tools for screening and follow-up in blood and urine. CONCLUSIONS: Presently, there are a number of promising MMs for diverse clinical questions, but the available data are not yet valid enough for routine, clinical application. We should comply with the demand for large multicenter prospective investigations, stratified for RCC type and treatment modalities, to lift the use of molecular markers in RCC to a practical level, thereby providing a better consultation for our patients regarding diagnosis, treatment, and follow-up.

  • 106. Eloranta, Sandra
    et al.
    Adolfsson, Jan
    Lambert, Paul C.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Akre, Olof
    Andersson, Therese M-L.
    Dickman, Paul W.
    How can we make cancer survival statistics more useful for patients and clinicians: an illustration using localized prostate cancer in Sweden2013In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, no 3, p. 505-515Article in journal (Refereed)
    Abstract [en]

    Studies of cancer patient survival typically report relative survival or cause-specific survival using data from patients diagnosed many years in the past. From a risk-communication perspective, such measures are suboptimal for several reasons; their interpretation is not transparent for non-specialists, competing causes of death are ignored and the estimates are unsuitable to predict the outcome of newly diagnosed patients. In this paper, we discuss the relative merits of recently developed alternatives to traditionally reported measures of cancer patient survival. In a relative survival framework, using a period approach, we estimated probabilities of death in the presence of competing risks. To illustrate the methods, we present estimates of survival among 23,353 initially untreated, or hormonally treated men with intermediate- or high-risk localized prostate cancer using Swedish population-based data. Among all groups of newly diagnosed patients, the probability of dying from prostate cancer, accounting for competing risks, was lower compared to the corresponding estimates where competing risks were ignored. Accounting for competing deaths was particularly important for patients aged more than 70 years at diagnosis in order to avoid overestimating the risk of dying from prostate cancer. We argue that period estimates of survival, accounting for competing risks, provide the tools to communicate the actual risk that cancer patients, diagnosed today, face to die from their disease. Such measures should offer a more useful basis for risk communication between patients and clinicians and we advocate their use as means to answer prognostic questions.

  • 107.
    Eriksson Spångberg, Andrea
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    The management of young and elderly patients with traumatic brain injuries - a survey from the county of Skåne 2013-20142015Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 108.
    Evelönn, Emma Andersson
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Köhn, Linda
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    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.
    DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC)2016In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 10219-10228Article in journal (Refereed)
    Abstract [en]

    Epigenetic alterations in the methylome have been associated with tumor development and progression in renal cell carcinoma (RCC). In this study, 45 tumor samples, 12 tumor-free kidney cortex tissues, and 24 peripheral blood samples from patients with clear cell RCC (ccRCC) were analyzed by genome-wide promoter-directed methylation arrays and related to clinicopathological parameters. Unsupervised hierarchical clustering separated the tumors into two distinct methylation groups (clusters A and B), where cluster B had higher average methylation and increased number of hypermethylated CpG sites (CpGs). Furthermore, tumors in cluster B had, compared with cluster A, a larger tumor diameter (p = 0.033), a higher morphologic grade (p < 0.001), a higher tumor-node-metastasis (TNM) stage (p < 0.001), and a worse prognosis (p = 0.005). Higher TNM stage was correlated to an increase in average methylation level (p = 0.003) and number of hypermethylated CpGs (p = 0.003), whereas a number of hypomethylated CpGs were mainly unchanged. However, the predicted age of the tumors based on methylation profile did not correlate with TNM stage, morphological grade, or methylation cluster. Differently methylated (DM) genes (n = 840) in ccRCC samples compared with tumor-free kidney cortex samples were predominantly hypermethylated and a high proportion were identified as polycomb target genes. The DM genes were overrepresented by transcription factors, ligands, and receptors, indicating functional alterations of significance for ccRCC progression. To conclude, increased number of hypermethylated genes was associated with increased TNM stage of the tumors. DNA methylation classification of ccRCC tumor samples at diagnosis can serve as a clinically applicable prognostic marker in ccRCC.

  • 109. Fernández-Pello, Sergio
    et al.
    Hofmann, Fabian
    Tahbaz, Rana
    Marconi, Lorenzo
    Lam, Thomas B
    Albiges, Laurence
    Bensalah, Karim
    Canfield, Steven E
    Dabestani, Saeed
    Giles, Rachel H
    Hora, Milan
    Kuczyk, Markus A
    Merseburger, Axel S
    Powles, Thomas
    Staehler, Michael
    Volpe, Alessandro
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bex, Axel
    A Systematic Review and Meta-analysis Comparing the Effectiveness and Adverse Effects of Different Systemic Treatments for Non-clear Cell Renal Cell Carcinoma.2017In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 71, no 3, p. 426-436Article, review/survey (Refereed)
    Abstract [en]

    CONTEXT: While vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibition are effective strategies in treating clear cell renal cell carcinoma (ccRCC), the most effective therapeutic approach for patients with non-clear cell RCC (non-ccRCC) is unknown.

    OBJECTIVE: To systematically review relevant literature comparing the oncological outcomes and adverse events of different systemic therapies for patients with metastatic non-ccRCC.

    EVIDENCE ACQUISITION: Relevant databases including MEDLINE, Embase, and the Cochrane Library were searched up to March 24, 2016. Only comparative studies were included. Risk of bias and confounding assessments were performed. A meta-analysis was planned for and only performed if methodologically appropriate; otherwise, a narrative synthesis was undertaken.

    EVIDENCE SYNTHESIS: The literature search identified 812 potential titles and abstracts. Five randomized controlled trials, recruiting a total of 365 patients, were included. Three studies compared sunitinib against everolimus, one of which reported the results for non-ccRCC as a subgroup rather than as an entire randomized cohort. Individually, the studies showed a trend towards favoring sunitinib in terms of overall survival and progression-free survival (PFS; Everolimus versus Sunitinib in Patients with Metastatic Non-clear Cell Renal Cell Carcinoma hazard ratio [HR]: 1.41, 80% confidence interval [CI] 1.03-1.92 and 1.41, 95% CI: 0.88-2.27, Evaluation in Metastatic Non-clear Cell Renal Cell Carcinoma HR: 1.16, 95% CI: 0.67-2.01, Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients with Metastatic Renal Cell Carcinoma HR: 1.5, 95% CI: 0.9-2.8), but this trend did not reach statistical significance in any study. Meta-analysis was performed on two studies which solely recruited patients with non-ccRCC reporting on PFS, the results of which were inconclusive (HR: 1.30, 95% CI: 0.91-1.86). Sunitinib was associated with more Grade 3-4 adverse events than everolimus, although this was not statistically significant.

    CONCLUSIONS: This systematic review and meta-analysis represent a robust summary of the evidence base for systemic treatment of metastatic non-ccRCC. The results show a trend towards favoring vascular endothelial growth factor-targeted therapy for PFS and overall survival compared with mammalian target of rapamycin inhibitors, although statistical significance was not reached. The relative benefits and harms of these treatments remain uncertain. Further research, either in the form of an individual patient data meta-analysis involving all relevant trials, or a randomized controlled trial with sufficient power to detect potential differences between treatments, is needed.

    PATIENT SUMMARY: We examined the literature to determine the most effective treatments for advanced kidney cancer patients whose tumors are not of the clear cell subtype. The results suggest that a drug called sunitinib might be more effective than everolimus, but the statistics supporting this statement are not yet entirely reliable. Further research is required to clarify this unmet medical need.

  • 110. Figueroa, Jonine D.
    et al.
    Han, Summer S.
    Garcia-Closas, Montserrat
    Baris, Dalsu
    Jacobs, Eric J.
    Kogevinas, Manolis
    Schwenn, Molly
    Malats, Nuria
    Johnson, Alison
    Purdue, Mark P.
    Caporaso, Neil
    Landi, Maria Teresa
    Prokunina-Olsson, Ludmila
    Wang, Zhaoming
    Hutchinson, Amy
    Burdette, Laurie
    Wheeler, William
    Vineis, Paolo
    Siddiq, Afshan
    Cortessis, Victoria K.
    Kooperberg, Charles
    Cussenot, Olivier
    Benhamou, Simone
    Prescott, Jennifer
    Porru, Stefano
    Bueno-de-Mesquita, H. Bas
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Clavel-Chapelon, Françoise
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth
    Tjønneland, Anne
    Brenan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Conti, David
    Gago-Dominguez, Manuela
    Stern, Mariana C.
    Pike, Malcolm C.
    Van den Berg, David
    Yuan, Jian-Min
    Hohensee, Chancellor
    Rodabough, Rebecca
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Chen, Constance
    De Vivo, Immaculata
    Giovannucci, Edward
    Hunter, David J.
    Kraft, Peter
    Lindstrom, Sara
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Karagas, Margaret R.
    Schned, Alan
    Armenti, Karla R.
    Hosain, G. M. Monawar
    Haiman, Chris A.
    Fraumeni, Joseph F., Jr.
    Chanock, Stephen J.
    Chatterjee, Nilanjan
    Rothman, Nathaniel
    Silverman, Debra T.
    Genome-wide interaction study of smoking and bladder cancer risk2014In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 35, no 8, p. 1737-1744Article in journal (Refereed)
    Abstract [en]

    Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 x 10(-5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 x 10(-7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 x 10-7). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.

