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  • 601. Verheus, Martijn
    et al.
    McKay, James D
    Kaaks, Rudolf
    Canzian, Federico
    Biessy, Carine
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Grobbee, Diederick E
    Peeters, Petra H M
    van Gils, Carla H
    Common genetic variation in the IGF-1 gene, serum IGF-I levels and breast density2008In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 112, no 1, p. 109-122Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: High breast density is one of the strongest known risk factors for developing breast cancer. Insulin-like growth factor I (IGF-I) is a strong mitogen and has been suggested to increase breast cancer risk by increasing the amount of dense tissue in the female breast. OBJECTIVES: We wanted to investigate the effect of common variation in the IGF-1 gene on serum IGF-I levels and on breast density. DESIGN AND METHODS: Mammograms and blood samples of 1,928 premenopausal participants of the Dutch Prospect-EPIC cohort were collected at baseline. Using a haplotype tagging approach, 16 single nucleotide polymorphisms (SNP) from three blocks covering the IGF-1 gene were genotyped in all study participants. Breast density was assessed using a quantitative computer-assisted method. For a subgroup of women, who went through menopause within 5 years after recruitment (n=656), premenopausal IGF-I levels and additionally postmenopausal breast density were determined. False positive report probabilities (FPRP) for statistically significant relations were calculated using the Wacholder method. RESULTS: The minor alleles of five SNPs in block 3 were significantly associated with elevated levels of IGF-I (rs9989002, rs2033178, rs7136446, rs978458, rs6220; P-values: 0.01-0.04). The same SNPs were related with modestly higher percent breast density before menopause and-in the subgroup of women that became postmenopausal during follow-up-with a modestly higher percent breast density after menopause. The most significant result, i.e. the relation between rs6220 and IGF-I levels, had an FPRP<0.5 assuming prior probabilities of 0.01 and higher. CONCLUSION: Common genetic variation in the IGF-1 gene is related to circulating levels of IGF-I, but the relationship with breast density is indecisive.

  • 602. Verhoest, G
    et al.
    Patard, Jj
    Oger, E
    Rioux-Leclercq, N
    Peyronnet, Benoit
    Bessède, T
    Laguna, P
    Barwari, K
    Rigaud, J
    Roupret, M
    Coffin, G
    Bernhard, Jc
    Long, Ja
    Zisman, A
    Berger, J
    Paparel, P
    Maurin, C
    Lechevallier, E
    Bertini, R
    Ouzaid, I
    Salomon, L
    Bex, A
    Farfara, R
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Rodriguez, A R
    Bensalah, K
    Predictive factors of chronic kidney disease stage V after partial nephrectomy in a solitary kidney: a multi-institutional study2014In: Urologic Oncology, ISSN 1078-1439, E-ISSN 1873-2496, Vol. 32, no 1, p. 28.e21-28.e26Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Partial Nephrectomy (PN) in a solitary kidney is at risk of chronic kidney disease (CKD) stage V and/or haemodialysis (HD). Our objective was to determine predictive factors of CKD stage V in this population. MATERIAL & METHODS: Data from 300 patients were retrospectively collected from 16 tertiary centres. Clinical and operative parameters, tumor characteristics and renal function before surgery were analyzed. Patients with and without CKD stage V (defined as MDRD<15ml/min) were compared using χ2 and Student-t tests for qualitative and quantitative variables, respectively. Predictive factors of CKD stage V were evaluated with a multivariable analysis using a Cox regression model. RESULTS: Median age and BMI were 63 years old and 26kg/m², respectively. Most of the patients (65%) were male with an anatomic solitary kidney (88.3%). Median tumor size was 4cm and 98% were malignant tumors. Median operative time, blood loss and clamping time were 180min, 350ml and 20min respectively. Renal cooling was used in 19.3% and clamping of the pedicle was performed in 61.6%. Twenty five patients (8.5%) presented post operative CKD stage V at last follow-up and 18 underwent HD (6%) post-operatively because of acute renal insufficiency. There was no difference between CKD stage V and non CKD stage V patients concerning Charlson index, operative time (180min vs 179min, p= 0.39), blood loss (475ml vs 350ml, p= 0.51), use of renal cooling and type of clamping. Patients with CKD stage V were older (70 vs 63 years old, p= 0.005), had a lower baseline renal function (clearance MDRD 41 vs. 62ml/min, p<0.0001) and an increased tumor size (p= 0.02). Complications occurred in 91 patients (30%) with 16% of minor (Clavien 1-2) and 14% of major (Clavien>2) complications, respectively. In multivariable analysis, baseline MDRD, BMI, and the occurrence of a minor complication were independent predictive factors of post operative CKD stage V. CONCLUSION: PN in a solitary kidney is at risk of post-operative CKD stage V and HD. Pre-operative altered renal function and post operative complications are the main predictive factors of permanent CKD stage V.

  • 603. Vogel, Christian
    et al.
    Ziegelmueller, Brigitte
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bensalah, Karim
    Bex, Axel
    Canfield, Steven
    Giles, Rachel H.
    Hora, Milan
    Kuczyk, Markus A.
    Merseburger, Axel S.
    Powles, Thomas
    Albiges, Laurence
    Stewart, Fiona
    Volpe, Allseandro
    Graser, Anno
    Schlemmer, Marcus
    Yuan, C.
    Lam, Thomas
    Staehler, Michael
    Imaging in Suspected Renal-Cell Carcinoma: Systematic Review2019In: Clinical Genitourinary Cancer, ISSN 1558-7673, E-ISSN 1938-0682, Vol. 17, no 2, p. E345-E355Article, review/survey (Refereed)
    Abstract [en]

    Objective: To systematically assessed the diagnostic performance of contrast-enhanced computed tomography (CT) compared to other imaging modalities for diagnosing and staging renal-cell carcinoma in adults.

    Methods: A comprehensive literature search was conducted through various electronic databases. Data from the selected studies were extracted and pooled, and median sensitivity and specificity were calculated wherever possible. Forty studies analyzing data of 4354 patients were included. They examined CT, magnetic resonance imaging (MRI), positron emission tomography-CT, and ultrasound (US).

    Results: For CT, median sensitivity and specificity were 88% (interquartile range [IQR] 81%-94%) and 75% (IQR 51%-90%), and for MRI they were 87.5% (IQR 75.25%-100%) and 89% (IQR 75%-96%). Staging sensitivity and specificity for CT were 87% and 74.5%, while MRI showed a median sensitivity of 90% and specificity of 75%. For US, the results varied greatly depending on the corresponding technique. Contrast-enhanced US had a median diagnostic sensitivity of 93% (IQR 88.75%-98.25%) combined with mediocre specificity. The diagnostic performance of unenhanced US was poor. For positron emission tomography-CT, diagnostic accuracy values were good but were based on only a small amount of data. Limitations include the strong heterogeneity of data due to the large variety in imaging techniques and tumor histotypes. Contrast-enhanced CT and MRI remain the diagnostic mainstay for renal-cell carcinoma, with almost equally high diagnostic and staging accuracy.

    Conclusion: For specific questions, a combination of different imaging techniques such as CT or MRI and contrast-enhanced US may be useful. There is a need for future large prospective studies to further increase the quality of evidence.

  • 604.
    Vollmer, Tino
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin-Brandenburg School for Regenerative Therapies (BSRT) & Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Berlin, Germany.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Jankowski, Vera
    Jankowski, Joachim
    Glorieux, Griet
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    An in-vitro assay using human spermatozoa to detect toxicity of biologically active substances2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 14525Article in journal (Refereed)
    Abstract [en]

    Identifying the key toxic players within an in-vivo toxic syndrome is crucial to develop targeted therapies. Here, we established a novel method that characterizes the effect of single substances by means of an ex-vivo incubation set-up. We found that primary human spermatozoa elicit a distinct motile response on a (uremic) toxic milieu. Specifically, this approach describes the influence of a bulk toxic environment (uremia) as well as single substances (uremic toxins) by real-time analyzing motile cellular behavior. We established the human spermatozoa-based toxicity testing (HSTT) for detecting single substance-induced toxicity to be used as a screening tool to identify in-vivo toxins. Further, we propose an application of the HSTT as a method of clinical use to evaluate toxin-removing interventions (hemodialysis).

  • 605. Wahlgren, T.
    et al.
    Harmenberg, U.
    Sandström, P.
    Lundstam, S.
    Kowalski, J.
    Jakobsson, M.
    Sandin, R.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Treatment and overall survival in renal cell carcinoma: a Swedish population-based study (2000-2008)2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, no 7, p. 1541-1549Article in journal (Refereed)
    Abstract [en]

    Background: This retrospective register study assessed overall survival (OS) and influential factors on OS in Swedish renal cell carcinoma (RCC) patients.

    Methods: Using three merged national health registers, Cox proportional-hazards analysis was conducted and, in three models, it was used to assess the impact of cytokine (interferon-α and tyrosine kinase inhibitor (TKI; sunitinib or sorafenib) treatment on OS in metastatic (m)RCC.

    Results: From 2000 to 2008, 8009 patients were diagnosed with RCC and 2753 with mRCC (2002-2008). Median OS in RCC patients diagnosed from 2006 to 2008 compared with 2000-2005 was not reached vs 47.9 months (P<0.001), and in mRCC patients diagnosed from 2006 to 2008 compared with 2002-2005, was 12.4 vs 9.6 months, respectively (P=0.004). Factors associated with significantly improved OS in RCC were female gender, lower age, and previous nephrectomy, and, in mRCC female gender, previous nephrectomy, and any TKI prescription (Model 1: median-adjusted OS, 19.4 months (TKI patients) vs 9.7 months (non-TKI patients); hazard ratio, 0.621; P<0.001).

    Conclusion: OS was improved in Swedish patients diagnosed with RCC and mRCC in the period 2006-2008 compared with 2000-2005 (RCC) and 2002-2005 (mRCC). Although multifactorial in origin, results suggest that increased nephrectomy rates and the use of TKIs contributed to the improvement seen in mRCC patients.

  • 606. Walker, Steven M
    et al.
    Knight, Laura A
    McCavigan, Andrena M
    Logan, Gemma E
    Berge, Viktor
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Pandha, Hardev
    Warren, Anne Y
    Davidson, Catherine
    Uprichard, Adam
    Blayney, Jaine K
    Price, Bethanie
    Jellema, Gera L
    Steele, Christopher J
    Svindland, Aud
    McDade, Simon S
    Eden, Christopher G
    Foster, Chris
    Mills, Ian G
    Neal, David E
    Mason, Malcolm D
    Kay, Elaine W
    Waugh, David J
    Harkin, D Paul
    Watson, R William
    Clarke, Noel W
    Kennedy, Richard D
    Molecular Subgroup of Primary Prostate Cancer Presenting with Metastatic Biology2017In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 72, no 4, p. 509-518Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy.

