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  • 51.
    Dabrosin, Charlotta
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Variability of vascular endothelial growth factor in normal human breast tissue in vivo during the menstrual cycle2003Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 88, nr 6, s. 2695-2698Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Exposure to sex steroids increases the risk of breast cancer, but the mechanisms are poorly understood. Angiogenesis is crucial in tumor development and progression. Very little is known about the regulation of angiogenesis in the normal breast. Vascular endothelial growth factor ( VEGF) has a key stimulatory role in angiogenesis. Interferon-inducible protein 10 (IP-10) is a potent inhibitor of angiogenesis in vivo. These factors function in autocrine/paracrine pathways, therefore, direct measurements in the target tissue are needed. I measured VEGF and IP-10 in normal human breast tissue in situ in healthy women, using microdialysis, in the follicular and luteal phase of the menstrual cycle. In breast tissue, VEGF levels increased in the luteal phase, compared with the follicular phase (17.8+/-4 pg/ml to 34+/-9 pg/ml, P<0.05). Plasma VEGF did not show a cyclic variation (10.6&PLUSMN,2.8 pg/ml vs. 14.6&PLUSMN,3.5 pg/liter, P=0.3). IP-10 levels did not vary during the menstrual cycle either in breast tissue (65&PLUSMN,17 pg/ml vs. 75&PLUSMN,21 pg/ml, P=0.6) or in plasma (64&PLUSMN,7 pg/ml vs. 81&PLUSMN,10 pg/ml, P=0.06). The data suggests that, in the luteal phase, VEGF and IP-10, in the normal human breast, exhibit a proangiogenic profile. This may be one mechanism by which sex steroids contribute to breast cancer development.

  • 52. De Angelo, DJ
    et al.
    Schiffer, C
    Stone, R
    Amrein, P
    Fernandez, H
    Bradstock, K
    Tallman, M
    Foran, J
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Liu, D
    Paul, C
    Russo, D
    Stenke, L
    Leopold, L
    Stevenson, D
    Richie, M
    Berger, M
    Interim analysis of a phase II study of the safety and efficacy of gemtuzumab ozogamicin (Mylotarg (R)) given in combination with cytarabine and daunorubicin to patients < 60 years old with untreated acute myeloid leukemia.2002Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 100, nr 11, s. 745-Konferansepaper (Annet vitenskapelig)
  • 53.
    de Azambuja, Evandro
    et al.
    Inst Jules Bordet, B-1000 Brussels, Belgium.
    McCaskill-Stevens, Worta
    NCI, NIH, Bethesda, MD 20892 USA.
    Francis, Prudence
    Peter MacCallum Canc Ctr, Melbourne, Vic, Australia.
    Quinaux, Emmanuel
    Int Inst Drug Dev, Louvain, Belgium.
    Crown, John P A
    St Vincents Hosp, Dublin 4, Ireland.
    Vicente, Malou
    Br EAST Data Ctr, Brussels, Belgium.
    Giuliani, Rosa
    S Camillo Forlanini Hosp, Med Oncol Unit, Rome, Italy.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gutierez, Jorge
    Clin Las Condes, Santiago, Chile.
    Andersson, Michael
    Copenhagen Univ Hosp, Rigshosp, Finsen Ctr, Dept Oncol, Copenhagen, Denmark.
    Margeli Vila, Mireia
    Hosp Badalona Germans Trias and Pujol, Badalona, Spain.
    Jakesz, Raimund
    Univ Vienna, Gen Hosp, Vienna, Austria.
    Demol, Jan
    Heilig Hart Ziekenhuis, Roeselare, Belgium.
    Dewar, Joanna
    Sir Charles Gairdner Hosp, Nedlands, WA 6009, Australia.
    Santoro, Armando
    Ist Clin Humanitas, Rozzano, Italy.
    Lluch, Ana
    Hosp Clin Univ, Valencia, Spain.
    Olsen, Steven
    Sanofi Aventis, Paris, France.
    Gelber, Richard D
    Dana Farber Canc Inst, Dept Biostat and Computat Biol, Boston, MA 02115 USA.
    Di Leo, Angelo
    Hosp Prato, Sandro Pitigliani Med Oncol Unit, Prato, Italy.
    Piccart-Gebhart, Martine
    Inst Jules Bordet, B-1000 Brussels, Belgium.
    The effect of body mass index on overall and disease-free survival in node-positive breast cancer patients treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: the experience of the BIG 02-98 trial2010Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 119, nr 1, s. 145-153Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Obesity has been shown to be an indicator of poor prognosis for patients with primary breast cancer (BC) regardless of the use of adjuvant systemic therapy. Patients and methods: This is a retrospective analysis of 2,887 node-positive BC patients enrolled in the BIG 02-98 adjuvant study, a randomised phase III trial whose primary objective was to evaluate disease-free survival (DFS) by adding docetaxel to doxorubicin-based chemotherapy. In the current analysis, the effect of body mass index (BMI) on DFS and overall survival (OS) was assessed. BMI was obtained before the first cycle of chemotherapy. Obesity was defined as a BMI a parts per thousand yen 30 kg/mA(2). Results: In total, 547 (19%) patients were obese at baseline, while 2,340 (81%) patients were non-obese. Estimated 5-year OS was 87.5% for non-obese and 82.9% for obese patients (HR 1.34; P = 0.013). Estimated 5-years DFS was 75.9% for non-obese and 70.0% for obese patients (HR 1.20; P = 0.041). In a multivariate model, obesity remained an independent prognostic factor for OS and DFS. Conclusions: In this study, obesity was associated with poorer outcome in node-positive BC patients. Given the increasing prevalence of obesity worldwide, more research on improving the treatment of obese BC patients is needed.

  • 54.
    Delforge, M.
    et al.
    Katholieke University.
    de Samblanx, H.
    ZNA Middelheim.
    Zervas, K.
    Theagene Anticancer Hospital.
    Katodritou, E.
    Theagen Cancer Centre.
    Sargin, D.
    Istanbul University.
    Hulin, C.
    Central Hospital University Nancy Brabois.
    Ahlberg, Lucia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    de la Rubia, J.
    Hospital La Fe.
    Abdulkadyrov, K.
    Russian Science Research Institute.
    Ganguly, R.
    Johnson & Johnson Pharmaceutical.
    Diels, J.
    Johnson & Johnson Pharmaceutical.
    Dhawan, R.
    Johnson & Johnson Pharmaceutical.
    SURVIVAL ANALYSIS OF PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA: AN INTERIM REPORT FROM AN INTERNATIONAL ELECTRONIC OBSERVATIONAL STUDY OF BORTEZOMIB2009Inngår i: in HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, vol 94, 2009, Vol. 94, s. 0956-Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 55.
    Di Leo, A
    et al.
    External - unknown .
    Francis, P
    External - unknown .
    P Crown, J
    External - unknown .
    E de, Azambuja
    External - unknown .
    Quinaux, E
    External - unknown .
    Gutierrez, J
    External - unknown .
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Andersson, M
    External - unknown .
    M Margeli, Vila
    External - unknown .
    Piccart-Gebhart, M
    External - unknown .
    Jakesz, R
    External - unknown .
    Viale, G
    External - unknown .
    R Olsen, S
    External - unknown .
    Overall Survival Benefit for Sequential Doxorubicin-Docetaxel Compared to Concomitant Doxorubicin and Docetaxel in Node-Positive Breast Cancer. 8-Yr. Results of the Breast International Group (BIG) 2-98 Phase III Adjuvant Trial in CANCER RESEARCH, vol 69, issue 24, pp 521S-521S2009Inngår i: CANCER RESEARCH, 2009, Vol. 69, nr 24, s. 521S-521SKonferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 56.
    Dimopoulos, Meletios A
    et al.
    Greek Myeloma Study Group, Greece.
    De Samblanx, Hadewijch M
    AZ Sint-Dimpna, ZNA Middelheim, Antwerp, Belgium.
    Roussou, Maria G
    School of Medicine, University of Athens, Athens, Greece.
    Zervas, Konstantinos
    Greek Myeloma Study Group, Greece.
    Katodritou, Eirini
    Department of Hematology, Theagenion Cancer Center, Thessaloniki, Greece.
    Sargin, Deniz
    Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
    Hulin, Cyrille
    Hematology, Centre Hospitalier of Nancy-Brabois, Vandoeuvre, France.
    Ahlberg, Lucia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    De La Rubia, Javier
    Hematology, Hospital La Fe, Valencia, Spain.
    Ganguly, Rita
    Johnson & Johnson Pharmaceuticals, Raritan, NJ, USA.
    Diels, Joris K
    Johnson & Johnson Pharmaceuticals, Beerse, Belgium.
    van de Velde, Helgi
    Johnson & Johnson Pharmaceuticals Research & Development, Beerse, Belgium.
    Dhawan, Ravinder
    Johnson & Johnson Pharmaceuticals, Raritan, NJ, USA.
    Spencer, Michael D
    Johnson & Johnson Pharmaceuticals, High Wycombe, United Kingdom.
    Delforge, Michel
    University Hospital Leuven, Leuven, Belgium .
    Efficacy of Bortezomib Plus Dexamethasone Versus Bortezomib Mono therapy In Patients with Relapsed/Refractory Multiple Myeloma An Interim Report from an International Electronic Observational Study2010Inngår i: BLOOD vol 116, issue 21 (ISSN 0006-4971), American Society of Hematology , 2010, Vol. 116, nr 21, s. 1247-1248Konferansepaper (Fagfellevurdert)
  • 57.
    Ding, Jun-Li
    et al.
    Sichuan University, Peoples R China .
    Zhou, Zong-Guang
    Sichuan University, Peoples R China .
    Zhou, Xiang-Yu
    Sichuan University, Peoples R China .
    Zhou, Bin
    Sichuan University, Peoples R China .
    Wang, Ling
    Sichuan University, Peoples R China .
    Wang, Rong
    Sichuan University, Peoples R China .
    Zhan, Lan
    Sichuan University, Peoples R China .
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Li, Yuan
    Sichuan University, Peoples R China .
    Attenuation of Acute Pancreatitis by Peroxisome Proliferator-Activated Receptor-α in Rats: The Effect on Toll-Like Receptor Signaling Pathways2013Inngår i: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 42, nr 1, s. 114-122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: The peroxisome proliferator-activated receptor-α (PPAR-α) has attracted considerable attention for its anti-inflammatory properties; however, Toll-like receptor (TLR) pathways have an essential proinflammatory role in acute pancreatitis (AP). This study aimed to evaluate the attenuation of inflammation by PPAR-α and to investigate the interaction between PPAR-α and TLR pathways in AP.

    Methods: Acute pancreatitis was induced in rats by administration of cerulein. The PPAR-α agonist WY14643 and/or antagonist MK886 was administered. The severity of AP was determined by measuring serum amylase, lipase, Ca2+, pathological changes, myeloperoxidase activity, serum levels of interleukin (IL)-6, and intercellular adhesion molecule-1 (ICAM-1). The TLR2 and TLR4 messenger RNA (mRNA) and proteins were determined by real-time reverse transcriptase polymerase chain reaction and Western blotting, respectively. The mRNA expressions of target molecules of TLR pathways, including IL-6, IL-10, ICAM-1, and tumor necrosis factor α were also measured.

    Results: Treatment with WY14643 significantly decreased amylase, lipase, myeloperoxidase activity, pathological scores, IL-6, and ICAM-1 levels. The TLR2 and TLR4 mRNA and proteins were markedly decreased after treatment with WY14643, along with IL-6, ICAM-1, and tumor necrosis factor α mRNA levels. However, these effects were completely reversed by the coadministration of MK886.

    Conclusions: Activation of PPAR-α played a protective role in AP, partially mediated by modulation of TLR pathways.