  • 111. Figueroa, Jonine D.
    et al.
    Middlebrooks, Candace D.
    Banday, A. Rouf
    Ye, Yuanqing
    Garcia-Closas, Montserrat
    Chatterjee, Nilanjan
    Koutros, Stella
    Kiemeney, Lambertus A.
    Rafnar, Thorunn
    Bishop, Timothy
    Furberg, Helena
    Matullo, Giuseppe
    Golka, Klaus
    Gago-Dominguez, Manuela
    Taylor, Jack A.
    Fletcher, Tony
    Siddiq, Afshan
    Cortessis, Victoria K.
    Kooperberg, Charles
    Cussenot, Olivier
    Benhamou, Simone
    Prescott, Jennifer
    Porru, Stefano
    Dinney, Colin P.
    Malats, Nuria
    Baris, Dalsu
    Purdue, Mark P.
    Jacobs, Eric J.
    Albanes, Demetrius
    Wang, Zhaoming
    Chung, Charles C.
    Vermeulen, Sita H.
    Aben, Katja K.
    Galesloot, Tessel E.
    Thorleifsson, Gudmar
    Sulem, Patrick
    Stefansson, Kari
    Kiltie, Anne E.
    Harland, Mark
    Teo, Mark
    Offit, Kenneth
    Vijai, Joseph
    Bajorin, Dean
    Kopp, Ryan
    Fiorito, Giovanni
    Guarrera, Simonetta
    Sacerdote, Carlotta
    Selinski, Silvia
    Hengstler, Jan G.
    Gerullis, Holger
    Ovsiannikov, Daniel
    Blaszkewicz, Meinolf
    Esteban Castelao, Jose
    Calaza, Manuel
    Martinez, Maria Elena
    Cordeiro, Patricia
    Xu, Zongli
    Panduri, Vijayalakshmi
    Kumar, Rajiv
    Gurzau, Eugene
    Koppova, Kvetoslava
    Bueno-De-Mesquita, H. Bas
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Clavel-Chapelon, Francoise
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth C.
    Tjonneland, Anne
    Brennan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Conti, David
    Stern, Marianna C.
    Pike, Malcolm C.
    Van den Berg, David
    Yuan, Jian-Min
    Hohensee, Chancellor
    Jeppson, Rebecca P.
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Turman, Constance
    De Vivo, Immaculata
    Giovannucci, Edward
    Hunter, David J.
    Kraft, Peter
    Lindstrom, Sara
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Kamat, Ashish M.
    Zhang, Liren
    Gong, Yilei
    Pu, Xia
    Hutchinson, Amy
    Burdett, Laurie
    Wheeler, William A.
    Karagas, Margaret R.
    Johnson, Alison
    Schned, Alan
    Hosain, G. M. Monawar
    Schwenn, Molly
    Kogevinas, Manolis
    Tardon, Adonina
    Serra, Consol
    Carrato, Alfredo
    Garcia-Closas, Reina
    Lloreta, Josep
    Andriole, Gerald, Jr.
    Grubb, Robert, III
    Black, Amanda
    Diver, W. Ryan
    Gapstur, Susan M.
    Weinstein, Stephanie
    Virtamo, Jarmo
    Haiman, Christopher A.
    Landi, Maria Teresa
    Caporaso, Neil E.
    Fraumeni, Joseph F., Jr.
    Vineis, Paolo
    Wu, Xifeng
    Chanock, Stephen J.
    Silverman, Debra T.
    Prokunina-Olsson, Ludmila
    Rothman, Nathaniel
    Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 6, p. 1203-1214Article in journal (Refereed)
    Abstract [en]

    Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

  • 112. Figueroa, Jonine D.
    et al.
    Ye, Yuanqing
    Siddiq, Afshan
    Garcia-Closas, Montserrat
    Chatterjee, Nilanjan
    Prokunina-Olsson, Ludmila
    Cortessis, Victoria K.
    Kooperberg, Charles
    Cussenot, Olivier
    Benhamou, Simone
    Prescott, Jennifer
    Porru, Stefano
    Dinney, Colin P.
    Malats, Nuria
    Baris, Dalsu
    Purdue, Mark
    Jacobs, Eric J.
    Albanes, Demetrius
    Wang, Zhaoming
    Deng, Xiang
    Chung, Charles C.
    Tang, Wei
    Bueno-De-Mesquita, H. Bas
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Clavel-Chapelon, Frangoise
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth
    Tjonneland, Anne
    Brenan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Conti, David
    Gago-Dominguez, Manuela
    Stern, Mariana C.
    Pike, Malcolm C.
    Van den Berg, David
    Yuan, Jian-Min
    Hohensee, Chancellor
    Rodabough, Rebecca
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Chen, Constance
    De Vivo, Immaculata
    Giovannucci, Edward
    Hunter, David J.
    Kraft, Peter
    Lindstrom, Sara
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Kamat, Ashish M.
    Lerner, Seth P.
    Grossman, H. Barton
    Lin, Jie
    Gu, Jian
    Pu, Xia
    Hutchinson, Amy
    Burdette, Laurie
    Wheeler, William
    Kogevinas, Manolis
    Tardon, Adonina
    Serra, Consol
    Carrato, Alfredo
    Garcia-Closas, Reina
    Lloreta, Josep
    Schwenn, Molly
    Karagas, Margaret R.
    Johnson, Alison
    Schned, Alan
    Armenti, Karla R.
    Hosain, G. M.
    Andriole, Gerald, Jr.
    Grubb, Robert, III
    Black, Amanda
    Diver, W. Ryan
    Gapstur, Susan M.
    Weinstein, Stephanie J.
    Virtamo, Jarmo
    Haiman, Chris A.
    Landi, Maria T.
    Caporaso, Neil
    Fraumeni, Joseph F., Jr.
    Vineis, Paolo
    Wu, Xifeng
    Silverman, Debra T.
    Chanock, Stephen
    Rothman, Nathaniel
    Genome-wide association study identifies multiple loci associated with bladder cancer risk2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 5, p. 1387-1398Article in journal (Refereed)
    Abstract [en]

    andidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.

  • 113. FitzGerald, L. M.
    et al.
    Zhao, S.
    Leonardson, A.
    Geybels, M. S.
    Kolb, S.
    Lin, D. W.
    Wright, J. L.
    Eeles, R.
    Kote-Jarai, Z.
    Govindasami, K.
    Giles, G. G.
    Southey, M. C.
    Schleutker, J.
    Tammela, T. L.
    Sipeky, C.
    Penney, K. L.
    Stampfer, M. J.
    Gronberg, H.
    Wiklund, F.
    Stattin, P.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Hugosson, J.
    Karyadi, D. M.
    Ostrander, E. A.
    Feng, Z.
    Stanford, J. L.
    Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: an analysis of 12,082 prostate cancer cases2018In: Prostate Cancer and Prostatic Diseases, ISSN 1365-7852, E-ISSN 1476-5608, Vol. 21, no 2, p. 228-237Article in journal (Refereed)
    Abstract [en]

    Background Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. Methods Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. Results Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 x 10(-2)) and IL4 (rs2070874; HR 1.22; p-value = 1.1 x 10(-3)) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 x 10(-2)). Conclusions This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

  • 114.
    Forsman, Ramona
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Common blood markers as possible predictors of response to neoadjuvant chemotherapy, in muscle-invasive urinary bladder cancer2017Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 115.
    Franck-Lissbrant, I
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, S
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Damber, J E
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Testosterone stimulates angiogenesis and vascular regrowth in the ventral prostate in castrated adult rats.1998In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 139, no 2, p. 451-6Article in journal (Refereed)
    Abstract [en]

    The castration-induced regression and testosterone stimulated regrowth of the vasculature in the rat ventral prostate lobe were studied using stereological techniques. Seven days after castration, the endothelial cell proliferation rate (bromodeoxyuridine labeling index); the total weights of blood vessel walls, blood vessel lumina, endothelial cells, glandular epithelial cells; and total organ weight were all decreased. Within 2 days after sc treatment with testosterone, the total weights of blood vessel walls, endothelial cells, and vascular lumina, as well as the endothelial cell proliferation rate, were all normalized. In contrast to the rapid response of the vasculature, the total weight of glandular epithelium and total organ weight were not normalized during the 4 days of testosterone treatment. Growth of the vasculature apparently precedes growth of the glandular epithelium. The testosterone- dependent factors stimulating the vasculature are unknown, but factors derived from epithelial cells, mast cells (which accumulate in the prostate during the first day of testosterone treatment), and tissue macrophages could all be involved. Castration-induced regression and testosterone-stimulated regrowth of the prostatic vasculature can be used as an experimental model to study factors regulating angiogenesis and organ growth in the prostate.

