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  • 151. Bjurberg, Maria
    et al.
    Kjellén, Elisabeth
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Department of Oncology, Lund University Hospital.
    Ohlsson, Tomas
    Bendahl, Pär-Ola
    Brun, Eva
    Prediction of patient outcome with 2-deoxy-2-[(18)F]fluoro-D-glucose-positron emission tomography early during radiotherapy for locally advanced cervical cancer2009Inngår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 19, nr 9, s. 1600-1605Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: It is difficult to assess the individual response of locally advanced cervical cancer to chemoradiation therapy during the course of treatment. We have investigated the predictive value of positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) early during treatment in relation to progression-free survival.

    Methods: This prospective single-center clinical trial included women with locally advanced cervical cancer from 2004 to 2008. 2-Deoxy-2-[(18)F]fluoro-D-glucose-PET/computed tomography was performed at baseline, during the third week of treatment and, finally, 3 months after the completion of treatment. The images were evaluated visually, semiquantitatively with the maximum standardized uptake value, and by calculating the metabolic rate of FDG. Thirty-two patients were eligible for full evaluation.

    Results: The median follow-up time was 28 months (range, 5-53 months). Visual metabolic complete response on FDG-PET, after a mean irradiation dose of 23 Gy (range, 16-27 Gy), was found in 7 patients, none of which relapsed. Eleven of the 25 patients with remaining malignant hypermetabolism on the second FDG-PET relapsed. Neither maximum standardized uptake value nor metabolic rate of FDG could further discriminate between patients with low risk and patients with high risk of relapse. The follow-up FDG-PET performed 3 months after the completion of treatment identified a group of patients with poor prognosis.

    Conclusions: In conclusion, FDG-PET early during chemoradiation therapy identified a small number of patients with an excellent prognosis. However, FDG-PET at this early point in time during treatment failed to predict the outcome for most patients. Future clinical trials to determine the optimal timing of predictive FDG-PET are thus warranted.

  • 152.
    Björ, Ove
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Damber, Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Edström, Clarence
    Nilsson, Tohr
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Long-term follow-up study of mortality and the incidence of cancer in a cohort of workers at a primary aluminum smelter in Sweden2008Inngår i: Scandinavian Journal of Work, Environment and Health, ISSN 0355-3140, E-ISSN 1795-990X, Vol. 34, nr 6, s. 463-470Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: Previous studies on mortality and the incidence of cancer among workers at primary aluminum smelters have produced conclusive results indicating an elevated risk of bladder cancer. An increased risk of lung cancer has also been reported several times. The objective of this study was to examine mortality and the incidence of cancer at a Swedish aluminum smelter when different neighboring reference populations were used to evaluate any relationships to the length of employment. METHODS: A historical cohort--comprised of 2264 male nonoffice workers employed from 1942 on and tracked up to the year 2000--was examined. With the use of three reference populations for mortality and four for cancer incidence, standardized mortality and incidence ratios were calculated, together with hazard ratios derived from Cox regression models. RESULTS: This study showed an excess risk of mortality due to chronic obstructive lung disease, mental disorders, and diseases of the digestive system among the short-term workers. An elevated risk of cancer was found for the lungs, central nervous system, and esophagus. The highest lung cancer risk was observed for the workers employed for > or = 10 years in the factory when they were compared with the reference group from northern Sweden (standardized incidence ratio 1.99, 95% confidence ratio 1.21-3.07). CONCLUSIONS: The results support previous studies that demonstrated an excess risk of lung cancer, but, in contrast to the results of most studies, cancer of the central nervous system was also elevated. This study did not, however, verify an association between this type of exposure and cancer of the urinary organs.

  • 153.
    Björeland, Ulrika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Jonsson, Joakim
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Alm, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Beckman, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Nyholm, Tufve
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Thellenberg-Karlsson, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Inter-fraction movements of the prostate and pelvic lymph nodes during IGRT2018Inngår i: Journal of radiation oncology, ISSN 1948-7894, Vol. 7, nr 4, s. 357-366Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectivities: The aim of this study was to evaluate inter-fraction movements of lymph node regions that are commonly included in the pelvic clinical target volume (CTV) for high-risk prostate cancer patients. We also aimed to evaluate if the movements affect the planning target volumes. Methods: Ten prostate cancer patients were included. The patients underwent six MRI scans, from treatment planning to near end of treatment. The CTV movements were analyzed with deformable registration technique with the CTV divided into sections. The validity of the deformable registration was assessed by comparing the results for individual lymph nodes that were possible to identify in all scans. Results: Using repetitive MRI, measurements showed that areas inside the CTV (lymph nodes) in some extreme cases were as mobile as the prostate and not fixed to the bones. The lymph node volumes closest to the prostate did not tend to follow the prostate motion. The more cranial lymph node volumes moved less, but still independently, and they were not necessarily fixed to the pelvic bones. In 95% of the cases, the lymph node motion in the R-L direction was 2-4mm, in the A-P direction 2-7mm, and in the C-C direction 2-5mm depending on the CTV section. Conclusion: Lymph nodes and prostate were most mobile in the A-P direction, followed by the C-C and R-L directions. This movement should be taken into account when deciding the margins for the planning target volumes (PTV).

  • 154.
    Björkblom, Benny
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Späth, Florentin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    PRE-DIAGNOSTIC PLASMA METABOLITES LINKED TO FUTURE BRAIN TUMOR DEVELOPMENT2018Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, s. 288-289Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    BACKGROUND: The Northern Sweden Health and Disease Study is a unique population-based biobank linked to the clinical data registries. The samples originate from over 133 000 individuals living in the northern part of Sweden, and primarily collected during health checkups from the age of 40 years. Our project aims to investigate alterations in metabolite signatures in blood plasma of healthy blood donors that later in life developed a tumor. Brain tumors, especially glioblastoma is associated with poor prognosis. To explore early events of metabolic reprograming linked to future diagnosis, we investigated alterations in metabolite concentrations in plasma collected several years before diagnosis with matched healthy controls. MATERIALS AND METHODS: In total 392 analytical samples (256 repeated timepoint and 136 single timepoint, case-control samples) were analyzed using GCTOFMS. Constrained randomization of run order was utilized to maximize information output and minimize the false discovery rate. By use of reference databases, we could with high confidence quantify and identify 150 plasma metabolites. We detected metabolites with significant alterations in concertation between pre-clinical glioma cases and healthy controls by the effect projection approach based on orthogonal partial least squares (OPLSEP). RESULTS AND CONCLUSIONS: For the repeated blood samples, we designed and applied a novel multivariate strategy for high resolution biomarker pattern discovery. We utilize the fact that we have available samples from two repeated time points prior to diagnosis for each future glioma case and their matched controls to construct a small design of experiment (DoE) of four samples for each match pair. The data for each individual DoE was evaluated by OPLS-EP to determine the effect of each individual metabolite in relation to control-case, time and their interaction. Finally, latent significance calculations by means of OPLS were used to extract and evaluate the correct latent biomarker and highlight true significance of individual metabolites. Our study presents an approach to minimize confounding effects due to systematic noise from sampling, the analytical method, as well as take into account personalized metabolic levels over time, enabling biomarker detection within a smaller sample group. We will present and discuss the latest results and biomarkers from this exploratory metabolomics study at the meeting

  • 155.
    Björkblom, Benny
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Tabatabaei, Pedram
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Bergström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Asklund, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergenheim, A. Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Metabolic response patterns in brain microdialysis fluids and serum during interstitial cisplatin treatment of high-grade glioma2019Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: High-grade gliomas are associated with poor prognosis. Tumour heterogeneity and invasiveness create challenges for effective treatment and use of systemically administrated drugs. Furthermore, lack of functional predictive response-assays based on drug efficacy complicates evaluation of early treatment responses.

    METHODS: We used microdialysis to deliver cisplatin into the tumour and to monitor levels of metabolic compounds present in the tumour and non-malignant brain tissue adjacent to tumour, before and during treatment. In parallel, we collected serum samples and used multivariate statistics to analyse the metabolic effects.

    RESULTS: We found distinct metabolic patterns in the extracellular fluids from tumour compared to non-malignant brain tissue, including high concentrations of a wide range of amino acids, amino acid derivatives and reduced levels of monosaccharides and purine nucleosides. We found that locoregional cisplatin delivery had a strong metabolic effect at the tumour site, resulting in substantial release of glutamic acid, phosphate, and spermidine and a reduction of cysteine levels. In addition, patients with long-time survival displayed different treatment response patterns in both tumour and serum. Longer survival was associated with low tumour levels of lactic acid, glyceric acid, ketoses, creatinine and cysteine. Patients with longer survival displayed lower serum levels of ketohexoses, fatty acid methyl esters, glycerol-3-phosphate and alpha-tocopherol, while elevated phosphate levels were seen in both tumour and serum during treatment.

    CONCLUSION: We highlight distinct metabolic patterns associated with high-grade tumour metabolism, and responses to cytotoxic cisplatin treatment.

    Fulltekst tilgjengelig fra 2020-12-10 07:00
  • 156.
    Björkblom, Benny
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mörén, Lina
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johannesen, Tom Borge
    langseth, Hilde
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Metabolomic screening of pre-diagnostic serum samples identifies association between alpha- and gamma-tocopherols and glioblastoma risk2016Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 24, s. 37043-37053Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glioblastoma is associated with poor prognosis with a median survival of one year. High doses of ionizing radiation is the only established exogenous risk factor. To explore new potential biological risk factors for glioblastoma, we investigated alterations in metabolite concentrations in pre-diagnosed serum samples from glioblastoma patients diagnosed up to 22 years after sample collection, and undiseased controls. The study points out a latent biomarker for future glioblastoma consisting of nine metabolites (gamma-tocopherol, alpha-tocopherol, erythritol, erythronic acid, myo-inositol, cystine, 2-keto-L-gluconic acid, hypoxanthine and xanthine) involved in antioxidant metabolism. We detected significantly higher serum concentrations of alpha-tocopherol (p=0.0018) and gamma-tocopherol (p=0.0009) in future glioblastoma cases. Compared to their matched controls, the cases showed a significant average fold increase of alpha- and gamma-tocopherol levels: 1.2 for alpha-T (p=0.018) and 1.6 for gamma-T (p=0.003). These tocopherol levels were associated with a glioblastoma odds ratio of 1.7 (alpha-T, 95% CI: 1.0-3.0) and 2.1 (gamma-T, 95% CI: 1.2-3.8). Our exploratory metabolomics study detected elevated serum levels of a panel of molecules with antioxidant properties as well as oxidative stress generated compounds. Additional studies are necessary to confirm the association between the observed serum metabolite pattern and future glioblastoma development.