  • 58.
    Ding, Yuan C
    et al.
    City Hope National Medical Centre, CA, USA .
    McGuffog, Lesley
    University of Cambridge Worts Causeway, England .
    Healey, Sue
    Royal Brisbane Hospital, Australia .
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Paluch-Shimon, Shani
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Kaufman, Bella
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Liljegren, Annelie
    Karolinska University Hospital, Sweden .
    Lindblom, Annika
    Karolinska University Hospital, Sweden .
    Olsson, Hakan
    University of Lund Hospital, Sweden .
    Kristoffersson, Ulf
    University of Lund Hospital, Sweden .
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Melin, Beatrice
    Umeå University, Sweden .
    Domchek, Susan M
    University of Penn, PA, USA .
    Nathanson, Katherine L
    University of Penn, PA, USA .
    Rebbeck, Timothy R
    University of Penn, PA, USA .
    Jakubowska, Anna
    Pomeranian Medical University, Poland .
    Lubinski, Jan
    Pomeranian Medical University, Poland .
    Jaworska, Katarzyna
    Pomeranian Medical University, Poland .
    Durda, Katarzyna
    Pomeranian Medical University, Poland .
    Gronwald, Jacek
    Pomeranian Medical University, Poland .
    Huzarski, Tomasz
    Pomeranian Medical University, Poland .
    Cybulski, Cezary
    Pomeranian Medical University, Poland .
    Byrski, Tomasz
    Pomeranian Medical University, Poland .
    Osorio, Ana
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain Spanish Network Rare Disease CIBERER, Spain .
    Ramony Cajal, Teresa
    Hospital Santa Creu and Sant Pau, Spain .
    Stavropoulou, Alexandra V
    National Centre Science Research Demokritos, Greece .
    Benitez, Javier
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain Spanish Network Rare Disease CIBERER, Spain .
    Hamann, Ute
    Deutsch Krebsforschungszentrum DKFZ, Germany .
    Rookus, Matti
    Netherlands Cancer Institute, Netherlands .
    Aalfs, Cora M
    University of Amsterdam, Netherlands .
    de Lange, Judith L
    Netherlands Cancer Institute, Netherlands .
    Meijers-Heijboer, Hanne E J
    Vrije University of Amsterdam Medical Centre, Netherlands .
    Oosterwijk, Jan C
    University of Groningen, Netherlands .
    van Asperen, Christi J
    Leiden University, Netherlands .
    Gomez Garcia, Encarna B
    MUMC, Netherlands .
    Hoogerbrugge, Nicoline
    Radboud University of Nijmegen, Netherlands .
    Jager, Agnes
    Erasmus University, Netherlands .
    van der Luijt, Rob B
    University of Medical Centre Utrecht, Netherlands .
    Easton, Douglas F
    University of Cambridge, England .
    Peock, Susan
    University of Cambridge, England .
    Frost, Debra
    University of Cambridge, England .
    Ellis, Steve D
    University of Cambridge, England .
    Platte, Radka
    University of Cambridge, England .
    Fineberg, Elena
    University of Cambridge, England .
    Evans, D Gareth
    Central Manchester University Hospital NHS Fdn Trust, England .
    Lalloo, Fiona
    Central Manchester University Hospital NHS Fdn Trust, England .
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust, England .
    Eeles, Ros
    Institute Cancer Research, England Royal Marsden NHS Fdn Trust, England .
    Adlard, Julian
    Yorkshire Regional Genet Serv, England .
    Davidson, Rosemarie
    Yorkhill Hospital, Scotland .
    Eccles, Diana
    University Hospital Southampton NHS Fdn Trust, England .
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, England .
    Cook, Jackie
    Sheffield Childrens Hospital, England .
    Brewer, Carole
    Royal Devon and Exeter Hospital, England .
    Tischkowitz, Marc
    University of Cambridge, England .
    Godwin, Andrew K
    University of Kansas, KS, USA .
    Pathak, Harsh
    University of Kansas, KS, USA .
    Stoppa-Lyonnet, Dominique
    Institute Curie, France Institute Curie, France University of Paris 05, France .
    Sinilnikova, Olga M
    University of Lyon 1, France Centre Hospital University of Lyon, France .
    Mazoyer, Sylvie
    University of Lyon 1, France .
    Barjhoux, Laure
    University of Lyon 1, France .
    Leone, Melanie
    Centre Hospital University of Lyon, France .
    Gauthier-Villars, Marion
    Institute Curie, France .
    Caux-Moncoutier, Virginie
    Institute Curie, France .
    de Pauw, Antoine
    Institute Curie, France .
    Hardouin, Agnes
    Centre Francois Baclesse, France .
    Berthet, Pascaline
    Centre Francois Baclesse, France .
    Dreyfus, Helene
    CHU Grenoble, France University of Grenoble, France .
    Fert Ferrer, Sandra
    Hotel Dieu Centre Hospital, France .
    Collonge-Rame, Marie-Agnes
    CHU Besancon, France .
    Sokolowska, Johanna
    Nancy University, France .
    Buys, Saundra
    University of Utah, UT, USA .
    Daly, Mary
    Fox Chase Cancer Centre, PA, USA .
    Miron, Alex
    Dana Farber Cancer Institute, MA, USA .
    Terry, Mary Beth
    Columbia University, NY, USA .
    Chung, Wendy
    Columbia University, NY, USA .
    John, Esther M
    Cancer Prevent Institute Calif, CA, USA Stanford University, CA, USA Stanford Cancer Institute, CA, USA .
    Southey, Melissa
    University of Melbourne, Australia .
    Goldgar, David
    University of Utah, UT, USA .
    Singer, Christian F
    Medical University of Vienna, Austria .
    Tea, Muy-Kheng Maria
    Medical University of Vienna, Austria .
    Gschwantler-Kaulich, Daphne
    Medical University of Vienna, Austria .
    Fink-Retter, Anneliese
    Medical University of Vienna, Austria .
    Hansen, Thomas V O
    Copenhagen University Hospital, Denmark .
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark .
    Johannsson, Oskar T
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
    Offit, Kenneth
    Clin Cancer Genet Lab, NY, USA .
    Sarrel, Kara
    Clin Cancer Genet Lab, NY, USA .
    Gaudet, Mia M
    Amer Cancer Soc, GA, USA .
    Vijai, Joseph
    Clin Cancer Genet Lab, NY, USA .
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY, USA .
    Piedmonte, Marion R
    Roswell Pk Cancer Institute, NY, USA .
    Andrews, Lesley
    Australia New Zealand Gynaecol Oncology Grp, Australia .
    Cohn, David
    Ohio State University, OH, USA .
    DeMars, Leslie R
    Dartmouth Hitchcock Medical Centre, NH, USA .
    DiSilvestro, Paul
    Brown University, RI, USA .
    Rodriguez, Gustavo
    NorthShore University of Health Syst, IL, USA .
    Ewart Toland, Amanda
    Ohio State University, OH, USA Ohio State University, OH, USA .
    Montagna, Marco
    Ist Oncology Veneto IOV IRCCS, Italy .
    Agata, Simona
    Ist Oncology Veneto IOV IRCCS, Italy .
    Imyanitov, Evgeny
    NN Petrov Oncology Research Institute, Russia .
    Isaacs, Claudine
    Georgetown University, DC, USA .
    Janavicius, Ramunas
    Vilnius University Hospital, Lithuania .
    Lazaro, Conxi
    Institute Catala Oncol, Spain .
    Blanco, Ignacio
    IDIBELL Catalan Institute Oncol, Spain .
    Ramus, Susan J
    University of So Calif, CA, USA .
    Sucheston, Lara
    Roswell Pk Cancer Institute, NY, USA .
    Karlan, Beth Y
    Cedars Sinai Medical Centre, CA, USA .
    Gross, Jenny
    Cedars Sinai Medical Centre, CA, USA .
    Ganz, Patricia A
    University of Calif Los Angeles, CA, USA .
    Beattie, Mary S
    University of Calif San Francisco, CA, USA .
    Schmutzler, Rita K
    University Hospital Cologne, Germany .
    Wappenschmidt, Barbara
    University Hospital Cologne, Germany .
    Meindl, Alfons
    Technical University of Munich, Germany .
    Arnold, Norbert
    University of Kiel, Germany .
    Niederacher, Dieter
    University of Dusseldorf, Germany .
    Preisler-Adams, Sabine
    University of Munster, Germany .
    Gadzicki, Dorotehea
    Hannover Medical Sch, Germany .
    Varon-Mateeva, Raymonda
    Charite, Germany .
    Deissler, Helmut
    University Hospital Ulm, Germany .
    Gehrig, Andrea
    University of Wurzburg, Germany .
    Sutter, Christian
    University of Heidelberg Hospital, Germany .
    Kast, Karin
    Technical University of Dresden, Germany .
    Nevanlinna, Heli
    University of Helsinki, Finland .
    Aittomaki, Kristiina
    Centre Hospital University of Quebec, Canada University of Laval, Canada .
    Spurdle, Amanda B
    Royal Brisbane Hospital, Australia .
    Beesley, Jonathan
    Royal Brisbane Hospital, Australia .
    Chen, Xiaoqing
    Royal Brisbane Hospital, Australia .
    Tomlinson, Gail E
    University of Texas Health Science Centre San Antonio, TX, USA.
    Weitzel, Jeffrey
    City Hope National Medical Centre, CA, USA .
    Garber, Judy E
    Harvard University, MA, USA .
    Olopade, Olufunmilayo I
    University of Chicago, IL, USA .
    Rubinstein, Wendy S
    NorthShore University of HealthSyst, IL, USA .
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA, USA .
    Blum, Joanne L
    Baylor Charles A Sammons Cancer Centre, TX, USA .
    Narod, Steven A
    Womens Coll Hospital, Canada .
    Brummel, Sean
    Harvard University, MA, USA .
    Gillen, Daniel L
    University of Calif Irvine, CA USA .
    Lindor, Noralane
    Mayo Clin, MN, USA .
    Fredericksen, Zachary
    Mayo Clin, MN, USA .
    Pankratz, Vernon S
    Mayo Clin, MN, USA .
    Couch, Fergus J
    Mayo Clin, MN, USA .
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Greene, Mark H
    NCI, MD, USA .
    Loud, Jennifer T
    NCI, MD, USA .
    Mai, Phuong L
    NCI, MD, USA .
    Andrulis, Irene L
    University of Toronto, Canada .
    Glendon, Gord
    University of Toronto, Canada .
    Gerdes, Anne-Marie
    Odense University Hospital, Denmark .
    Birk Jensen, Uffe
    Skejby Hospital, Denmark .
    Skytte, Anne-Bine
    Vejle Hospital, Denmark .
    Caligo, Maria A
    University of Pisa, Italy University Hospital Pisa, Italy .
    Lee, Andrew
    University of Cambridge Worts Causeway, England .
    Chenevix-Trench, Georgia
    Royal Brisbane Hospital, Australia .
    Antoniou, Antonis C
    University of Cambridge Worts Causeway, England .
    Neuhausen, Susan L
    City Hope National Medical Centre, CA, USA .
    A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers2012Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, nr 8, s. 1362-1370Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. less thanbrgreater than less thanbrgreater thanMethods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. less thanbrgreater than less thanbrgreater thanResults: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P-difference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). less thanbrgreater than less thanbrgreater thanConclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. less thanbrgreater than less thanbrgreater thanImpact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

  • 59.
    Ding, Zhen-Yu
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Liu, Gui-Hong
    Sichuan University, China.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells2013Inngår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 34, nr 2, s. 683-693Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The antiapoptotic factor Livin has been considered critical for tumor progression and poor prognosis for variant types of tumors. However, there are only limited reports regarding its expression and biological functions in colon cancer. Here, we examined Livin expression in four colon cancer cell lines (HCT116, RKO, KM12C, and SW620) in the presence or absence of cisplatin that was used as a model reagent. We found the different response to cisplatin was related to endogenous Livin expression level. From among a panel of apoptosis-related factors (p53, Bcl-2, Bcl-XL, BAX, and survivin), the expression of Livin was upregulated after cisplatin treatment in a dose-dependent manner. Both immunocytochemistry and nuclear cytoplasmic fractionation indicated Livin remained in the cytoplasm after treatment with cisplatin. In an attempt to explore the mechanism, we found the elevated expression of Livin was not due to the decreased degradation by proteosome but was enhanced at the mRNA level. Besides, cisplatin treatment activated the mammalian target of rapamycin (mTOR) pathway as shown by increased phosphorylation of Akt1, mTOR, S6K, and 4E-BP1, together with the elevated Livin. The PI3K inhibitor LY294002 inhibited both the phosphorylation of mTOR and upregulation of Livin. The stable overexpression of Livin inhibited the activation of caspase-3 and led to resistance to cisplatin, while the knockdown of Livin by siRNA rendered colon cancer cells more sensitive to cisplatin. Our study, along with others, highlighted the potential of Livin for cancer therapy in colon cancer.

  • 60.
    Ding, Zhen-Yu
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Zhang, Hong
    University of Örebro, Sweden .
    Adell, Gunnar
    Karolinska University Hospital, Sweden .
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Livin expression is an independent factor in rectal cancer patients with or without preoperative radiotherapy2013Inngår i: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 8, nr 281Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: This study was aimed to investigate the expression significance of Livin in relation to radiotherapy (RT), clinicopathological and biological factors of rectal cancer patients. Methods: This study included 144 primary rectal cancer patients who participated in a Swedish clinical trial of preoperative radiotherapy. Tissue microarray samples from the excised primary rectal cancers, normal mucosa and lymph node metastases were immunostained with Livin antibody. The proliferation of colon cancer cell lines SW620 and RKO was assayed after Livin knock-down. Results: The expression of Livin was significantly increased from adjacent (P = 0.051) or distant (P = 0.028) normal mucosa to primary tumors. 15.4% (2/13) and 39.7% (52/131) patients with Livin-negative and positive tumors died at 180 months after surgery, and the difference tended to be statistically significant (P = 0.091). In multivariate analyses, the difference achieved statistical significance, independent of TNM stage, local and distant recurrence, grade of differentiation, gender, and age (odds ratio = 5.09, 95% CI: 1.01-25.64, P = 0.048). The in vitro study indicated colon cancer cells with Livin knock-down exhibited decreased proliferation compared with controls after RT. Conclusions: The expression of Livin was was independently related to survival in rectal cancer patients, suggesting Livin as a useful prognostic factor for rectal cancer patients.

  • 61.
    Djerf, Emelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Studies on the effect of ErbB tyrosine kinase inhibitors on malignant melanoma growth and survival in vitro2009Licentiatavhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Malignant melanoma has one of the fastest increasing incidences among the different types of cancerin the Western world. This raise can partly be ascribed to the change in sun habits that has takenplace during the last decades, since the major external risk factor for melanoma is exposure toultraviolet radiation. Patients with early stages of melanoma can often be cured by surgery, howeverfor patients suffering from metastatic melanoma there are only a few treatment options available.Unfortunately malignant melanoma is often resistant to radio-, bio- and chemotherapy and treatmentwith the currently most frequently used agent, dacarbazine, is characterized by a very low clinicalresponse rate. Therefore, there is an urgent need for new treatment strategies which can increase theoverall survival and cause less severe side effects.