  • 116.
    Fransson, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Damber, Jan-Erik
    Department of Urology, Göteborg University, Göteborg, Sweden.
    Tomic, Radisa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Modig, Hans
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nyberg, Gunnar
    Department of Urology, Boden Hospital, Boden, Sweden.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Quality of life and symptoms in a randomized trial of radiotherapy versus deferred treatment of localized prostate carcinoma2001In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 92, no 12, p. 3111-3119Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Treatment of localized prostate carcinoma (LPC) using radiotherapy (RT) can induce disturbances in a patient's quality of life (QOL) and urinary and intestinal function. Late symptoms and QOL were evaluated in a randomized trial between RT and deferred treatment (DT).

    METHODS: Quality of life was evaluated with European Organization for Research and Treatment of Cancer's QLQ-C30 (+3) formula. Urinary and intestinal problems were evaluated with a validated symptom specific self-assessment questionnaire, QUFW94. The questionnaires were sent to 108 randomized patients with LPC and to an age-matched control group (n = 68). Mean age was 72 years. Mean total dose was 65 grays (Gy; 62.3-70 Gy). The median follow-up time from randomization was 40.6 months for the RT group and 30.4 months for the DT group.

    RESULTS: Social functioning was the only QOL scale in which a significant difference was found between the two patient groups and compared with the control group. Multivariate regression analysis showed that hematuria, incontinence, mucus, and planning of daily activities in response to intestinal problems caused this decrease in QOL in the RT group. A significant increase of intestinal problems was observed in the RT versus DT groups regarding mucus, stool leakage, intestinal blood, and planning of daily activity in response to intestinal problems.

    CONCLUSIONS: The RT patients showed increased levels of minor intestinal side effects compared with the DT patients and the controls, but the RT patients reported no decreased QOL except for decreased social functioning. This could be because this group developed coping skills or because of a low magnitude of side effects to influence the QOL.

  • 117.
    Fridriksson, Jon Örn
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Adverse effects of curative treatment of prostate cancer2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Screening for prostate cancer is debated, there is conflicting data on the net benefit of screening. Men who consider screening need to be informed on the pros and cons. Rehospitalization after surgery can be used as an indicator of general quality of care. For radical prostatectomy, little is known on the readmission rate after surgery. Men diagnosed with low- and intermediate-risk prostate cancer have low prostate-cancer specific mortality. However, adverse effects after curative treatment can be severe and decrease quality of life. Curative treatments for prostate cancer differ mainly in the pattern of adverse effects but detailed analysis of long-term adverse effects is lacking.

    The aim of this thesis was to assess the perioperative quality of radical prostatectomy and the risk of adverse effects after curative treatment for prostate cancer.

    Material and Methods In this thesis, data from the National Prostate Cancer Register (NPCR) and other nationwide Swedish registers were used. By use of the Swedish personal identity number, NPCR was cross-linked to other registers creating Prostate Cancer data Base Sweden (PCBaSe), a large dataset for research.

    Results The proportion of men who had received information on the pros and cons of screening for prostate cancer with PSA testing was low (14%) indicating that the majority of men who were screened did not make an informed decision. The risk of rehospitalization within 90 days after radical prostatectomy was approximately 10% and similar after retropubic and robot-assisted radical prostatectomy. Compared to controls, there was an increased risk of adverse effects after both radiotherapy and radical prostatectomy up to twelve years after treatment and the overall risk was quite similar after retropubic and robot-assisted radical prostatectomy.

    Conclusion Improved information to men on the pros and cons of PSA screening is warranted. The risk of adverse effects was elevated up to 12 years after curative treatment for prostate cancer. The pattern of adverse effects was different after radiotherapy and radical prostatectomy but quite similar after retropubic and robot-assisted radical prostatectomy.

  • 118.
    Fridriksson, Jon Örn
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Folkvaljon, Y
    Lundström, KJ
    Robinson, D
    Carlsson, S
    Stattin, P
    Long-term adverse effects after open retropubic and robot-assisted radical prostatectomyManuscript (preprint) (Other academic)
  • 119.
    Fridriksson, Jon Örn
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Folkvaljon, Yasin
    Lundström, Karl-Johan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Robinson, David
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Ryhov Hospital, Jönköping, Sweden.
    Carlsson, Stefan
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Long-term adverse effects after retropubic and robot-assisted radical prostatectomy: Nationwide, population-based study2017In: Journal of Surgical Oncology, ISSN 0022-4790, E-ISSN 1096-9098, Vol. 116, no 4, p. 500-506Article in journal (Refereed)
    Abstract [en]

    Background and Objectives: Surgery for prostate cancer is associated with adverse effects. We studied long-term risk of adverse effects after retropubic (RRP) and robot-assisted radical prostatectomy (RARP).

    Methods: In the National Prostate Cancer Register of Sweden, men who had undergone radical prostatectomy (RP) between 2004 and 2014 were identified. Diagnoses and procedures indicating adverse postoperative effects were retrieved from the National Patient Register. Relative risk (RR) of adverse effects after RARP versus RRP was calculated in multivariable analyses adjusting for year of surgery, hospital surgical volume, T stage, Gleason grade, PSA level at diagnosis, patient age, comorbidity, and educational level.

    Results: A total of 11 212 men underwent RRP and 8500 RARP. Risk of anastomotic stricture was lower after RARP than RRP, RR for diagnoses 0.51 (95%CI = 0.42-0.63) and RR for procedures 0.46 (95%CI = 0.38-0.55). Risk of inguinal hernia was similar after RARP and RRP but risk of incisional hernia was higher after RARP, RR for diagnoses 1.48 (95%CI = 1.01-2.16), and RR for procedures 1.52 (95%CI = 1.02-2.26).

    Conclusions: The postoperative risk profile for RARP and RRP was quite similar. However, risk of anastomotic stricture was lower and risk of incisional hernia higher after RARP.

  • 120.
    Fridriksson, Jón O.
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Folkvaljon, Yasin
    Nilsson, Per
    Robinson, David
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Ryhov Hospital, J€onk€oping, Sweden.
    Franck-Lissbrant, Ingela
    Ehdaie, Behfar
    Eastham, James A.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Karlsson, Camilla T.
    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. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Long-term adverse effects after curative radiotherapy and radical prostatectomy: population-based nationwide register study2016In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 50, no 5, p. 338-345Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to assess the risk of serious adverse effects after radiotherapy (RT) with curative intention and radical prostatectomy (RP).

    Materials and methods: Men who were diagnosed with prostate cancer between 1997 and 2012 and underwent curative treatment were selected from the Prostate Cancer data Base Sweden. For each included man, five prostate cancer-free controls, matched for birth year and county of residency, were randomly selected. In total, 12,534 men underwent RT, 24,886 underwent RP and 186,624 were controls. Adverse effects were defined according to surgical and diagnostic codes in the National Patient Registry. The relative risk (RR) of adverse effects up to 12 years after treatment was compared to controls and the risk was subsequently compared between RT and RP in multivariable analyses.

    Results: Men with intermediate- and localized high-risk cancer who underwent curative treatment had an increased risk of adverse effects during the full study period compared to controls: the RR of undergoing a procedures after RT was 2.64 [95% confidence interval (CI) 2.56–2.73] and after RP 2.05 (95% CI 2.00–2.10). The risk remained elevated 10–12 years after treatment. For all risk categories of prostate cancer, the risk of surgical procedures for urinary incontinence was higher after RP (RR 23.64, 95% CI 11.71–47.74), whereas risk of other procedures on the lower urinary tract and gastrointestinal tract or abdominal wall was higher after RT (RR 1.67, 95% CI 1.44–1.94, and RR 1.86, 95% CI 1.70–2.02, respectively).

    Conclusion: The risk of serious adverse effects after curative treatment for prostate cancer remained significantly elevated up to 12 years after treatment.

  • 121. Fritz, Helena K.
    et al.
    Gustafsson, Anna
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ceder, Yvonne
    Axelson, Hakan
    Dahlback, Bjorn
    The Axl-Regulating Tumor Suppressor miR-34a Is Increased in ccRCC but Does Not Correlate with Axl mRNA or Axl Protein Levels2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 8, article id e0135991Article in journal (Refereed)
    Abstract [en]

    High expression of the receptor tyrosine kinase Axl is associated with poor prognosis in patients with Renal Cell Carcinoma (RCC), the most common malignancy of the kidney. The miR-34a has been shown to directly regulate Axl in cancer cells. The miR-34a is a mediator of p53-dependent tumor suppression, and low expression of miR-34a has been associated with worse prognosis in several cancers. Our aim was to elucidate whether miR-34a or the other members of the miR-34 family (miR-34b/c) regulate Axl in RCC.