  • 157. Bjørge, Tone
    et al.
    Häggström, Christel
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden..
    Ghaderi, Sara
    Nagel, Gabriele
    Manjer, Jonas
    Tretli, Steinar
    Ulmer, Hanno
    Harlid, Sophia
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rosendahl, Ann H.
    Lang, Alois
    Stattin, Pär
    Stocks, Tanja
    Engeland, Anders
    BMI and weight changes and risk of obesity-related cancers: a pooled European cohort study2019Inngår i: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Obesity is an established risk factor for several cancers. Adult weight gain has been associated with increased cancer risk, but studies on timing and duration of adult weight gain are relatively scarce. We examined the impact of BMI (body mass index) and weight changes over time, as well as the timing and duration of excess weight, on obesity- and non-obesity-related cancers.

    Methods: We pooled health data from six European cohorts and included 221 274 individuals with two or more height and weight measurements during 1972–2014. Several BMI and weight measures were constructed. Cancer cases were identified through linkage with national cancer registries. Hazard ratios (HRs) of cancer with 95% confidence intervals (CIs) were derived from time-dependent Cox-regression models.

    Results: During follow-up, 27 881 cancer cases were diagnosed; 9761 were obesity-related. The HR of all obesity-related cancers increased with increasing BMI at first and last measurement, maximum BMI and longer duration of overweight (men only) and obesity. Participants who were overweight before age 40 years had an HR of obesity-related cancers of 1.16 (95% CI 1.02, 1.32) and 1.15 (95% CI 1.04, 1.27) in men and women, respectively, compared with those who were not overweight. The risk increase was particularly high for endometrial (70%), male renal-cell (58%) and male colon cancer (29%). No positive associations were seen for cancers not regarded as obesity-related.

    Conclusions: Adult weight gain was associated with increased risk of several major cancers. The degree, timing and duration of overweight and obesity also seemed to be important. Preventing weight gain may reduce the cancer risk.

  • 158.
    Bjørge, Tone
    et al.
    Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway.
    Lukanova, Annekatrin
    Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Jonsson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Tretli, Steinar
    Cancer Registry of Norway, Institute of Populationbased Cancer Research, Montebello, Oslo, Norway.
    Ulmer, Hanno
    Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Innsbruck, Austria.
    Manjer, Jonas
    Department of Surgery, Malmö University Hospital, Lund University, Malmö, Sweden.
    Stocks, Tanja
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Selmer, Randi
    Norwegian Institute of Public Health, Oslo/Bergen, Norway.
    Nagel, Gabriele
    Institute of Empidemiology, Ulm Univesity, Ulm, Germany.
    Almquist, Martin
    Department of Surgery, Lund University Hospital, Lund University, Malmö, Sweden.
    Concin, Hans
    Agency for Preventive and Social Medicine, Bregenz, Austria.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Häggström, Christel
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Engeland, Anders
    Department of Public Health and Primary Health Care, University of Bergen, Bergen, Norway.
    Metabolic syndrome and breast cancer in the me-can (metabolic syndrome and cancer) project.2010Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, nr 7, s. 1737-1745Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Few studies have assessed the metabolic syndrome (MetS) as an entity in relation to breast cancer risk, and results have been inconsistent. We aimed to examine the association between MetS factors (individually and combined) and risk of breast cancer incidence and mortality. METHODS: Two hundred ninety thousand women from Austria, Norway, and Sweden were enrolled during 1974-2005, with measurements of height, weight, blood pressure, and levels of glucose, cholesterol, and triglycerides. Relative risks (RR) of breast cancer were estimated using Cox proportional hazards regression for each MetS factor in quintiles and for standardized levels (z-scores) and for a composite z-score for the MetS. RESULTS: There were 4,862 incident cases of breast cancer and 633 deaths from breast cancer identified. In women below age 50, there was a decreased risk of incident cancer for the MetS (per 1-unit increment of z-score; RR, 0.83; 95% confidence interval, 0.76-0.90) as well as for the individual factors (except for glucose). The lowest risks were seen among the heaviest women. In women above age 60, there was an increased risk of breast cancer mortality for the MetS (RR, 1.23; 95% confidence interval, 1.04-1.45) and for blood pressure and glucose. The strongest association with mortality was seen for increased glucose concentrations. CONCLUSIONS: The MetS was associated with a decreased risk of incident breast cancer in women below age 50 with high body mass index, and with an increased risk of breast cancer mortality in women above 60. IMPACT: Lifestyle interventions as recommended for cardiovascular disease prevention may be of value to prevent breast cancer mortality in postmenopausal women.

  • 159. Blein, Sophie
    et al.
    Bardel, Claire
    Danjean, Vincent
    McGuffog, Lesley
    Healey, Sue
    Barrowdale, Daniel
    Lee, Andrew
    Dennis, Joe
    Kuchenbaecker, Karoline B.
    Soucy, Penny
    Terry, Mary Beth
    Chung, Wendy K.
    Goldgar, David E.
    Buys, Saundra S.
    Janavicius, Ramunas
    Tihomirova, Laima
    Tung, Nadine
    Dorfling, Cecilia M.
    van Rensburg, Elizabeth J.
    Neuhausen, Susan L.
    Ding, Yuan Chun
    Gerdes, Anne-Marie
    Ejlertsen, Bent
    Nielsen, Finn C.
    Hansen, Thomas V. O.
    Osorio, Ana
    Benitez, Javier
    Andres Conejero, Raquel
    Segota, Ena
    Weitzel, Jeffrey N.
    Thelander, Margo
    Peterlongo, Paolo
    Radice, Paolo
    Pensotti, Valeria
    Dolcetti, Riccardo
    Bonanni, Bernardo
    Peissel, Bernard
    Zaffaroni, Daniela
    Scuvera, Giulietta
    Manoukian, Siranoush
    Varesco, Liliana
    Capone, Gabriele L.
    Papi, Laura
    Ottini, Laura
    Yannoukakos, Drakoulis
    Konstantopoulou, Irene
    Garber, Judy
    Hamann, Ute
    Donaldson, Alan
    Brady, Angela
    Brewer, Carole
    Foo, Claire
    Evans, D. Gareth
    Frost, Debra
    Eccles, Diana
    Douglas, Fiona
    Cook, Jackie
    Adlard, Julian
    Barwell, Julian
    Walker, Lisa
    Izatt, Louise
    Side, Lucy E.
    Kennedy, M. John
    Tischkowitz, Marc
    Rogers, Mark T.
    Porteous, Mary E.
    Morrison, Patrick J.
    Platte, Radka
    Eeles, Ros
    Davidson, Rosemarie
    Hodgson, Shirley
    Cole, Trevor
    Godwin, Andrew K.
    Isaacs, Claudine
    Claes, Kathleen
    De Leeneer, Kim
    Meindl, Alfons
    Gehrig, Andrea
    Wappenschmidt, Barbara
    Sutter, Christian
    Engel, Christoph
    Niederacher, Dieter
    Steinemann, Doris
    Plendl, Hansjoerg
    Kast, Karin
    Rhiem, Kerstin
    Ditsch, Nina
    Arnold, Norbert
    Varon-Mateeva, Raymonda
    Schmutzler, Rita K.
    Preisler-Adams, Sabine
    Markov, Nadja Bogdanova
    Wang-Gohrke, Shan
    de Pauw, Antoine
    Lefol, Cedrick
    Lasset, Christine
    Leroux, Dominique
    Rouleau, Etienne
    Damiola, Francesca
    Dreyfus, Helene
    Barjhoux, Laure
    Golmard, Lisa
    Uhrhammer, Nancy
    Bonadona, Valerie
    Sornin, Valerie
    Bignon, Yves-Jean
    Carter, Jonathan
    Van Le, Linda
    Piedmonte, Marion
    DiSilvestro, Paul A.
    de la Hoya, Miguel
    Caldes, Trinidad
    Nevanlinna, Heli
    Aittomaki, Kristiina
    Jager, Agnes
    van den Ouweland, Ans M. W.
    Kets, Carolien M.
    Aalfs, Cora M.
    van Leeuwen, Flora E.
    Hogervorst, Frans B. L.
    Meijers-Heijboer, Hanne E. J.
    Oosterwijk, Jan C.
    van Roozendaal, Kees E. P.
    Rookus, Matti A.
    Devilee, Peter
    van der Luijt, Rob B.
    Olah, Edith
    Diez, Orland
    Teule, Alex
    Lazaro, Conxi
    Blanco, Ignacio
    Del Valle, Jesus
    Jakubowska, Anna
    Sukiennicki, Grzegorz
    Gronwald, Jacek
    Lubinski, Jan
    Durda, Katarzyna
    Jaworska-Bieniek, Katarzyna
    Agnarsson, Bjarni A.
    Maugard, Christine
    Amadori, Alberto
    Montagna, Marco
    Teixeira, Manuel R.
    Spurdle, Amanda B.
    Foulkes, William
    Olswold, Curtis
    Lindor, Noralane M.
    Pankratz, Vernon S.
    Szabo, Csilla I.
    Lincoln, Anne
    Jacobs, Lauren
    Corines, Marina
    Robson, Mark
    Vijai, Joseph
    Berger, Andreas
    Fink-Retter, Anneliese
    Singer, Christian F.
    Rappaport, Christine
    Kaulich, Daphne Geschwantler
    Pfeiler, Georg
    Tea, Muy-Kheng
    Greene, Mark H.
    Mai, Phuong L.
    Rennert, Gad
    Imyanitov, Evgeny N.
    Mulligan, Anna Marie
    Glendon, Gord
    Andrulis, Irene L.
    Tchatchou, Sandrine
    Toland, Amanda Ewart
    Pedersen, Inge Sokilde
    Thomassen, Mads
    Kruse, Torben A.
    Jensen, Uffe Birk
    Caligo, Maria A.
    Friedman, Eitan
    Zidan, Jamal
    Laitman, Yael
    Lindblom, Annika
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Arver, Brita
    Loman, Niklas
    Rosenquist, Richard
    Olopade, Olufunmilayo I.
    Nussbaum, Robert L.
    Ramus, Susan J.
    Nathanson, Katherine L.
    Domchek, Susan M.
    Rebbeck, Timothy R.
    Arun, Banu K.
    Mitchell, Gillian
    Karlan, Beth Y.
    Lester, Jenny
    Orsulic, Sandra
    Stoppa-Lyonnet, Dominique
    Thomas, Gilles
    Simard, Jacques
    Couch, Fergus J.
    Offit, Kenneth
    Easton, Douglas F.
    Chenevix-Trench, Georgia
    Antoniou, Antonis C.
    Mazoyer, Sylvie
    Phelan, Catherine M.
    Sinilnikova, Olga M.
    Cox, David G.
    An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers2015Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, artikkel-id 61Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

  • 160. Blomberg, Carl
    et al.
    Nilsson, Jonas
    Holgersson, Georg
    Edlund, Per
    Bergqvist, Michael
    Adwall, Linda
    Ekman, Simon
    Brattström, Daniel
    Bergström, Stefan
    Randomized Trials of Systemic Medically-treated Malignant Mesothelioma: A Systematic Review.2015Inngår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 35, nr 5Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Malignant pleural mesothelioma (MPM) is a rare but aggressive malignancy mainly localized to the pleura. Malignant mesothelioma grows highly invasive into surrounding tissue and has a low tendency to metastasize. The median overall survival (OS) of locally advanced or metastatic disease without treatment is 4-13 months but, during recent years, improvement in survival has been achieved since treatment for patients with mesothelioma has improved with better palliative care, systemic medical treatment, surgery and improved diagnostics methods. The present review aims at describing available data from randomized trials considering systemic medical treatment for this patient category.