    The aim of this thesis was to investigate the anti-tumor effect of two different tyrosine kinaseinhibitors (TKIs), gefitinib and canertinib, on two different human malignant melanoma (RaH3 andRaH5) cell lines. We investigate the effect of these two drugs on cell proliferation and survival andstudied the effect of gefitinib and canertinib on ErbB1-4 receptor phosphorylation, as well as Akt,Erk1/2 and Stat3 activity.

    Our results showed that phosphorylation of ErbB1, ErbB2 and ErbB3 decreased followingtreatment with both gefitinib and canertinib and that the subsequent downstream signaling via Akt,Erk1/2 and Stat3 was inhibited after TKI treatment. However, it was noted that the gefitinibinducedinhibition of Akt, and particularly Erk1/2, was transient and only a weak inhibition of Stat3phosphorylation was seen. Gefitinib treatment of the RaH3 and RaH5 cells resulted in anaccumulation of the cells in the G1 phase of the cell cycle without any induction of apoptosis.Canertinib caused a more pronounced inhibition of Akt, Erk1/2, and Stat3 phosphorylation thangefitinib. This might be one explanation to why canertinib induced apoptosis in RaH3 and RaH5cells whereas gefitinib only caused cell cycle arrest. In conclusion, gefitinib and canertinib displaypromising anti-tumor effects on ErbB expressing malignant melanoma and might be used in futurestudies in combination with conventional chemotherapy or other targeted therapies in the treatmentof malignant melanoma.

    Delarbeid
    1. ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839)
    Åpne denne publikasjonen i ny fane eller vindu >>ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839)
    Vise andre…
    2009 (engelsk)Inngår i: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, ISSN 0960-8931, Vol. 19, nr 3, s. 156-166Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Members of the epidermal growth factor (EGF) family of structurally related tyrosine kinase receptors, known as the ErbB receptors (EGFR/ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) and their respective ligands, have been suggested to be involved in the development and progression of malignant melanoma. Here we investigate the effects of the ErbB1 tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) on human malignant melanoma cells (RaH3 and RaH5) in vitro. ZD1839 inhibited proliferation of exponentially growing RaH3 and RaH5 cells in a dose-dependent manner with a half-maximally effective dose of 3.5 and 2.0 mu mol/l, respectively. Cell growth was inhibited at 0.1 mu mol/l ZD1839 in both cell lines. Maximal inhibition was accomplished at 10 mu mol/l ZD1839; however, the effect was not complete as both cell lines showed a continuous slow growth during the treatment period. Flow cytometry analysis of cell-cycle distribution showed that ZD1839 treatment caused accumulation of RaH3 and RaH5 cells in the G, phase. The growth arrest induced by ZD1839 coincided with upregulation of the cyclin-dependent kinase inhibitor p27(KIP1). There was no increase in apoptosis as determined by analysis of plasma phosphatidyl serine redistribution. Western blot analysis revealed that ZD1839 substantially reduced tyrosine phosphorylation of ErbB1 as well as ErbB2 and ErbB3. This was accompanied by a concomitant decrease in Akt-phosphorylation, Erk1/2-phosphorylation, and Stat3-phosphorylation. Our results show that ZD1839 interferes with the growth of human malignant melanoma cells by cytostatic effects. These findings indicate the possible use of ErbB receptor kinase inhibitors as a novel treatment strategy in malignant melanoma.

    Emneord
    antiproliferative, ErbB receptors, gefitinib, melanoma, tyrosine kinase inhibitor
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-19129 (URN)10.1097/CMR.0b013e32832c6339 (DOI)
    Tilgjengelig fra: 2009-06-12 Laget: 2009-06-12 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo
    Åpne denne publikasjonen i ny fane eller vindu >>The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo
    Vise andre…
    2011 (engelsk)Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 414, nr 3, s. 563-568Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 mu M and by 5 mu M both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 mu M canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24 h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 mu M canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses less than= 5 mu M canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.

    sted, utgiver, år, opplag, sider
    Elsevier, 2011
    Emneord
    Malignant melanoma; Tyrosine kinase inhibitor; Canertinib; ErbB-receptor; Apoptosis
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-73740 (URN)10.1016/j.bbrc.2011.09.118 (DOI)000298519500021 ()
    Merknad

    On the day of the defence date the status of this article was Manuscript and the title "The pan-ErbB receptor tyrosine kinase inhibitor Canertinib (CI-1033)promotes cell cycle arrest and apoptosis of human malignantmelanoma in vitro".

    Tilgjengelig fra: 2012-01-12 Laget: 2012-01-12 Sist oppdatert: 2017-12-08
  • 62.
    Djerf, Emelie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Trinks, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Abdiu, Avni
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Rekonstruktionscentrum, Hand- och plastikkirurgiska kliniken US.
    Thunell, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Walz, Thomas M
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839)2009Inngår i: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, ISSN 0960-8931, Vol. 19, nr 3, s. 156-166Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Members of the epidermal growth factor (EGF) family of structurally related tyrosine kinase receptors, known as the ErbB receptors (EGFR/ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) and their respective ligands, have been suggested to be involved in the development and progression of malignant melanoma. Here we investigate the effects of the ErbB1 tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) on human malignant melanoma cells (RaH3 and RaH5) in vitro. ZD1839 inhibited proliferation of exponentially growing RaH3 and RaH5 cells in a dose-dependent manner with a half-maximally effective dose of 3.5 and 2.0 mu mol/l, respectively. Cell growth was inhibited at 0.1 mu mol/l ZD1839 in both cell lines. Maximal inhibition was accomplished at 10 mu mol/l ZD1839; however, the effect was not complete as both cell lines showed a continuous slow growth during the treatment period. Flow cytometry analysis of cell-cycle distribution showed that ZD1839 treatment caused accumulation of RaH3 and RaH5 cells in the G, phase. The growth arrest induced by ZD1839 coincided with upregulation of the cyclin-dependent kinase inhibitor p27(KIP1). There was no increase in apoptosis as determined by analysis of plasma phosphatidyl serine redistribution. Western blot analysis revealed that ZD1839 substantially reduced tyrosine phosphorylation of ErbB1 as well as ErbB2 and ErbB3. This was accompanied by a concomitant decrease in Akt-phosphorylation, Erk1/2-phosphorylation, and Stat3-phosphorylation. Our results show that ZD1839 interferes with the growth of human malignant melanoma cells by cytostatic effects. These findings indicate the possible use of ErbB receptor kinase inhibitors as a novel treatment strategy in malignant melanoma.

  • 63.
    Djerf, Emelie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Trinks, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Abdiu, Avni
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Hand- och plastikkirurgiska kliniken US.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Walz, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo2011Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 414, nr 3, s. 563-568Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 mu M and by 5 mu M both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 mu M canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24 h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 mu M canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses less than= 5 mu M canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.

  • 64.
    Djerf Svenningsson, Emelie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Olausson, Patrik
    Linköpings universitet, Institutionen för medicin och hälsa, Rehabiliteringsmedicin. Linköpings universitet, Hälsouniversitetet.
    Ghafouri, Bijar
    Linköpings universitet, Institutionen för medicin och hälsa, Rehabiliteringsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Smärt och rehabiliteringscentrum.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hallbeck, Anna-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Walz, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Resistance to gefitinib in malignant melanoma cells is related to increased expression of Met and the insulin receptor and sustained Akt signaling2012Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: Acquired resistance to cancer therapy, including targeted therapies such as epidermal growth factor receptor (ErbB) tyrosine kinase inhibitors (TKIs), constitutes a major clinical problem in treating patients with malignant disease. Several drug resistance mechanisms for ErbB1 TKIs involving abnormal activation of growth factor receptors or activation of intracellular signaling pathways have been discovered. ErbB TKIs have recently been shown to inhibit growth in melanoma cells. This study was undertaken to develop a gefitinib-resistant melanoma cell line in order to find any resistance mechanism to gefitinib in melanoma cells lacking activating mutation in BRAF or NRAS.

    Material and methods: A malignant melanoma cell line (RaH5) was made resistant to the ErbB1 TKI gefitinib by continuous culture with stepwise increasing concentrations of the drug up to 10 μM. The phosphorylation status of 42 different human receptor tyrosine kinases was screened in a protein array in resistant (RaH5ZDR) and wild-type RaH5 cells treated with or without gefitinib. The PI3K, MAPK and Stat3 signaling pathways were studied in an analogous way by Western blot analysis; 2-D gel electrophoresis was performed to determine other potential proteins involved in gefitinib resistance in RaH5 cells. In addition, the effect of the pan-ErbB TKI canertinib on gefitinib-resistant cells was investigated.

    Results: Protein array experiments showed that only Met and the insulin receptor (IR) exhibited substantially increased activation in RaH5ZDR cells as compared to their nonresistant counterparts. Interestingly, following gefitinib treatment ErbB2 and ErbB3 receptor signaling in resistant cells were equally well suppressed as in non-resistant cells. However, downstream Akt and Erk1/2 phosphorylation was inhibited to a greater extent in non-resistant RaH5 cells.

    Conclusion: Resistance to gefitinib in RaH5 cells appears to be related to an increased expression of Met and IR and linked to a more persistent signaling through Akt and Erk1/2. However, additional studies are required to further elucidate the resistance to gefitinib in our experimental system.

  • 65.
    E Johnsen, H
    et al.
    Aarhus University Hospital.
    Geisler, C
    Rigshosp, Copenhagen, Denmark .
    Juvonen, E
    University Hospital, Helsinki.
    Remes, K
    Turku University Hospital.
    Juliusson, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Hornsten, P
    University Hospital, Umea.
    Kvaloy, S
    Radiumhospitalet, Oslo.
    Kvalheim, G
    Radiumhospitalet, Oslo.
    Jurgensen, G W
    Herlev University Hospital.
    Pedersen, L M
    Herlev University Hospital.
    Bergmann, O J
    Herlev University Hospital.
    Schmitz, A
    Aarhus University Hospital.
    Boegsted, M
    Aarhus University Hospital.
    Priming with r-metHuSCF and filgrastim or chemotherapy and filgrastim in patients with malignant lymphomas: a randomized phase II pilot study of mobilization and engraftment2011Inngår i: BONE MARROW TRANSPLANTATION, ISSN 0268-3369, Vol. 46, nr 1, s. 44-51Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    SCF has been shown to synergize with G-CSF to mobilize CD34(+) PBPCs. In this study we report results from this combination after a phase II trial of 32 patients with malignant lymphoma randomized to receive recombinant methionyl human SCF (ancestim, r-metHuSCF) in combination with recombinant methionyl human G-CSF (filgrastim, r-metHuG-CSF) (experimental arm A) or routine chemotherapy plus filgrastim (conventional arm B). The primary objective was to evaluate the side effects and toxicity during priming and mobilization. The secondary objectives were efficacy by the level of blood-circulating PBPCs, the number of harvest days and the time to three-lineage engraftment after autografting. First, during priming 5 patients had 8 serious events, 4 in each arm. A summary of all adverse events revealed 30 (94%) patients suffering from 132 events of all grading. Second, neutropenia and thrombocytopenia was documented in arm B. Third, 9/14 (64%) patients in arm A reached the target of 5 million CD34(+) cells/kg body weight (bw) compared with 13/15 (87%) in arm B. The results represent the first randomized trial of growth factor plus chemotherapy priming and indicate that a formal phase III trial very unlikely may challenge chemotherapy plus r-metHuG-CSF priming in candidates for high-dose therapy.

  • 66.
    Ejlertsen, B.
    et al.
    Department of Oncology, Copenhagen University Hospital, Bldg. 5012, Rigshospitalet, 9. Blegdamsvej, DK-2100 Copenhagen, Denmark.
    Mouridsen, H.T.
    Department of Oncology, Copenhagen University Hospital, Bldg. 5012, Rigshospitalet, 9. Blegdamsvej, DK-2100 Copenhagen, Denmark, DBCG Registry, Copenhagen, Denmark.
    Jensen, M.-B.
    DBCG Registry, Copenhagen, Denmark.
    Andersen, J.
    Department of Oncology, Aarhus Hospital, Aarhus University, Denmark.
    Cold, S.
    Department of Oncology, Esbjerg County Hospital, Esbjerg, Denmark.
    Edlund, P.
    Department of Oncology, Odense University Hospital, Odense, Denmark.
    Ewertz, M.
    Department of Oncology, Gaavle County Hospital, Gaavle, Sweden.
    Jensen, B.B.
    Department of Oncology, Aalborg Hospital, Aarhus University, Denmark.
    Kamby, C.
    Department of Oncology, Herlev University Hospital, Herlev, Denmark.
    Nordenskjöld, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Bergh, J.
    Radiumhemmet, Stockholm Oncology, Karolinska Institute, University Hospital, Stockholm, Sweden.
    Improved outcome from substituting methotrexate with epirubicin: Results from a randomised comparison of CMF versus CEF in patients with primary breast cancer2007Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 43, nr 5, s. 877-884Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We compared the efficacy of CEF (cyclophosphamide, epirubicin, and fluorouracil) against CMF (cyclophosphamide, methotrexate, and fluorouracil) in moderate or high risk breast cancer patients. We randomly assigned 1224 patients with completely resected unilateral breast cancer to receive nine cycles of three-weekly intravenous CMF or CEF. Patients were encouraged to take part in a parallel trial comparing oral pamidronate 150 mg twice daily for 4 years versus control (data not shown). Substitution of methotrexate with epirubicin significantly reduced the unadjusted hazard for disease-free survival (DFS) by 16% (hazard ratio 0.84, 95% CI, 0.71-0.99) and for overall survival by 21% (hazard ratio 0.79, 95% CI, 0.66-0.94). The risk of secondary leukaemia and congestive heart failure was similar in the two groups. Overall CEF was superior over CMF in terms of DFS and OS in patients with operable breast cancer without subsequent increase in late toxicities. © 2007 Elsevier Ltd. All rights reserved.