  • 122. Fritz, Helena K. M.
    et al.
    Lindgren, David
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Axelson, Håkan
    Dahlbäck, Björn
    The miR(21/10b) ratio as a prognostic marker in clear cell renal cell carcinoma2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 10, p. 1758-1765Article in journal (Refereed)
    Abstract [en]

    Purpose: Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer in the adult kidney, and the prognosis of metastatic ccRCC remains poor with high mortality. In ccRCC, microRNAs (miRs) differentially expressed in tumour tissue have been identified and have been proposed to predict prognosis. The purpose of this study was to evaluate candidate miR markers identified from analysis of The Cancer Genome Atlas (TCGA) datasets in a large RCC cohort and to elucidate whether a ratio of miRs provided additional prognostic information. Experimental design: Deep sequencing data from TCGA datasets were analysed using biostatistical methods to identify candidate miRs that correlate with factors such as survival and stage of disease. Candidate miRs were analysed by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in a cohort of 198 RCC tumours (ccRCC, n = 152) and 50 normal kidney samples. Results: Four candidate miRs (miR-10b, miR-21, miR-101 and miR-223) were selected from the TCGA analysis and analysed in our cohort. Of these, miR-21 and miR-10b were differentially expressed in RCC subtypes and in ccRCC nuclear grades. Individually, the two miRs demonstrated a non-significant trend to correlate with survival. Importantly, the ratio of miR-21/miR10b (miR(21/10b),) correlated significantly with disease severity and survival, a high miR(21/10b) being associated with poor prognosis (P = 0.0095). In particular, the miR(21/10b) was found to be an independent prognostic factor in metastasis-free patients (P = 0.016; confidence interval (CI) 1.201-5.736). Conclusions: We have shown that the miR(21/10b) ratio is an independent prognostic factor for M0 ccRCC patients, which could be useful to identify high-risk M0 patients who could benefit from increased surveillance.

  • 123. Fritz, Helena K. M.
    et al.
    Lindgren, David
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Axelson, Håkan
    Dahlbäck, Björn
    The miR21/10b ratio as a prognostic marker in metastasis-free clear cell renal cell carcinoma patients2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, p. S143-S144Article in journal (Other academic)
  • 124.
    Friðriksson, Jón Örn
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Holmberg, Erik
    Adolfsson, Jan
    Lambe, Mats
    Bill-Axelson, Anna
    Carlsson, Stefan
    Hugosson, Jonas
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Rehospitalization after radical prostatectomy in a nationwide, population-based study2014In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 192, no 1, p. 112-119Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate readmission frequencies during the 90 days following radical prostatectomy and to assess readmission risk associated with potentially related variables.

    MATERIALS AND METHODS: Using the population-based, nationwide database Prostate Cancer data Base Sweden (PCBaSe), we identified men diagnosed with incident prostate cancer between 2000 and 2011 who underwent radical prostatectomy (RP) as their primary treatment, and we used logistic regression analysis to examine the association of the risk of 90-day postoperative readmission with surgical method, calendar period, tumor risk category, hospital case load, and patient characteristics.

    RESULTS: During the 90 postoperative days, 2,317 (10%) of the 24,122 men identified were non-electively readmitted, specifically 10% after retropubic radical prostatectomy (RRP), 9% after robot-assisted RP (RALP) and 11% after laparoscopic RP (LRP). The range in the readmission frequency between hospitals was 0-35%. A higher risk of readmission was associated with early calendar period (2009-2011 vs. 2000-2002: odds ratio (OR), 0.71; 95% confidence interval (CI), 0.61-0.83), greater age (≥70 years vs. <60 years: OR, 1.17; 95% CI, 1.00-1.36), higher risk category (high vs. low-risk category: OR, 1.78; 95% CI, 1.57-2.03), high comorbidity (Charlson comorbidity index ≥3 vs. 0: OR, 1.77; 95% CI, 1.29-2.44), and low hospital surgical volume (≥150 vs. <30 RPs per year: OR, 0.70; 95% CI, 0.60-0.81).

    CONCLUSIONS: Readmission rates after different RP methods were similar, ranging from 9% to 11%, with a wide variation between hospitals. Readmission rates can be used as an indicator of perioperative care quality, but potential confounders need to be adjusted to avoid bias.

  • 125. Fu, Yi-Ping
    et al.
    Kohaar, Indu
    Moore, Lee E.
    Lenz, Petra
    Figueroa, Jonine D.
    Tang, Wei
    Porter-Gill, Patricia
    Chatterjee, Nilanjan
    Scott-Johnson, Alexandra
    Garcia-Closas, Montserrat
    Muchmore, Brian
    Baris, Dalsu
    Paquin, Ashley
    Ylaya, Kris
    Schwenn, Molly
    Apolo, Andrea B.
    Karagas, Margaret R.
    Tarway, McAnthony
    Johnson, Alison
    Mumy, Adam
    Schned, Alan
    Guedez, Liliana
    Jones, Michael A.
    Kida, Masatoshi
    Hosain, G. M. Monawar
    Malats, Nuria
    Kogevinas, Manolis
    Tardon, Adonina
    Serra, Consol
    Carrato, Alfredo
    Garcia-Closas, Reina
    Lloreta, Josep
    Wu, Xifeng
    Purdue, Mark
    Andriole, Gerald L., Jr.
    Grubb, Robert L., III
    Black, Amanda
    Landi, Maria T.
    Caporaso, Neil E.
    Vineis, Paolo
    Siddiq, Afshan
    Bueno-de-Mesquita, H. Bas
    Trichopoulos, Dimitrios
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Severi, Gianluca
    Weiderpass, Elisabete
    Krogh, Vittorio
    Dorronsoro, Miren
    Travis, Ruth C.
    Tjonneland, Anne
    Brennan, Paul
    Chang-Claude, Jenny
    Riboli, Elio
    Prescott, Jennifer
    Chen, Constance
    De Vivo, Immaculata
    Govannucci, Edward
    Hunter, David
    Kraft, Peter
    Lindstrom, Sara
    Gapstur, Susan M.
    Jacobs, Eric J.
    Diver, W. Ryan
    Albanes, Demetrius
    Weinstein, Stephanie J.
    Virtamo, Jarmo
    Kooperberg, Charles
    Hohensee, Chancellor
    Rodabough, Rebecca J.
    Cortessis, Victoria K.
    Conti, David V.
    Gago-Dominguez, Manuela
    Stern, Mariana C.
    Pike, Malcolm C.
    Van Den Berg, David
    Yuan, Jian-Min
    Haiman, Christopher A.
    Cussenot, Olivier
    Cancel-Tassin, Geraldine
    Roupret, Morgan
    Comperat, Eva
    Porru, Stefano
    Carta, Angela
    Pavanello, Sofia
    Arici, Cecilia
    Mastrangelo, Giuseppe
    Grossman, H. Barton
    Wang, Zhaoming
    Deng, Xiang
    Chung, Charles C.
    Hutchinson, Amy
    Burdette, Laurie
    Wheeler, William
    Fraumeni, Joseph, Jr.
    Chanock, Stephen J.
    Hewitt, Stephen M.
    Silverman, Debra T.
    Rothman, Nathaniel
    Prokunina-Olsson, Ludmila
    The 19q12 Bladder Cancer GWAS Signal: Association with Cyclin E Function and Aggressive Disease2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 20, p. 5808-5818Article in journal (Refereed)
    Abstract [en]

    A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) >= 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 x 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (P-trend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models.

  • 126.
    Fåhræus, Bengt
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Renal structure and function in hypothyroidism and hyperparathyroidism: an experimental study in the pig1974Doctoral thesis, comprehensive summary (Other academic)
  • 127. Gakis, Georgios
    et al.
    Witjes, J. Alfred
    Comperat, Eva
    Cowan, Nigel C.
    De Santis, Maria
    Lebret, Thierry
    Ribal, Maria J.
    Sherif, Amir M.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    EAU Guidelines on Primary Urethral Carcinoma2013In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 64, no 5, p. 823-830Article in journal (Refereed)
    Abstract [en]

    Context: The European Association of Urology (EAU) Guidelines Group on Muscle-Invasive and Metastatic Bladder Cancer prepared these guidelines to deliver current evidence-based information on the diagnosis and treatment of patients with primary urethral carcinoma (UC).

    Objective: To review the current literature on the diagnosis and treatment of patients with primary UC and assess its level of scientific evidence.

    Evidence acquisition: A systematic literature search was performed to identify studies reporting urethral malignancies. Medline was searched using the controlled vocabulary of the Medical Subject Headings database, along with a free-text protocol.

    Evidence synthesis: Primary UC is considered a rare cancer, accounting for <1% of all malignancies. Risk factors for survival include age, tumour stage and grade, nodal stage, presence of distant metastasis, histologic type, tumour size, tumour location, and modality of treatment. Pelvic magnetic resonance imaging is the preferred method to assess the local extent of urethral tumour; computed tomography of the thorax and abdomen should be used to assess distant metastasis. In localised anterior UC, urethra-sparing surgery is an alternative to primary urethrectomy in both sexes, provided negative surgical margins can be achieved. Patients with locally advanced UC should be discussed by a multidisciplinary team of urologists, radiation oncologists, and oncologists. Patients with noninvasive UC or carcinoma in situ of the prostatic urethra and prostatic ducts can be treated with a urethra-sparing approach with transurethral resection and bacillus Calmette-Guerin (BCG). Cystoprostatectomy with extended pelvic lymphadenectomy should be reserved for patients not responding to BCG or as a primary treatment option in patients with extensive ductal or stromal involvement.

    Conclusions: The 2013 guidelines document on primary UC is the first publication on this topic by the EAU. It aims to increase awareness in the urologic community and provide scientific transparency to improve outcomes of this rare urogenital malignancy.