    OBJECTIVE: To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy.

    DESIGN, SETTING, AND PARTICIPANTS: Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months.

    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis.

    RESULTS AND LIMITATIONS: A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; p<0.0001 and HR=7.53 [4.13-13.73]; p<0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation.

    CONCLUSIONS: The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential.

    PATIENT SUMMARY: The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in this higher-risk population.

  • 607. Wang, Zhaoming
    et al.
    Zhu, Bin
    Zhang, Mingfeng
    Parikh, Hemang
    Jia, Jinping
    Chung, Charles C
    Sampson, Joshua N
    Hoskins, Jason W
    Hutchinson, Amy
    Burdette, Laurie
    Ibrahim, Abdisamad
    Hautman, Christopher
    Raj, Preethi S
    Abnet, Christian C
    Adjei, Andrew A
    Ahlbom, Anders
    Albanes, Demetrius
    Allen, Naomi E
    Ambrosone, Christine B
    Aldrich, Melinda
    Amiano, Pilar
    Amos, Christopher
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andriole, Gerald
    Andrulis, Irene L
    Arici, Cecilia
    Arslan, Alan A
    Austin, Melissa A
    Baris, Dalsu
    Barkauskas, Donald A
    Bassig, Bryan A
    Beane Freeman, Laura E
    Berg, Christine D
    Berndt, Sonja I
    Bertazzi, Pier Alberto
    Biritwum, Richard B
    Black, Amanda
    Blot, William
    Boeing, Heiner
    Boffetta, Paolo
    Bolton, Kelly
    Boutron-Ruault, Marie-Christine
    Bracci, Paige M
    Brennan, Paul
    Brinton, Louise A
    Brotzman, Michelle
    Bueno-de-Mesquita, H Bas
    Buring, Julie E
    Butler, Mary Ann
    Cai, Qiuyin
    Cancel-Tassin, Geraldine
    Canzian, Federico
    Cao, Guangwen
    Caporaso, Neil E
    Carrato, Alfredo
    Carreon, Tania
    Carta, Angela
    Chang, Gee-Chen
    Chang, I-Shou
    Chang-Claude, Jenny
    Che, Xu
    Chen, Chien-Jen
    Chen, Chih-Yi
    Chen, Chung-Hsing
    Chen, Constance
    Chen, Kuan-Yu
    Chen, Yuh-Min
    Chokkalingam, Anand P
    Chu, Lisa W
    Clavel-Chapelon, Francoise
    Colditz, Graham A
    Colt, Joanne S
    Conti, David
    Cook, Michael B
    Cortessis, Victoria K
    Crawford, E David
    Cussenot, Olivier
    Davis, Faith G
    De Vivo, Immaculata
    Deng, Xiang
    Ding, Ti
    Dinney, Colin P
    Di Stefano, Anna Luisa
    Diver, W Ryan
    Duell, Eric J
    Elena, Joanne W
    Fan, Jin-Hu
    Feigelson, Heather Spencer
    Feychting, Maria
    Figueroa, Jonine D
    Flanagan, Adrienne M
    Fraumeni, Joseph F
    Freedman, Neal D
    Fridley, Brooke L
    Fuchs, Charles S
    Gago-Dominguez, Manuela
    Gallinger, Steven
    Gao, Yu-Tang
    Gapstur, Susan M
    Garcia-Closas, Montserrat
    Garcia-Closas, Reina
    Gastier-Foster, Julie M
    Gaziano, J Michael
    Gerhard, Daniela S
    Giffen, Carol A
    Giles, Graham G
    Gillanders, Elizabeth M
    Giovannucci, Edward L
    Goggins, Michael
    Gokgoz, Nalan
    Goldstein, Alisa M
    Gonzalez, Carlos
    Gorlick, Richard
    Greene, Mark H
    Gross, Myron
    Grossman, H Barton
    Grubb, Robert
    Gu, Jian
    Guan, Peng
    Haiman, Christopher A
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hankinson, Susan E
    Harris, Curtis C
    Hartge, Patricia
    Hattinger, Claudia
    Hayes, Richard B
    He, Qincheng
    Helman, Lee
    Henderson, Brian E
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hoffman-Bolton, Judith
    Hohensee, Chancellor
    Holly, Elizabeth A
    Hong, Yun-Chul
    Hoover, Robert N
    Hosgood, H Dean
    Hsiao, Chin-Fu
    Hsing, Ann W
    Hsiung, Chao Agnes
    Hu, Nan
    Hu, Wei
    Hu, Zhibin
    Huang, Ming-Shyan
    Hunter, David J
    Inskip, Peter D
    Ito, Hidemi
    Jacobs, Eric J
    Jacobs, Kevin B
    Jenab, Mazda
    Ji, Bu-Tian
    Johansen, Christoffer
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Johnson, Alison
    Kaaks, Rudolf
    Kamat, Ashish M
    Kamineni, Aruna
    Karagas, Margaret
    Khanna, Chand
    Khaw, Kay-Tee
    Kim, Christopher
    Kim, In-Sam
    Kim, Jin Hee
    Kim, Yeul Hong
    Kim, Young-Chul
    Kim, Young Tae
    Kang, Chang Hyun
    Jung, Yoo Jin
    Kitahara, Cari M
    Klein, Alison P
    Klein, Robert
    Kogevinas, Manolis
    Koh, Woon-Puay
    Kohno, Takashi
    Kolonel, Laurence N
    Kooperberg, Charles
    Kratz, Christian P
    Krogh, Vittorio
    Kunitoh, Hideo
    Kurtz, Robert C
    Kurucu, Nilgun
    Lan, Qing
    Lathrop, Mark
    Lau, Ching C
    Lecanda, Fernando
    Lee, Kyoung-Mu
    Lee, Maxwell P
    Le Marchand, Loic
    Lerner, Seth P
    Li, Donghui
    Liao, Linda M
    Lim, Wei-Yen
    Lin, Dongxin
    Lin, Jie
    Lindstrom, Sara
    Linet, Martha S
    Lissowska, Jolanta
    Liu, Jianjun
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lloreta, Josep
    Lu, Daru
    Ma, Jing
    Malats, Nuria
    Mannisto, Satu
    Marina, Neyssa
    Mastrangelo, Giuseppe
    Matsuo, Keitaro
    McGlynn, Katherine A
    McKean-Cowdin, Roberta
    McNeill, Lorna H
    McWilliams, Robert R
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Meltzer, Paul S
    Mensah, James E
    Miao, Xiaoping
    Michaud, Dominique S
    Mondul, Alison M
    Moore, Lee E
    Muir, Kenneth
    Niwa, Shelley
    Olson, Sara H
    Orr, Nick
    Panico, Salvatore
    Park, Jae Yong
    Patel, Alpa V
    Patino-Garcia, Ana
    Pavanello, Sofia
    Peeters, Petra H M
    Peplonska, Beata
    Peters, Ulrike
    Petersen, Gloria M
    Picci, Piero
    Pike, Malcolm C
    Porru, Stefano
    Prescott, Jennifer
    Pu, Xia
    Purdue, Mark P
    Qiao, You-Lin
    Rajaraman, Preetha
    Riboli, Elio
    Risch, Harvey A
    Rodabough, Rebecca J
    Rothman, Nathaniel
    Ruder, Avima M
    Ryu, Jeong-Seon
    Sanson, Marc
    Schned, Alan
    Schumacher, Fredrick R
    Schwartz, Ann G
    Schwartz, Kendra L
    Schwenn, Molly
    Scotlandi, Katia
    Seow, Adeline
    Serra, Consol
    Serra, Massimo
    Sesso, Howard D
    Severi, Gianluca
    Shen, Hongbing
    Shen, Min
    Shete, Sanjay
    Shiraishi, Kouya
    Shu, Xiao-Ou
    Siddiq, Afshan
    Sierrasesumaga, Luis
    Sierri, Sabina
    Loon Sihoe, Alan Dart
    Silverman, Debra T
    Simon, Matthias
    Southey, Melissa C
    Spector, Logan
    Spitz, Margaret
    Stampfer, Meir
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stern, Mariana C
    Stevens, Victoria L
    Stolzenberg-Solomon, Rachael Z
    Stram, Daniel O
    Strom, Sara S
    Su, Wu-Chou
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sung, Sook Whan
    Swerdlow, Anthony
    Tan, Wen
    Tanaka, Hideo
    Tang, Wei
    Tang, Ze-Zhang
    Tardon, Adonina
    Tay, Evelyn
    Taylor, Philip R
    Tettey, Yao
    Thomas, David M
    Tirabosco, Roberto
    Tjonneland, Anne
    Tobias, Geoffrey S
    Toro, Jorge R
    Travis, Ruth C
    Trichopoulos, Dimitrios
    Troisi, Rebecca
    Truelove, Ann
    Tsai, Ying-Huang
    Tucker, Margaret A
    Tumino, Rosario
    Van Den Berg, David
    Van Den Eeden, Stephen K
    Vermeulen, Roel
    Vineis, Paolo
    Visvanathan, Kala
    Vogel, Ulla
    Wang, Chaoyu
    Wang, Chengfeng
    Wang, Junwen
    Wang, Sophia S
    Weiderpass, Elisabete
    Weinstein, Stephanie J
    Wentzensen, Nicolas
    Wheeler, William
    White, Emily
    Wiencke, John K
    Wolk, Alicja
    Wolpin, Brian M
    Wong, Maria Pik
    Wrensch, Margaret
    Wu, Chen
    Wu, Tangchun
    Wu, Xifeng
    Wu, Yi-Long
    Wunder, Jay S
    Xiang, Yong-Bing
    Xu, Jun
    Yang, Hannah P
    Yang, Pan-Chyr
    Yatabe, Yasushi
    Ye, Yuanqing
    Yeboah, Edward D
    Yin, Zhihua
    Ying, Chen
    Yu, Chong-Jen
    Yu, Kai
    Yuan, Jian-Min
    Zanetti, Krista A
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Zhou, Baosen
    Mirabello, Lisa
    Savage, Sharon A
    Kraft, Peter
    Chanock, Stephen J
    Yeager, Meredith
    Landi, Maria Terese
    Shi, Jianxin
    Chatterjee, Nilanjan
    Amundadottir, Laufey T
    Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.332014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 24, p. 6616-6633Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

  • 608. Watts, Eleanor L.
    et al.
    Appleby, Paul N.
    Albanese, Demetrius
    Black, Amanda
    Chan, June M.
    Chen, Chu
    Cirillo, Piera M.
    Cohn, Barbara A.
    Cook, Michael B.
    Donovan, Jenny L.
    Ferrucci, Luigi
    Garland, Cedric F.
    Giles, Graham G.
    Goodman, Phyllis J.
    Habel, Laurel A.
    Haiman, Christopher A.
    Holly, Jeff M. P.
    Hoover, Robert N.
    Kaaks, Rudolf
    Knekt, Paul
    Kolonel, Laurence N.
    Kubo, Tatsuhiko
    Le Marchand, Loic
    Luostarinen, Tapio
    Maclnnis, Robert J.
    Maenpaa, Hanna O.
    Mannisto, Satu
    Metter, E. Jeffrey
    Milne, Roger L.
    Nomura, Abraham M. Y.
    Oliver, Steven E.
    Parsons, J. Kellogg
    Peeters, Petra H.
    Platz, Elizabeth A.
    Riboli, Elio
    Ricceri, Fulvio
    Rinaldi, Sabina
    Rissanen, Harri
    Sawada, Norie
    Schaefer, Catherine A.
    Schenk, Jeannette M.
    Stanczyk, Frank Z.
    Stampfer, Meir
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stenman, Ulf-Hakan
    Tjonneland, Anne
    Trichopoulou, Antonia
    Thompson, Ian M.
    Tsugane, Shoichiro
    Vatten, Lars
    Whittemore, Alice S.
    Ziegler, Regina G.
    Allen, Naomi E.
    Key, Timothy J.
    Travis, Ruth C.
    Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0187741Article in journal (Refereed)
    Abstract [en]

    Introduction: Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease-risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin.