  • 67.
    Eriksson, Hanna
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Lyth, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Månsson-Brahme, Eva
    Karolinska Institutet, Stockholm, Sweden.
    Frohm-Nilsson, Margareta
    Karolinska Institutet, Stockholm, Sweden.
    Ingvar, Christian
    Lund University, Sweden .
    Lindholm, Christer
    Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Naredi, Peter
    Umeå University, Sweden .
    Stierner, Ulrika
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Wagenius, Gunnar
    Uppsala University, Sweden .
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Hansson, Johan
    Karolinska Institutet, Stockholm, Sweden.
    Low level of education is associated with later stage at diagnosis and reduced survival in cutaneous malignant melanoma: A nationwide population-based study in Sweden2013Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, nr 12, s. 2705-2716Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    A worse outcome has been reported for cutaneous malignant melanoma (CMM) patients with low socioeconomic status. We have investigated the association between level of education, clinical stage at diagnosis (stage at diagnosis) and CMM-specific survival in Sweden.

    METHODS:

    We identified 27,235 patients from the Swedish Melanoma Register diagnosed with a primary invasive CMM between 1990 and 2007 and linked data to nationwide, population-based, health and census registers with a follow-up to 2010.

    RESULTS:

    The odds ratio (OR) of higher disease stage at diagnosis was significantly increased in lower education groups (OR stage II versus I=1.6; 95% confidence interval (CI)=1.5-1.7. OR stage III-IV versus I=2.3; 95% CI=1.8-2.9). The risk of dying of CMM, was significantly increased in patients with low (hazard ratio (HR) low versus high=2.02; 95% CI=1.80-2.26; p<0.0001) and intermediate (HR intermediate versus high=1.35; 95% CI=1.20-1.51; p<0.0001) level of education. After adjustment for age, gender, stage at diagnosis and other known prognostic factors, the HRs remained significant for low versus high (HR=1.13; 95% CI=1.01-1.27; p=0.04) but not for intermediate versus high (HR=1.11; 95% CI=0.99-1.24; p=0.08) education. The HR associated with low level of education was significantly higher among female patients, patients <55years, patients with truncal tumours and during the first 5years after diagnosis.

    CONCLUSION:

    Lower level of education is associated with reduced CMM-specific survival, which may at least partially be attributed to a more advanced stage at diagnosis. These results emphasise the need for improved early detection strategies.

  • 68.
    Farnebo, Lovisa
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Tiefenböck, Katharina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Ansell, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet.
    Thunell, Lena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Garvin, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Roberg, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Sinnescentrum, Öron- näsa- och halskliniken US.
    Strong expression of survivin is associated with positive response to radiotherapy and improved overall survival in head and neck squamous cell carcinoma patients2013Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, nr 8, s. 1994-2003Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Head and neck squamous cell carcinoma (HNSCC) is a malignancy that is associated with severe mortality despite advances in therapy. Todays standard treatment most commonly includes radiotherapy, often combined with chemotherapy or surgery. There are so far no established biomarkers to predict response to radiation, and thus the aim of this study was to investigate a series of markers that could potentially identify HNSCC patients who would benefit from radiotherapy. The selected markers, both proteins (epidermal growth factor receptor, survivin and p53), and single nucleotide polymorphisms (SNPs) in the genes of XRCC3, XRCC1, XPC, XPD, MDM2, p53 and FGFR4 were correlated to the response to radiotherapy and overall survival. Investigations were performed on pretreatment tumor biopsies from patients classified as responders or nonresponders to radiotherapy. Protein expression was examined using immunohistochemistry and the genotyping of specific SNPs was analyzed using PCR-RFLP or pyrosequencing. We found that survivin expression was significantly stronger in the responder group (p = 0.003) and that patients with a strong survivin expression had a significantly better overall survival (p andlt; 0.001). Moreover, downregulation of survivin by siRNA in two HNSCC cell lines significantly decreased their sensitivity to radiation. Among the SNPs analyzed, patients with the XPD Lys751Gln SNP had a significantly shorter overall survival (p = 0.048), and patients with the FGFR4 Gly388Arg SNP had a significantly longer overall survival (p = 0.010). In conclusion, our results suggest that survivin plays an important role in the response to radiotherapy and may be a useful marker for predicting radiotherapy response in patients with HNSCC. less thanbrgreater than less thanbrgreater thanWhats new? Resistance to radiation therapy is a significant problem in the treatment of head and neck squamous cell carcinoma (HNSCC) and has created a need for the discovery of markers predictive of radiotherapy response. One promising marker is survivin, an inhibitor of apoptosis. Here, in pre-treatment biopsies from 40 patients with HNSCC, strong survivin expression was significantly associated with response to radiotherapy and increased overall survival. The data also indicate that single nucleotide polymorphisms in the genes XPD and FGFR4 are other possible predictors of overall survival after radiotherapy.

  • 69.
    Fohlin, Helena
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fornander, Tommy
    Karolinska University Hospital, Sweden.
    Skoog, Lambert
    Karolinska University Hospital, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Akt2 expression is associated with good long-term prognosis in oestrogen receptor positive breast cancer2013Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 49, nr 6, s. 1196-1204Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction

    Akt is a signalling modulator for many cellular processes, including metabolism, cell proliferation, cell survival and cell growth. Three isoforms of Akt have been identified, but only a few studies have concerned the isoform-specific roles in the prognosis of breast cancer patients. The aim of this study was to investigate the prognostic value of v-akt murine thymoma viral oncogene homologue 1 (Akt1) and v-akt murine thymoma viral oncogene homologue 2 (Akt2) in oestrogen receptor positive (ER+) and oestrogen receptor negative (ER–) breast cancer with long-term follow-up.

    Material and methods

    The expression of Akt in tumour tissue was analysed with immunohistochemistry in a cohort of 272 postmenopausal patients with stage II breast cancer. The median follow-up time was 19 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox’s proportional hazards model.

    Results

    The risk of distant recurrence was reduced for patients with ER+ tumours expressing Akt2 compared to patients with no Akt2 expression (HR = 0.49, 95% CI 0.29–0.82, p = 0.007). When adjusting for important clinical tumour characteristics and treatment, Akt2 was still an independent prognostic factor (HR = 0.38, 95% CI 0.21–0.68, p = 0.001) and the association remained long-term. The prognostic value of Akt2 increased with higher oestrogen receptor levels from no effect among patients with ER– tumours to 68% risk reduction for the group with high ER-levels (P for trend = 0.042). Akt1 showed no significant prognostic information.

    Conclusion

    Our results indicate that Akt2 expression is associated with a lower distant recurrence rate for patients with ER+ tumours and that this association remains long-term. The prognostic value of Akt2 increases with higher oestrogen receptor expression, motivating further mechanistic studies on the role of Akt2 in ER+ breast cancer.

  • 70. Francis, Prudence
    et al.
    Crown, John
    Di Leo, Angelo
    Buyse, Marc
    Balil, Ana
    Andersson, Michael
    Nordenskjöld, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Lang, Istvan
    Jakesz, Raimund
    Vorobiof, Daniel
    Gutiérrez, Jorge
    van Hazel, Guy
    Dolci, Stella
    Jamin, Sophie
    Bendahmane, Belguendouz
    Gelber, Richard D.
    Goldhirsch, Aron
    Castiglione-Gertsch, Monica
    Piccart-Gebhart, Martine
    Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial2008Inngår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 100, nr 2, s. 121-133Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Docetaxel is more effective than doxorubicin for patients with advanced breast cancer. The Breast International Group 02-98 randomized trial tested the effect of incorporating docetaxel into anthracycline-based adjuvant chemotherapy and compared sequential vs concurrent administration of doxorubicin and docetaxel. Methods: Patients with lymph node-positive breast cancer (n = 2887) were randomly assigned to one of four treatments: 1) sequential control (four cycles of doxorubicin at 75 mg/m2, followed by three cycles of cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]), 2) concurrent control (four cycles of doxorubicin at 60 mg/m2 plus cyclophosphamide at 600 mg/m2, followed by three cycles of CMF), 3) sequential docetaxel (three cycles of doxorubicin at 75 mg/m2, followed by three cycles of docetaxel at 100 mg/m2, followed by three cycles of CMF), 4) concurrent docetaxel (four cycles of doxorubicin at 50 mg/m2 plus docetaxel at 75 mg/m2, followed by three cycles of CMF). The primary comparison evaluated the efficacy of including docetaxel regardless of schedule and was planned after 1215 disease-free survival (DFS) events (ie, relapse, second primary cancer, or death from any cause). Docetaxel and control treatment groups were compared by log-rank tests, and hazard ratios (HR) of DFS events were calculated by Cox modeling. All statistical tests were two-sided. Results: Due to a lower-than-anticipated rate of relapse, this analysis was performed after 5 years with 732 events. Patients in control arms had a 5-year DFS of 73% (95% confidence interval [CI] = 70% to 75%). Docetaxel treatment resulted in an improvement in DFS of borderline statistical significance compared with control treatment (HR = 0.86, 95% CI = 0.74 to 1.00, P =. 05). However, DFS in the sequential docetaxel arm was better than that in the concurrent docetaxel arm (HR = 0.83, 95% CI = 0.69 to 1.00) and in the sequential control arm (HR = 0.79, 95% CI = 0.64 to 0.98). Conclusions: Incorporating docetaxel into anthracycline-based therapy resulted in an improvement in DFS that was of borderline statistical significance. However, important differences may be related to doxorubicin and docetaxel scheduling, with sequential but not concurrent administration, appearing to produce better DFS than anthracycline-based chemotherapy. © The Author(s).

  • 71.
    Frisk, Jessica
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken i Östergötland.
    Carlhäll, S.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet.
    Källström, Ann-Christin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Lindh-Åstrand, Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Malmström, Annika
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Hammar, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Long-term follow-up of acupuncture and hormone therapy on hot flushes in women with breast cancer: a prospective, randomized, controlled multicenter trial2008Inngår i: Climacteric, ISSN 1369-7137, E-ISSN 1473-0804, Vol. 11, nr 2, s. 166-174Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To evaluate the effects of electro-acupuncture (EA) and hormone therapy (HT) on vasomotor symptoms in women with a history of breast cancer.

    Methods: Forty-five women were randomized to EA (n = 27) for 12 weeks or HT (n = 18) for 24 months. The number of and distress caused by hot flushes were registered daily before, during and up to 24 months after start of treatment.

    Results: In 19 women who completed 12 weeks of EA, the median number of hot flushes/24 h decreased from 9.6 (interquartile range (IQR) 6.6-9.9) at baseline to 4.3 (IQR 1.0-7.1) at 12 weeks of treatment (p < 0.001). At 12 months after start of treatment, 14 women with only the initial 12 weeks of EA had a median number of flushes/24 h of 4.9 (IQR 1.8-7.3), and at 24 months seven women with no other treatment than EA had 2.1 (IQR 1.6-2.8) flushes/24 h. Another five women had a decreased number of flushes after having additional EA. The 18 women with HT had a baseline median number of flushes/24 h of 6.6 (IQR 4.0-8.9), and 0.0 (IQR 0.0-1.6; p = 0.001) at 12 weeks.

    Conclusion: Electro-acupuncture is a possible treatment of vasomotor symptoms for women with breast cancer and should be further studied for this group of women.

  • 72.
    Frisk, Jessica
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken i Östergötland.
    Källström, Ann-Christin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Wall, Najme
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Hammar, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Long term follow up of acupuncture and hormone therapy on hot flushes and well-being in women with breast cancer - a prospective, randomized multi centre trial in CANCER RESEARCH, vol 69, issue 2, pp 204S-204S2009Inngår i: CANCER RESEARCH, 2009, Vol. 69, nr 2, s. 204S-204SKonferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 73.
    Frisk, Jessica
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken i Östergötland.
    Källström, Ann-Christine
    Clinical Department of Surgery, Division of Oncology, Helsingborg Hospital, Helsingborg, Sweden.
    Wall, Najme
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fredrikson, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Yrkes- och miljömedicin. Linköpings universitet, Hälsouniversitetet.
    Hammar, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Obstetrik och gynekologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Barn- och kvinnocentrum, Kvinnokliniken i Linköping.
    Acupuncture improves health-related quality-of-life (HRQoL) and sleep in women with breast cancer and hot flushes2012Inngår i: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 20, nr 4, s. 715-724Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Evaluate effects of electro-acupuncture (EA) and hormone therapy (HT) on health-related quality-of-life (HRQoL) and sleep in breast cancer survivors with vasomotor symptoms.

    METHODS: Forty-five women, randomized to EA (n = 27) for 12 weeks or HT (n = 18) for 24 months, were followed for up to 2 years. Distress caused by, and numbers of, hot flushes, hours slept and times woken up/night, Psychological and General Well-being Index (PGWB) and Women's Health Questionnaire (WHQ) were registered before and during treatment and at 6, 9, 12, 18 and 24 months after start of treatment.

    RESULTS: After 12 weeks of EA (n = 19), WHQ improved from 0.32 (IQR 0.23-0.53) at baseline to 0.24 (IQR 0.12-0.39; p < 0.001) and PGWB from 78 (IQR 53-89) to 79 (IQR 68-93; p = 0.002). All sleep parameters improved and Hot Flush Score (HFS) decreased by 80%. At 12 months, WHQ, PGWB and all sleep parameters remained significantly improved (n = 14) and HFS decreased by 65%. After 12 weeks of HT (n = 18), WHQ improved from 0.29 (IQR 0.15-0.44) at baseline to 0.15 (IQR 0.05-0.22; p = 0.001), PGWB from 75 (IQR 59-88) to 90 (62-97; p = 0.102) and three of five sleep parameters improved.