  • 161. Blumel, Edda
    et al.
    Willerslev-Olsen, Andreas
    Gluud, Maria
    Lindahl, Lise M.
    Fredholm, Simon
    Nastasi, Claudia
    Krejsgaard, Thorbjorn
    Surewaard, Bas G. J.
    Koralov, Sergei B.
    Hu, Tengpeng
    Persson, Jenny L.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten). Clinical Research Center, Lund University, Sweden.
    Bonefeld, Charlotte Menne
    Geisler, Carsten
    Iversen, Lars
    Becker, Juergen C.
    Andersen, Mads Hald
    Woetmann, Anders
    Buus, Terkild Brink
    Odum, Niels
    Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4+ T cells in cutaneous T-cell lymphoma2019Inngår i: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 8, nr 11, artikkel-id e1641387Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Staphylococcus aureus is implicated in disease progression in cutaneous T-cell lymphoma (CTCL). Here, we demonstrate that malignant T cell lines derived from CTCL patients as well as primary malignant CD4+ T cells from Sézary syndrome patients are considerably more resistant to alpha-toxin-induced cell death than their non-malignant counterparts. Thus, in a subset of Sézary syndrome patients the ratio between malignant and non-malignant CD4+ T cells increases significantly following exposure to alpha-toxin. Whereas toxin-induced cell death is ADAM10 dependent in healthy CD4+ T cells, resistance to alpha-toxin in malignant T cells involves both downregulation of ADAM10 as well as other resistance mechanisms. In conclusion, we provide first evidence that Staphylococcus aureus derived alpha-toxin can tilt the balance between malignant and non-malignant CD4+ T cells in CTCL patients. Consequently, alpha-toxin may promote disease progression through positive selection of malignant CD4+ T cells, identifying alpha-toxin as a putative drug target in CTCL.

  • 162.
    Bodén, Stina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Myte, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wennberg, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för hållbar hälsa.
    Harlid, Sophia
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Tandläkarutbildning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för hållbar hälsa.
    Shivappa, Nitin
    Hébert, James R
    van Guelpen, Bethany
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM).
    Nilsson, Lena Maria
    Umeå universitet, Arktiskt centrum vid Umeå universitet (Arcum). Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för hållbar hälsa.
    The inflammatory potential of diet in determining cancer risk: a prospective investigation of two dietary pattern scores2019Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 4, artikkel-id e0214551Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Inflammation-related mechanisms may contribute to the link between diet and cancer. We sought to investigate the inflammatory impact of diet on cancer risk using the Dietary inflammatory index (DII) and an adapted Mediterranean diet score (MDS).

    METHODS: This population-based, prospective cohort study used self-reported dietary data from the Västerbotten Intervention Programme, including 100,881 participants, of whom 35,393 had repeated measures. Associations between dietary patterns and cancer risk were evaluated using Cox proportional hazards regression. We also used restricted cubic splines to test for potential non-linear associations.

    RESULTS: A total of 9,250 incident cancer cases were diagnosed during a median follow-up of 15 years. The two dietary patterns were moderately correlated to each other and had similar associations with cancer risk, predominantly lung cancer in men (DII per tertile decrease: Hazard ratio (HR) 0.81 (0.66-0.99), MDS per tertile increase: HR 0.86 (0.72-1.03)), and gastric cancer in men (DII: 0.73 (0.53-0.99), MDS: 0.73 (0.56-0.96)). Associations were, in general, found to be linear. We found no longitudinal association between 10-year change in diet and cancer risk.

    CONCLUSION: We confirm small, but consistent and statistically significant associations between a more anti-inflammatory or healthier diet and reduced risk of cancer, including a lower risk of lung and gastric cancer in men. The dietary indexes produced similar associations with respect to the risk of cancer.

  • 163. Bojesen, Stig E.
    et al.
    Pooley, Karen A.
    Johnatty, Sharon E.
    Beesley, Jonathan
    Michailidou, Kyriaki
    Tyrer, Jonathan P.
    Edwards, Stacey L.
    Pickett, Hilda A.
    Shen, Howard C.
    Smart, Chanel E.
    Hillman, Kristine M.
    Mai, Phuong L.
    Lawrenson, Kate
    Stutz, Michael D.
    Lu, Yi
    Karevan, Rod
    Woods, Nicholas
    Johnstonw, Rebecca L.
    French, Juliet D.
    Chen, Xiaoqing
    Weischer, Maren
    Nielsen, Sune F.
    Maranian, Melanie J.
    Ghoussaini, Maya
    Ahmed, Shahana
    Baynes, Caroline
    Bolla, Manjeet K.
    Wang, Qin
    Dennis, Joe
    McGuffog, Lesley
    Barrowdale, Daniel
    Lee, Andrew
    Healey, Sue
    Lush, Michael
    Tessier, Daniel C.
    Vincent, Daniel
    Bacot, Francis
    Vergote, Ignace
    Lambrechts, Sandrina
    Despierre, Evelyn
    Risch, Harvey A.
    Gonzalez-Neira, Anna
    Rossing, Mary Anne
    Pita, Guillermo
    Doherty, Jennifer A.
    Alvarez, Nuria
    Larson, Melissa C.
    Fridley, Brooke L.
    Schoof, Nils
    Chang-Claude, Jenny
    Cicek, Mine S.
    Peto, Julian
    Kalli, Kimberly R.
    Broeks, Annegien
    Armasu, Sebastian M.
    Schmidt, Marjanka K.
    Braaf, Linde M.
    Winterhoff, Boris
    Nevanlinna, Heli
    Konecny, Gottfried E.
    Lambrechts, Diether
    Rogmann, Lisa
    Guenel, Pascal
    Teoman, Attila
    Milne, Roger L.
    Garcia, Joaquin J.
    Cox, Angela
    Shridhar, Vijayalakshmi
    Burwinkel, Barbara
    Marme, Frederik
    Hein, Rebecca
    Sawyer, Elinor J.
    Haiman, Christopher A.
    Wang-Gohrke, Shan
    Andrulis, Irene L.
    Moysich, Kirsten B.
    Hopper, John L.
    Odunsi, Kunle
    Lindblom, Annika
    Giles, Graham G.
    Brenner, Hermann
    Simard, Jacques
    Lurie, Galina
    Fasching, Peter A.
    Carney, Michael E.
    Radice, Paolo
    Wilkens, Lynne R.
    Swerdlow, Anthony
    Goodman, Marc T.
    Brauch, Hiltrud
    Garcia-Closas, Montserrat
    Hillemanns, Peter
    Winqvist, Robert
    Durst, Matthias
    Devilee, Peter
    Runnebaum, Ingo
    Jakubowska, Anna
    Lubinski, Jan
    Mannermaa, Arto
    Butzow, Ralf
    Bogdanova, Natalia V.
    Doerk, Thilo
    Pelttari, Liisa M.
    Zheng, Wei
    Leminen, Arto
    Anton-Culver, Hoda
    Bunker, Clareann H.
    Kristensen, Vessela
    Ness, Roberta B.
    Muir, Kenneth
    Edwards, Robert
    Meindl, Alfons
    Heitz, Florian
    Matsuo, Keitaro
    du Bois, Andreas
    Wu, Anna H.
    Harter, Philipp
    Teo, Soo-Hwang
    Schwaab, Ira
    Shu, Xiao-Ou
    Blot, William
    Hosono, Satoyo
    Kang, Daehee
    Nakanishi, Toru
    Hartman, Mikael
    Yatabe, Yasushi
    Hamann, Ute
    Karlan, Beth Y.
    Sangrajrang, Suleeporn
    Kjaer, Susanne Kruger
    Gaborieau, Valerie
    Jensen, Allan
    Eccles, Diana
    Hogdall, Estrid
    Shen, Chen-Yang
    Brown, Judith
    Woo, Yin Ling
    Shah, Mitul
    Azmi, Mat Adenan Noor
    Luben, Robert
    Omar, Siti Zawiah
    Czene, Kamila
    Vierkant, Robert A.
    Nordestgaard, Borge G.
    Flyger, Henrik
    Vachon, Celine
    Olson, Janet E.
    Wang, Xianshu
    Levine, Douglas A.
    Rudolph, Anja
    Weber, Rachel Palmieri
    Flesch-Janys, Dieter
    Iversen, Edwin
    Nickels, Stefan
    Schildkraut, Joellen M.
    Silva, Isabel Dos Santos
    Cramer, Daniel W.
    Gibson, Lorna
    Terry, Kathryn L.
    Fletcher, Olivia
    Vitonis, Allison F.
    van der Schoot, C. Ellen
    Poole, Elizabeth M.
    Hogervorst, Frans B. L.
    Tworoger, Shelley S.
    Liu, Jianjun
    Bandera, Elisa V.
    Li, Jingmei
    Olson, Sara H.
    Humphreys, Keith
    Row, Irene
    Blomqvist, Carl
    Rodriguez-Rodriguez, Lorna
    Aittomaki, Kristiina
    Salvesen, Helga B.
    Muranen, Taru A.
    Wik, Elisabeth
    Brouwers, Barbara
    Krakstad, Camilla
    Wauters, Els
    Halle, Mari K.
    Wildiers, Hans
    Kiemeney, Lambertus A.
    Mulot, Claire
    Aben, Katja K.
    Laurent-Puig, Pierre
    Altena, Anne Mvan
    Truong, Therese
    Massuger, Leon F. A. G.
    Benitez, Javier
    Pejovic, Tanja
    Arias Perez, Jose Ignacio
    Hoatlin, Maureen
    Zamora, M. Pilar
    Cook, Linda S.
    Balasubramanian, Sabapathy P.
    Kelemen, Linda E.
    Schneeweiss, Andreas
    Le, Nhu D.
    Sohn, Christof
    Brooks-Wilson, Angela
    Tomlinson, Ian
    Kerin, Michael J.
    Miller, Nicola
    Cybulski, Cezary
    Henderson, Brian E.
    Menkiszak, Janusz
    Schumacher, Fredrick
    Wentzensen, Nicolas
    Marchand, Loic Le
    Yang, Hannah P.
    Mulligan, Anna Marie
    Glendon, Gord
    Engelholm, Svend Aage
    Knight, Julia A.
    Hogdall, Claus K.
    Apicella, Carmel
    Gore, Martin
    Tsimiklis, Helen
    Song, Honglin
    Southey, Melissa C.
    Jager, Agnes
    den Ouweland, Ans M. Wvan
    Brown, Robert
    Martens, John W. M.
    Flanagan, James M.
    Kriege, Mieke
    Paul, James
    Margolin, Sara
    Siddiqui, Nadeem
    Severi, Gianluca
    Whittemore, Alice S.
    Baglietto, Laura
    McGuire, Valerie
    Stegmaier, Christa
    Sieh, Weiva
    Mueller, Heiko
    Arndt, Volker
    Labreche, France
    Gao, Yu-Tang
    Goldberg, Mark S.
    Yang, Gong
    Dumont, Martine
    McLaughlin, John R.
    Hartmann, Arndt
    Ekici, Arif B.
    Beckmann, Matthias W.
    Phelan, Catherine M.
    Lux, Michael P.
    Permuth-Wey, Jenny
    Peissel, Bernard
    Sellers, Thomas A.
    Ficarazzi, Filomena
    Barile, Monica
    Ziogas, Argyrios
    Ashworth, Alan
    Gentry-Maharaj, Aleksandra
    Jones, Michael
    Ramus, Susan J.
    Orr, Nick
    Menon, Usha
    Pearce, Celeste L.
    Bruening, Thomas
    Pike, Malcolm C.
    Ko, Yon-Dschun
    Lissowska, Jolanta
    Figueroa, Jonine
    Kupryjanczyk, Jolanta
    Chanock, Stephen J.
    Dansonka-Mieszkowska, Agnieszka
    Jukkola-Vuorinen, Arja
    Rzepecka, Iwona K.
    Pylkas, Katri
    Bidzinski, Mariusz
    Kauppila, Saila
    Hollestelle, Antoinette
    Seynaeve, Caroline
    Tollenaar, Rob A. E. M.
    Durda, Katarzyna
    Jaworska, Katarzyna
    Hartikainen, Jaana M.
    Kosma, Veli-Matti
    Kataja, Vesa
    Antonenkova, Natalia N.
    Long, Jirong
    Shrubsole, Martha
    Deming-Halverson, Sandra
    Lophatananon, Artitaya
    Siriwanarangsan, Pornthep
    Stewart-Brown, Sarah
    Ditsch, Nina
    Lichtner, Peter
    Schmutzler, Rita K.
    Ito, Hidemi
    Iwata, Hiroji
    Tajima, Kazuo
    Tseng, Chiu-Chen
    Stram, Daniel O.
    van den Berg, David
    Yip, Cheng Har
    Ikrarn, M. Kamran
    Teh, Yew-Ching
    Cai, Hui
    Lu, Wei
    Signorello, Lisa B.
    Cai, Qiuyin
    Noh, Dong-Young
    Yoo, Keun-Young
    Miao, Hui
    Iau, Philip Tsau-Choong
    Teo, Yik Ying
    McKay, James
    Shapiro, Charles
    Ademuyiwa, Foluso
    Fountzilas, George
    Hsiung, Chia-Ni
    Yu, Jyh-Cherng
    Hou, Ming-Feng
    Healey, Catherine S.
    Luccarini, Craig
    Peock, Susan
    Stoppa-Lyonnet, Dominique
    Peterlongo, Paolo
    Rebbeck, Timothy R.
    Piedmonte, Marion
    Singer, Christian F.
    Friedman, Eitan
    Thomassen, Mads
    Offit, Kenneth
    Hansen, Thomas V. O.
    Neuhausen, Susan L.
    Szabo, Csilla I.
    Blanco, Ignacio
    Garber, Judy
    Narod, Steven A.
    Weitzel, Jeffrey N.
    Montagna, Marco
    Olah, Edith
    Godwin, Andrew K.
    Yannoukakos, Drakoulis
    Goldgar, David E.
    Caldes, Trinidad
    Imyanitov, Evgeny N.
    Tihomirova, Laima
    Arun, Banu K.
    Campbell, Ian
    Mensenkamp, Arjen R.
    van Asperen, Christi J.
    van Roozendaa, Kees E. P.
    Meijers-Heijboer, Hanne
    Collee, J. Margriet
    Oosterwijk, Jan C.
    Hooning, Maartje J.
    Rookus, Matti A.
    van der Luijt, Rob B.
    Os, Theo A. Mvan
    Evans, D. Gareth
    Frost, Debra
    Fineberg, Elena
    Barwell, Julian
    Walker, Lisa
    Kennedy, M. John
    Platte, Radka
    Davidson, Rosemarie
    Ellis, Steve D.
    Cole, Trevor
    Bressac-de Paillerets, Brigitte
    Buecher, Bruno
    Damiola, Francesca
    Faivre, Laurence
    Frenay, Marc
    Sinilnikova, Olga M.
    Caron, Olivier
    Giraud, Sophie
    Mazoyer, Sylvie
    Bonadona, Valerie
    Caux-Moncoutier, Virginie
    Toloczko-Grabarek, Aleksandra
    Gronwald, Jacek
    Byrski, Tomasz
    Spurdle, Amanda B.
    Bonanni, Bernardo
    Zaffaroni, Daniela
    Giannini, Giuseppe
    Bernard, Loris
    Dolcetti, Riccardo
    Manoukian, Siranoush
    Arnold, Norbert
    Engel, Christoph
    Deissler, Helmut
    Rhiem, Kerstin
    Niederacher, Dieter
    Pendl, Hansjoerg
    Sutter, Christian
    Wappenschmidt, Barbara
    Borg, Ake
    Mein, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Rantala, Johanna
    Soller, Maria
    Nathanson, Katherine L.
    Domchek, Susan M.
    Rodriguez, Gustavo C.
    Salani, Ritu
    Kaulich, Daphne Gschwantler
    Tea, Muy-Kheng
    Paluch, Shani Shimon
    Laitman, Yael
    Skytte, Anne-Bine
    Kruse, Torben A.
    Jensen, Uffe Birk
    Robson, Mark
    Gerdes, Anne-Marie
    Ejlertsen, Bent
    Foretova, Lenka
    Savage, Sharon A.
    Lesterm, Jenny
    Soucy, Penny
    Kuchenbaecker, Karoline B.
    Olswold, Curtis
    Cunningham, Julie M.
    Slager, Susan
    Pankratz, Vernon S.
    Dicks, Ed
    Lakhani, Sunil R.
    Couch, Fergus J.
    Hall, Per
    Monteiro, Alvaro N. A.
    Gayther, Simon A.
    Pharoah, Paul D. P.
    Reddel, Roger R.
    Goode, Ellen L.
    Greene, Mark H.
    Easton, Douglas F.
    Berchuck, Andrew
    Antoniou, Antonis C.
    Chenevix-Trench, Georgia
    Dunning, Alison M.
    Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer2013Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, nr 4, s. 371-384Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