    Methods: Statistical analyses of individual participant data from 12,330 male controls aged 25–85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates.

    Results: Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones.

    Conclusion: Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption.

  • 609. Weikert, Steffen
    et al.
    Boeing, Heiner
    Pischon, Tobias
    Olsen, Anja
    Tjonneland, Anne
    Overvad, Kim
    Becker, Nikolaus
    Linseisen, Jacob
    Lahmann, Petra H
    Arvaniti, Athina
    Kassapa, Christina
    Trichoupoulou, Antonia
    Sieri, Sabina
    Palli, Domenico
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    van Gils, Carla H
    Peeters, Petra H M
    Bueno-de-Mesquita, H Bas
    Büchner, Frederike L
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Berglund, Göran
    Wirfält, Elisabet
    Pera, Guillem
    Dorronsoro, Miren
    Gurrea, Aurelio Barricarte
    Navarro, Carmen
    Martinez, Carmen
    Quirós, J Ramón
    Allen, Naomi
    Roddam, Andrew
    Bingham, Sheila
    Jenab, Mazda
    Slimani, Nadia
    Norat, Teresa
    Riboli, Elio
    Fruits and vegetables and renal cell carcinoma: findings from the European prospective investigation into cancer and nutrition (EPIC).2006In: International Journal of Cancer, ISSN 0020-7136, Vol. 118, no 12, p. 3133-9Article in journal (Refereed)
  • 610. Weikert, Steffen
    et al.
    Boeing, Heiner
    Pischon, Tobias
    Weikert, Cornelia
    Olsen, Anja
    Tjonneland, Anne
    Overvad, Kim
    Becker, Nikolaus
    Linseisen, Jakob
    Trichopoulou, Antonia
    Mountokalakis, Theodore
    Trichopoulos, Dimitrios
    Sieri, Sabina
    Palli, Domenico
    Vineis, Paolo
    Panico, Salvatore
    Peeters, Petra H M
    Bueno-de-Mesquita, H Bas
    Verschuren, W M Monique
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Berglund, Goran
    González, Carlos A
    Dorronsoro, Miren
    Barricarte, Aurelio
    Tormo, M J
    Allen, Naomi
    Roddam, Andrew
    Bingham, Sheila
    Khaw, Kay-Tee
    Rinaldi, Sabina
    Ferrari, Pietro
    Norat, Teresa
    Riboli, Elio
    Blood pressure and risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition.2008In: Am J Epidemiol, ISSN 1476-6256, Vol. 167, no 4, p. 438-46Article in journal (Refereed)
  • 611. Weikert, Steffen
    et al.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Contemporary epidemiology of renal cell carcinoma: perspectives of primary prevention.2010In: World journal of urology, ISSN 0724-4983, E-ISSN 1433-8726, Vol. 28, no 3, p. 247-252Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Epidemiological research of recent years has produced evidence for a role of lifestyle-associated risk factors in the etiology of renal cell carcinoma (RCC), the most common renal tumor. In this review, we give an overview of recent trends in incidence and mortality and summarize the current knowledge on risk factors of RCC. METHODS: Data on incidence and mortality in the literature were reviewed. Global incidence data were derived from the Globocan database. A literature review of epidemiological studies on risk factors of kidney cancer was performed, with special emphasis on recent studies with high level of evidence, i.e., meta-analyses and prospective cohort studies. RESULTS: The incidence of renal malignancies has increased over recent decades in the context of the more widespread use of diagnostic imaging. However, time trends and geographic variations in incidence and mortality may also relate to changes in the prevalence of risk factors. Cigarette smoking, excess body weight and uncontrolled blood pressure are the most important and modifiable risk factors for RCC with a high prevalence in the general population. Moreover, dietary habits associated with a Western lifestyle were proposed as potential risk factors, but no food or food group has consistently been related to RCC risk. CONCLUSION: Based on the current evidence, reductions in the prevalence of cigarette smoking, overweight and hypertension are preventive strategies for RCC. More research is needed to establish the underlying mechanisms linking these risk factors and renal carcinogenesis.

  • 612.
    Wennberg, Simon
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Neoadjuvant chemotherapy in relation to fungal infections in muscle-invasive bladder cancer:: A retrospective multi-center study2016Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 613.
    Westberg, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Duchek, Milos
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Sandlund, Mikael
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lynöe, Niels
    Department of Learning, Informatics, Management & Ethics, Karolinska Institutet, Stockholm, Sweden.
    Informed consent for clinical education: randomized study of two different strategies at a urology surgery2004In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 38, no 6, p. 490-494Article in journal (Refereed)
    Abstract [en]

    Objective: To study whether or not the provision of written information in advance might influence patients' inclination to participate in the clinical education of medical students at a urology surgery.

    Material and Methods: A total of 169 outpatients referred to the urological surgery were randomly allocated either to receive information in advance or not, together with a notice of appointment that all patients receive by mail ≈2 weeks prior to their visit. Patients in the experimental group received a written information letter in advance about medical education, whereas the control patients did not receive any written information, according to the standard procedure of the surgery. The patients were not told about the study until afterwards and neither the doctors/teachers nor the students knew in advance to which group a certain patient had been allocated. At the end of the visit the patients were asked to complete a questionnaire.

    Results: The randomization procedure resulted in 83 patients being informed in advance and 86 control patients not being informed. Forty‐two patients completed the questionnaire: 19 in the experimental group and 23 in the control group. There was no difference between the groups with regard to reasons for dropping out.

    Conclusions: This study indicates that the provision of information in advance does not negatively influence patients' inclination to participate in the clinical training of medical students.

  • 614. Westerlund, A.
    et al.
    Steineck, G.
    Bälter, K
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Grönberg, H
    Hedelin, M
    Dietary supplement use patterns in men with prostate cancer: the Cancer Prostate Sweden study2011In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 22, no 4, p. 967-72Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In a European setting, we know little about the use of dietary supplements among men with prostate cancer (PCa) and to what extent lifestyle, disease or other factors influence such use.

    PATIENTS AND METHODS: We evaluated supplement use in 1127 men with incident PCa and in 900 population controls in Sweden. Age-adjusted binary regression with an identity link was carried out to estimate prevalence differences and corresponding 95% confidence intervals (CIs). Modifying effects of lifestyle- and diet-related factors were explored by statistical assessment of additive interaction.

    RESULTS: Among men with PCa, 542 individuals (48%) had used supplements, which was a 10% (95% CI: 5.9%-15%) higher prevalence than among population controls. Among individuals with high intake of fatty fish, vegetables, and phytoestrogens, but low intake of saturated fat, supplement use was 29% (95% CI: 18%-41%) more common in men with PCa than in population controls. We found no evidence of heterogeneity by categories of education, smoking history, body mass index, fiber, fruit, or phytoestrogen intake, treatment, or disease stage.

    CONCLUSION: Supplement use is common in Swedish men with PCa, especially among those with a healthy dietary pattern.

  • 615. Wiklund, Fredrik E
    et al.
    Adami, Hans-Olov
    Zheng, Sigun L
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Isaacs, William B
    Grönberg, Henrik
    Xu, Jianfeng
    Established prostate cancer susceptibility variants are not associated with disease outcome.2009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 5, p. 1659-62Article in journal (Refereed)
    Abstract [en]

    Recent genome-wide association studies have been successful in identifying common sequence variants associated with prostate cancer risk; however, their importance in prostate cancer prognosis remains unknown. To assess confirmed prostate cancer susceptibility variants with prostate cancer prognosis, we genotyped 16 established susceptibility variants in a Swedish cohort of 2,875 prostate cancer cases, ascertained between 2001 and 2003, with complete follow-up regarding vital status through January 2008. Cox regression models, adjusted for age, clinical stage, pathologic grade, nodal or distant metastases, and diagnostic serum levels of prostate-specific antigen level, were used to assess association between risk variants and prostate cancer-specific survival. During follow-up, 626 men died, and of those, 440 had prostate cancer classified as their underlying cause of death. We found no association between any of the explored sequence variants and prostate cancer-specific mortality, either in exploring individual variants or in assessing the cumulative effect of all variants. We conclude that hitherto established prostate cancer susceptibility variants are not associated with the lethal potential of prostate cancer.

  • 616. Wiklund, Fredrik E
    et al.
    Bennet, Anna M
    Magnusson, Patrik K E
    Eriksson, Ulrika K
    Lindmark, Fredrik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Wu, Liyun
    Yaghoutyfam, Nasreen
    Marquis, Christopher P
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Pedersen, Nancy L
    Adami, Hans-Olov
    Grönberg, Henrik
    Breit, Samuel N
    Brown, David A
    Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality2010In: Aging Cell, ISSN 1474-9718, E-ISSN 1474-9726, Vol. 9, no 6, p. 1057-1064Article in journal (Refereed)
    Abstract [en]

    Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a member of the TGF-b superfamily, previously studied in cancer and inflammation. In addition to regulating body weight, MIC-1/GDF15 may be used to predict mortality and/or disease course in cancer, cardiovascular disease (CVD), chronic renal and heart failure, as well as pulmonary embolism. These data suggested that MIC-1/GDF15 may be a marker of all-cause mortality. To determine whether serum MIC-1/GDF15 estimation is a predictor of all-cause mortality, we examined a cohort of 876 male subjects aged 35-80 years, selected from the Swedish Population Registry, and followed them for overall mortality. Serum MIC-1/GDF15 levels were determined for all subjects from samples taken at study entry. A second (independent) cohort of 324 same-sex twins (69% female) from the Swedish Twin Registry was similarly examined. All the twins had telomere length measured and 183 had serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP) available. Patients were followed for up to 14 years and had cause-specific and all-cause mortality determined. Serum MIC-1/GDF15 levels predicted mortality in the all-male cohort with an adjusted odds ratio (OR) of death of 3.38 (95%CI 1.38-8.26). This finding was validated in the twin cohort. Serum MIC-1/GDF15 remained an independent predictor of mortality when further adjusted for telomere length, IL-6 and CRP. Additionally, serum MIC-1/GDF15 levels were directly correlated with survival time independently of genetic background. Serum MIC-1/GDF15 is a novel predictor of all-cause mortality.