    CONCLUSION: Both EA and HT increased HRQoL and sleep, probably through decreasing numbers of and distress by hot flushes. Although flushes decreased less in the EA group than in the HT group, HRQoL improved at least to the same extent maybe due to other effects of EA, not induced by HT, e.g. on anxiety, vitality and sleep, supported by subscale analyses. EA should be further evaluated as treatment for women with breast cancer and climacteric complaints, since HT no longer can be recommended for these women.

  • 74.
    Gao, Jingfang
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Molecular and Biological Characteristics of Stroma and Tumor Cells in Colorectal Cancer2008Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Carcinogenesis is a progressive process involving multiple genetic alterations in tumor cells and complex interactions in the tumor-host microenvironment. To better understand the contribution of molecular alterations in tumor cells and stromal variables to the development of colorectal cancer (CRC) and identify prognostic factors, in this study we examined the clinicopathological and biological significance of stromal variables, including particularly interesting new cysteine-histidine rich protein (PINCH), inflammatory infiltration, angiogenesis and lymphangiogenesis, as well as hRAD50/hMRE11/hNBS1 proteins and hRAD50 mutation in tumor cell in CRC.

    PINCH protein expression in the stroma was increased from normal mucosa to primary tumors and further to lymph node metastases. In particular, PINCH expression was most intense at the tumor invasive margin, which was related to low inflammatory infiltration and independently related to an unfavorable prognosis. Low inflammatory infiltration at the tumor invasive margin was related to advanced tumor stage, worse differentiation and microsatellite instability (MSI). Further, it was independently related to an unfavorable prognosis. Increased blood and lymphatic vessel density was observed in the primary tumors compared with the corresponding normal mucosa. However, neither angiogenesis nor lymphangiogenesis was associated with tumor stage and patients’ survival. Moreover, PINCH was present in a proportion of endothelial cells of the tumor vasculature, and PINCH expression in tumor-associated stroma was positively related to blood vessel density.

    In primary tumor cells of CRC, strong expression of hRAD50, hMRE11 or hNBS1 was related to microsatellite stability (MSS). A high percentage of hMRE11 expression was associated with less local recurrence and high apoptotic activity. Further, we observed that the expression of hRAD50, hMRE11 or hNBS1 among normal mucosa, primary tumors and metastases in MSS CRC differed from that in MSI CRC. In MSS CRC, the expression intensity of hRAD50, hMRE11 and hNBS1 was consistently increased with respect to normal mucosa, but there was no difference between the primary tumors and metastases. In the primary MSS tumors, the expression of individual or combination of hRAD50/hMRE11/hNBS1 was associated with a favorable prognosis in the same series of the CRCs. Moreover, strong/high hRAD50 in MSS primary tumors was related to earlier tumor stage, better differentiation and high inflammatory infiltration, whereas strong hNBS1 expression tended to be independently related to a favorable prognosis in MSS CRC with earlier tumor stage. However, in MSI CRC, there were neither differences in the expression of hRAD50/hMRE11/hNBS1 among normal mucosa, primary tumors and metastases, nor any association of the protein expressions with clinicopathological variables. On the other hand, frameshift mutations of (A)9 at coding region of hRAD50 were only found in MSI CRC.

    Our study indicates that 1) PINCH is likely a regulator of angiogenesis, and PINCH expression at the tumor invasive margin is an independent prognostic indicator in CRC. 2) Inflammatory infiltration at the tumor invasive margin is also an independent prognostic indicator in CRC. The lack of association between high inflammatory infiltration and MSI may help to explain the non-association of MSI with survival in CRC patients. 3) Angiogenesis and lymphangiogenesis occur in the early stage of CRC development, but do not associate with CRC progression and patients’ prognosis. 4) hRAD50/hMRE11/hNBS1 may act dependently and independently, playing different roles in MSS and MSI CRC development. In MSS CRC, the strong expression of the three proteins, associated with a favorable prognosis, may present the cellular response against tumor progression. Expression of hNBS1 may be a prognostic indicator for MSS CRC patients in the earlier tumor stage. In MSI CRC, the frameshift mutations at the coding region of hRAD50 may contribute to tumor development.

    Delarbeid
    1. Stromal staining for PINCH is an independent prognostic indicator in colorectal cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Stromal staining for PINCH is an independent prognostic indicator in colorectal cancer
    2004 (engelsk)Inngår i: Neoplasia, ISSN 1522-8002, Vol. 6, nr 6, s. 796-801Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Particularly interesting new cysteine-histidine-rich protein (PINCH), a LIM domain adapter protein that functions in the integrin and growth factor signal transduction pathway, is upregulated in stroma associated with many common cancers. The finding suggested that PINCH may be involved in promoting tumor-stromal interactions that support tumor progression, and, if so, tumors with abundant PINCH stromal staining may have a worse prognosis. To test this hypothesis, 174 primary colorectal adenocarcinomas with 39 distant normal mucosa samples and 26 metastases in the lymph nodes were studied by immunohistochemistry, and 7 additional colon tumors were studied by Western blot analysis and immunofluorescence. The abundance of PINCH protein in stroma increased from normal mucosa to primary tumor to metastasis (P < .05), and was more intense at the invasive margin than it was in the intratumoral stroma. Strong stromal immunostaining for PINCH was shown to predict a worse outcome (rate ratio 2.1, 95% CI 1.16-3.37, P = .01), independent of Dukes stage, growth pattern, and tumor differentiation. PINCH was detected in fibroblasts, myofibroblasts, and a proportion of endothelial cells of the tumor vasculature, supporting the involvement of PINCH in promoting tumor-stromal interactions that support tumor progression. Interestingly, stromal staining for PINCH was an independent prognostic indicator in colorectal cancer.

    Emneord
    colorectal cancer, PINCH, prognosis, protein expression
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-12867 (URN)10.1593/neo.04304 (DOI)
    Tilgjengelig fra: 2008-01-07 Laget: 2008-01-07 Sist oppdatert: 2009-08-18
    2. Relationships of tumor inflammatory infiltration and necrosis with microsatellite instability in colorectal cancers
    Åpne denne publikasjonen i ny fane eller vindu >>Relationships of tumor inflammatory infiltration and necrosis with microsatellite instability in colorectal cancers
    Vise andre…
    2005 (engelsk)Inngår i: World Journal of Gastroenterology, ISSN 1007-9327, Vol. 11, nr 14, s. 2179-2183Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Aim: The relationships between microsatellite instability (MSI) and survival in colorectal cancer patients are not consistent. The favorable survival of patient with MSI has been suggested to be related to pronounced inflammatory infiltration; however, the reason for non-association of MSI with survival is unclear. Our aims were to investigate the associations of inflammatory infiltration and tumor necrosis (TN) with microsatellite status and clinicopathological factors in colorectal cancer patients in whom MSI was not related to survival.

    Methods: Three hundred and one colorectal adenocar-cinomas were evaluated for inflammatory infiltration and 300 for TN under light microscope.

    Results: Low infiltration at invasive margin (c2 = 3.94, P = 0.047) and in whole tumor stroma (c2 = 3.89, P = 0.049) was associated with MSI, but TN was not (c2 = 0.10, P = 0.75). Low infiltration was related to advanced stage (c2 = 8.67, P = 0.03), poorer differentiation (c2 = 8.84, P = 0.03), DNA non-diploid (c2 = 10.04, P = 0.002), higher S-phase fraction (c2 = 11.30, P = 0.004), positive p53 expression (c2 = 7.94, P = 0.01), and worse survival (P = 0.03 for both univariate and multivariate analyses). Abundant TN was related to advanced stage (c2 = 17.74, P = 0.001) and worse survival (P = 0.02 for univariate, and P = 0.05 for multivariate analysis).

    Conclusion: The result that high inflammatory infiltration was not related to MSI might help explain the non-association of MSI with survival in colorectal cancer patients.

    Emneord
    Inflammatory infiltration; Necrosis; Microsatellite instability; Prognosis; Colorectal cancer
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-12868 (URN)
    Tilgjengelig fra: 2008-01-07 Laget: 2008-01-07 Sist oppdatert: 2009-05-14
    3. Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer
    Vise andre…
    2009 (engelsk)Inngår i: DIGESTIVE AND LIVER DISEASE, ISSN 1590-8658, Vol. 41, nr 2, s. 116-122Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose. The aim of this study was to get a deeper understanding into how adults with cerebral palsy (CP) experience physiotherapy and physical activity in a perspective from childhood to adulthood; and how personal and environmental factors influence possibilities for physiotherapy and physical activity. Method. Data was collected through interviews with 22 community-living adults (35-68 years) with CP, from five counties in Sweden. The questions were open-ended and the interviews were taped and transcribed to written language. The material was analysed through qualitative content analysis, a classification process resulting in different themes. Results. The narratives from the 22 informants, based on experiences from childhood to adulthood, resulted in a description of prerequisites for carrying out physiotherapy and physical activity. Five different themes were identified: (i) Being enjoyable, (ii) Giving effects, (iii) Being comprehensible, (iv) Being integrated in daily life, and (v) Supportive healthcare with competent professionals. Conclusion. The information from the interviews elucidates the importance of a lifelong support from healthcare professionals. Physiotherapists with attentiveness to different life situations in combination with good understanding and knowledge in CP could facilitate continuous physical activity in people growing up and ageing with CP.

    Emneord
    Angiogenesis, Colorectal cancer, Lymphangiogenesis
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-16973 (URN)10.1016/j.dld.2008.07.315 (DOI)
    Merknad
    Original Publication:Jingfang Gao, Annica Knutsen, G Arbman, John Carstensen, B Franlund and Xiao-Feng Sun, Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer, 2009, DIGESTIVE AND LIVER DISEASE, (41), 2, 116-122.http://dx.doi.org/10.1016/j.dld.2008.07.315Copyright: Elsevier Science B.V., Amsterdamhttp://www.elsevier.com/Tilgjengelig fra: 2009-03-24 Laget: 2009-02-27 Sist oppdatert: 2011-03-04bibliografisk kontrollert
    4. The different roles of hRAD50 in microsatellite stable and unstable colorectal cancers
    Åpne denne publikasjonen i ny fane eller vindu >>The different roles of hRAD50 in microsatellite stable and unstable colorectal cancers
    2008 (engelsk)Inngår i: Disease Markers, ISSN 0278-0240, E-ISSN 1875-8630, Vol. 24, nr 2, s. 127-134Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    RAD50 protein is essential for DNA double-strand break repair and maintaining genomic integrity. In this study, we investigated the clinicopathological significance of hRAD50 expression and mutation in microsatellite stable (MSS) and unstable (MSI) colorectal cancers (CRCs). hRAD50 expression was examined in primary CRC (n=268), the corresponding distant (n=69) and adjacent normal mucosa (n=138), and lymph node metastasis (n=44) by immunohistochemistry. hRAD50 mutation was analyzed in 87 primary CRCs by PCR-SSCP-DNA sequencing. hRAD50 expression was increased in MSS primary CRCs, but not MSI ones, compared with distant/adjacent normal mucosa (p<0.05). There was no difference in the hRAD50 expression between primary and metastatic CRCs. The increased hRAD50 expression in MSS primary CRCs was related (p<0.05) or tended to be related (p=0.05) to early tumor stage, better differentiation, high inflammatory infiltration, p53 overexpression. Frameshift mutations of (A)_{9} at coding region of hRAD50 were only found in MSI CRCs. Our results suggest that hRAD50 may play different roles in the development of MSS and MSI CRCs: increased hRAD50 expression in MSS CRCs {may be a cellular response against tumor from further progression}, while hRAD50 mutation may be involved in the development of MSI CRCs.

    Emneord
    Colorectal cancer, hRAD50, immunohistochemistry, microsatellite instability, microsatellite stability
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-12870 (URN)10.1155/2008/724796 (DOI)
    Tilgjengelig fra: 2008-01-07 Laget: 2008-01-07 Sist oppdatert: 2017-12-14
    5. RAD50/MRE11/NBS1 proteins in relation to tumour development and prognosis in patients with microsatellite stable colorectal cancer
    Åpne denne publikasjonen i ny fane eller vindu >>RAD50/MRE11/NBS1 proteins in relation to tumour development and prognosis in patients with microsatellite stable colorectal cancer
    2008 (engelsk)Inngår i: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 23, s. 1495-1502Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    RAD50/MRE11/NBS1 complex is essential for DNA double-strand break repair and for maintaining genomic integrity. In this study, we immunohisto-chemically examined MRE11, NBS1 and RAD50 expression in primary CRCs (n=208), the corresponding distant (n=41) and adjacent normal mucosa (n=130), and lymph node metastases (n=26), and investigated their clinicopathological significance in colorectal cancers (CRCs). We found that the intensity and percentage of MRE11 and NBS1 in primary CRCs were positively correlated with each other and with RAD50 (P<0.0001). Strong expression of MRE11, NBS1 or combined RAD50/MRE11/NBS1 was related to MSS, positive hMLH1 expression, earlier tumour stage (TNM stage I and II) and favourable survival (P<0.05). A high percentage of MRE11 expression was associated with less local recurrence and high apoptotic activity (P<0.05). In MSS CRCs, the expression of MRE11 and NBS1 was stronger than that in normal mucosa (P<0.05), and strong expression of NBS1 in primary tumour was related to favourable survival of patients in TNM stage I and II (univariate analysis: P=0.03; multivariate analysis: P=0.07). In MSI CRCs, neither MRE11 nor NBS1 expression showed differences among normal mucosa, primary tumour and metastasis, or among clinicopathological variables. In conclusion, RAD50/MRE11/NBS1 proteins interacted with each other, which had different clinicopathlogical significance in MSS and MSI CRCs, and further, each component of the complex might have additional roles. NBS1 might be a prognostic factor for patients with MSS tumour in TNM stage I and II.