  • 164.
    Boldrup, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Coates, P J
    Laurell, G
    Wilms, Torben
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Fahraeus, R
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Downregulation of miRNA-424: a sign of field cancerisation in clinically normal tongue adjacent to squamous cell carcinoma2015Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, nr 11, s. 1760-1765Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The overall survival for patients with squamous cell carcinoma of the tongue is low and the search for early diagnostic and prognostic markers is thus essential. MicroRNAs have been suggested as potential prognostic and diagnostic candidates in squamous cell carcinoma of head and neck in general. Methods: On the basis of the known differences between sub-sites within the oral cavity, we investigated the expression and role of microRNA-424 in squamous cell carcinoma arising in tongue. MicroRNA levels were measured by qRT-PCR in both tissue and plasma samples. Results: Levels of microRNA-424 were upregulated in tongue squamous cell carcinoma, but not in tumours originating from gingiva or floor of the mouth. Interestingly, microRNA-424 was downregulated in clinically normal tongue tissue next to tumour compared with completely healthy tongue, indicating that microRNA-424 could be a marker of field cancerisation in this tumour type. However, expression of microRNA-424 in a tongue-derived epithelial cell line revealed no significant changes in the expression profile of proteins and genes. Conclusions: Our patient data show that microRNA-424 alterations are a marker of field cancerisation specific for tongue tumourigenesis, which also could have a role in development of tongue squamous cell carcinoma.

  • 165.
    Boldrup, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Coates, Philip J
    Laurell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Differences in p63 expression in SCCHN tumours of different sub-sites within the oral cavity2011Inngår i: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 47, nr 9, s. 861-865Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Squamous cell carcinoma of the head and neck, SCCHN, the sixth most common cancer in the world, comprises tumours of differentanatomical sites. The overall survival is low, and there are no good prognostic or predictive markers available. The p53 homologue, p63, plays an important role in development of epithelial structures and has also been suggested to be involved in development of SCCHN. However, most studies on p63 in SCCHN have not taken into account the fact that this group of tumours is heterogeneous in terms of the particular site of origin of the cancer. Mapping and comparing p63 expression levels in tumours and corresponding clinically normal tissue in SCCHN from gingiva, tongue and tongue/floor of the mouth revealed clear differences between these regions. In normal samples from tongue and gingiva, tongue samples showed 2.5-fold higher median p63 expression and also more widespread expression compared to gingival samples. These results emphasise the importance of taking sub-site within the oral cavity into consideration in analyses of SCCHN.

  • 166.
    Boldrup, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Coates, Philip J
    Laurell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    p63 transcriptionally regulates BNC1, a Pol I and Pol II transcription factor that regulates ribosomal biogenesis and epithelial differentiation2012Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 48, nr 9, s. 1401-1406Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The p53-family member, p63 is a transcription factor that influences cellular adhesion, motility, proliferation, survival and apoptosis, and has a major role in regulating epithelial stem cells. Expression of p63 is often dysregulated in squamous cell carcinomas of the head and neck. In this study we show that p63 induces the expression of the basal epithelial transcription factor, Basonuclin 1. Basonuclin 1 is an unusual transcription factor that interacts with a subset of promoters of genes that are transcribed by both RNA polymerase-I and -II and has roles in maintaining ribosomal biogenesis and the proliferative potential of immature epithelial cells. Chromatin immunoprecipitation and reporter assays demonstrate that Basonuclin 1 is a direct transcriptional target of p63 and we also show that up-regulation of Basonuclin 1 is a common event in squamous cell carcinomas of the head and neck. These data identify a new transcriptional programme mediated by p63 regulation of the Basonuclin 1 transcription factor in squamous cell carcinomas and provide a novel link of p63 with the regulation of ribosomal biogenesis in epithelial cancer.

  • 167.
    Boldrup, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Coates, Philip J
    Tayside Tissue Bank Division of Medical Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
    Wahlgren, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Laurell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Subsite-based alterations in miR-21, miR-125b, and miR-203 in squamous cell carcinoma of the oral cavity and correlation to important target proteins.2012Inngår i: Journal of Carcinogenesis, ISSN 0974-6773, E-ISSN 1477-3163, Vol. 11, s. 18-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNA molecules with an essential role in regulation of gene expression. miRNA expression profiles differ between tumor and normal control tissue in many types of cancers and miRNA profiling is seen as a promising field for finding new diagnostic and prognostic tools.