  • 617. Wiklund, Fredrik
    et al.
    Zheng, S Lilly
    Sun, Jielin
    Adami, Hans-Olov
    Lilja, Hans
    Hsu, Fang-Chi
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Adolfsson, Jan
    Cramer, Scott D
    Duggan, David
    Carpten, John D
    Chang, Bao-Li
    Isaacs, William B
    Grönberg, Henrik
    Xu, Jianfeng
    Association of reported prostate cancer risk alleles with PSA levels among men without a diagnosis of prostate cancer.2009In: The Prostate, ISSN 1097-0045, Vol. 69, no 4, p. 419-27Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prostate specific antigen (PSA) is widely used for prostate cancer screening but its levels are influenced by many non cancer-related factors. The goal of the study is to estimate the effect of genetic variants on PSA levels. METHODS: We evaluated the association of SNPs that were reported to be associated with prostate cancer risk in recent genome-wide association studies with plasma PSA levels in a Swedish study population, including 1,722 control subjects without a diagnosis of prostate cancer. RESULTS: Of the 16 SNPs analyzed in control subjects, significant associations with PSA levels (P < or = 0.05) were found for six SNPs. These six SNPs had a cumulative effect on PSA levels; the mean PSA levels in men were almost twofold increased across increasing quintile of number of PSA associated alleles, P-trend = 3.4 x 10(-14). In this Swedish study population risk allele frequencies were similar among T1c case patients (cancer detected by elevated PSA levels alone) as compared to T2 and above prostate cancer case patients. CONCLUSIONS: Results from this study may have two important clinical implications. The cumulative effect of six SNPs on PSA levels suggests genetic-specific PSA cutoff values may be used to improve the discriminatory performance of this test for prostate cancer; and the dual associations of these SNPs with PSA levels and prostate cancer risk raise a concern that some of reported prostate cancer risk-associated SNPs may be confounded by the prevalent use of PSA screening.

  • 618. Wikström, P
    et al.
    Lindh, G
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, A
    Damber, J E
    Alterations of transforming growth factor beta1 (TGF-beta1) and TGFbeta receptor expressions with progression in Dunning rat prostatic adenocarcinoma sublines.1999In: Urological research, ISSN 0300-5623, E-ISSN 1434-0879, Vol. 27, no 3, p. 185-93Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-beta1 (TGF-beta1) inhibits epithelial cell proliferation in the normal prostate. Prostate tumours express high levels of TGF-beta1, and seem to acquire resistance to its anti-proliferative effects with tumour progression. In this study, TGFbeta variations with tumour progression were examined in the Dunning prostatic adenocarcinoma model. Expression of TGF-beta1 and TGFbeta receptor type I and type II (TGFbeta-RI and TGFbeta-RII) in rat dorsolateral prostate (DLP) and Dunning tumour sublines (PAP, AT-1, AT-2, AT-3 and MatLyLu) was examined in vitro and in vivo, using competitive reverse transcription-polymerase chain reaction (RT-PCR), Northern and Western blot, and immunohistochemistry. All tumours expressed elevated levels of TGF-beta1 and TGFbeta-RI mRNA, when compared with the DLP (P < or = 0.05). All tumours except MatLyLu also expressed elevated levels of TGFbeta-RII mRNA (P < or = 0.05). Interestingly, TGFbeta-RII protein levels were very low in the highly metastatic AT-3 and MatLyLu tumours in vivo, when compared with levels in the PAP, AT-1, and AT-2 tumours. This difference was not detected for the AT-1, AT-2, and AT-3 cells in vitro. Immunostaining of TGF-beta1, TGFbeta-RI, and TGFbeta-RII was localised principally in normal and tumour epithelial cells, and occasionally in smooth muscle cells. In conclusion, high expression of TGF-beta1 and TGFbeta-RI and low expression of TGFbeta-RII may contribute to tumour progression and metastasis in the Dunning prostatic adenocarcinoma model.

  • 619.
    Wikström, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Bylund, Annika
    Umeå University, Faculty of Medicine, Community Medicine and Rehabilitation, Geriatric Medicine. Geriatrik.
    Zhang, Jie-Xian
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Nutritional Research.
    Hallmans, Goran
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Nutritional Research.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Rye bran diet increases epithelial cell apoptosis and decreases epithelial cell volume in TRAMP (transgenic adenocarcinoma of the mouse prostate) tumors.2005In: Nutrition Cancer, ISSN 0163-5581, Vol. 53, no 1, p. 111-6Article in journal (Refereed)
  • 620.
    Wikström, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Marusic, Josip
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Low stroma androgen receptor level in normal and tumor prostate tissue is related to poor outcome in prostate cancer patients.2009In: The Prostate, ISSN 1097-0045, Vol. 69, no 8, p. 799-809Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The role of androgen receptors (ARs) in the prostate tumor cell environment is largely unknown. METHODS: AR immunostaining was evaluated in relation to stroma morphology, expression of AR co-activator ARA55, tumor characteristics and clinical outcome in normal and prostate cancer (PCa) tissue obtained at transurethral resection in men treated with expectancy, and in diagnostic transrectal core biopsies in men treated with surgical castration. Stroma composition was studied by Masson-trichrome and desmin staining. Levels of AR and ARA55 mRNA were quantified by laser micro-dissection and RT-PCR. RESULTS: The percentage of cells with positive nuclear AR immunostaining in the tumor and normal stroma was inversely related to Gleason score, tumor size, tumor stage, metastasis, response to castration therapy, and cancer-specific survival. The AR staining in the normal stroma provided independent prognostic information in Cox multiple linear regression analysis. Loss of stroma AR staining was linked to low expression of ARA55 in stroma smooth muscle cells, and in tumors also to gradual disappearance of this cell type. CONCLUSIONS: PCa aggressiveness and efficacy of castration therapy are related to AR levels in the tumor stroma and importantly to AR levels in the surrounding normal prostate tissue stroma. .

  • 621.
    Wikström, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Ohlson, Nina
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Nuclear androgen receptors recur in the epithelial and stromal compartments of malignant and non-malignant human prostate tissue several months after castration therapy.2007In: Prostate, ISSN 0270-4137, Vol. 67, no 12, p. 1277-84Article in journal (Refereed)
  • 622. Williams, Ariel A
    et al.
    Higgins, John PT
    Zhao, Hongjuan
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Brooks, James D
    CD9 and vimentin distinguish clear cell from chormophobe renal cell carcinoma.2009In: BMC Clinical Pathology, ISSN 1472-6890, E-ISSN 1472-6890, Vol. 9, no 9Article in journal (Refereed)
    Abstract [en]

    Background: Clear cell renal cell carcinoma (ccRCC) and chromophobe renal cell carcinoma(chRCC) can usually be distinguished by histologic characteristics. Occasionally, diagnosis proveschallenging and diagnostic difficulty will likely increase as needle biopsies of renal lesions becomemore common.Methods: To identify markers that aid in differentiating ccRCC from chRCC, we used geneexpression profiles to identify candidate markers that correlate with histology. 39 antisera andantibodies, including 35 for transcripts identified from gene expression profiling, were evaluated.Promising markers were tested on a tissue microarray (TMA) containing 428 renal neoplasms.Strength of staining of each core on the TMA was formally scored and the distribution of stainingacross different types of renal neoplasms was analyzed.Results: Based on results from initial immunohistochemical staining of multitissue titer arrays, 23of the antisera and antibodies were selected for staining of the TMA. For 7 of these markers,strength of staining of each core on the TMA was formally scored. Vimentin (positive in ccRCC)and CD9 (positive in chRCC) best distinguished ccRCC from chRCC. The combination of vimentinnegativity and CD9 positivity was found to distinguish chRCC from ccRCC with a sensitivity of100.0% and a specificity of 95.2%.Conclusion: Based on gene expression analysis, we identify CD9 and vimentin as candidatemarkers for distinguishing between ccRCC and chRCC. In difficult cases and particularly when theamount of diagnostic tissue is limited, vimentin and CD9 staining could serve as a useful adjunct inthe differential diagnosis of ccRCC and chRCC.

  • 623. Wilson, Kathryn M.
    et al.
    Markt, Sarah C.
    Fang, Fang
    Nordenvall, Caroline
    Rider, Jennifer R.
    Ye, Weimin
    Adami, Hans-Olov
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Nyrén, Olof
    Mucci, Lorelei A.
    Snus use, smoking and survival among prostate cancer patients2016In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 139, no 12, p. 2753-2759Article in journal (Refereed)
    Abstract [en]

    Smoking is associated with prostate cancer mortality. The Scandinavian smokeless tobacco product snus is a source of nicotine but not the combustion products of smoke and has not been studied with respect to prostate cancer survival. The study is nested among 9,582 men with incident prostate cancer within a prospective cohort of 336,381 Swedish construction workers. Information on tobacco use was collected at study entry between 1971 and 1992, and categorized into (i) never users of any tobacco, (ii) exclusive snus: ever users of snus only, (iii) exclusive smokers: ever smokers (cigarette, cigar and/or pipe) only and (iv) ever users of both snus and smoking. Hazard ratios for prostate cancer-specific and total mortality for smoking and snus use based on Cox proportional hazards models adjusted for age, calendar period at diagnosis and body mass index at baseline. During 36 years of follow-up, 4,758 patients died-2,489 due to prostate cancer. Compared to never users of tobacco, exclusive smokers were at increased risk of prostate cancer mortality (HR 1.15, 95% CI: 1.05-1.27) and total mortality (HR 1.17, 95% CI: 1.09-1.26). Exclusive snus users also had increased risks for prostate cancer mortality (HR 1.24, 95% CI: 1.03-1.49) and total mortality (HR 1.19, 95% CI: 1.04-1.37). Among men diagnosed with nonmetastatic disease, the HR for prostate cancer death among exclusive snus users was 3.17 (95% CI: 1.66-6.06). The study is limited by a single assessment of tobacco use prior to diagnosis. Snus use was associated with increased risks of prostate cancer and total mortality among prostate cancer patients. This suggests that tobacco-related components such as nicotine or tobacco-specific carcinogens may promote cancer progression independent of tobacco's combustion products.