  • 128. Gnanapragasam, V. J.
    et al.
    Bratt, O.
    Muir, K.
    Lees, L. S.
    Huang, H. H.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Lophatananon, A.
    The Cambridge Prognostic Groups for improved prediction of disease mortality at diagnosis in primary non-metastatic prostate cancer: a validation study2018In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 16, article id 31Article in journal (Refereed)
    Abstract [en]

    Background: The purpose of this study is to validate a new five-tiered prognostic classification system to better discriminate cancer-specific mortality in men diagnosed with primary non-metastatic prostate cancer.

    Methods: We applied a recently described five-strata model, the Cambridge Prognostic Groups (CPGs 1-5), in two international cohorts and tested prognostic performance against the current standard three-strata classification of low-, intermediate- or high-risk disease. Diagnostic clinico-pathological data for men obtained from the Prostate Cancer data Base Sweden (PCBaSe) and the Singapore Health Study were used. The main outcome measure was prostate cancer mortality (PCM) stratified by age group and treatment modality.

    Results: The PCBaSe cohort included 72,337 men, of whom 7162 died of prostate cancer. The CPG model successfully classified men with different risks of PCM with competing risk regression confirming significant intergroup distinction (p < 0.0001). The CPGs were significantly better at stratified prediction of PCM compared to the current three-tiered system (concordance index (C-index) 0.81 vs. 0.77, p < 0.0001). This superiority was maintained for every age group division (p < 0.0001). Also in the ethnically different Singapore cohort of 2550 men with 142 prostate cancer deaths, the CPG model outperformed the three strata categories (C-index 0.79 vs. 0.76, p < 0.0001). The model also retained superior prognostic discrimination in the treatment sub-groups: radical prostatectomy (n =3D 20,586), C-index 0.77 vs. 074; radiotherapy (n =3D 11,872), C-index 0.73 vs. 0.69; and conservative management (n =3D 14,950), C-index 0.74 vs. 0.73. The CPG groups that sub-divided the old intermediate-risk (CPG2 vs. CPG3) and high-risk categories (CPG4 vs. CPG5) significantly discriminated PCM outcomes after radical therapy or conservative management (p < 0.0001).

    Conclusions: This validation study of nearly 75,000 men confirms that the CPG five-tiered prognostic model has superior discrimination compared to the three-tiered model in predicting prostate cancer death across different age and treatment groups. Crucially, it identifies distinct sub-groups of men within the old intermediate-risk and high-risk criteria who have very different prognostic outcomes. We therefore propose adoption of the CPG model as a simple-to-use but more accurate prognostic stratification tool to help guide management for men with newly diagnosed prostate cancer.

  • 129. Grabe, Magnus J.
    et al.
    Lundström, Karl-Johan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tailored perioperative antimicrobial prophylaxis in urological surgery: myth or reality?2017In: Current Opinion in Urology, ISSN 0963-0643, E-ISSN 1473-6586, Vol. 27, no 2, p. 112-119Article, review/survey (Refereed)
    Abstract [en]

    Purpose of review The controversies surrounding perioperative antimicrobial prophylaxis (AMP) are about the use and especially misuse of antibiotics. The overall lack of evidence to facilitate a rational perioperative AMP policy in urological surgery and the postoperative infectious complications remain a challenge. Therefore, a basic tool to aid decision-making would be useful. A model based on the patients' risk factors, the level of contamination and grading of surgical procedures is discussed.

    Recent findings A series of studies have shown that infectious complications and healthcare-associated infections remain consistently at an average of 10%, with a great variation in frequency dependent on the patients' preoperative status and the type, severity and contamination level of the surgical procedure. Preoperative patient assessment and preparation are key factors for well tolerated surgery and recovery. Adherence to the guidelines appears to reduce both the prescription of antimicrobials and the total costs without risking the patient outcome. Several studies of a series of interventions such as cystoscopy, endoscopic stone surgery and selected clean-contaminated interventions give support to the model. Bacteriuria, upgrading the patient to the contaminated level, requires preoperative control.

    Summary The discussed model assists the urologists in decision-making on perioperative AMP and contributes to a responsible use of antibiotics.

  • 130. Gram, I T
    et al.
    Norat, T
    Rinaldi, S
    Dossus, L
    Lukanova, A
    Téhard, B
    Clavel-Chapelon, F
    van Gils, C H
    van Noord, P A H
    Peeters, P H M
    Bueno-de-Mesquita, H B
    Nagel, G
    Linseisen, J
    Lahmann, P H
    Boeing, H
    Palli, D
    Sacerdote, C
    Panico, S
    Tumino, R
    Sieri, S
    Dorronsoro, M
    Quirós, J R
    Navarro, C A
    Barricarte, A
    Tormo, M-J
    González, C A
    Overvad, K
    Paaske Johnsen, S
    Olsen, A
    Tjønneland, A
    Travis, R
    Allen, N
    Bingham, S
    Khaw, K-T
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Trichopoulou, A
    Kalapothaki, V
    Psaltopoulou, T
    Casagrande, C
    Riboli, E
    Kaaks, R
    Body mass index, waist circumference and waist-hip ratio and serum levels of IGF-I and IGFBP-3 in European women.2006In: Int J Obes (Lond), ISSN 0307-0565, Vol. 30, no 11, p. 1623-31Article in journal (Refereed)
  • 131. Granfors, Torvald
    et al.
    Modig, Hans
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Damber, Jan-Erik
    Tomic, Radisa
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Long-term followup of a randomized study of locally advanced prostate cancer treated with combined orchiectomy and external radiotherapy versus radiotherapy alone.2006In: J Urol, ISSN 0022-5347, Vol. 176, no 2, p. 544-7Article in journal (Refereed)
  • 132. Granfors, Torvald
    et al.
    Tomic, Radisa
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Downstaging and survival benefits of neoadjuvant radiotherapy before cystectomy for patients with invasive bladder carcinoma.2009In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 43, no 4, p. 293-299Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To compare the long-term outcomes of a series of patients treated with neoadjuvant radiotherapy combined with cystectomy against a later series of patients treated with immediate cystectomy. MATERIAL AND METHODS: A total of 187 consecutive patients, surgically treated with cystectomy due to cT1-3 transitional cell bladder carcinoma with (n=90) or without (n=97) neoadjuvant radiotherapy, was included in a retrospective analysis. The clinical stage at the primary bladder resection and the pathological reports after the cystectomy were re-evaluated and progression-free, disease-specific and overall survival were calculated. RESULTS: Seven of 97 (7%) patients treated without any neoadjuvant therapy had pT0 in the bladder specimen. In contrast, 51 of 90 patients (57%) treated with neoadjuvant radiotherapy downstaged to pT0. Among cT3 tumours none of 16 patients (0%) treated without radiotherapy downstaged to pT0, while 19 (56%) of 34 patients treated with radiotherapy did so. The progression-free survival was significantly longer for patients with pT0 than for those with a remaining tumour (pT1-4) in the cystectomy specimen (p<0.001). A high T stage correlated with adverse overall survival. Patients with cT3 tumours treated with neoadjuvant radiotherapy followed by cystectomy had significantly longer disease-specific survival time (p=0.007) than those undergoing cystectomy only. In a Cox regression analysis, cT stage as well as pT stage and occurrence of carcinoma in situ in the cystectomy specimens remained as independent prognostic factors. CONCLUSIONS: In this retrospective study neoadjuvant radiotherapy before the cystectomy resulted in significant downstaging of invasive bladder transitional cell carcinoma. This downstaging was most significant for patients with cT3 tumours leading to prolonged survival.

  • 133. Grimm, Marc-Oliver
    et al.
    Bex, Axel
    De Santis, Maria
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Catto, James W. F.
    Rouprêt, Morgan
    Hussain, Syed A.
    Bellmunt, Joaquim
    Powles, Tom
    Wirth, Manfred
    Van Poppel, Hendrik
    Safe Use of Immune Checkpoint Inhibitors in the Multidisciplinary Management of Urological Cancer: The European Association of Urology Position in 20192019In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 76, no 3, p. 368-380Article, review/survey (Refereed)
    Abstract [en]

    Immune checkpoint inhibitors (ICIs) are now used routinely to treat advanced or metastatic urothelial and renal cell carcinoma, among other cancers. Furthermore, multiple trials are currently exploring their role in adjuvant, neoadjuvant, and noninvasive (eg, high-grade non-muscle-invasive bladder cancer) settings. Consequently, urologists are increasingly confronted with patients who are on, have recently received, or will be treated with ICI therapy. The care of these patients is likely to be shared between urologists and medical oncologists, with additional occasional support of other medical specialties. Therefore, it is important that urologists have good knowledge of immune-related side effects. Here, we provide advice on prevention, early diagnosis, and clinical management of the most relevant toxicities to strengthen urologists' insight and, thus, role in the multidisciplinary management in the new immunotherapy era. Patient summary: Immune therapy is a common treatment for many patients with advanced cancer. We describe common side effects of this treatment, and advise how they are best prevented and managed.