    Emneord
    RAD50, MRE11, NBS1, Prognosis, Colorectal cancer
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-12871 (URN)
    Tilgjengelig fra: 2008-01-07 Laget: 2008-01-07 Sist oppdatert: 2017-12-14
  • 75.
    Gao, Jingfang
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Arbman, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    He, L..
    Zhang, Zhiyong
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Zhao, Z.
    Rosell, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Sun, Xiao-Feng
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    MANBA polymorphism was related to increased risk of colorectal cancer in Swedish but not in Chinese populations2008Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 47, nr 3, s. 372-378Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    β-mannosidase, encoded by MANBA, has been suggested to be implicated in cancers, while genetic variations in the MANBA in relation to colorectal cancer (CRC) risk has not been examined. In this study, we investigated the relationship of a polymorphic CA repeat in MANBA gene with CRC risk in 152 Swedish CRC patients and 441 Swedish controls, and 196 Chinese CRC patients and 577 Chinese controls, as well as the clinicopathologic significance of this polymorphism on CRC patients, by using capillary electrophoresis. The MANBA genotypes were related to CRC risk in the Swedish population (p=0.03), but not in the Chinese population. In the Swedish population, individuals with < 22 CAs/> 22 CAs had significantly increased risk for CRC compared with those with ≥22 CAs/≥ 22 CAs (gender-age-adjusted analysis: OR 1.93, 95% CI 1.06-3.51). There was no relationship between the polymorphism and clinicopathologic variables. These findings suggest the different susceptibilities of this polymorphism to CRC development in the two populations. © 2008 Taylor & Francis.

  • 76.
    Gao, Jingfang
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Arbman, Gunnar
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Rearden, Ann
    Department of Pathology, University of California-San Diego, La Jolla, CA, USA.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Stromal staining for PINCH is an independent prognostic indicator in colorectal cancer2004Inngår i: Neoplasia, ISSN 1522-8002, Vol. 6, nr 6, s. 796-801Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Particularly interesting new cysteine-histidine-rich protein (PINCH), a LIM domain adapter protein that functions in the integrin and growth factor signal transduction pathway, is upregulated in stroma associated with many common cancers. The finding suggested that PINCH may be involved in promoting tumor-stromal interactions that support tumor progression, and, if so, tumors with abundant PINCH stromal staining may have a worse prognosis. To test this hypothesis, 174 primary colorectal adenocarcinomas with 39 distant normal mucosa samples and 26 metastases in the lymph nodes were studied by immunohistochemistry, and 7 additional colon tumors were studied by Western blot analysis and immunofluorescence. The abundance of PINCH protein in stroma increased from normal mucosa to primary tumor to metastasis (P < .05), and was more intense at the invasive margin than it was in the intratumoral stroma. Strong stromal immunostaining for PINCH was shown to predict a worse outcome (rate ratio 2.1, 95% CI 1.16-3.37, P = .01), independent of Dukes stage, growth pattern, and tumor differentiation. PINCH was detected in fibroblasts, myofibroblasts, and a proportion of endothelial cells of the tumor vasculature, supporting the involvement of PINCH in promoting tumor-stromal interactions that support tumor progression. Interestingly, stromal staining for PINCH was an independent prognostic indicator in colorectal cancer.

  • 77.
    Gao, Jingfang
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Wadhra, Tabasum Imran
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Zhang, Hong
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Relationships of tumor inflammatory infiltration and necrosis with microsatellite instability in colorectal cancers2005Inngår i: World Journal of Gastroenterology, ISSN 1007-9327, Vol. 11, nr 14, s. 2179-2183Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: The relationships between microsatellite instability (MSI) and survival in colorectal cancer patients are not consistent. The favorable survival of patient with MSI has been suggested to be related to pronounced inflammatory infiltration; however, the reason for non-association of MSI with survival is unclear. Our aims were to investigate the associations of inflammatory infiltration and tumor necrosis (TN) with microsatellite status and clinicopathological factors in colorectal cancer patients in whom MSI was not related to survival.

    Methods: Three hundred and one colorectal adenocar-cinomas were evaluated for inflammatory infiltration and 300 for TN under light microscope.

    Results: Low infiltration at invasive margin (c2 = 3.94, P = 0.047) and in whole tumor stroma (c2 = 3.89, P = 0.049) was associated with MSI, but TN was not (c2 = 0.10, P = 0.75). Low infiltration was related to advanced stage (c2 = 8.67, P = 0.03), poorer differentiation (c2 = 8.84, P = 0.03), DNA non-diploid (c2 = 10.04, P = 0.002), higher S-phase fraction (c2 = 11.30, P = 0.004), positive p53 expression (c2 = 7.94, P = 0.01), and worse survival (P = 0.03 for both univariate and multivariate analyses). Abundant TN was related to advanced stage (c2 = 17.74, P = 0.001) and worse survival (P = 0.02 for univariate, and P = 0.05 for multivariate analysis).

    Conclusion: The result that high inflammatory infiltration was not related to MSI might help explain the non-association of MSI with survival in colorectal cancer patients.

  • 78.
    Gao, Jingfang
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Knutsen Holmqvist, Annica
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Filosofiska fakulteten.
    Franlund, B
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer2009Inngår i: DIGESTIVE AND LIVER DISEASE, ISSN 1590-8658, Vol. 41, nr 2, s. 116-122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose. The aim of this study was to get a deeper understanding into how adults with cerebral palsy (CP) experience physiotherapy and physical activity in a perspective from childhood to adulthood; and how personal and environmental factors influence possibilities for physiotherapy and physical activity. Method. Data was collected through interviews with 22 community-living adults (35-68 years) with CP, from five counties in Sweden. The questions were open-ended and the interviews were taped and transcribed to written language. The material was analysed through qualitative content analysis, a classification process resulting in different themes. Results. The narratives from the 22 informants, based on experiences from childhood to adulthood, resulted in a description of prerequisites for carrying out physiotherapy and physical activity. Five different themes were identified: (i) Being enjoyable, (ii) Giving effects, (iii) Being comprehensible, (iv) Being integrated in daily life, and (v) Supportive healthcare with competent professionals. Conclusion. The information from the interviews elucidates the importance of a lifelong support from healthcare professionals. Physiotherapists with attentiveness to different life situations in combination with good understanding and knowledge in CP could facilitate continuous physical activity in people growing up and ageing with CP.

  • 79.
    Gao, Jingfang
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Zhang, Hong
    Division of Biomedicine, School of Life Science, Skövde University, Skövde, Sweden.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    RAD50/MRE11/NBS1 proteins in relation to tumour development and prognosis in patients with microsatellite stable colorectal cancer2008Inngår i: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 23, s. 1495-1502Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    RAD50/MRE11/NBS1 complex is essential for DNA double-strand break repair and for maintaining genomic integrity. In this study, we immunohisto-chemically examined MRE11, NBS1 and RAD50 expression in primary CRCs (n=208), the corresponding distant (n=41) and adjacent normal mucosa (n=130), and lymph node metastases (n=26), and investigated their clinicopathological significance in colorectal cancers (CRCs). We found that the intensity and percentage of MRE11 and NBS1 in primary CRCs were positively correlated with each other and with RAD50 (P<0.0001). Strong expression of MRE11, NBS1 or combined RAD50/MRE11/NBS1 was related to MSS, positive hMLH1 expression, earlier tumour stage (TNM stage I and II) and favourable survival (P<0.05). A high percentage of MRE11 expression was associated with less local recurrence and high apoptotic activity (P<0.05). In MSS CRCs, the expression of MRE11 and NBS1 was stronger than that in normal mucosa (P<0.05), and strong expression of NBS1 in primary tumour was related to favourable survival of patients in TNM stage I and II (univariate analysis: P=0.03; multivariate analysis: P=0.07). In MSI CRCs, neither MRE11 nor NBS1 expression showed differences among normal mucosa, primary tumour and metastasis, or among clinicopathological variables. In conclusion, RAD50/MRE11/NBS1 proteins interacted with each other, which had different clinicopathlogical significance in MSS and MSI CRCs, and further, each component of the complex might have additional roles. NBS1 might be a prognostic factor for patients with MSS tumour in TNM stage I and II.

  • 80.
    Gao, Jingfang
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Zhang, Hong
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    The different roles of hRAD50 in microsatellite stable and unstable colorectal cancers2008Inngår i: Disease Markers, ISSN 0278-0240, E-ISSN 1875-8630, Vol. 24, nr 2, s. 127-134Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    RAD50 protein is essential for DNA double-strand break repair and maintaining genomic integrity. In this study, we investigated the clinicopathological significance of hRAD50 expression and mutation in microsatellite stable (MSS) and unstable (MSI) colorectal cancers (CRCs). hRAD50 expression was examined in primary CRC (n=268), the corresponding distant (n=69) and adjacent normal mucosa (n=138), and lymph node metastasis (n=44) by immunohistochemistry. hRAD50 mutation was analyzed in 87 primary CRCs by PCR-SSCP-DNA sequencing. hRAD50 expression was increased in MSS primary CRCs, but not MSI ones, compared with distant/adjacent normal mucosa (p<0.05). There was no difference in the hRAD50 expression between primary and metastatic CRCs. The increased hRAD50 expression in MSS primary CRCs was related (p<0.05) or tended to be related (p=0.05) to early tumor stage, better differentiation, high inflammatory infiltration, p53 overexpression. Frameshift mutations of (A)_{9} at coding region of hRAD50 were only found in MSI CRCs. Our results suggest that hRAD50 may play different roles in the development of MSS and MSI CRCs: increased hRAD50 expression in MSS CRCs {may be a cellular response against tumor from further progression}, while hRAD50 mutation may be involved in the development of MSI CRCs.

  • 81.
    Gao, Xueshan
    et al.
    University of Louisville.
    Li Campian, Jian
    University of Louisville.
    Qian, Mingwei
    University of Louisville.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Wallace Eaton, John
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Mitochondrial DNA Damage in Iron Overload2009Inngår i: JOURNAL OF BIOLOGICAL CHEMISTRY, ISSN 0021-9258, Vol. 284, nr 8, s. 4767-4775Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chronic iron overload has slow and insidious effects on heart, liver, and other organs. Because iron-driven oxidation of most biologic materials (such as lipids and proteins) is readily repaired, this slow progression of organ damage implies some kind of biological "memory." We hypothesized that cumulative iron-catalyzed oxidant damage to mtDNA might occur in iron overload, perhaps explaining the often lethal cardiac dysfunction. Real time PCR was used to examine the " intactness" of mttDNA in cultured H9c2 rat cardiac myocytes. After 3 -5 days exposure to high iron, these cells exhibited damage to mtDNA reflected by diminished amounts of near full-length 15.9-kb PCR product with no change in the amounts of a 16.1-kb product from a nuclear gene. With the loss of intact mtDNA, cellular respiration declined and mRNAs for three electron transport chain subunits and 16 S rRNA encoded by mtDNA decreased, whereas no decrements were found in four subunits encoded by nuclear DNA. To examine the importance of the interactions of iron with metabolically generated reactive oxygen species, we compared the toxic effects of iron in wild-type and rhoo cells. In wild-type cells, elevated iron caused increased production of reactive oxygen species, cytostasis, and cell death, whereas the rhoo cells were unaffected. We conclude that long-term damage to cells and organs in iron-overload disorders involves interactions between iron and mitochondrial reactive oxygen species resulting in cumulative damage to mtDNA, impaired synthesis of respiratory chain subunits, and respiratory dysfunction.

  • 82.
    Gao, Xueshan
    et al.
    University of Louisville.
    Li Campian, Jian
    University of Louisville.
    Qian, Mingwei
    University of Louisville.
    Willer, Sharon S
    University of Louisville.
    Sun, Xiao-Feng
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Eaton, John W
    University of Louisville.
    DNA Damage Underlies the Cytotoxic Effects of Free Iron2008Inngår i: Free Radical Biology and Medicine: Volume 45, Supplement 1: SFRBM's 15th Annual Meeting, 2008, Vol. 45, s. S144-S144Konferansepaper (Fagfellevurdert)
  • 83.
    Gao, Xueshan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Qian, Mingwei
    James Graham Brown Cancer Centre.
    Li Campian, Jian
    James Graham Brown Cancer Centre.
    Marshall, James
    University of Louisville.
    Zhou, Zhanxiang
    University of Louisville.
    Roberts, Andrew M.
    University of Louisville.
    Kang, Y. James
    University of Louisville.
    Prabhu, Sumanth D.
    University of Louisville.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Eaton, John W.
    University of Louisville.
    Mitochondrial dysfunction may explain the cardiomyopathy of chronic iron overload2010Inngår i: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 49, nr 3, s. 401-407Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In patients with hemochromatosis, cardiac dysfunction may appear years after they have reached a state of iron overload. We hypothesized that cumulative iron-catalyzed oxidant damage to mitochondrial DNA (mtDNA) might explain the cardiomyopathy of chronic iron overload. Mice were given repetitive injections of iron dextran for a total of 4 weeks after which the iron-loaded mice had elevated cardiac iron, modest cardiac hypertrophy, and cardiac dysfunction. OCR amplification of near-full-length (similar to 16 kb) mtDNA revealed greater than50% loss of full-length product, whereas amounts of a OCR product of a nuclear gene (13 kb region of beta globin) were unaffected. Quantitative rtPCR analyses revealed 60-70% loss of mRNA for proteins encoded by mtDNA with no change in mRNA abundance for nuclear-encoded respiratory subunits. These changes coincided with proportionate reductions in complex I and IV activities and decreased respiration of isolated cardiac mitochondria. We conclude that chronic iron overload leads to cumulative iron-mediated damage to mtDNA and impaired synthesis of mitochondrial respiratory chain subunits. The resulting respiratory dysfunction may explain the slow development of cardiomyopathy in chronic iron overload and similar accumulation of damage to mtDNA may also explain the mitochondrial dysfunction observed in slowly progressing diseases such as neurodegenerative disorders.