  • 624. Winerdal, Malin E.
    et al.
    Krantz, David
    Hartana, Ciputra A.
    Zirakzadeh, Ali A .
    Department of Medicine, Unit of Allergy and Immunology, Karolinska Institutet, Stockholm, Sweden.
    Linton, Ludvig
    Bergman, Emma A.
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Stockholm South General Hospital, Karolinska Institutet, Stockholm, Sweden.
    Vasko, Janos
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Alamdari, Farhood
    Hansson, Johan
    Holmström, Benny
    Johansson, Markus
    Winerdal, Max
    Marits, Per
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Urinary Bladder Cancer Tregs Suppress MMP2 and Potentially Regulate Invasiveness2018In: Cancer immunology research, ISSN 2326-6074, Vol. 6, no 5, p. 528-538Article in journal (Refereed)
    Abstract [en]

    Regulatory T cells (Tregs) have long been considered one-sided suppressors of antitumor immune responses and hence associated to poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This discrepancy has partly been attributed to the shear misidentification of Tregs, but also to the inflammatory profile of the tumor. Our aim was to determine whether tumor-infiltrating Forkhead box P3+ (FOXP3+) cells confer a stable Treg phenotype and to investigate putative beneficial Treg functions, focusing on tumor-promoting inflammatory pathways in UBC. Patients (n = 52) with suspected UBC were prospectively included. We show, by employing a broad range of analytical approaches, that tumor-infiltrating CD4+FOXP3+ T cells in UBC phenotypically, functionally, and epigenetically represent a true Treg population. At the invasive front of UBC tumors, we found an inverse relationship between Treg frequency and expression of matrix metalloproteinase 2 (MMP2), a key pro-invasive factor induced by tumor-promoting inflammation. Correspondingly, a significant, dose-dependent Treg-mediated downregulation of MMP2 protein and mRNA expression was observed in both macrophages and urinary bladder cancer cells. Also, we found that Treg frequency specifically at the invasive front positively correlated with survival. Thus, we identify Treg-mediated suppression of MMP2 in the tumor microenvironment as a mechanism explaining the paradoxical positive prognostic impact of tumor-infiltrating Tregs in UBC.

  • 625.
    Wiren, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Drevin, Linda
    Regional Cancer Centre, Uppsala University Hospital, Uppsala, Sweden.
    Akre, Olof
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Robinson, David
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Fathering of dizygotic twins and risk of prostate cancer: nationwide, population-based case-control study2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e110506-Article in journal (Refereed)
    Abstract [en]

    Background: An association between male fertility and risk of prostate cancer has been suggested, possibly through lower androgen levels in subfertile men. We evaluated male fertility in relation to risk of prostate cancer by assessing the frequency of fathering of dizygotic twins, a marker of high fertility, among cases of prostate cancer and controls. Methods: We performed a case-control study in Prostate Cancer data Base Sweden (PCBaSe), a nationwide, population-based cohort. PCBaSe was linked to the Swedish twin register for information on zygosity for same-sex twins and to other nationwide health care registers and demographic databases for information on socioeconomic factors, comorbidity, and tumor characteristics for 96 301 prostate cancer cases and 378 583 matched controls. To account for the influence of in vitro fertilization on dizygotic twinning, analyses were restricted to men who had fathered children before 1991, when in vitro fertilization was still uncommon in Sweden. Results: 1 112 cases and 4 538 controls had fathered dizygotic twins. Men with dizygotic twins had no increased risk of prostate cancer compared to fathers of singletons; neither for total prostate cancer odds ratio (OR) 0.95(95% CI 0.89-1.02), nor for any risk category, OR 0.97 (95% CI 0.84-1.12) for low-risk disease, and OR 1.04 (95% CI 0.90-1.22) for metastatic disease. Conclusion: The lack of association between fathering of dizygotic twins and prostate cancer risk give no support for an association between male fertility and prostate cancer risk.

  • 626.
    Wirén, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Drevin, Linda I
    Carlsson, Sigrid V
    Akre, Olof
    Holmberg, Erik C
    Robinson, David E
    Garmo, Hans G
    Stattin, Pär E
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgery, Urology Service, Memorial Sloan-Kettering Cancer Center, New York, NY.
    Fatherhood status and risk of prostate cancer: nationwide, population-based case-control study2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 4, p. 937-943Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown a decreased risk of prostate cancer for childless men; however, the cause of the association remains to be elucidated. The aim of our study was to assess the risk of prostate cancer by fatherhood status, also considering potential confounding factors. In a case–control study in Prostate Cancer data Base Sweden 2.0, a nationwide, population-based cohort, data on number of children, marital status, education, comorbidity and tumor characteristics obtained through nationwide healthcare registers and demographic databases for 117,328 prostate cancer cases and 562,644 controls, matched on birth year and county of residence, were analyzed. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for prostate cancer overall and by risk category, adjusting for marital status and education. Childless men had a decreased risk of prostate cancer compared to fathers, OR = 0.83 (95% CI = 0.82–0.84), and risk was lower for low-risk prostate cancer, OR = 0.74 (95% CI = 0.72–0.77), than for metastatic prostate cancer, OR = 0.93 (95% CI = 0.90–0.97). Adjustment for marital status and education attenuated the association in the low-risk category, adjusted OR = 0.87 (95% CI = 0.84–0.91), whereas OR for metastatic cancer remained virtually unchanged, adjusted OR = 0.92 (95% CI = 0.88–0.96). Our data indicate that the association between fatherhood status and prostate cancer to a large part is due to socioeconomic factors influencing healthcare-seeking behavior including testing of prostate-specific antigen levels.

  • 627.
    Wirén, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ulmer, Hanno
    Manjer, Jonas
    Bjørge, Tone
    Nagel, Gabriele
    Johansen, Dorthe
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Engeland, Anders
    Concin, Hans
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Selmer, Randi
    Tretli, Steinar
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Pooled cohort study on height and risk of cancer and cancer death2014In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 25, no 2, p. 151-159Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To assess the association between height and risk of cancer and cancer death.

    METHODS: The metabolic syndrome and cancer project is a prospective pooled cohort study of 585,928 participants from seven cohorts in Austria, Norway, and Sweden. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer incidence and death were estimated in height categories and per 5-cm increment for each cancer site using Cox proportional hazards model.

    RESULTS: During a mean follow-up of 12.7 years (SD = 7.2), 38,862 participants were diagnosed with cancer and 13,547 participants died of cancer. Increased height (per 5-cm increment) was associated with an increased overall cancer risk in women, HR 1.07 (95 % CI 1.06-1.09), and in men, HR 1.04 (95 % CI 1.03-1.06). The highest HR was seen for malignant melanoma in women, HR 1.17 (95 % CI 1.11-1.24), and in men HR 1.12 (95 % CI 1.08-1.19). Height was also associated with increased risk of cancer death in women, HR 1.03 (95 % CI 1.01-1.16), and in men, HR 1.03 (95 % CI 1.01-1.05). The highest HR was observed for breast cancer death in postmenopausal women (>60 years), HR 1.10 (95 % CI 1.00-1.21), and death from renal cell carcinoma in men, HR 1.18 (95 % CI 1.07-1.30). All these associations were independent of body mass index.

    CONCLUSION: Height was associated with risk of cancer and cancer death indicating that factors related to height such as hormonal and genetic factors stimulate both cancer development and progression.

  • 628.
    Wirén, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Androgens and prostate cancer risk2008In: Baillière's Best Practice & Research. Clinical Endocrinology & Metabolism, ISSN 1521-690X, E-ISSN 1532-1908, Vol. 22, no 4, p. 601-613Article in journal (Refereed)
    Abstract [en]

    Androgens have been implicated in prostate tumourigenesis. However, no association between circulating levels of androgens and prostate cancer risk was found in a recent large pooled analysis of prospective studies. A decreased risk of prostate cancer among men treated with finasteride, a 5α-reductase inhibitor which reduces levels of dihydrotestosterone, was observed in the Prostate Cancer Prevention Trial (PCPT), a large clinical trial. In the PCPT, a higher number of high-grade tumours was found in the finasteride group than in the control group; the reason for this finding is still unclear. Treatment of symptoms of late-onset hypogonadism – such as decreased muscle and bone mass and decreased cognition and libido – has become more prevalent with the advent of new forms of administration of testosterone replacement therapy. One small placebo-controlled study showed no increase in incidence of prostate cancer after 6 months of testosterone therapy, but data on the safety of testosterone replacement therapy remain limited.

  • 629.
    Wirén, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Corrigendum to ‘‘Androgens and prostate cancer’’: [Best Practice & Research Clinical Endocrinology & Metabolism 2008; 22 (4): 601–613]2009Other (Other academic)
  • 630.
    Wirén, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Forskning på kvalitetsregister ger klinisk nytta2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 26-28, p. 1294-1297Article in journal (Other academic)
  • 631.
    Wirén, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. null.
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Rinaldi, Sabina
    null.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. null.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Stenman, Ulf-Håkan
    null.
    Kaaks, Rudolf
    null.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Androgens and prostate cancer risk: a prospective study2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 11, p. 1230-1237Article in journal (Refereed)
    Abstract [en]

    Background: Androgens have been implicated in prostate tumorigenesis, but prospective studies have overall reported no association between circulating levels of androgens and risk of prostate cancer. However, some recent studies have shown that a high level of testosterone increase the risk of non-aggressive tumors but is associated with a decreased risk of aggressive tumors.

    Methods: We prospectively measured plasma levels of total testosterone, androstanediol glucuronide (A-diol-g) and sex hormone binding globuline (SHBG) and calculated estimated levels of free testosterone, in a nested case-control study of 392 cases and 392 matched controls.

    Results: None of the studied hormones were significantly associated with prostate cancer risk in the full study group or in subgroups according to tumor aggressiveness. Odds ratios in the full study group, for top versus bottom quartile, was for total testosterone 1.25 (95% CI = 0.79–2.00; Ptrend = 0.51); free testosterone, 1.31 (95% CI = 0.82–2.07; Ptrend = 0.35); A-diol-g, 0.88 (95% CI = 0.59–1.33; Ptrend = 0.77); and for SHBG, 1.01 (95% CI = 0.64–1.58; Ptrend = 0.94).

    Conclusions: We found no significant associations between androgen levels and risk of prostate cancer in this population-based, non-screened cohort.