  • 134.
    Groth, Maria
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Resursförbrukning vid utredning, behandling och uppföljning av urinblåsecancer2016Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 135. Grotta, Alessandra
    et al.
    Bottai, Matteo
    Adami, Hans-Olov
    Adams, Swann Arp
    Akre, Olof
    Blair, Steven Noel
    Mariosa, Daniela
    Nyrén, Olof
    Ye, Weimin
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bellocco, Rino
    Trolle Lagerros, Ylva
    Physical activity and body mass index as predictors of prostate cancer risk2015In: World journal of urology, ISSN 0724-4983, E-ISSN 1433-8726, Vol. 33, no 10, p. 1495-1502Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Physical activity and body mass index (BMI) are involved in prostate cancer etiology; possible biologic mechanisms include their effects on hormonal levels. Our aim was to investigate the relationship between physical activity, obesity, and prostate cancer.

    METHODS: We followed a cohort of 13,109 Swedish men for 13 years and investigated the association of self-reported physical activity and BMI at baseline with prostate cancer incidence. We further analyzed whether BMI could modulate effects of physical activity. Occupational, recreational, and total physical activity were analyzed in relation to overall, localized, and advanced prostate cancer.

    RESULTS: During the study follow-up, we observed a total of 904 cases of prostate cancer (429 localized, 407 advanced, and 68 unclassified). High levels of occupational physical activity were associated with a nonsignificantly decreased risk of overall (HR 0.81, 95 % CI 0.61-1.07), localized (HR 0.75, 95 % CI 0.51-1.12), and advanced (HR 0.85, 95 % CI 0.55-1.31) prostate cancer. We found no association between high BMI and risk of prostate cancer incidence: We observed, however, a significant interaction between BMI and leisure physical activity.

    CONCLUSION: No association was confirmed between total physical activity and localized or advanced prostate cancer. The highest, relative to the lowest, level of occupational physical activity tended to be linked to a lower risk of prostate cancer, with a suggested dose-response relationship. We found no association between high BMI and risk of prostate cancer incidence; however, our analyses suggested an interaction between BMI and physical activity during recreational time that merits further investigation in future studies.

  • 136. Grundmark, B.
    et al.
    Garmo, H.
    Zethelius, B.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lambe, M.
    Holmberg, L.
    Anti-androgen prescribing patterns, patient treatment adherence and influencing factors; results from the nationwide PCBaSe Sweden2012In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 68, no 12, p. 1619-1630Article in journal (Refereed)
    Abstract [en]

    Adherence has not been studied in male oncology populations. The aim of this study on both the prescriber and user perspectives in prostate cancer treatment was to analyse real-life prescribing patterns of anti-androgens (AA), primarily bicalutamide, and factors influencing the patients' adherence to treatment. A nationwide clinical cohort of incident prostate cancer, PCBaSe, was linked to the Swedish Prescribed Drug Register. Men with a planned first line monotherapy AA treatment were identified; dosages and extent of off-label treatment were investigated. Cumulative incidence proportions for reasons for drug discontinuation were calculated. Factors potentially influencing adherence were explored using the medical possession ratio based on the individual prescribed daily dose. First line monotherapy AA was planned in 4.4 % of all incident cases and in 2.1 % of low risk disease cases. Among 1,406 men prescribed bicalutamide, 1,109 (79 %) received the approved daily dose of 150 mg. Discontinuation reasons differed with disease severity. Off-label, low-dose prescription associated with age above 75 years and disease categorised as low risk was noted in 297 men (21 %). Sixty percent of the men adhered well, i.e. to a parts per thousand yen80 %. Age above 75 years and less severe disease were both negatively associated with adherence. Patient age and tumour risk group influenced the prescriber's choice of dose, pointing to important issues for critical reflection. Possible over-treatment was noted in low risk disease. Interventions to increase adherence in older men and in men with less severe disease are worth considering after critically reviewing the appropriateness of the treatment indication, especially in the latter case.

  • 137.
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prostate cancer: epidemiological studies1995Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Prostate cancer is a large and increasing medical problem both in Sweden and in the rest of the developed world, with about 300.000 new cases diagnosed world wide annually. Despite the high incidence of this disease, little is known about the aetiology of prostate cancer. The aim of this study was to try to understand more about the natural history and to find possible a etiological risk factors for this tumour.

    In a population based study of prostate cancer cases in northern Sweden it was found that the large increase in prostate cancer during the last two decades was mainly caused by well (Gl) and moderately (G2) differentiated tumours. However, the incidence of poorly differentiated (G3) tumours remained unchanged. The introduction of new diagnostic methods is the most plausible explanation for the increase of these low grade tumours.

    The relative survival in prostate cancer was found to be independent of patient age at diagnosis, indicating that tumour proliferation and the aggressiveness of this disease is equal in all ages. However, due to the increasing occurrence of concurrent diseases with growing age the number of lost years caused by prostate cancer decreases dramatically in older age groups. The overall cause specific mortality for prostate cancer was found to be around 50%. In accordance with most other cancer tumours, the annual mortality rate decreased with longer survival also for prostate cancer patients.

    In a study from the Swedish Twin Register it was found that the proband concordance rates for prostate cancer were 4,5 time greater among monozygotic compared to dizygotic twins. In a large nation-wide cohort study of men who had a father with prostate cancer, the overall standardised incidence ratio (SIR) was 1.70 for prostate cancer. Younger age at diagnosis among the fathers were associated with an increased risk among sons. This cohort study and the twin study indicates that both inherited and familial factors are of importance in a subgroup of prostate cancer patients.

    In a prospective case-control study, both a high body mass index (BMI) and a high food intake were found to be independent risk factors for prostate cancer. Both BMI and a high food intake might be indicators of a high fat diet, which so far is the most consistent exogenous risk factor for prostate cancer. The use of tobacco or alcoholic beverages were not associated with prostate cancer risk.

  • 138. Gu, Fangyi
    et al.
    Schumacher, Fredrick R
    Canzian, Federico
    Allen, Naomi E
    Albanes, Demetrius
    Berg, Christine D
    Berndt, Sonja I
    Boeing, Heiner
    Bueno-de-Mesquita, H Bas
    Buring, Julie E
    Chabbert-Buffet, Nathalie
    Chanock, Stephen J
    Clavel-Chapelon, Françoise
    Dumeaux, Vanessa
    Gaziano, J Michael
    Giovannucci, Edward L
    Haiman, Christopher A
    Hankinson, Susan E
    Hayes, Richard B
    Henderson, Brian E
    Hunter, David J
    Hoover, Robert N
    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.
    Key, Timothy J
    Khaw, Kay-Tee
    Kolonel, Laurence N
    Lagiou, Pagona
    Lee, I-Min
    LeMarchand, Loic
    Lund, Eiliv
    Ma, Jing
    Onland-Moret, N Charlotte
    Overvad, Kim
    Rodriguez, Laudina
    Sacerdote, Carlotta
    Sánchez, Maria-José
    Stampfer, Meir J
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stram, Daniel O
    Thomas, Gilles
    Thun, Michael J
    Tjønneland, Anne
    Trichopoulos, Dimitrios
    Tumino, Rosario
    Virtamo, Jarmo
    Weinstein, Stephanie J
    Willett, Walter C
    Yeager, Meredith
    Zhang, Shumin M
    Kaaks, Rudolf
    Riboli, Elio
    Ziegler, Regina G
    Kraft, Peter
    Eighteen insulin-like growth factor pathway genes, circulating levels of IGF-I and its binding protein, and risk of prostate and breast cancer2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 11, p. 2877-2887Article in journal (Refereed)
    Abstract [en]

    Background: Circulating levels of insulin-like growth factor I (IGF-I) and its main binding protein, IGF binding protein 3 (IGFBP-3), have been associated with risk of several types of cancer. Heritable factors explain up to 60% of the variation in IGF-I and IGFBP-3 in studies of adult twins.

    Methods: We systematically examined common genetic variation in 18 genes in the IGF signaling pathway for associations with circulating levels of IGF-I and IGFBP-3. A total of 302 single nucleotide polymorphisms (SNP) were genotyped in >5,500 Caucasian men and 5,500 Caucasian women from the Breast and Prostate Cancer Cohort Consortium.

    Results: After adjusting for multiple testing, SNPs in the IGF1 and SSTR5 genes were significantly associated with circulating IGF-I (P < 2.1 × 10−4); SNPs in the IGFBP3 and IGFALS genes were significantly associated with circulating IGFBP-3. Multi-SNP models explained R2 = 0.62% of the variation in circulating IGF-I and 3.9% of the variation in circulating IGFBP-3. We saw no significant association between these multi-SNP predictors of circulating IGF-I or IGFBP-3 and risk of prostate or breast cancers.

    Conclusion: Common genetic variation in the IGF1 and SSTR5 genes seems to influence circulating IGF-I levels, and variation in IGFBP3 and IGFALS seems to influence circulating IGFBP-3. However, these variants explain only a small percentage of the variation in circulating IGF-I and IGFBP-3 in Caucasian men and women.

    Impact: Further studies are needed to explore contributions from other genetic factors such as rare variants in these genes and variation outside of these genes.