    MATERIALS AND METHODS: In this study, we have analyzed expression of three miRNAs, miR-21, miR-125b, and miR-203, and their potential target proteins p53 and p63, known to be deregulated in squamous cell carcinoma of the head and neck (SCCHN), in two distinct and one mixed subsite in squamous cell carcinoma in the oral cavity.

    RESULTS: We demonstrate that levels of miRNA differ between tumors of different subsites with tongue tumors showing significant deregulation of all three miRNAs, whereas gingival tumors only showed significant downregulation of miR-125b and the mixed group of tumors in tongue/floor of the mouth showed significant deregulation of miR-21 and miR-125b. In the whole group of oral squamous cell carcinoma (SCC), a significant negative correlation was seen between miR-125b and p53 as well as a significant correlation between TP53 mutation status and miR-125b.

    CONCLUSION: The present data once again emphasize the need to take subsite into consideration when analyzing oral SCC and clearly show that data from in vitro studies cannot be transferred directly to the in vivo situation.

  • 168.
    Boldrup, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Gu, Xiaolian
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Coates, Philip J.
    Norberg-Spaak, Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Fåhraeus, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. RECAMO, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic; Institut de Génétique Moléculaire, Université Paris 7, Hôpital St. Louis, 75010 Paris, France.
    Laurell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar. Department of Surgical Sciences/ENT, Uppsala University, 752 36 Uppsala, Sweden.
    Wilms, Torben
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Gene expression changes in tumor free tongue tissue adjacent to tongue squamous cell carcinoma2017Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 12, s. 19389-19402Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Due to the high frequency of loco-regional recurrences, which could be explained by changes in the field surrounding the tumor, patients with squamous cell carcinoma of head and neck show poor survival. Here we identified a total of 554 genes as dysregulated in clinically tumor free tongue tissue in patients with tongue tumors when compared to healthy control tongue tissue. Among the top dysregulated genes when comparing control and tumor free tissue were those involved in apoptosis (CIDEC, MUC1, ZBTB16, PRNP, ECT2), immune response (IFI27) and differentiation (KRT36). Data suggest that these are important findings which can aid in earlier diagnosis of tumor development, a relapse or a novel squamous cell carcinoma of the tongue, in the absence of histological signs of a tumor.

  • 169.
    Boldrup, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Troiano, Giuseppe
    Gu, Xiaolian
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Coates, Philip
    Fåhraeus, Robin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wilms, Torben
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Norberg-Spaak, Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Öron- näs- och halssjukdomar.
    Wang, Lixiao
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nylander, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Evidence that circulating proteins are more promising than miRNAs for identification of patients with squamous cell carcinoma of the tongue2017Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 61, s. 103437-103448Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite intense research, squamous cell carcinoma of the tongue remains a devastating disease with a five-year survival of around 60%. Late detection and recurrence are the main causes for poor survival. The identification of circulating factors for early diagnosis and/or prognosis of cancer is a rapidly evolving field of interest, with the hope of finding stable and reliable markers of clinical significance. The aim of this study was to evaluate circulating miRNAs and proteins as potential factors for distinguishing patients with tongue squamous cell carcinoma from healthy controls. Array-based profiling of 372 miRNAs in plasma samples showed broad variations between different patients and did not show any evidence for their use in diagnosis of tongue cancer. Although one miRNA, miR-150, was significantly down-regulated in plasma from patients compared to controls. Surprisingly, the corresponding tumor tissue showed an up-regulation of miR-150. Among circulating proteins, 23 were identified as potential markers of squamous cell carcinoma of the tongue. These findings imply that circulating proteins are a more promising source of biomarkers for tongue squamous cell carcinomas than circulating miRNAs. The data also highlight that circulating markers are not always directly associated with tumor cell properties.

  • 170.
    Boman, Karin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Endometrial carcinoma: steroid hormones and receptors in relation to proliferation1993Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The significance of the hormonal milieu for endometrial changes is as well-known as its link with endometrial carcinoma. Unopposed oestradiol treatment is shown to increase the incidence for this cancer. Obesity leads to elevated levels of oestrogens and is a risk factor for endometrial carcinoma. An association between high tumour proliferation and prognosis is a general feature of human cancer. Tumour growth can be expressed as proliferation rate and flow cytometry (FCM) is a sensitive and reproducable method to estimate S-phase fraction (SPF) and ploidy level. Both parameters have been shown to correlate with prognosis. Sex steroid hormone levels were analysed together with clinical parameters, SPF, and receptors in established endometrial carcinoma.

    The study consisted of postmenopausal women with endometrial adeno­carcinoma. H ormones were analysed in 127 patients, 99 were analysed for FCM and 60 for oestrogen and progesterone receptors. RIA technique was used for hormone assay of oestrone, oestradiol, progesterone, androstenedione and testosterone plasma levels. The receptors were analysed with an immunohistochemical method, and SPF and ploidy level by flow cytometry.

    A wide range of oestrogen concentrations was found. Some patients had levels comparable to fertile women. Strong correlations were found between body mass index, weight and depth of uterine cavity. No relations were found between receptors and SPF, apart from oestrogen- receptor positive tumours having a lower SPF when compared with receptor negative tumours. The influence of oestradiol on tumour proliferation expressed as SPF was ambiguous. SPF was increased with higher oestradiol levels in the group of peri-diploid, well-differentiated tumours, while a negative correlation was found for the peri-diploid, moderately differentiated tumours. The aneuploid and poorly differenti­ated tumours had a high SPF regardless of oestradiol concentration. The association between progesterone concentration and SPF was of a more general nature. Progesterone above a threshold level was related to a lower SPF in well-differentiated and moderately differentiated tumours. Thus endogenous progesterone seems to play a role in controlling the tumour’s proliferation activity, in contrast to oestradiol, that had a role which did not appear to relate to proliferation activity in any specific direction. The only stimulative association was seen in well-differentiated tumours, but SPF was still below the mean value for all diploid tumours.

  • 171. Bondy, Melissa
    et al.
    Bainbridge, Matthew
    Jhangiani, Shalini
    Jalali, Ali
    Plon, Sharon E.
    Armstrong, Georgina
    Bernstein, Jonine
    Claus, Elizabeth
    Davis, Faith
    Houlston, Richard
    Il'yasova, Dora
    Jenkins, Robert
    Johansen, Christoffer
    Lachance, Daniel
    Lai, Rose
    Lau, Ching
    Merrell, Ryan
    Olson, Sara
    Sadetzki, Siegal
    Schildkraut, Joellen
    Shete, Sanjay
    Barnholtz-Sloan, Jill
    Wrensch, Margaret
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Gibbs, Richard A.
    POT1 GERMLINE MUTATIONS MAY EXPLAIN A SUBSET OF FAMILIAL GLIOMA: A REPORT FROM THE GLIOGENE CONSORTIUM2013Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, nr Supplement: 3, s. 89-89Artikkel i tidsskrift (Annet vitenskapelig)
  • 172. Bonn, S. E.
    et al.
    Wiklund, F.
    Sjölander, A.
    Szulkin, R.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Holmberg, E.
    Grönberg, H.
    Bälter, K.
    Body Mass Index and Weight Change in Men with Prostate Cancer: Progression and Mortality2015Inngår i: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, s. 141-142Artikkel i tidsskrift (Annet vitenskapelig)
  • 173. Bonn, Stephanie E.
    et al.
    Sjölander, Arvid
    Lagerros, Ylva Trolle
    Wiklund, Fredrik
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Holmberg, Erik
    Grönberg, Henrik
    Bälter, Katarina
    Physical Activity and Survival among Men Diagnosed with Prostate Cancer2015Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, nr 1, s. 57-64Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Few studies have investigated the association between post-diagnosis physical activity and mortality among men diagnosed with prostate cancer. The aim of this study was to investigate the effect of physical activity after a prostate cancer diagnosis on both overall and prostate cancer-specific mortality in a large cohort. Methods: Data from 4,623 men diagnosed with localized prostate cancer 1997-2002 and followed-up until 2012 were analyzed. HRs with 95% confidence intervals (CI) were estimated using Cox proportional hazards models to examine the association between post-diagnosis recreational MET-h/d, time spent walking/bicycling, performing household work or exercising, and time to overall and prostate cancer-specific death. All models were adjusted for potential confounders. Results: During the follow-up, 561 deaths of any cause and 194 deaths from prostate cancer occurred. Statistically significantly lower overall mortality rates were found among men engaged in 5 recreationalMET-h/d (HR, 0.63; 95% CI, 0.52-0.77), walking/ bicycling 20 min/d (HR, 0.70; 95% CI, 0.57-0.86), performing householdwork > 1 h/d (HR, 0.71; 95% CI, 0.59-0.86), or exercising > 1 h/wk (HR, 0.74; 95% CI, 0.61-0.90), compared with less active men within each activity type. For prostate cancer-specific mortality, statistically significantly lower mortality rates were seen among men walking/bicycling >= 20 min/d (HR, 0.61; 95% CI, 0.43-0.87) or exercising 1 h/wk (HR, 0.68; 95% CI, 0.48-0.94). Conclusions: Higher levels of physical activity were associated with reduced rates of overall and prostate cancer-specific mortality. Impact: Our study further strengthens previous results indicating beneficial effects of physical activity on survival among men with prostate cancer. Cancer Epidemiol Biomarkers Prev; 24(1); 57-64.

  • 174. Bonn, Stephanie E.
    et al.
    Wiklund, Fredrik
    Sjölander, Arvid
    Szulkin, Robert
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Holmberg, Erik
    Grönberg, Henrik
    Bälter, Katarina
    Body mass index and weight change in men with prostate cancer: progression and mortality2014Inngår i: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 25, nr 8, s. 933-943Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Body mass index (BMI) is a modifiable lifestyle factor that has been associated with an increased risk of fatal prostate cancer and biochemical recurrence. The main purpose of the present study was to investigate the association between the exposure BMI at the time of a prostate cancer diagnosis and weight change after diagnosis, and the outcomes of prostate cancer progression and mortality in a large cohort study. Data from 4,376 men diagnosed with clinically localized prostate cancer between 1997 and 2002 were analyzed. BMI and weight change were self-reported in 2007. Hazard ratios (HRs) with 95 % confidence intervals (CIs) were estimated in complete-case analysis (n = 3,214) using Cox proportional hazards models. Progression was experienced among 639 (14.6 %) of the study participants, and in total, 450 (10.3 %) deaths of any cause and 134 (3.1 %) prostate cancer-specific deaths were recorded during follow-up. Obese men had a 47 % increased rate of overall mortality compared to normal weight men (HR 1.47, 95 % CI 1.03-2.10). No statistically significant associations were found for BMI and prostate cancer progression or prostate cancer-specific mortality. A weight loss > 5 % after diagnosis almost doubled the rate of overall mortality compared to maintaining a stable weight (HR 1.94, 95 % CI 1.41-2.66), while a weight gain > 5 % was associated with an almost doubled increased rate of prostate cancer-specific mortality (HR 1.93, 95 % CI 1.18-3.16). Being obese was associated with an increased rate of overall mortality, and gaining weight after a prostate cancer diagnosis was associated with an increased rate of prostate cancer-specific mortality.