  • 632. Witjes, J Alfred
    et al.
    Babjuk, Marek
    Bellmunt, Joaquim
    Bruins, H Maxim
    De Reijke, Theo M
    De Santis, Maria
    Gillessen, Silke
    James, Nicholas
    Maclennan, Steven
    Palou, Juan
    Powles, Tom
    Ribal, Maria J
    Shariat, Shahrokh F
    Der Kwast, Theo Van
    Xylinas, Evanguelos
    Agarwal, Neeraj
    Arends, Tom
    Bamias, Aristotle
    Birtle, Alison
    Black, Peter C
    Bochner, Bernard H
    Bolla, Michel
    Boormans, Joost L
    Bossi, Alberto
    Briganti, Alberto
    Brummelhuis, Iris
    Burger, Max
    Castellano, Daniel
    Cathomas, Richard
    Chiti, Arturo
    Choudhury, Ananya
    Compérat, Eva
    Crabb, Simon
    Culine, Stephane
    De Bari, Berardino
    De Blok, Willem
    J L De Visschere, Pieter
    Decaestecker, Karel
    Dimitropoulos, Konstantinos
    Dominguez-Escrig, Jose L
    Fanti, Stefano
    Fonteyne, Valerie
    Frydenberg, Mark
    Futterer, Jurgen J
    Gakis, Georgios
    Geavlete, Bogdan
    Gontero, Paolo
    Grubmüller, Bernhard
    Hafeez, Shaista
    Hansel, Donna E
    Hartmann, Arndt
    Hayne, Dickon
    Henry, Ann M
    Hernandez, Virginia
    Herr, Harry
    Herrmann, Ken
    Hoskin, Peter
    Huguet, Jorge
    Jereczek-Fossa, Barbara A
    Jones, Rob
    Kamat, Ashish M
    Khoo, Vincent
    Kiltie, Anne E
    Krege, Susanne
    Ladoire, Sylvain
    Lara, Pedro C
    Leliveld, Annemarie
    Linares-Espinós, Estefania
    Løgager, Vibeke
    Lorch, Anja
    Loriot, Yohann
    Meijer, Richard
    Mir, M Carmen
    Moschini, Marco
    Mostafid, Hugh
    Müller, Arndt-Christian
    Müller, Christoph R
    N'Dow, James
    Necchi, Andrea
    Neuzillet, Yann
    Oddens, Jorg R
    Oldenburg, Jan
    Osanto, Susanne
    J G Oyen, Wim
    Pacheco-Figueiredo, Luís
    Pappot, Helle
    Patel, Manish I
    Pieters, Bradley R
    Plass, Karin
    Remzi, Mesut
    Retz, Margitta
    Richenberg, Jonathan
    Rink, Michael
    Roghmann, Florian
    Rosenberg, Jonathan E
    Rouprêt, Morgan
    Rouvière, Olivier
    Salembier, Carl
    Salminen, Antti
    Sargos, Paul
    Sengupta, Shomik
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Smeenk, Robert J
    Smits, Anita
    Stenzl, Arnulf
    Thalmann, George N
    Tombal, Bertrand
    Turkbey, Baris
    Lauridsen, Susanne Vahr
    Valdagni, Riccardo
    Der Heijden, Antoine G Van
    Van Poppel, Hein
    Vartolomei, Mihai D
    Veskimäe, Erik
    Vilaseca, Antoni
    Rivera, Franklin A Vives
    Wiegel, Thomas
    Wiklund, Peter
    Williams, Andrew
    Zigeuner, Richard
    Horwich, Alan
    EAU-ESMO Consensus Statements on the Management of Advanced and Variant Bladder Cancer-An International Collaborative Multistakeholder Effort: Under the Auspices of the EAU-ESMO Guidelines Committees.2019In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, article id S0302-2838(19)30763-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.

    OBJECTIVE: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.

    DESIGN: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.

    SETTING: Online Delphi survey and consensus conference.

    PARTICIPANTS: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.

    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Statements were ranked by experts according to their level of agreement: 1-3 (disagree), 4-6 (equivocal), and 7-9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).

    RESULTS AND LIMITATIONS: Overall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.

    CONCLUSIONS: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.

    PATIENT SUMMARY: This report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.

  • 633. Witjes, J. Alfred
    et al.
    Compérat, Eva
    Cowan, Nigel C.
    De Santis, Maria
    Gakis, Georgios
    Lebret, Thierry
    Ribal, Maria J.
    Van der Heijden, Antoine G.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2013 Guidelines2014In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 65, no 4, p. 778-792Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The European Association of Urology (EAU) guidelines panel on Muscle-invasive and Metastatic bladder cancer (BCa) updates its guidelines yearly. This updated summary provides a synthesis of the 2013 guidelines document, with emphasis on the latest developments.

    OBJECTIVE: To provide graded recommendations on the diagnosis and treatment of patients with muscle-invasive BCa (MIBC), linked to a level of evidence.

    EVIDENCE ACQUISITION: For each section of the guidelines, comprehensive literature searches covering the past 10 yr in several databases were conducted, scanned, reviewed, and discussed both within the panel and with external experts. The final results are reflected in the recommendations provided.

    EVIDENCE SYNTHESIS: Smoking and work-related carcinogens remain the most important risk factors for BCa. Computed tomography (CT) and magnetic resonance imaging can be used for staging, although CT is preferred for pulmonary evaluation. Open radical cystectomy with an extended lymph node dissection (LND) remains the treatment of choice for treatment failures in non-MIBC and T2-T4aN0M0 BCa. For well-informed, well-selected, and compliant patients, however, multimodality treatment could be offered as an alternative, especially if cystectomy is not an option. Comorbidity, not age, should be used when deciding on radical cystectomy. Patients should be encouraged to actively participate in the decision-making process, and a continent urinary diversion should be offered to all patients unless there are specific contraindications. For fit patients, cisplatinum-based neoadjuvant chemotherapy should always be discussed, since it improves overall survival. For patients with metastatic disease, cisplatin-containing combination chemotherapy is recommended. For unfit patients, carboplatin combination chemotherapy or single agents can be used.

    CONCLUSIONS: This 2013 EAU Muscle-invasive and Metastatic BCa guidelines updated summary aims to increase the quality of care and outcome for patients with muscle-invasive or metastatic BCa.

    PATIENT SUMMARY: In this paper we update the EAU guidelines on Muscle-invasive and Metastatic bladder cancer. We recommend that chemotherapy be administered before radical treatment and that bladder removal be the standard of care for disease confined to the bladder.

  • 634. Wood, Christopher
    et al.
    Srivastava, Pramod
    Bukowski, Ronald
    Lacombe, Louis
    Gorelov, Andrei I
    Gorelov, Sergei
    Mulders, Peter
    Zielinski, Henryk
    Hoos, Axel
    Teofilovici, Florentina
    Isakov, Leah
    Flanigan, Robert
    Figlin, Robert
    Gupta, Renu
    Escudier, Bernard
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial.2008In: Lancet, ISSN 1474-547X, Vol. 372, no 9633, p. 145-54Article in journal (Refereed)
  • 635. Wozniak, Magdalena B.
    et al.
    Brennan, Paul
    Brenner, Darren R.
    Overvad, Kim
    Olsen, Anja
    Tjonneland, Anne
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Fagherazzi, Guy
    Katzke, Verena
    Kuehn, Tilman
    Boeing, Heiner
    Bergmann, Manuela M.
    Steffen, Annika
    Naska, Androniki
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Saieva, Calogero
    Grioni, Sara
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Bueno-de-Mesquita, H. B(as)
    Peeters, Petra H.
    Hjartaker, Anette
    Weiderpass, Elisabete
    Arriola, Larraitz
    Molina-Montes, Esther
    Duell, Eric J.
    Santiuste, Carmen
    Alonso de la Torre, Ramon
    Barricarte Gurrea, Aurelio
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Wareham, Nick
    Khaw, Kay-Tee
    Travis, Ruth C.
    Cross, Amanda J.
    Murphy, Neil
    Riboli, Elio
    Scelo, Ghislaine
    Alcohol consumption and the risk of renal cancers in the European prospective investigation into cancer and nutrition (EPIC)2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 8, p. 1953-1966Article in journal (Refereed)
    Abstract [en]

    Epidemiologic studies have reported that moderate alcohol consumption is inversely associated with the risk of renal cancer. However, there is no information available on the associations in renal cancer subsites. From 1992 through to 2010, 477,325 men and women in the European Prospective Investigation into Cancer and Nutrition cohort were followed for incident renal cancers (n=931). Baseline and lifetime alcohol consumption was assessed by country-specific, validated dietary questionnaires. Information on past alcohol consumption was collected by lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models. In multivariate analysis, total alcohol consumption at baseline was inversely associated with renal cancer; the HR and 95% CI for the increasing categories of total alcohol consumption at recruitment versus the light drinkers category were 0.78 (0.62-0.99), 0.82 (0.64-1.04), 0.70 (0.55-0.90), 0.91 (0.63-1.30), respectively, (p(trend)=0.001). A similar relationship was observed for average lifetime alcohol consumption and for all renal cancer subsites combined or for renal parenchyma subsite. The trend was not observed in hypertensive individuals and not significant in smokers. In conclusion, moderate alcohol consumption was associated with a decreased risk of renal cancer. What's new? Previous studies have indicated that environmental or lifestyle factors may be involved in the etiology of renal cancer, and that moderate alcohol consumption may reduce the risk of this type of cancer. In this very large European study (nearly 500,000 subjects), the authors found that, indeed, total alcohol consumption was inversely associated with renal cancer overall (for all subsites combined), and also with cancers of the renal parenchyma.