  • 139. Gudmundsson, E. O.
    et al.
    Erikson, S.
    Hosseinnia, S.
    Lundstam, S.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Significant regional differences in the treatment of small renal cancers in Sweden2012In: European urology. Supplement, ISSN 1569-9056, E-ISSN 1878-1500, Vol. 11, no 1, p. E135-E135Article in journal (Other academic)
  • 140. Gudmundsson, Julius
    et al.
    Sulem, Patrick
    Rafnar, Thorunn
    Bergthorsson, Jon T
    Manolescu, Andrei
    Gudbjartsson, Daniel
    Agnarsson, Bjarni A
    Sigurdsson, Asgeir
    Benediktsdottir, Kristrun R
    Blondal, Thorarinn
    Jakobsdottir, Margret
    Stacey, Simon N
    Kostic, Jelena
    Kristinsson, Kari T
    Birgisdottir, Birgitta
    Ghosh, Shyamali
    Magnusdottir, Droplaug N
    Thorlacius, Steinunn
    Thorleifsson, Gudmar
    Zheng, S Lilly
    Sun, Jielin
    Chang, Bao-Li
    Elmore, J Bradford
    Breyer, Joan P
    McReynolds, Kate M
    Bradley, Kevin M
    Yaspan, Brian L
    Wiklund, Fredrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Lindström, Sara
    Adami, Hans-Olov
    McDonnell, Shannon K
    Schaid, Daniel J
    Cunningham, Julie M
    Wang, Liang
    Cerhan, James R
    St Sauver, Jennifer L
    Isaacs, Sara D
    Wiley, Kathleen E
    Partin, Alan W
    Walsh, Patrick C
    Polo, Sonia
    Ruiz-Echarri, Manuel
    Navarrete, Sebastian
    Fuertes, Fernando
    Saez, Berta
    Godino, Javier
    Weijerman, Philip C
    Swinkels, Dorine W
    Aben, Katja K
    Witjes, J Alfred
    Suarez, Brian K
    Helfand, Brian T
    Frigge, Michael L
    Kristjansson, Kristleifur
    Ober, Carole
    Jonsson, Eirikur
    Einarsson, Gudmundur V
    Xu, Jianfeng
    Gronberg, Henrik
    Smith, Jeffrey R
    Thibodeau, Stephen N
    Isaacs, William B
    Catalona, William J
    Mayordomo, Jose I
    Kiemeney, Lambertus A
    Barkardottir, Rosa B
    Gulcher, Jeffrey R
    Thorsteinsdottir, Unnur
    Kong, Augustine
    Stefansson, Kari
    Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer.2008In: Nat Genet, ISSN 1546-1718, Vol. 40, no 3, p. 281-3Article in journal (Refereed)
  • 141. Guomundsson, Eirikur
    et al.
    Hellborg, Henrik
    Lundstam, Sven
    Erikson, Stina
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Metastatic potential in renal cell carcinomas <= 7 cm: swedish kidney cancer quality register data2011In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 60, no 5, p. 975-982Article in journal (Refereed)
    Abstract [en]

    Background: Renal cell carcinoma(RCC) represents 2-3% of all malignancies and accounts for approximately 90% of all kidney malignancies. An increasing proportion of RCCs are discovered incidentally, and the average tumor diameter at diagnosis has decreased over the last few decades. Small RCCs have often been regarded by many as relatively harmless.

    Objective: The objective was to evaluate the incidence of local T-category distribution and lymph node and distant metastases in relation to tumor size in RCCs <= 7 cm in a nationally based patient population. Design, setting, and participants: Data were extracted from the National Swedish Kidney Cancer Register containing 3489 RCCs diagnosed between 2005 and 2008. This is a population-based registry including 99% of all RCCs diagnosed nationwide. The study included 2033 patients having a tumor <= 7 cm in diameter.

    Measurements: The size of the tumors was compared with sex, age, cause of diagnosis, Fuhrman grade, RCC type, and TNM category.

    Results and limitations: Most RCCs were discovered incidentally and incidence correlated inversely to tumor size. There were 887 (43%) patients with category T1a tumors, 836 (40%) with category T1b, 174 (8%) with T3a, 131 (6%) with T3b/c, and 12 (1%) patients had invasion of adjacent organs (T4). A total of 309 (15%) patients had lymph node and/or distant metastases. Of the 177 1- to 2-cm RCCs, category T3 tumors were identified in three patients and lymph node and/or distant metastases were identified in 8 (5%). Only for tumors <= 1 cm was there neither advanced stage nor metastasis. The occurrence of locally advanced growth, lymph node and distant metastases, and high tumor grade correlated to tumor size. Patients with Fuhrman grade III or IV had a fourfold greater risk of metastases than grades I or II.

    Conclusions: Lymph node and distant metastases occur even in small RCCs. Risk of metastases increases with tumor size. The data clearly show that small RCCs also have a malignant potential and should be properly evaluated and adequately treated. (C) 2011 European Association of Urology. Published by Elsevier B. V. All rights reserved.

  • 142. Gusev, Alexander
    et al.
    Shi, Huwenbo
    Kichaev, Gleb
    Pomerantz, Mark
    Li, Fugen
    Long, Henry W
    Ingles, Sue A
    Kittles, Rick A
    Strom, Sara S
    Rybicki, Benjamin A
    Nemesure, Barbara
    Isaacs, William B
    Zheng, Wei
    Pettaway, Curtis A
    Yeboah, Edward D
    Tettey, Yao
    Biritwum, Richard B
    Adjei, Andrew A
    Tay, Evelyn
    Truelove, Ann
    Niwa, Shelley
    Chokkalingam, Anand P
    John, Esther M
    Murphy, Adam B
    Signorello, Lisa B
    Carpten, John
    Leske, M Cristina
    Wu, Suh-Yuh
    Hennis, Anslem J M
    Neslund-Dudas, Christine
    Hsing, Ann W
    Chu, Lisa
    Goodman, Phyllis J
    Klein, Eric A
    Witte, John S
    Casey, Graham
    Kaggwa, Sam
    Cook, Michael B
    Stram, Daniel O
    Blot, William J
    Eeles, Rosalind A
    Easton, Douglas
    Kote-Jarai, ZSofia
    Al Olama, Ali Amin
    Benlloch, Sara
    Muir, Kenneth
    Giles, Graham G
    Southey, Melissa C
    Fitzgerald, Liesel M
    Gronberg, Henrik
    Wiklund, Fredrik
    Aly, Markus
    Henderson, Brian E
    Schleutker, Johanna
    Wahlfors, Tiina
    Tammela, Teuvo L J
    Nordestgaard, Børge G
    Key, Tim J
    Travis, Ruth C
    Neal, David E
    Donovan, Jenny L
    Hamdy, Freddie C
    Pharoah, Paul
    Pashayan, Nora
    Khaw, Kay-Tee
    Stanford, Janet L
    Thibodeau, Stephen N
    McDonnell, Shannon K
    Schaid, Daniel J
    Maier, Christiane
    Vogel, Walther
    Luedeke, Manuel
    Herkommer, Kathleen
    Kibel, Adam S
    Cybulski, Cezary
    Wokolorczyk, Dominika
    Kluzniak, Wojciech
    Cannon-Albright, Lisa
    Teerlink, Craig
    Brenner, Hermann
    Dieffenbach, Aida K
    Arndt, Volker
    Park, Jong Y
    Sellers, Thomas A
    Lin, Hui-Yi
    Slavov, Chavdar
    Kaneva, Radka
    Mitev, Vanio
    Batra, Jyotsna
    Spurdle, Amanda
    Clements, Judith A
    Teixeira, Manuel R
    Pandha, Hardev
    Michael, Agnieszka
    Paulo, Paula
    Maia, Sofia
    Kierzek, Andrzej
    Conti, David V
    Albanes, Demetrius
    Berg, Christine
    Berndt, Sonja I
    Campa, Daniele
    Crawford, E David
    Diver, W Ryan
    Gapstur, Susan M
    Gaziano, J Michael
    Giovannucci, Edward
    Hoover, Robert
    Hunter, David J
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Kraft, Peter
    Le Marchand, Loic
    Lindström, Sara
    Navarro, Carmen
    Overvad, Kim
    Riboli, Elio
    Siddiq, Afshan
    Stevens, Victoria L
    Trichopoulos, Dimitrios
    Vineis, Paolo
    Yeager, Meredith
    Trynka, Gosia
    Raychaudhuri, Soumya
    Schumacher, Frederick R
    Price, Alkes L
    Freedman, Matthew L
    Haiman, Christopher A
    Pasaniuc, Bogdan
    Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 10979Article in journal (Refereed)
    Abstract [en]

    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

  • 143. Gustafsson, Anna
    et al.
    Boström, Anna-Karin
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Axelson, Håkan
    Dahlbäck, Björn
    Gas6 and the receptor tyrosine kinase Axl in clear cell renal cell carcinoma.2009In: PloS one, ISSN 1932-6203, Vol. 4, no 10, p. e7575-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The molecular biology of renal cell carcinoma (RCC) is complex and not fully understood. We have recently found that the expression of the receptor tyrosine kinase Axl in the RCC tumors independently correlates with survival of the patients. PRINCIPAL FINDINGS: Here, we have investigated the role of Axl and its ligand Gas6, the vitamin-K dependent protein product of the growth arrest-specific gene 6, in clear cell RCC (ccRCC) derived cells. The Axl protein was highly expressed in ccRCC cells deficient in functional von Hippel-Lindau (VHL) protein, a tumor suppressor gene often inactivated in ccRCC. VHL reconstituted cells expressed decreased levels of Axl protein, but not Axl mRNA, suggesting VHL to regulate Axl expression. Gas6-mediated activation of Axl in ccRCC cells resulted in Axl phosphorylation, receptor down-regulation, decreased cell-viability and migratory capacity. No effects of the Gas6/Axl system could be detected on invasion. Moreover, in ccRCC tumor tissues, Axl was phosphorylated and Gas6 gamma-carboxylated, suggesting these molecules to be active in vivo. SIGNIFICANCE: These results provide novel information regarding the complex function of the Gas6/Axl system in ccRCC.