  • 175.
    Bordás, Pál
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Evaluation of the effectiveness of mammography screening in Northern Sweden.2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Service screening with mammography was implemented in Northern Sweden between 1989 and 1998, covering 190,000 women aged 40-74 years constituting the target population in the area.

    The aim of this thesis was the evaluation of mammography screening in Northern Sweden with special focus on selected screening performance indicators and on the disease outcome.

    We analysed interval cancer (IC) incidence and episode sensitivity in the Norrbotten Mammography Screening Programme (NMSP) for the period 1989-2002. An overall IC rate at 1.1/1000 and IC rate ratio at 38% was found and epsiode sensitivity was estimated at 62-73%, in concert with reference values of the European guidelines.

    Radiological classification of the IC cases in three rounds of the NMSP showed that true, occult, missed and minimal signs IC, were present in 48%, 10%, 14% and 28% of the cases.

    We analysed early death from breast cancer (n=342) in Northern Sweden during the first five years of mammography service screening. Most fatal cases were advanced and incurable on diagnosis. In a few screen-detected cases with favourable prognostic factors the fatal outcome was unexpected.

    We estimated breast cancer survival by detection mode in 5120 women with breast cancer. We found a significantly favourable survival among IC cases compared to cases among uninvited.

    We studied breast cancer mortality in relation to mammography screening. Our findings indicated a long-term reduction of breast cancer mortality by 26-30% among women invited to screening and by 31-35% among women screened compared to not screened.

    We conclude from our evaluation of the mammography screening in Northern Sweden that women benefited from this public health intervention in form of improved survival and reduced mortality.

  • 176.
    Bordás, Pál
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Jonsson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nyström, Lennarth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och folkhälsovetenskap.
    Cajander, Stefan
    Lenner, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Early breast cancer deaths in women aged 40-74 years diagnosed during the first 5 years of organised mammography service screening in north Sweden2004Inngår i: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 13, nr 4, s. 276-283Artikkel i tidsskrift (Fagfellevurdert)
  • 177.
    Bordás, Pál
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Jonsson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nyström, Lennarth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och folkhälsovetenskap.
    Lenner, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Interval cancer incidence and episode sensitivity in the Norrbotten mammography screening programme, Sweden2009Inngår i: Journal of Medical Screening, ISSN 0969-1413, E-ISSN 1475-5793, Vol. 16, nr 1, s. 39-45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: To estimate the interval cancer incidence, its determinants and the episode sensitivity in the Norrbotten Mammography Screening Programme (NMSP).

    SETTING: Since 1989, women aged 40-74 years (n = 55,000) have been invited to biennial screening by the NMSP, Norrbotten county, Sweden.

    METHODS: Data on 1047 invasive breast cancers from six screening rounds of the NMSP (1989-2002) were collected. We estimated the invasive interval cancer rates, rate ratios and the episode sensitivity using the detection and incidence methods. A linear Poisson-model was used to analyse association between interval cancer incidence and sensitivity.

    RESULTS: 768 screen-detected and 279 interval cancer cases were identified. The rate ratio of interval cancer decreased with age. The 50-59 year age group showed the highest rate ratio (RR = 0.52, 95% CI 0.41-0.65) and the 70-74 year age group the lowest (RR = 0.23, 95% CI 0.15-0.36). The rate ratios for the early (0-12 months) and late (13-24 months) interval cancers were similar (RR = 0.18, 95% CI 0.15-0.22 and 0.20, 95% CI 0.17-0.24). There was a significantly lower interval cancer incidence in the prevalence round as compared with the incidence rounds. According to the detection method the episode sensitivity increased with age from 57% in the age group 40-49 years to 84% in the age group 70-74 years. The corresponding figures for the incidence method were 50% and 77%, respectively.

    CONCLUSION: Our study showed an interval cancer incidence of 38% and the episode sensitivity of 62-73%, depending on the method of calculation. Our results are of clinically acceptable level and concert with the reference values of the European guidelines.

  • 178.
    Bordás, Pál
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Jonsson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nyström, Lennarth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och folkhälsovetenskap.
    Lenner, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Survival from invasive breast cancer among interval cases in the mammography screening programmes of northern Sweden2007Inngår i: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 16, nr 1, s. 47-54Artikkel i tidsskrift (Fagfellevurdert)
  • 179.
    Bordás, Pál
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Jonsson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nyström, Lennarth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Péntek, Zoltán
    Lenner, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Radiological review of interval cancer in the Norrbotten mammography screening program, SwedenManuskript (preprint) (Annet vitenskapelig)
  • 180. Borena, Wegene
    et al.
    Edlinger, Michael
    Bjørge, Tone
    Häggström, Christel
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Lindkvist, Björn
    Nagel, Gabriele
    Engeland, Anders
    Stocks, Tanja
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Institute of Preventive Medicine, Copenhagen University Hospital, Copenhagen, Denmark.
    Strohmaier, Susanne
    Manjer, Jonas
    Selmer, Randi
    Tretli, Steinar
    Concin, Hans
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Jonsson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Ulmer, Hanno
    A prospective study on metabolic risk factors and gallbladder cancer in the metabolic syndrome and cancer (Me-Can) collaborative study2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 2, s. e89368-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To investigate the association between metabolic risk factors (individually and in combination) and risk of gallbladder cancer (GBC). Methods: The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden with data on 578,700 men and women. We used Cox proportional hazard regression models to calculate relative risks of GBC by body mass index (BMI), blood pressure, and plasma levels of glucose, cholesterol, and triglycerides as continuous standardised variables and their standardised sum of metabolic syndrome (MetS) z-score. The risk estimates were corrected for random error in measurements. Results: During an average follow-up of 12.0 years (SD = 7.8), 184 primary gallbladder cancers were diagnosed. Relative risk of gallbladder cancer per unit increment of z-score adjusted for age, smoking status and BMI (except for BMI itself) and stratified by birth year, sex and sub-cohorts, was for BMI 1.31 (95% confidence interval 1.11, 1.57) and blood glucose 1.76 (1.10, 2.85). Further analysis showed that the effect of BMI on GBC risk is larger among women in the premenopausal age group (1.84 (1.23, 2.78)) compared to those in the postmenopausal age group (1.29 (0.93, 1.79)). For the other metabolic factors no significant association was found (mid blood pressure 0.96 (0.71, 1.31), cholesterol 0.84 (0.66, 1.06) and serum triglycerides 1.16 (0.82, 1.64)). The relative risk per one unit increment of the MetS z-score was 1.37 (1.07, 1.73). Conclusion: This study showed that increasing BMI and impaired glucose metabolism pose a possible risk for gallbladder cancer. Beyond the individual factors, the results also showed that the metabolic syndrome as an entity presents a risk constellation for the occurrence of gallbladder cancer.

  • 181. Borena, Wegene
    et al.
    Stocks, Tanja
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Jonsson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Strohmaier, Susanne
    Nagel, Gabriele
    Bjørge, Tone
    Manjer, Jonas
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Selmer, Randi
    Almquist, Martin
    Häggström, Christel
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Engeland, Anders
    Tretli, Steinar
    Concin, Hans
    Strasak, Alexander
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Ulmer, Hanno
    Serum triglycerides and cancer risk in the metabolic syndrome and cancer (Me-Can) collaborative study2011Inngår i: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 22, nr 2, s. 291-299Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Data from our study provided evidence for a possible role of serum triglycerides in cancer development.

  • 182. Borena, Wegene
    et al.
    Strohmaier, Susanne
    Lukanova, Annekatrin
    Bjørge, Tone
    Lindkvist, Björn
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Edlinger, Michael
    Stocks, Tanja
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Nagel, Gabriele
    Manjer, Jonas
    Engeland, Anders
    Selmer, Randi
    Häggström, Christel
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Tretli, Steinar
    Concin, Hans
    Jonsson, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Ulmer, Hanno
    Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults2012Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, nr 1, s. 193-200Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Initial studies have indicated diabetes and obesity to be risk factors for hepatocellular carcinoma; but the association between other metabolic risk factors and primary liver cancer (PLC) has not been investigated. The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria and Sweden with data on 578,700 subjects. We used Cox proportional hazard models to calculate relative risks (RRs) of PLC by body mass index (BMI), blood pressure and plasma levels of glucose, cholesterol and triglycerides as continuous standardized variables (z-score with mean = 0 and standard deviation (SD) = 1) and their standardized sum of metabolic syndrome (MetS) z-score. RRs were corrected for random error in measurements. During an average follow-up of 12.0 years (SD = 7.8), 266 PLCs were diagnosed among cohort members. RR of liver cancer per unit increment of z-score adjusted for age, smoking status and BMI and stratified by birth year, sex and sub-cohorts, was for BMI 1.39 (95% confidence interval (CI) 1.24-1.58), mid blood pressure 2.08 (0.95-4.73), blood glucose 2.13 (1.55-2.94) cholesterol 0.62 (0.51-0.76) and serum triglycerides 0.85 (0.65-1.10). The RR per one unit increment of the MetS z-score was 1.35 (1.12-1.61). BMI, glucose and a composite MetS score were positively and cholesterol negatively associated with risk of liver cancer.

  • 183. Borgfeldt, Christer
    et al.
    Kalapotharakos, Grigorios
    Asciutto, Katrin C.
    Löfgren, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Högberg, Thomas
    A population-based registry study evaluating surgery in newly diagnosed uterine cancer2016Inngår i: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 95, nr 8, s. 901-911Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction. The aim was to evaluate surgical treatment of newly diagnosed uterine cancer in a Swedish population. Material and methods. Data in the GynOp registry from 2008 to 2014 were analyzed. Results. In total, 3443 cases were included: 430 (12%) were robotic-assisted laparoscopic, 272 (8%) laparoscopic, and 2741 (80%) abdominal operations. There was an increasing trend in minimally invasive surgery from 2008 to 2014 (41%). Women with lymph nodes removed in the robotic-assisted laparoscopic group experienced less blood loss (mean 105 vs. 377 mL), shorter length of hospital stay (2.4 vs. 4.1 days), and fewer days to normal activities of daily living (6.5 vs. 12.7 days) (all p < 0.001) compared with the abdominal group, but operating time did not differ. Similar results were found in women with no lymph node removal and in women with body mass index 35. Major complications during hospital stay, reoperations, and time to work were less in both minimally invasive groups. More lymph nodes were retrieved in the abdominal (mean 34.4) than in the robotic-assisted laparoscopic (mean 26.0) group, but the number of women with lymph node metastases did not differ, totaling 211/960 (21.9%; 95% CI 19.4-24.7%). Isolated para-aortic lymph node metastases were found in 3.9% (95% CI 2.4-5.6%) of women. Conclusions. Minimally invasive surgery in uterine cancer patients reduces days to normal activities of daily living, number of days to return to work, length of hospital stay, and blood loss in patients without and with lymph node dissection and in obese patients.