  • 636. Wu, Xifeng
    et al.
    Scelo, Ghislaine
    Purdue, Mark P.
    Rothman, Nathaniel
    Johansson, Mattias
    International Agency for Research on Cancer (IARC), Lyon, France.
    Ye, Yuanqing
    Wang, Zhaoming
    Zelenika, Diana
    Moore, Lee E.
    Wood, Christopher G.
    Prokhortchouk, Egor
    Gaborieau, Valerie
    Jacobs, Kevin B.
    Chow, Wong-Ho
    Toro, Jorge R.
    Zaridze, David
    Lin, Jie
    Lubinski, Jan
    Trubicka, Joanna
    Szeszenia-Dabrowska, Neonilia
    Lissowska, Jolanta
    Rudnai, Peter
    Fabianova, Eleonora
    Mates, Dana
    Jinga, Viorel
    Bencko, Vladimir
    Slamova, Alena
    Holcatova, Ivana
    Navratilova, Marie
    Janout, Vladimir
    Boffetta, Paolo
    Colt, Joanne S.
    Davis, Faith G.
    Schwartz, Kendra L.
    Banks, Rosamonde E.
    Selby, Peter J.
    Harnden, Patricia
    Berg, Christine D.
    Hsing, Ann W.
    Grubb, Robert L., III
    Boeing, Heiner
    Vineis, Paolo
    Clavel-Chapelon, Francoise
    Palli, Domenico
    Tumino, Rosario
    Krogh, Vittorio
    Panico, Salvatore
    Duell, Eric J.
    Ramon Quiros, Jose
    Sanchez, Maria-Jose
    Navarro, Carmen
    Ardanaz, Eva
    Dorronsoro, Miren
    Khaw, Kay-Tee
    Allen, Naomi E.
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H. M.
    Trichopoulos, Dimitrios
    Linseisen, Jakob
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Overvad, Kim
    Tjonneland, Anne
    Romieu, Isabelle
    Riboli, Elio
    Stevens, Victoria L.
    Thun, Michael J.
    Diver, W. Ryan
    Gapstur, Susan M.
    Pharoah, Paul D.
    Easton, Douglas F.
    Albanes, Demetrius
    Virtamo, Jarmo
    Vatten, Lars
    Hveem, Kristian
    Fletcher, Tony
    Koppova, Kvetoslava
    Cussenot, Olivier
    Cancel-Tassin, Geraldine
    Benhamou, Simone
    Hildebrandt, Michelle A.
    Pu, Xia
    Foglio, Mario
    Lechner, Doris
    Hutchinson, Amy
    Yeager, Meredith
    Fraumeni, Joseph F., Jr.
    Lathrop, Mark
    Skryabin, Konstantin G.
    McKay, James D.
    Gu, Jian
    Brennan, Paul
    Chanock, Stephen J.
    A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.232012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 2, p. 456-462Article in journal (Refereed)
    Abstract [en]

    Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome- wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 x 10(-10) and P = 6.07 x 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.

  • 637. Xu, Jianfeng
    et al.
    Zheng, Siqun Lilly
    Isaacs, Sarah D
    Wiley, Kathleen E
    Wiklund, Fredrik
    Sun, Jielin
    Kader, A Karim
    Li, Ge
    Purcell, Lina D
    Kim, Seong-Tae
    Hsu, Fang-Chi
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Hugosson, Jonas
    Adolfsson, Jan
    Walsh, Patrick C
    Trent, Jeffrey M
    Duggan, David
    Carpten, John
    Grönberg, Henrik
    Isaacs, William B
    Inherited genetic variant predisposes to aggressive but not indolent prostate cancer.2010In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 107, no 5, p. 2136-2140Article in journal (Refereed)
    Abstract [en]

    Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNPs showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the TT genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 x 10(-8) under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non-organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated.

  • 638. Yeager, Meredith
    et al.
    Chatterjee, Nilanjan
    Ciampa, Julia
    Jacobs, Kevin B
    Gonzalez-Bosquet, Jesus
    Hayes, Richard B
    Kraft, Peter
    Wacholder, Sholom
    Orr, Nick
    Berndt, Sonja
    Yu, Kai
    Hutchinson, Amy
    Wang, Zhaoming
    Amundadottir, Laufey
    Feigelson, Heather Spencer
    Thun, Michael J
    Diver, W Ryan
    Albanes, Demetrius
    Virtamo, Jarmo
    Weinstein, Stephanie
    Schumacher, Fredrick R
    Cancel-Tassin, Geraldine
    Cussenot, Olivier
    Valeri, Antoine
    Andriole, Gerald L
    Crawford, E David
    Haiman, Christopher A
    Henderson, Brian
    Kolonel, Laurence
    Le Marchand, Loic
    Siddiq, Afshan
    Riboli, Elio
    Key, Timothy J
    Kaaks, Rudolf
    Isaacs, William
    Isaacs, Sarah
    Wiley, Kathleen E
    Gronberg, Henrik
    Wiklund, Fredrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Xu, Jianfeng
    Zheng, S Lilly
    Sun, Jielin
    Vatten, Lars J
    Hveem, Kristian
    Kumle, Merethe
    Tucker, Margaret
    Gerhard, Daniela S
    Hoover, Robert N
    Fraumeni, Joseph F
    Hunter, David J
    Thomas, Gilles
    Chanock, Stephen J
    Identification of a new prostate cancer susceptibility locus on chromosome 8q24.2009In: Nature genetics, ISSN 1546-1718, Vol. 41, no 10, p. 1055-7Article in journal (Refereed)
    Abstract [en]

    We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. We identify a new association with prostate cancer risk on chromosome 8q24 (rs620861, P = 1.3 x 10(-10), heterozygote OR = 1.17, 95% CI 1.10-1.24; homozygote OR = 1.33, 95% CI 1.21-1.45). This defines a new locus associated with prostate cancer susceptibility on 8q24.

  • 639. Yusenko, Maria V
    et al.
    Kuiper, Roland P
    Boethe, Tamas
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    van Kessel, Ad Geurts
    Kovacs, Gyula
    High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas.2009In: BMC cancer, ISSN 1471-2407, Vol. 9, p. 152-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The diagnosis of benign renal oncocytomas (RO) and chromophobe renal cell carcinomas (RCC) based on their morphology remains uncertain in several cases. METHODS: We have applied Affymetrix GeneChip Mapping 250 K NspI high-density oligoarrays to identify small genomic alterations, which may occur beyond the specific losses of entire chromosomes, and also Affymetrix GeneChip HG-U133 Plus2.0 oligoarrays for gene expression profiling. RESULTS: By analysing of DNA extracted from 30 chRCCs and 42 ROs, we have confirmed the high specificity of monosomies of chromosomes 1, 2, 6, 10, 13, 17 and 21 in 70-93% of the chRCCs, while ROs displayed loss of chromosome 1 and 14 in 24% and 5% of the cases, respectively. We demonstrated that chromosomal gene expression biases might correlate with chromosomal abnormalities found in chromophobe RCCs and ROs. The vast majority genes downregulated in chromophobe RCC were mapped to chromosomes 2, 6, 10, 13 and 17. However, most of the genes overexpressed in chromophobe RCCs were located to chromosomes without any copy number changes indicating a transcriptional regulation as a main event. CONCLUSION: The SNP-array analysis failed to detect recurrent small deletions, which may mark loci of genes involved in the tumor development. However, we have identified loss of chromosome 2, 10, 13, 17 and 21 as discriminating alteration between chromophobe RCCs and ROs. Therefore, detection of these chromosomal changes can be used for the accurate diagnosis in routine histology.

  • 640. Zeleniuch-Jacquotte, Anne
    et al.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Micheli, Andrea
    Koenig, Karen L
    Lenner, Per
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Muti, Paola
    Shore, Roy E
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Odontology, Cariology.
    Krogh, Vittorio
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Afanasyeva, Yelena
    Rinaldi, Sabina
    Arslan, Alan A
    Kaaks, Rudolf
    Berrino, Franco
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Nutritional Research.
    Toniolo, Paolo
    Adlercreutz, Herman
    Circulating enterolactone and risk of endometrial cancer2006In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 119, no 10, p. 2376-2381Article in journal (Refereed)
    Abstract [en]

    It has been suggested that phytoestrogens protect against hormone-dependent cancers. Lignans are the main class of phytoestrogens in Western diets. We conducted a prospective study of endometrial cancer and circulating levels of the main human lignan, enterolactone. The design was a case-control study nested within 3 prospective cohort studies, in New York, Sweden and Italy. Serum or plasma samples had been collected at enrollment and stored at -80 degrees C. A total of 153 cases, diagnosed a median of 5.3 years after blood donation, and 271 matched controls were included. No difference in circulating enterolactone was observed between cases (median, 19.2 nmol/L) and controls (18.5 nmol/L). Adjusting for body mass index, the odds ratio for the top tertile of enterolactone, as compared to the lowest was 1.2 (95% CI, 0.7-2.0; p for trend = 0.53). Lack of association was observed in both pre- and postmenopausal women. No correlation was observed between enterolactone and circulating estrogens or SHBG in healthy postmenopausal women. These results do not support a protective role of circulating lignans, in the range of levels observed, against endometrial cancer.

  • 641. Zhang, Lu
    et al.
    Hu, Jin
    Zirakzadeh, Ali A .
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Medicine, Immunology and Allergy Unit, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
    Rosvall, Jesper
    Hedlund, Mats
    Hu, Ping Sheng
    P A Wallin, Robert
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Detection of micro-metastases by flow cytometry in lymph nodes from patients with penile cancer2018In: BMC Urology, ISSN 1471-2490, E-ISSN 1471-2490, Vol. 18, no 1, article id 86Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The tumor draining lymph node concept was first described in penile cancer for staging. Immunohistochemistry and histopathology evaluations are routinely used in clinical practice to examine lymph nodes for metastasis. However, these methods are time-consuming with low diagnostic accuracy and micro-metastases might be missed. In this study, we aim to evaluate detection of metastatic cells in draining lymph nodes by flow cytometry.

    METHODS: To assess the sensitivity of micro-metastasis detection by FACS (Fluorescence-activated cell sorting), HeLa cells were titrated into Peripheral blood mononuclear cells (PBMCs) and expression of pan-cytokeratin AE1/AE3 was analyzed. Single cell suspensions were separately prepared from 10 regional lymph nodes obtained from 5 patients with invasive penile cancer undergoing radical surgery and lymph node dissection. Lymph node dereived cells were examined for cell surface expression of EpCAM, E-cadherin and intracellular expression of pan-cytokeratin AE1/AE3 by FACS.

    RESULTS: Ten lymph nodes from 5 penile cancer patients were investigated in a head-to-head comparison between FACS and pathology examination of sections. All metastatic lymph nodes verified by pathology examination were also identified by FACS. Two additional lymph nodes with micro-metastases were diagnosed by FACS only.

    CONCLUSIONS: FACS analyses of pan-cytokeratin AE1/AE3 stained single cells from tumor draining lymph nodes can be used to detect micro-metastases in patients with penile cancer patients.