  • 84.
    Garvin, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Effects of sex steroids and tamoxifen on VEGF in the breast2006Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Sex steroid exposure constitutes a risk factor for breast cancer, but little is known about the effects of sex steroids on factors mediating angiogenesis, the development of new blood vessels, in normal and malignant breast tissue. In this thesis we have investigated the effects of estradiol, progesterone, and the nonsteroidal anti-estrogen tamoxifen on vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1 and VEGFR-2) in normal human breast tissue, endothelial cells, and breast cancer. We have applied the technique of microdialysis to provide in situ sampling of estradiol and VEGF in tumors and normal breast tissue of breast cancer patients in vivo. Furthermore, we present a novel method of culturing normal human breast tissue ex vivo.

    Our results suggest a pro-angiogenic effect of estradiol and an anti-angiogenic effect of tamoxifen in the breast. Estradiol increased extracellular levels of VEGF in normal human breast tissue and breast cancer cells in vitro. In addition, estradiol decreased sVEGFR-1 in breast cancer cells and indirectly increased VEGFR-2 in endothelial cells. Compared to estradiol treatment alone, estradiol + tamoxifen increased sVEGFR-1 and decreased VEGF in breast cancer cells in vitro. Furthermore, estradiol + tamoxifen decreased tumor VEGF levels and tumor vasculature in human breast cancer xenografts in vivo. In breast cancer patients, a significant correlation was found between in vivo levels of estradiol and VEGF sampled by microdialysis in normal human breast tissue, suggesting that estradiol may be a potent regulator of VEGF in the breast in vivo. Tumor levels of VEGF were significantly higher than in normal breast tissue in vivo, supporting the role of VEGF in tumor angiogenesis. For studies of normal human breast, whole breast tissue may be cultured in vitro for up to one week with preserved morphology. Using this method, estradiol, and not progesterone, appears to be the main sex steroid regulator of extracellular VEGF in normal breast tissue. In conclusion, the data suggest that sex steroids and tamoxifen exert pro- and anti-angiogenic effects in normal breast tissue and breast cancer.

    Delarbeid
    1. Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo
    Åpne denne publikasjonen i ny fane eller vindu >>Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo
    2003 (engelsk)Inngår i: Cancer research, ISSN 0008-5472, Vol. 63, s. 8742-8748Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Vascular endothelial growth factor (VEGF) is considered a key mediator of tumor angiogenesis, including neovascularization in human breast cancer. High tissue VEGF levels appear to correlate with poor prognosis and decreased overall survival in node-positive and node-negative breast cancer patients. Hormonal regulation of VEGF expression has been demonstrated, and some reports indicate that tamoxifen, a partial estrogen receptor agonist, increases VEGF mRNA in breast cancer cells. These results appear to contradict the efficacy of tamoxifen as an adjuvant for estrogen-dependent breast cancer, yet clinical data show that tamoxifen prevents metastasis and increases overall survival. In this study, we confirmed previous studies showing that intracellular levels of VEGF in vitro increased in response to tamoxifen to levels similar to those observed after estrogen treatment. To further study hormonal effects on the release of VEGF, we used microdialysis to sample the extracellular space, where VEGF is biologically active, in solid tumors in situ. We show for the first time that tamoxifen decreased extracellular VEGF in vivo in solid MCF-7 tumors in nude mice. These in vivo findings were confirmed in vitro where extracellular VEGF in the cell culture medium was decreased significantly by tamoxifen treatment. Furthermore, we illustrate that microdialysis is a viable method that may be applied in human breast tissue to detect soluble VEGF in situ released by the tumor.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-13938 (URN)
    Tilgjengelig fra: 2006-08-29 Laget: 2006-08-29 Sist oppdatert: 2009-02-12
    2. Effects of estradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of estradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells
    2005 (engelsk)Inngår i: British journal of cancer, ISSN 0007-0920, Vol. 93, nr 9, s. 1005-1010Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Angiogenesis is regulated by the balance between pro- and antiangiogenic factors. Vascular endothelial growth factor (VEGF), acting via the receptors VEGFR-1 and VEGFR-2, is a key mediator of tumour angiogenesis. The soluble form of the VEGF receptor-1 (sVEGFR-1) is an important negative regulator of VEGF-mediated angiogenesis. The majority of breast cancers are oestrogen dependent, but it is not fully understood how oestrogen and the antioestrogen, tamoxifen, affect the balance of angiogenic factors. Angiogenesis is a result of the interplay between cancer and endothelial cells, and sex steroids may exert effects on both cell types. In this study we show that oestradiol decreased secreted sVEGFR-1, increased secreted VEGF, and decreased the ratio of sVEGFR-1/VEGF in MCF-7 human breast cancer cells. The addition of tamoxifen opposed these effects. Moreover, human umbilical vein endothelial cells (HUVEC) incubated with supernatants from oestradiol-treated MCF-7 cells exhibited higher VEGFR-2 levels than controls. In vivo, MCF-7 tumours from oestradiol+tamoxifen-treated nude mice exhibited decreased tumour vasculature. Our results suggest that tamoxifen and oestradiol exert dual effects on the angiogenic environment in breast cancer by regulating cancer cell-secreted angiogenic ligands such as VEGF and sVEGFR-1 and by affecting VEGFR-2 expression of endothelial cells.

    Emneord
    breast cancer, flt-1, flk-1, KDR, MCF-7, nude mice
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-13939 (URN)10.1038/sj.bjc.6602824 (DOI)
    Tilgjengelig fra: 2006-08-29 Laget: 2006-08-29
    3. In vivo measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients
    Åpne denne publikasjonen i ny fane eller vindu >>In vivo measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients
    2008 (engelsk)Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 73, nr 8Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Angiogenesis, crucial for tumor progression, is a process regulated in the tissue micro-environment. Vascular endothelial growth factor (VEGF) is a potent stimulatory factor of angiogenesis and a negative prognostic indicator of breast cancer. VEGF is biologically active in the extracellular space and hitherto, there has been a lack of techniques enabling sampling of angiogenic molecules such as VEGF in situ. The majority of breast cancers are estrogen-dependent, and estrogen has been shown to regulate VEGF in normal breast tissue and experimental breast cancer. We investigated if microdialysis may be applicable in human breast cancer for sampling of extracellular VEGF in situ and to explore if there is an association with local estradiol and VEGF levels in normal and cancerous breast tissue.

    Methods: Microdialysis was used to sample VEGF and estradiol in tumors and adjacent normal breast tissue in postmenopausal breast cancer patients. VEGF and estradiol were also measured in plasma, and immunohistochemical staining for VEGF was performed on tumor sections.

    Results: We show that in vivo levels of extracellular VEGF were significantly higher in breast cancer tumors than in normal adjacent breast tissue. There was a significant positive correlation between estradiol and extracellular VEGF in normal breast tissue. However, no correlation was detected between estradiol and VEGF in tumors or between tumor VEGF and plasma VEGF.

    Conclusion: We conclude that VEGF and estradiol correlates significantly in normal breast tissue. Microdialysis may be used to provide novel insight in breast tumor biology and the regulation of molecules in the extracellular space of human breast tumors in vivo.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-13940 (URN)10.1186/1471-2407-8-73 (DOI)
    Tilgjengelig fra: 2006-08-29 Laget: 2006-08-29 Sist oppdatert: 2017-12-13
    4. Estradiol increases VEGF in normal human breast studied by whole-tissue culture
    Åpne denne publikasjonen i ny fane eller vindu >>Estradiol increases VEGF in normal human breast studied by whole-tissue culture
    Vise andre…
    2006 (engelsk)Inngår i: Cell Tissue Research, ISSN 0302-766X, Vol. 325, nr 2, s. 245-251Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Sex steroid exposure constitutes a risk factor for breast cancer, but little is known about the effects of sex steroids on the normal breast, largely because of the lack of convenient models. We have developed a method of culturing normal breast tissue ex vivo. We have applied this method to investigate the effects of estradiol and progesterone on the key angiogenic mediator, vascular endothelial growth factor (VEGF), in the breast. Whole breast tissue was obtained from routine reduction mammoplasty. Tissue biopsies were cultured in vitro for 1–3 weeks, and the expression of luminal cytokeratin 18 was determined by immunohistochemistry. As an application, tissue biopsies were treated in vitro for 1 week with or without estradiol or estradiol and progesterone. Estrogen receptor, progesterone receptor, and Ki–67 were analyzed, and VEGF levels were examined by quantitative immunoassay and immunohistochemistry. Whole breast tissue was cultured ex vivo for 1 week with preserved morphology. Increased detachment of the luminal epithelium was observed after 2 weeks. Estradiol increased extracellular levels of VEGF in normal breast tissue biopsy medium. The addition of progesterone had neither stimulatory nor inhibitory effects on secreted VEGF. The method of whole breast tissue culturing thus provide a means by which to explore the biology of normal breast tissue. Our results suggest that estradiol exerts pro-angiogenic effects in normal breast by increasing levels of biologically active VEGF.

    Emneord
    Angiogenesis, Vascular endothelial growth factor, Cytokeratin 18, Extracellular expression, Luminal expression, Estradiol, Progesterone, Human
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-13941 (URN)10.1007/s00441-006-0159-7 (DOI)
    Tilgjengelig fra: 2006-08-29 Laget: 2006-08-29
  • 85.
    Garvin, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    In vivo measurement of tumor estradiol and Vascular Endothelial Growth Factor in breast cancer patients2008Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 73, nr 8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Angiogenesis, crucial for tumor progression, is a process regulated in the tissue micro-environment. Vascular endothelial growth factor (VEGF) is a potent stimulatory factor of angiogenesis and a negative prognostic indicator of breast cancer. VEGF is biologically active in the extracellular space and hitherto, there has been a lack of techniques enabling sampling of angiogenic molecules such as VEGF in situ. The majority of breast cancers are estrogen-dependent, and estrogen has been shown to regulate VEGF in normal breast tissue and experimental breast cancer. We investigated if microdialysis may be applicable in human breast cancer for sampling of extracellular VEGF in situ and to explore if there is an association with local estradiol and VEGF levels in normal and cancerous breast tissue.

    Methods: Microdialysis was used to sample VEGF and estradiol in tumors and adjacent normal breast tissue in postmenopausal breast cancer patients. VEGF and estradiol were also measured in plasma, and immunohistochemical staining for VEGF was performed on tumor sections.

    Results: We show that in vivo levels of extracellular VEGF were significantly higher in breast cancer tumors than in normal adjacent breast tissue. There was a significant positive correlation between estradiol and extracellular VEGF in normal breast tissue. However, no correlation was detected between estradiol and VEGF in tumors or between tumor VEGF and plasma VEGF.

    Conclusion: We conclude that VEGF and estradiol correlates significantly in normal breast tissue. Microdialysis may be used to provide novel insight in breast tumor biology and the regulation of molecules in the extracellular space of human breast tumors in vivo.

  • 86.
    Garvin, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Tamoxifen inhibits secretion of vascular endothelial growth factor in breast cancer in vivo2003Inngår i: Cancer research, ISSN 0008-5472, Vol. 63, s. 8742-8748Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) is considered a key mediator of tumor angiogenesis, including neovascularization in human breast cancer. High tissue VEGF levels appear to correlate with poor prognosis and decreased overall survival in node-positive and node-negative breast cancer patients. Hormonal regulation of VEGF expression has been demonstrated, and some reports indicate that tamoxifen, a partial estrogen receptor agonist, increases VEGF mRNA in breast cancer cells. These results appear to contradict the efficacy of tamoxifen as an adjuvant for estrogen-dependent breast cancer, yet clinical data show that tamoxifen prevents metastasis and increases overall survival. In this study, we confirmed previous studies showing that intracellular levels of VEGF in vitro increased in response to tamoxifen to levels similar to those observed after estrogen treatment. To further study hormonal effects on the release of VEGF, we used microdialysis to sample the extracellular space, where VEGF is biologically active, in solid tumors in situ. We show for the first time that tamoxifen decreased extracellular VEGF in vivo in solid MCF-7 tumors in nude mice. These in vivo findings were confirmed in vitro where extracellular VEGF in the cell culture medium was decreased significantly by tamoxifen treatment. Furthermore, we illustrate that microdialysis is a viable method that may be applied in human breast tissue to detect soluble VEGF in situ released by the tumor.