  • 184. Borgå, Olof
    et al.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bjermo, Helena
    Lilienberg, Elsa
    Heldring, Nina
    Loman, Niklas
    Maximum Tolerated Dose and Pharmacokinetics of Paclitaxel Micellar in Patients with Recurrent Malignant Solid Tumours: A Dose-Escalation Study2019Inngår i: Advances in Therapy, ISSN 0741-238X, E-ISSN 1865-8652, Vol. 36, nr 5, s. 1150-1163Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: A water-soluble Cremophor EL-free formulation of paclitaxel, in which retinoic acid derivates solubilize paclitaxel by forming micelles (paclitaxel micellar), was studied for the first time in man to establish the maximum tolerated dose (MTD) and to characterize the pharmacokinetics (PK).

    Methods: This was an open-label, one-arm, dose-escalating study in patients with advanced solid malignant tumours, for which no standard therapy was available or had failed. Paclitaxel micellar was given as 1-h intravenous infusion every 21 days for 3 cycles, mainly without premedication. Plasma samples were collected during 24 h at the first cycle and paclitaxel concentrations were assayed by high-performance liquid chromatography. PK was evaluated using a two-compartment model.

    Results: Thirty-four patients received paclitaxel micellar at doses ranging between 90 and 275 mg/m2. MTD was established as 250 mg/m2. Fatigue and neuropathy were the most frequent dose-limiting toxicities. No hypersensitivity reactions were observed. PK of paclitaxel was evaluated in 25 data sets. Paclitaxel micellar had a rapid initial distribution phase, mean half-life 0.55 h, estimated to be completed 3 h after dosing and a mean terminal half-life of 8.8 h. Mean clearance was 13.4 L/h/m2 with fivefold interindividual variability. The residual areas after 10 h and 24 h were 15.7 ± 8.6% and 5.7 ± 3.9% of the area under the plasma concentration–time curve to infinite time (AUCinf), respectively.

    Conclusion: No new side effects unknown for paclitaxel were observed. Maximum plasma concentration (Cmax) and AUCinf showed a tendency to increase linearly with dose within the 150–275 mg/m2dose range. The possibility to administer paclitaxel micellar without steroid premedication makes it an attractive candidate for further studies in combination with immunotherapy.

    Trial Registration: EudraCT no: 2004-001821-54.

  • 185.
    Borssen, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Palmqvist, Lars
    Karrman, Kristina
    Abrahamsson, Jonas
    Behrendtz, Mikael
    Heldrup, Jesper
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6, s. e65373-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided.

    Design and Methods: Genome wide promoter DNA methylation analysis was performed in pediatric T-ALL samples (n = 43) using arrays covering >27000 CpG sites. Clinical outcome was evaluated in relation to methylation status and compared with a contemporary T-ALL group not tested for methylation (n = 32).

    Results: Based on CpG island methylator phenotype (CIMP), T-ALL samples were subgrouped as CIMP+ (high methylation) and CIMP- (low methylation). CIMP- T-ALL patients had significantly worse overall and event free survival (p = 0.02 and p = 0.001, respectively) compared to CIMP+ cases. CIMP status was an independent factor for survival in multivariate analysis including age, gender and white blood cell count. Analysis of differently methylated genes in the CIMP subgroups showed an overrepresentation of transcription factors, ligands and polycomb target genes.

    Conclusions: We identified global promoter methylation profiling as being of relevance for subgrouping and prognostication of pediatric T-ALL.

  • 186.
    Borssén, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    DNA methylation as a prognostic marker i acute lymphoblastic leukemia2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Most ALL cases originate from immature B-cells (BCP-ALL) and are characterized by reoccurring structural genetic aberrations. These aberrations hold information of the pathogenesis of ALL and are used for risk stratification in treatment. Despite increased knowledge of genetic aberrations in pediatric T-cell ALL (T-ALL), no reliable molecular genetic markers exist for identifying patients with higher risk of relapse. The lack of molecular prognostic markers is also evident in patients with relapsed ALL. During the last decades, aberrant epigenetic mechanisms including DNA methylation have emerged as important components in cancer development. Telomere maintenance is another important factor in malignant transformation and is crucial for long-term cell survival. Like DNA methylation, telomere length maintenance has also been implicated to reflect outcomes for patients with leukemia.

    In this thesis, the prognostic relevance of DNA methylation and telomere length was investigated in pediatric ALL at diagnosis and relapse. The telomere length (TL) was significantly shorter in diagnostic ALL samples compared to normal bone marrow samples collected at cessation of therapy, reflecting the proliferation associated telomere length shortening. Prognostic relevance of TL was shown in low-risk BCP-ALL patients where longer telomeres at diagnosis were associated with higher risk of relapse.

    Genome-wide methylation characterization by arrays in diagnostic T-ALL samples identified two distinct methylation subgroups denoted CIMP+ (CpG Island Methylator Phenotype high) and CIMP- (low). CIMP- T-ALL patients had significantly worse outcome compared to CIMP+ cases. These results were confirmed in a Nordic cohort treated according to the current NOPHO-ALL2008 protocol.  By combining minimal residual disease (MRD) status at treatment day 29 and CIMP status at diagnosis we could further separate T-ALL patients into risk groups.

    Likewise, the CIMP profile could separate relapsed BCP-ALL patients into risk groups, where the CIMP- cases had a significantly worse outcome compared to CIMP+ cases.  From these data we conclude that DNA methylation subgrouping is a promising prognostic marker in T-ALL, as well as in relapsed BCP-ALL two groups where reliable prognostic markers are currently missing. By elucidating the biology behind the different CIMP profiles, the pathogenesis of ALL will be further understood and may contribute to new treatment strategies.

  • 187.
    Borssén, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Haider, Zahra
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Norén-Nyström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Schmiegelow, Kjeld
    Åsberg, Ann E.
    Kanerva, Jukka
    Madsen, Hans O.
    Marquart, Hanne
    Heyman, Mats
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Department of Paediatrics, University Hospital of Trondheim, Norway.
    DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia2016Inngår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, nr 7, s. 1185-1192Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.

  • 188. Bosco, Cecilia
    et al.
    Garmo, Hans
    Adolfsson, Jan
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Holmberg, Lars
    Nilsson, Per
    Gunnlaugsson, Adalsteinn
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Van Hemelrijck, Mieke
    Prostate Cancer Radiation Therapy and Risk of Thromboembolic Events2017Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 97, nr 5, s. 1026-1031Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To investigate the risk of thromboembolic disease (TED) after radiation therapy (RT) with curative intent for prostate cancer (PCa). Patients and Methods: We identified all men who received RT as curative treatment (n=9410) and grouped according to external beam RT (EBRT) or brachytherapy (BT). By comparing with an age-and county-matched comparison cohort of PCa-free men (n = 46,826), we investigated risk of TED after RT using Cox proportional hazard regression models. The model was adjusted for tumor characteristics, demographics, comorbidities, PCa treatments, and known risk factors of TED, such as recent surgery and disease progression. Results: Between 2006 and 2013, 6232 men with PCa received EBRT, and 3178 underwent BT. A statistically significant association was found between EBRT and BT and risk of pulmonary embolism in the crude analysis. However, upon adjusting for known TED risk factors these associations disappeared. No significant associations were found between BT or EBRT and deep venous thrombosis. Conclusion: Curative RT for prostate cancer using contemporary methodologies was not associated with an increased risk of TED.

  • 189. Bosse, Yohan
    et al.
    Li, Zhonglin
    Xia, Jun
    Manem, Venkata
    Carreras-Torres, Robert
    Gabriel, Aurelie
    Gaudreault, Nathalie
    Albanes, Demetrius
    Aldrich, Melinda C.
    Andrew, Angeline
    Arnold, Susanne
    Bickeboeller, Heike
    Bojesen, Stig E.
    Brennan, Paul
    Brunnstrom, Hans
    Caporaso, Neil
    Chen, Chu
    Christiani, David C.
    Field, John K.
    Goodman, Gary
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Houlston, Richard
    Johansson, Mattias
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Kiemeney, Lambertus A.
    Lam, Stephen
    Landi, Maria T.
    Lazarus, Philip
    Le Marchand, Loic
    Liu, Geoffrey
    Melander, Olle
    Rennert, Gadi
    Risch, Angela
    Rosenberg, Susan M.
    Schabath, Matthew B.
    Shete, Sanjay
    Song, Zhuoyi
    Stevens, Victoria L.
    Tardon, Adonina
    Wichmann, H-Erich
    Woll, Penella
    Zienolddiny, Shan
    Obeidat, Ma'en
    Timens, Wim
    Hung, Rayjean J.
    Joubert, Philippe
    Amos, Christopher I.
    McKay, James D.
    Transcriptome-wide association study reveals candidate causal genes for lung cancer2019Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large‐scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome‐wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never‐ and ever‐smokers). We performed replication analysis using lung data from the Genotype‐Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever‐smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E−99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E−6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3‐adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E−5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.

  • 190. Bossi, A.
    et al.
    Dearnaley, D.
    McKenzie, M.
    Baskin-Bey, E.
    Tyler, R.
    Tombal, B.
    Freedland, S. J.
    Roach, M. , I I I
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Dicker, A. P.
    Wiegel, T.
    Shore, N.
    Smith, M.
    Yu, M.
    Kheoh, T.
    Thomas, S.
    Sandler, H. M.
    ATLAS: A phase 3 trial evaluating the efficacy of apalutamide (ARN-509) in patients with high-risk localized or locally advanced prostate cancer receiving primary radiation therapy2016Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 27Artikkel i tidsskrift (Fagfellevurdert)
  • 191.
    Boström, Petrus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Haapamaki, Markku M.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Matthiessen, P.
    Ljung, R.
    Rutegård, Jörgen
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    Rutegård, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
    High arterial ligation and risk of anastomotic leakage in anterior resection for rectal cancer in patients with increased cardiovascular risk2015Inngår i: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 17, nr 11, s. 1018-1027Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: Controversy still exists as to whether division of the inferior mesenteric artery close to the aorta influences the risk of anastomotic leakage after anterior resection for rectal cancer. This population-based study was carried out to evaluate the independent association between high arterial ligation and anastomotic leakage in patients with increased cardiovascular risk.

    Method: All 2673 cases of registered anterior resection for rectal cancer from 2007 to 2010 were identified from the Swedish Colorectal Cancer Registry and cross-referenced with the Prescribed Drugs Registry, rendering a cohort of all patients with increased cardiovascular risk. Operative charts and registered data were reviewed for 722 patients. The association between high tie and anastomotic leakage, as quantified by ORs and 95% CIs, was evaluated in a logistic regression model, with adjustment for confounding, including assessment of interaction.