  • 144. Gustafsson, Anna
    et al.
    Martuszewska, Danuta
    Johansson, Martin
    Ekman, Carl
    Hafizi, Sassan
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Dahlbäck, Björn
    Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival2009In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 15, no 14, p. 4742-4749Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Overexpression of the receptor tyrosine kinase Axl is implicated in several cancers. Therefore, we conducted this study to determine the expression of Axl and its ligand Gas6 in various renal cell carcinoma (RCC) types and in oncocytoma.

    EXPERIMENTAL DESIGN: Real-time quantitative reverse transcription-PCR was used to quantify tumor mRNA levels for Axl and Gas6 in a cohort (n = 221) of RCC patients. Serum levels of soluble sAxl and Gas6 proteins were measured using specific ELISA assays (n = 282). The presence of Axl protein in tumor tissue was evaluated by immunohistochemistry (n = 294). Results were correlated to tumor-associated variables, clinical biochemical tests, and patient survival.

    RESULTS: Tumor Axl mRNA levels correlated independently to survival when assessed against tumor stage and grade. In the study group, the median cancer-specific survival of all RCC patients during 307 months of follow-up was 55 months (confidence interval, +/-40.4). The 25% of patients with lowest tumor Axl mRNA levels had significantly better survival than the rest (P = 0.0005), with 70% of the patients still alive at the end of follow-up. In contrast, in patients with medium-high Axl mRNA, only 25% were alive at the end of follow-up. Tumor Gas6 mRNA levels correlated to survival, tumor-associated variables, and disease severity as did serum levels of soluble sAxl and Gas6 protein. However, no correlation between Axl protein in tumor tissue and survival was found.

    CONCLUSIONS: Axl and Gas6 expression in RCC are associated with tumor advancement and patient survival. In particular, low tumor Axl mRNA levels independently correlated with improved survival.

  • 145.
    Hagel, Eva
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Garmo, Hans
    Bill-Axelson, Anna
    Bratt, Ola
    Johansson, Jan-Erik
    Adolfsson, Jan
    Lambe, Mats
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    PCBaSe Sweden: a register-based resource for prostate cancer research2009In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 43, no 5, p. 342-349Article in journal (Refereed)
    Abstract [en]

    Objective. To construct a database for clinical epidemiological prostate cancer research based on linkages between the National Prostate Cancer Register (NPCR) of Sweden, a population-based, nationwide quality database, and other nationwide registries. Material and methods. By use of the individually unique Swedish Personal Identity Number, the NPCR was linked to the Swedish Cancer Registry, the Cause of Death Register, the Prescribed Drug Register, the National Patient Register and the Acute Myocardial Infarction Register, all held at the Centre for Epidemiology at the National Board of Health and Welfare, and the Register of the Total Population, the Longitudinal Integration Database for Health Insurance and Labor Market Studies and the Multi-Generation Register, held at Statistics Sweden, and to the Swedish Hernia Register. Results. Record linkages between the NPCR and the Swedish Cancer Registry, the Cause of Death Register and the Register of the Total Population generated a database, named PCBaSe Sweden, including 80 079 prostate cancer cases, diagnosed between 1 January 1996 and 31 December 2006. Record linkage between PCBaSe Sweden and the Prescribed Drug Register generated 59 721 unique matches and linkage to the Acute Myocardial Infarction Register resulted in 11 459 matches. Conclusion. PCBaSe Sweden is a newly created and unique database with over 80 000 cases of prostate cancer with comprehensive data on inpatient and outpatient care, patterns of use of prescribed drugs and socioeconomic and familial factors. Many topics in clinical prostate cancer epidemiology can be investigated. using PCBaSe Sweden.

  • 146.
    Halin Bergström, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nilsson, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Adamo, Hanibal
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jernberg, Emma
    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.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Extratumoral Heme Oxygenase-1 (HO-1) Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, article id e0157280Article in journal (Refereed)
    Abstract [en]

    Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1). To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RTPCR showed that the main site of HO-1 synthesis was HO-1(+) macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1(+) macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1(+) macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1(+) macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1(+) macrophages may have an important role in prostate cancer.

  • 147.
    Halin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Doll, Jennifer A
    Crawford, Susan E
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pigment epithelium-derived factor stimulates tumor macrophage recruitment and is downregulated by the prostate tumor microenvironment2010In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 12, no 4, p. 336-345Article in journal (Refereed)
    Abstract [en]

    Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis but whether it has additional effects on the tumor microenvironment is largely unexplored. We show that overexpression of PEDF in orthotopic MatLyLu rat prostate tumors increased tumor macrophage recruitment. The fraction of macrophages expressing inducible nitric oxide synthase, a marker of cytotoxic M1 macrophages, was increased, suggesting that PEDF could enhance antitumor immunity. In addition, PEDF overexpression reduced vascular growth both in the tumor and in the surrounding normal tissue, slowed tumor growth, and decreased lymph node metastasis. Contrary, extratumoral lymphangiogenesis was increased. PEDF expression is, for reasons unknown, often decreased or lost during prostate tumor progression. When AT-1 rat prostate tumor cells, expressing high levels of PEDF messenger RNA (mRNA) and protein, were injected into the prostate, PEDF is markedly downregulated, suggesting that factors in the microenvironment suppressed its expression. One such factor could be macrophage-derived tumor necrosis factor alpha (TNFα). A fraction of the accumulating macrophages expressed TNFα, and TNFα treatment downregulated the expression of PEDF protein and mRNA in prostate AT-1 tumor cells in vitro and in the rat ventral prostate in vivo. PEDF apparently has multiple effects in prostate tumors: it suppresses angiogenesis and metastasis, but it also causes macrophage accumulation. Accumulating macrophages may inhibit tumor growth, but they may also suppress PEDF and enhance lymph angiogenesis and, in this way, eventually enhance tumor growth.

  • 148.
    Halin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Häggström Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Van Rooijen, Nico
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Extratumoral macrophages promote tumor and vascular growth in an orthotopic rat prostate tumor model.2009In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 11, no 2, p. 177-186Article in journal (Refereed)
    Abstract [en]

    Tumor-associated macrophages are involved in angiogenesis and tumor progression, but their role and specific site of action in prostate cancer remain unknown. To explore this, Dunning R-3327 AT-1 rat prostate tumor cells were injected into the prostate of syngenic and immunocompetent Copenhagen rats and analyzed at different time points for vascular proliferation and macrophage density. Endothelial proliferation increased with tumor size both in the tumor and importantly also in the extratumoral normal prostate tissue. Macrophages accumulated in the tumor and in the extratumoral normal prostate tissue and were most abundant in the invasive zone. Moreover, only extratumoral macrophages showed strong positive associations with tumor size and extratumoral vascular proliferation. Treatment with clodronate-encapsulated liposomes reduced the monocyte/macrophage infiltration and resulted in a significant inhibition of tumor growth. This was accompanied by a suppressed proliferation in microvessels and in the extratumoral prostate tissue also in arterioles and venules. The AT-1 tumors produced, as examined by RT(2) Profiler PCR arrays, numerous factors promoting monocyte recruitment, angiogenesis, and tissue remodeling. Several, namely, chemokine (C-C) ligand 2, fibroblast growth factor 2, matrix metalloproteinase 9, interleukin 1beta, interferon gamma, and transforming growth factor beta, were highly upregulated by the tumor in vivo compared with tumor cells in vitro, suggesting macrophages as a plausible source. In conclusion, we here show the importance of extratumoral monocytes/macrophages for prostate tumor growth, angiogenesis, and extratumoral arteriogenesis. Our findings identify tumor-associated macrophages and several chemotactic and angiogenic factors as potential targets for prostate cancer therapy.

  • 149.
    Halin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Rudolfsson, Stina
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Doll, Jennifer A
    Crawford, Susan E
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Decreased pigment epithelium-derived factor is associated with metastatic phenotype in human and rat prostate tumors.2004In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 64, no 16, p. 5664-71Article in journal (Refereed)
  • 150.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Halin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Häggström Rudolfsson, Stina
    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.
    Inhibitory effects of castration in an orthotopic model of androgen-independent prostate cancer can be mimicked and enhanced by angiogenesis inhibition.2006In: Clinical Cancer Research, ISSN 1078-0432, Vol. 12, no 24, p. 7431-7436Article in journal (Refereed)
1234567 101 - 150 of 647
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