  • 642. Zhang, Lu
    et al.
    Hu, Jin
    Zirakzadeh, Ali
    Rosvall, Jesper
    Hedlund, Mats
    Hu, Pingsheng
    Wallin, Robert
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Immune responses against Human Papilloma virus in draining lymph nodes from patients with penile cancer2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 339-339Article in journal (Other academic)
  • 643. Zhao, Hongjuan
    et al.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Rasmuson, Torgny
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Tibshirani, Robert
    Brooks, James D
    Gene expression profiling predicts survival in conventional renal cell carcinoma2006In: PLoS Med, ISSN 1549-1676, Vol. 3, no 1, p. e13-Article in journal (Refereed)
  • 644. Zhao, Hongjuan
    et al.
    Zongming Ma,
    Tibshirani, Robert
    Higgins, John P T
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Brooks, James D
    Alteration of gene expression signatures of cortical differentiation and wound response in lethal clear cell renal cell carcinomas.2009In: PloS one, ISSN 1932-6203, Vol. 4, no 6, p. e6039-Article in journal (Refereed)
    Abstract [en]

    Clear cell renal cell carcinoma (ccRCC) is the most common malignancy of the adult kidney and displays heterogeneity in clinical outcomes. Through comprehensive gene expression profiling, we have identified previously a set of transcripts that predict survival following nephrectomy independent of tumor stage, grade, and performance status. These transcripts, designated as the SPC (supervised principal components) gene set, show no apparent biological or genetic features that provide insight into renal carcinogenesis or tumor progression. We explored the relationship of this gene list to a set of genes expressed in different anatomical segments of the normal kidney including the cortex (cortex gene set) and the glomerulus (glomerulus gene set), and a gene set expressed after serum stimulation of quiescent fibroblasts (the core serum response or CSR gene set). Interestingly, the normal cortex, glomerulus (part of the normal renal cortex), and CSR gene sets captured more than 1/5 of the genes in the highly prognostic SPC gene set. Based on gene expression patterns alone, the SPC gene set could be used to sort samples from normal adult kidneys by the anatomical regions from which they were dissected. Tumors whose gene expression profiles most resembled the normal renal cortex or glomerulus showed better survival than those that did not, and those with expression features more similar to CSR showed poorer survival. While the cortex, glomerulus, and CSR signatures predicted survival independent of traditional clinical parameters, they were not independent of the SPC gene list. Our findings suggest that critical biological features of lethal ccRCC include loss of normal cortical differentiation and activation of programs associated with wound healing.

  • 645. Zheng, S Lilly
    et al.
    Sun, Jielin
    Wiklund, Fredrik
    Smith, Shelly
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Li, Ge
    Adami, Hans-Olov
    Hsu, Fang-Chi
    Zhu, Yi
    Bälter, Katarina
    Kader, A Karim
    Turner, Aubrey R
    Liu, Wennuan
    Bleecker, Eugene R
    Meyers, Deborah A
    Duggan, David
    Carpten, John D
    Chang, Bao-Li
    Isaacs, William B
    Xu, Jianfeng
    Grönberg, Henrik
    Cumulative association of five genetic variants with prostate cancer.2008In: N Engl J Med, ISSN 1533-4406, Vol. 358, no 9, p. 910-9Article in journal (Refereed)
  • 646. Zirakzadeh, A Ali
    et al.
    Kinn, Johan
    Krantz, David
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Urology, Stockholm South General Hospital, Karolinska Institutet, Stockholm, Sweden.
    Winerdal, Malin E
    Hu, Jin
    Hartana, Ciputra Adijaya
    Lundgren, Christian
    Bergman, Emma Ahlén
    Johansson, Markus
    Holmström, Benny
    Hansson, Johan
    Sidikii, Alexander
    Vasko, Janos
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marits, Per
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Doxorubicin enhances the capacity of B cells to activate T cells in urothelial urinary bladder cancer2017In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 176, p. 63-70Article in journal (Refereed)
    Abstract [en]

    Cancer is currently treated by a combination of therapies, including chemotherapy which is believed to suppress the immune system. Combination of immunotherapy and chemotherapy correlates with improved survival but needs careful planning in order to achieve a synergistic effect. In this study, we have demonstrated that doxorubicin treatment of B cells resulted in increased expression of CD86 and concordantly increased CD4(+) T cell activation in the presence of superantigen, an effect that was inhibited by the addition of a CD86 blocking antibody. Furthermore, doxorubicin resulted in decreased expression of the anti-inflammatory cytokines IL-10 and TNF-α. Finally, B cells from urinary bladder cancer patients, treated with a neoadjuvant regiment containing doxorubicin, displayed increased CD86-expression. We conclude that doxorubicin induces CD86 expression on B cells and hence enhances their antigen-presenting ability in vitro, a finding verified in patients. Development of tailored time and dose schedules may increase the effectiveness of combining chemotherapy and immunotherapy.

  • 647. Zirakzadeh, A. Ali
    et al.
    Marits, Per
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Multiplex B Cell Characterization in Blood, Lymph Nodes, and Tumors from Patients with Malignancies2013In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, no 11, p. 5847-5855Article in journal (Refereed)
    Abstract [en]

    B lymphocytes contribute to immune surveillance, by tumor-specific Abs and Ag presentation to T lymphocytes, but are insufficiently studied in humans. In this article, we report a flow cytometric investigation of B lymphocyte subpopulations in blood, lymph nodes (LNs), and malignant tissues from 20 patients operated on because of advanced solid tumors. The CD19(+) compartment in peripheral blood was essentially unaltered in patients, as compared with healthy control subjects. In metastatic LNs, signs of B lymphocyte activation were observed, as evidenced by increased proportions of plasmablasts and CD86-expressing cells. In tumor-infiltrating B lymphocytes (TIL-B), both switched memory cells and plasmablasts were expanded, as compared with nonmalignant epithelium. Moreover, pronounced skewing of Ig lambda/Ig kappa ratio was evident among TIL-Bs. By spectratype analysis on IgH, we confirmed a monoclonal expansion of the Vh7 family in TIL-B, also present in a tumor-associated LN. Sequencing the clonally expanded Vh7 revealed signs of somatic hypermutation. In conclusion, B lymphocytes in cancer patients exhibit signs of activation in tumor-associated tissues, likely induced by recognition of tumor Ags. Increased numbers of switched memory cells and plasmablasts in combination with clonal expansion and signs of somatic hypermutation suggest a CD4(+) T lymphocyte-dependent antitumoral response, which may be exploited for immunotherapy.

  • 648. Zirakzadeh, A Ali
    et al.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Rosenblatt, Robert
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ahlén Bergman, Emma
    Winerdal, Max
    Yang, David
    Cederwall, Johanna
    Jakobsson, Vivianne
    Hyllienmark, Martin
    Winqvist, Ola
    Marits, Per
    Tumour-associated B cells in urothelial urinary bladder cancer.2019In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, article id e12830Article in journal (Refereed)
    Abstract [en]

    Tumour infiltrating B cells and CD38+ plasma cells have been correlated with survival in different malignancies but their role in urinary bladder cancer is unclear. IL-10 is a multifunctional cytokine with both anti-inflammatory and immunostimulatory properties, that can be released by regulatory B cells (Bregs). We have stained paraffin-embedded tumour sections from 31 patients with invasive urothelial urinary bladder cancer with respect to CD20+ B cells, CD38+ cells, IL-10-expressing cells, IgG, C1q and C3a and analysed the impact of these markers on survival. Interestingly, we observe tumour-associated CD20+ B cells forming follicle-like structures in tumours of some patients. We demonstrate that follicle-like structures, tumour-associated CD38+ cells, IL-10 produced by non-B cells, tumour infiltrating IgG and activation of the complement system, may associate to longer survival of urinary bladder cancer patients. IL-10 expression by tumour-associated Bregs may instead negatively affect prognosis. More research is needed to fully understand the role of B cells and IL-10 in urinary bladder cancer.

  • 649.
    Åstrand, Anders
    et al.
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Andersson, Britt
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Jalkanen, Ville
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Börje, Ljungberg
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Anders, Bergh
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lindahl, Olof
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Prostate cancer detection with a tactile resonance sensor: measurement considerations and clinical setup2017In: Sensors, ISSN 1424-8220, E-ISSN 1424-8220, Vol. 17, no 11, article id 2453Article in journal (Refereed)
    Abstract [en]

    Tumors in the human prostate are usually stiffer compared to surrounding non-malignant glandular tissue, and tactile resonance sensors measuring stiffness can be used to detect prostate cancer. To explore this further, we used a tactile resonance sensor system combined with a rotatable sample holder where whole surgically removed prostates could be attached to detect tumors on, and beneath, the surface ex vivo. Model studies on tissue phantoms made of silicone and porcine tissue were performed. Finally, two resected human prostate glands were studied. Embedded stiff silicone inclusions placed 4 mm under the surface could be detected in both the silicone and biological tissue models, with a sensor indentation of 0.6 mm. Areas with different amounts of prostate cancer (PCa) could be distinguished from normal tissue (p < 0.05), when the tumor was located in the anterior part, whereas small tumors located in the dorsal aspect were undetected. The study indicates that PCa may be detected in a whole resected prostate with an uneven surface and through its capsule. This is promising for the development of a clinically useful instrument to detect prostate cancer during surgery.

  • 650.
    Åstrand, Anders
    et al.
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Andersson, Britt M
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Jalkanen, Ville
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The first study on whole human prostate ex vivo using a tactile resonance sensor for cancer detectionArticle in journal (Other academic)
    Abstract [en]

    Prostate cancer (PCa) is the most common form of cancer among males in Europe and the USA. A prostatectomy i.e. the removal of the prostate is the most common form of curative treatment. Prostate cancer can be suspected by a blood test for a prostate specific antigen (PSA) and a digital rectal examination (DRE) where a physician palpates the prostate through the rectum and where stiff nodules on the prostate is an indication for PCa. The final diagnosis of PCa is made by microscopic evaluation of ultrasound-guided biopsies taken from suspicious parts of the gland. After a prostatectomy the entire prostate is histopathologically analysed. One area of interest is the superficial part of the prostate gland as tumour growth on the surface suggests that the cancer has spread to other parts of the body.

     

    Tactile resonance sensors can be used to detect areas of different stiffness in soft tissue through a stiffness parameter. It is suggested that tactile resonance sensors can be used to detect prostate cancer since tumours in the human prostate usually is stiffer compared to surrounding healthy glandular tissue.

     

    The aim of the study was to detect tumours on, and beneath the surface, of whole human prostate glands ex vivo using a tactile resonance sensor system (TRSS). Model studies on spherical shaped tissue phantoms made of silicone and porcine tissue were performed to evaluate the ability of the TRSS to detect stiffer volumes at a distance beneath the surface. Finally two resected human prostate glands ex vivo from patients undergoing surgery for prostate cancer were studied.

     

    From the results it was concluded that the clamping force from the rotatable sample holder did not affect the magnitude of the stiffness parameter for the silicone samples. For the porcine muscle samples, the stiffness parameter showed to be affected by clamping forces larger than about 800 mN. The embedded stiff silicone nodules placed about 4 mm under the surface could be detected in both the silicone and biological tissue models with a sensor indentation distance of 0.6 mm. The measurements on resected whole human prostates showed that areas with elevated stiffness parameter values correlated (p < 0.05) with areas where cancer tumours were detected using histolopathological evaluation of the prostate. The tumours were significantly stiffer than the healthy tissue in the dorsal region. This is promising for the development of a clinically useful instrument to detect superficial prostate cancer.

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