    Results: Symptomatic anastomotic leakage occurred in 12.3% (41/334) of patients in the high tie group and in 10.6% (41/388) in the low tie group. The use of high tie was not independently associated with a higher risk of anastomotic leakage (OR = 1.05; 95% CI: 0.61–1.84). In a post-hoc analysis, patients with a history of manifest cardiovascular disease and American Society of Anesthesiologists (ASA) score III–IV seemed to be at greater risk (OR = 3.66; 95% CI: 1.04–12.85).

    Conclusion: In the present population-based, observational setting, high tie was not independently associated with an increased risk of symptomatic anastomotic leakage after anterior resection for rectal cancer. However, this conclusion may not hold for patients with severe cardiovascular disease.

  • 192. Botling, Johan
    et al.
    Edlund, Karolina
    Lohr, Miriam
    Hellwig, Birte
    Holmberg, Lars
    Lambe, Mats
    Berglund, Anders
    Ekman, Simon
    Bergqvist, Michael
    Pontén, Fredrik
    König, André
    Fernandes, Oswaldo
    Karlsson, Mats
    Helenius, Gisela
    Karlsson, Christina
    Rahnenführer, Jörg
    Hengstler, Jan G
    Micke, Patrick
    Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis, and tissue microarray validation.2013Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, nr 1Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap.

    EXPERIMENTAL DESIGN: Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860).

    RESULTS: The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate <1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.

    CONCLUSIONS: Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics.

  • 193. Botteri, E.
    et al.
    Ferrari, P.
    Roswall, N.
    Tjonneland, A.
    Hjartaker, A.
    Huerta, J. M.
    Fortner, R. T.
    Trichopoulou, A.
    Karakatsani, A.
    La Vecchia, C.
    Pala, V.
    Perez-Cornago, A.
    Sonestedt, E.
    Liedberg, F.
    Overvad, K.
    Sanchez, M. J.
    Gram, I. T.
    Stepien, M.
    Trijsburg, L.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Johansson, M.
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Kuehn, T.
    Panico, S.
    Tumino, R.
    Bueno-de-Mesquita, H. B.
    Weiderpass, E.
    Alcohol consumption and risk of urothelial cell bladder cancer in the European prospective investigation into cancer and nutrition cohort2017Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 141, nr 10, s. 1963-1970Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Findings on the association between alcohol consumption and bladder cancer are inconsistent. We investigated that association in the European Prospective Investigation into Cancer and Nutrition cohort. We included 476,160 individuals mostly aged 35-70 years, enrolled in ten countries and followed for 13.9 years on average. Hazard ratios (HR) for developing urothelial cell carcinoma (UCC; 1,802 incident cases) were calculated using Cox proportional hazards models. Alcohol consumption at baseline and over the life course was analyzed, as well as different types of beverages (beer, wine, spirits). Baseline alcohol intake was associated with a statistically nonsignificant increased risk of UCC (HR 1.03; 95% confidence interval (CI) 1.00-1.06 for each additional 12 g/day). HR in smokers was 1.04 (95% CI 1.01-1.07). Men reporting high baseline intakes of alcohol (>96 g/day) had an increased risk of UCC (HR 1.57; 95% CI 1.03-2.40) compared to those reporting moderate intakes (<6 g/day), but no dose-response relationship emerged. In men, an increased risk of aggressive forms of UCC was observed even at lower doses (>6 to 24 g/day). Average lifelong alcohol intake was not associated with the risk of UCC, however intakes of spirits>24 g/day were associated with an increased risk of UCC in men (1.38; 95% CI 1.01-1.91) and smokers (1.39; 95% CI 1.01-1.92), compared to moderate intakes. We found no association between alcohol and UCC in women and never smokers. In conclusion, we observed some associations between alcohol and UCC in men and in smokers, possibly because of residual confounding by tobacco smoking.

  • 194. Bottomley, A.
    et al.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Taphoorn, M. J. B.
    Cloughesy, T.
    Wick, W.
    Mason, W.
    Saran, F.
    Nishikawa, R.
    Ravelo, A.
    Chinot, O. L.
    Health-related quality of life (HRQoL) in AVAglio, a randomized, placebo (P)-controlled phase III study of bevacizumab (B), temozolomide (T) and radiotherapy (RI) in patients (pts) with newly diagnosed glioblastoma (GBM)2013Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, nr Supplement 2, s. S780-S780, Meeting Abstract: 3316Artikkel i tidsskrift (Annet vitenskapelig)
  • 195.
    Bovinder Ylitalo, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Molecular heterogeneity of prostate cancer bone metastasis2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Castration-resistant prostate cancer (CRPC) develops after androgen deprivation therapy of advanced PC, often with metastatic growth in bone. Patients with metastatic CRPC have very poor prognosis. Growth of CRPC, in most but not all patients, seems to involve androgen receptor (AR) activity, despite castrate levels of serum testosterone. Multiple mechanisms behind AR activation in castrated patients have been described, such as AR amplification, AR mutations, expression of constitutively active AR variants, and intra-tumoral steroid synthesis. However, other mechanisms beside AR activation are also involved and CRPC patients with tumors circumventing the need for AR stimulation will probably not benefit from AR targeting therapies but will need alternative treatments.

    Available treatments for CRPC are chemotherapy, AR antagonists or inhibition of androgen-synthesis. Novel drugs are constantly under development and several new therapies has recently been approved for clinical use. These include, in addition to new AR targeting therapies also immunotherapy, osteoclast inhibitors and bone-targeting radiopharmaceuticals. Due to heterogeneous mechanisms behind CRPC and that newly developed therapies are based on different mechanisms of action, there are reasons to believe that CRPC patients show different therapy responses due to diverse molecular properties of individual tumors. Although there are promising prospects, no biomarkers are used today for patient stratification into different treatments. Another important aspect is that, when effective, any therapy will probably induce tumor responses that subsequently cause further molecular diversities and alternative paths for development of tumor relapse and castration-resistance. Such mechanisms are important to understand in order to develop new treatment strategies.

    In this thesis, global gene expression and methylation patterns were studied in bone metastases obtained from PC patients going through metastasis surgery for spinal cord compression. Gene expression patterns were analyzed by multivariate statistics and ontology analysis with the aim to identify subgroups of biological/pathological relevance. Interesting findings from array analysis were verified using qRT-PCR and immunohistochemical analysis. In addition, a xenograft mouse model was used to study the effects of abiraterone (steroidogenesis inhibitor) and cabazitaxel (taxane), and subsequently developed resistance mechanisms in the 22Rv1 PC cell line expressing high levels of AR-V7; a constitutively active AR splice variant associated with a poor prognosis and resistance to AR targeting therapies.

    In summary, results showed that the majority of CRPC bone metastases were AR-driven, defined from high levels of AR-regulated gene transcripts, while a smaller sub-group was non-AR-driven (paper I). AR-driven bone metastases had high metabolic activity in combination with downregulated immune responses while non-AR-driven cases had a more pronounced immune response (paper I) and higher bone cell activity (paper II). Paper III identified pronounced hypermethylation in primary prostate tumors probably causing a suppressed anti-tumor immune-response whereas metastases showed a different methylation pattern related to increased AR activity and patient outcome. In paper IV, 22Rv1 xenografts showed poor response to abiraterone and initially excellent response to cabazitaxel, but eventually resistance occurred probably due to an upregulation of the ABCB1 transporter protein. Anti-androgens partly reversed the resistance.

    In conclusion, we have identified molecular heterogeneities in clinical bone metastases associated with biological characteristics, which could perhaps be used both for stratifying patients into treatment modalities, and to aid in further development of effective therapies for CRPC.

  • 196.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nordstrand, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lerner, Ulf H.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases2018Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 16, s. 50-50Artikkel i tidsskrift (Annet vitenskapelig)
  • 197.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Egevad, Lars
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Subgroups of castration-resistant prostate cancer bone metastases defined through an inverse relationship between androgen receptor activity and immune response2017Inngår i: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 71, nr 5, s. 776-787Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Novel therapies for men with castration-resistant prostate cancer (CRPC) are needed, particularly for cancers not driven by androgen receptor (AR) activation. Objectives: To identify molecular subgroups of PC bone metastases of relevance for therapy.

    Design, setting, and participants: Fresh-frozen bone metastasis samples from men with CRPC (n = 40), treatment-naïve PC (n = 8), or other malignancies (n = 12) were characterized using whole-genome expression profiling, multivariate principal component analysis (PCA), and functional enrichment analysis. Expression profiles were verified by reverse transcription–polymerase chain reaction (RT-PCR) in an extended set of bone metastases (n = 77) and compared to levels in malignant and adjacent benign prostate tissue from patients with localized disease (n = 12). Selected proteins were evaluated using immunohistochemistry. A cohort of PC patients (n = 284) diagnosed at transurethral resection with long follow-up was used for prognostic evaluation.

    Results and limitations: The majority of CRPC bone metastases (80%) was defined as AR-driven based on PCA analysis and high expression of the AR, AR co-regulators (FOXA1, HOXB13), and AR-regulated genes (KLK2, KLK3, NKX3.1, STEAP2, TMPRSS2); 20% were non–AR-driven. Functional enrichment analysis indicated high metabolic activity and low immune responses in AR-driven metastases. Accordingly, infiltration of CD3+ and CD68+ cells was lower in AR-driven than in non–AR-driven metastases, and tumor cell HLA class I ABC immunoreactivity was inversely correlated with nuclear AR immunoreactivity. RT-PCR analysis showed low MHC class I expression (HLA-A, TAP1, and PSMB9 mRNA) in PC bone metastases compared to benign and malignant prostate tissue and bone metastases of other origins. In primary PC, low HLA class I ABC immunoreactivity was associated with high Gleason score, bone metastasis, and short cancer-specific survival. Limitations include the limited number of patients studied and the single metastasis sample studied per patient.

    Conclusions: Most CRPC bone metastases show high AR and metabolic activities and low immune responses. A subgroup instead shows low AR and metabolic activities, but high immune responses. Targeted therapy for these groups should be explored. Patient summary: We studied heterogeneities at a molecular level in bone metastasis samples obtained from men with castration-resistant prostate cancer. We found differences of possible importance for therapy selection in individual patients.

  • 198.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Integrated DNA methylation and gene expression analysis of molecular heterogeneity in prostate cancer bone metastasisManuskript (preprint) (Annet vitenskapelig)
  • 199.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thellenberg-Karlsson, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Josefsson, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Brattsand, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Dermatologi och venereologi. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Excellent cabazitaxel response in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of resistance development by anti-androgensManuskript (preprint) (Annet vitenskapelig)
  • 200.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thellenberg-Karlsson, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lundholm, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Josefsson, Andreas
    Umeå universitet, Medicinska fakulteten, Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM). Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Department of Urology, Sahlgrenska Cancer Center, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Brattsand, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Marked response to cabazitaxel in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of acquired resistance by anti-androgens2019Inngår i: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

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

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

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

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