  • 87.
    Garvin, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Ulrika W.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Effects of estradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells2005Inngår i: British journal of cancer, ISSN 0007-0920, Vol. 93, nr 9, s. 1005-1010Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Angiogenesis is regulated by the balance between pro- and antiangiogenic factors. Vascular endothelial growth factor (VEGF), acting via the receptors VEGFR-1 and VEGFR-2, is a key mediator of tumour angiogenesis. The soluble form of the VEGF receptor-1 (sVEGFR-1) is an important negative regulator of VEGF-mediated angiogenesis. The majority of breast cancers are oestrogen dependent, but it is not fully understood how oestrogen and the antioestrogen, tamoxifen, affect the balance of angiogenic factors. Angiogenesis is a result of the interplay between cancer and endothelial cells, and sex steroids may exert effects on both cell types. In this study we show that oestradiol decreased secreted sVEGFR-1, increased secreted VEGF, and decreased the ratio of sVEGFR-1/VEGF in MCF-7 human breast cancer cells. The addition of tamoxifen opposed these effects. Moreover, human umbilical vein endothelial cells (HUVEC) incubated with supernatants from oestradiol-treated MCF-7 cells exhibited higher VEGFR-2 levels than controls. In vivo, MCF-7 tumours from oestradiol+tamoxifen-treated nude mice exhibited decreased tumour vasculature. Our results suggest that tamoxifen and oestradiol exert dual effects on the angiogenic environment in breast cancer by regulating cancer cell-secreted angiogenic ligands such as VEGF and sVEGFR-1 and by affecting VEGFR-2 expression of endothelial cells.

  • 88.
    Garvin, Stina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nilsson, Ulrika W.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Huss, Fredrik R. M.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Brännskadevård. Linköpings universitet, Hälsouniversitetet.
    Kratz, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Hand och plastikkirurgi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Estradiol increases VEGF in normal human breast studied by whole-tissue culture2006Inngår i: Cell Tissue Research, ISSN 0302-766X, Vol. 325, nr 2, s. 245-251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sex steroid exposure constitutes a risk factor for breast cancer, but little is known about the effects of sex steroids on the normal breast, largely because of the lack of convenient models. We have developed a method of culturing normal breast tissue ex vivo. We have applied this method to investigate the effects of estradiol and progesterone on the key angiogenic mediator, vascular endothelial growth factor (VEGF), in the breast. Whole breast tissue was obtained from routine reduction mammoplasty. Tissue biopsies were cultured in vitro for 1–3 weeks, and the expression of luminal cytokeratin 18 was determined by immunohistochemistry. As an application, tissue biopsies were treated in vitro for 1 week with or without estradiol or estradiol and progesterone. Estrogen receptor, progesterone receptor, and Ki–67 were analyzed, and VEGF levels were examined by quantitative immunoassay and immunohistochemistry. Whole breast tissue was cultured ex vivo for 1 week with preserved morphology. Increased detachment of the luminal epithelium was observed after 2 weeks. Estradiol increased extracellular levels of VEGF in normal breast tissue biopsy medium. The addition of progesterone had neither stimulatory nor inhibitory effects on secreted VEGF. The method of whole breast tissue culturing thus provide a means by which to explore the biology of normal breast tissue. Our results suggest that estradiol exerts pro-angiogenic effects in normal breast by increasing levels of biologically active VEGF.

  • 89.
    Ghafouri, Bijar
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Yrkes- och miljömedicin. Linköpings universitet, Hälsouniversitetet.
    Karlsson, Helen
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Lewander, Andreas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Tagesson, Christer
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Yrkes- och miljömedicin. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Peptide mass fingerprint data from silver stained proteins can be improved by using 2,5-dihydroxybenzoic acid instead of α-cyano-4-hydroxycinnamic acid as matrix in MALDI-TOF MS2007Artikkel i tidsskrift (Fagfellevurdert)
  • 90.
    Gimsing, Peter
    et al.
    Rigshosp, Copenhagen.
    Carlson, Kristina
    Uppsala University.
    Turesson, Ingemar
    Lund University.
    Fayers, Peter
    University Aberdeen.
    Waage, Anders
    St Olavs University Hospital.
    Vangsted, Annette
    Herlev University Hospital.
    Mylin, Anne
    Rigshosp, Copenhagen.
    Gluud, Christian
    Rigshosp, Copenhagen.
    Juliusson, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Gregersen, Henrik
    University Hospital Aalborg.
    Hjorth-Hansen, Henrik
    St Olavs University Hospital.
    Nesthus, Ingerid
    Haukeland Hospital.
    Marie S Dahl, Inger
    University Tromso Hospital.
    Westin, Jan
    Sahlgrens University Hospital.
    Lanng Nielsen, Johan
    Arhus University Hospital.
    Meldgaard Knudsen, Lene
    Herlev University Hospital.
    Ahlberg, Lucia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Hjorth, Martin
    Lidkoping Hospital.
    Abildgaard, Niels
    Odense University Hospital.
    Frost Andersen, Niels
    Arhus University Hospital.
    Linder, Olle
    Orebro University Hospital.
    Wisloeff, Finn
    Ullevaal University Hospital.
    Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial2010Inngår i: LANCET ONCOLOGY, ISSN 1470-2045, Vol. 11, nr 10, s. 973-982Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma. Methods This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials. gov, number NCT00376883. Findings From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62.9-70.0) in the 90 mg group and 68 points (64.6-71.4) in the 30 mg group (95% CI of difference -6.6 to 3.3; p=0.52). Median time to first skeletal-related event in patients who had such an event was 9.2 months (8.1-10.7) in the 90 mg group and 10-2 months (7.3-14.0) in the 30 mg group (p=0.63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group. Interpretation Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma.

  • 91.
    Glimelius, B.
    et al.
    Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Sorbye, H.
    Sørbye, H., Department of Oncology, Haukeland University Hospital, Bergen, Norway.
    Balteskard, L.
    Department of Oncology, University Hospital, Tromsö, Norway.
    Bystrom, P.
    Byström, P., Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Pfeiffer, P.
    Department of Oncology, University Hospital, Odense, Denmark.
    Tveit, K.
    Department of Oncology, Ullevål University Hospital, Oslo, Norway.
    Heikkila, R.
    Heikkilä, R., Department of Hemato-Oncology, Stavanger University Hospital, Stavanger, Norway.
    Keldsen, N.
    Department of Oncology, Central Hospital, Herning, Denmark.
    Albertsson, M.
    Department of Oncology, University Hospital, Malmö, Sweden.
    Starkhammar, Hans
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Garmo, H.
    Regional Oncologic Center, Uppsala, Sweden.
    Berglund, A.
    Berglund, Å., Department of Oncology, Radiology and Clinical Immunology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
    A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer2008Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 19, nr 5, s. 909-914Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: To compare irinotecan with the Nordic 5-fluorouracil (5-FU) and folinic acid (FA) bolus schedule [irinotecan 180 mg/m2 on day 1, 5-FU 500 mg/m2 and FA 60 mg/m2 on day 1 and 2 (FLIRI)] or the Lv5FU2 schedule [irinotecan 180 mg/m2 on day 1, FA 200 mg/m2, 5-FU bolus 400 mg/m2 and infused 5-FU 600 mg/m2 on day 1 and 2 (Lv5FU2-IRI)] due to uncertainties about how to administrate 5-FU with irinotecan. Patients and methods: Patients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS). Results: Patient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%. Conclusions: Irinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

  • 92.
    Gnosa, Sebastian
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Shen, Yang Mei
    Sichuan University, China.
    Wang, Chao-Jie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Zhang, Hong
    Skövde University, Sweden.
    Stratmann, Johannes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken ViN.
    Expression of AEG-1 mRNA and protein in colorectal cancer patients and colon cancer cell lines2012Inngår i: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 10, nr 109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Astrocyte elevated gene 1 (AEG-1), an important oncogene, has been shown to be overexpressed in several types of cancers. In colorectal cancer (CRC), the protein level of AEG-1 is up-regulated in tumour tissue compared to normal mucosa, showing prognostic significance. Since little is known about the transcriptional level of AEG-1 expression and its biological pathway in CRC the aim of the present study was to examine the relationship of AEG-1 mRNA expression, the protein level and clinicopathological variables as well as its biology pathway in CRC. less thanbrgreater than less thanbrgreater thanMaterial and methods: The mRNA expression of AEG-1 was analysed by qPCR in fresh frozen patient samples including 156 primary tumours, along with the corresponding normal mucosa, and in five colon cancer cell lines, SW480, SW620, KM12C, KM12SM and KM12L4a. AEG-1 protein expression was investigated by immunohistochemistry in paraffin-embedded materials from 74 distant normal mucosa, 107 adjacent mucosa, 158 primary tumour, 35 lymph node metastasis and 9 liver metastasis samples. In addition, the AEG-1 protein expression was elucidated in the cell lines by Western blot. less thanbrgreater than less thanbrgreater thanResults: The lymph node metastatic cell line SW620 had a significantly higher AEG-1 mRNA (0.27 +/- 0.02) expression compared to the primary tumour cell line SW480 (0.17 +/- 0.04, p = 0.026). AEG-1 expression at the mRNA level and/or the protein level was significantly up-regulated gradually from normal mucosa to primary CRC, and then to lymph node metastasis and finally to liver metastasis (p andlt; 0.05). There were significant associations of AEG-1 mRNA expression with tumour location (p = 0.047), as well as mRNA and protein expression with the tumour stage (p andlt; 0.03). Furthermore AEG-1 protein expression was positively related to biological variables including NF-kappa B, p73, Rad50 and apoptosis (p andlt; 0.05). less thanbrgreater than less thanbrgreater thanConclusion: AEG-1 is up-regulated, at the mRNA and the protein level, during CRC development and aggressiveness, and is related to tumour location and stage. It may play its role in CRC through the NF-kappa B signaling pathway.

  • 93. Goldhahn, Jörg
    et al.
    Scheele, Wim H.
    Mitlak, Bruce H.
    Abadie, Eric
    Aspenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Augat, Peter
    Brandi, Maria-Luisa
    Burlet, Nansa
    Chines, Arkadi
    Delmas, Pierre D.
    Dupin-Roger, Isabelle
    Ethgen, Dominique
    Hanson, Beate
    Hartl, Florian
    Kanis, John A.
    Kewalramani, Reshma
    Laslop, Andrea
    Marsh, David
    Ormarsdottir, Sif
    Rizzoli, René
    Santora, Art
    Schmidmaier, Gerhard
    Wagener, Michael
    Reginster, Jean-Yves
    Clinical evaluation of medicinal products for acceleration of fracture healing in patients with osteoporosis2008Inngår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 43, nr 2, s. 343-347Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pre-clinical studies indicate that pharmacologic agents can augment fracture union. If these pharmacologic approaches could be translated into clinical benefit and offered to patients with osteoporosis or patients with other risks for impaired fracture union (e.g. in subjects with large defects or open fractures with high complication rate), they could provide an important adjunct to the treatment of fractures. However, widely accepted guidelines are important to encourage the conduct of studies to evaluate bioactive substances, drugs, and new agents that may promote fracture union and subsequent return to normal function. A consensus process was initiated to provide recommendations for the clinical evaluation of potential therapies to augment fracture repair in patients with meta- and diaphyseal fractures. Based on the characteristics of fracture healing and fixation, the following study objectives of a clinical study may be appropriate: a) acceleration of fracture union, b) acceleration of return to normal function and c) reduction of fracture healing complications. The intended goal(s) should determine subsequent study methodology. While an acceleration of return to normal function or a reduction of fracture healing complications in and of themselves may be sufficient primary study endpoints for a phase 3 pivotal study, acceleration of fracture union alone is not. Radiographic evaluation may either occur at multiple time points during the healing process with the aim of measuring the time taken to reach a defined status (e.g. cortical bridging of three cortices or disappearance of fracture lines), or could be obtained at a single pre-determined timepoint, were patients are expected to reach a common clinical milestone (i.e. pain free full weight-bearing in weight-bearing fracture cases). Validated Patient Reported Outcomes (PRO's) measures will need to support the return to normal function co-primary endpoints. If reduction of complication rate (e.g. non-union) is the primary objective, the anticipated complications must be defined in the study protocol, along with their possible associations with the specified fracture type and fixation device. The study design should be randomized, parallel, double-blind, and placebo-controlled, and all fracture subjects should receive a standardized method of fracture fixation, defined as Standard of Care. © 2008 Elsevier Inc. All rights reserved.

  • 94. Gorin, Norbert-Claude
    et al.
    Labopin, Myriam
    Boiron, Jean-Michel
    Theorin, Niklas
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Littlewood, Tim
    Slavin, Shimon
    Greinix, Hildegard
    Cahn, Jean Yves
    Alessandrino, E. Paolo
    Rambaldi, Alessandro
    Nagler, Arnon
    Polge, Emmanuelle
    Rocha, Vanderson
    Results of genoidentical hemopoietic stem cell transplantation with reduced intensity conditioning for acute myelocytic leukemia: Higher doses of stem cells infused benefit patients receiving transplants in second remission or beyond - The acute leukemia 2006Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 24, nr 24, s. 3959-3966Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose Nucleated cell dose is an important and modifiable factor in hematopoietic stem cell transplantation (HSCT), however its association with outcomes in the context of reduced intensity conditioning regimen (RIC) HSCT for adults with acute myelocytic leukemia (AML) is not known. Patients and Methods From 1998 to 2003, 253 patients with de novo AML, received transplants with RIC and peripheral blood from a genoidentical donor. Median age was 55 years (range, 18 to 72) and the median follow-up was 17 months (range, 2 to 67). One hundred forty one patients received transplants in first remission (CRI), 47 received transplants in second remission (CR2), and 65 patients received transplants in a more advanced phase. Fludarabin-based RIC was used in, 91%, of patients and low-dose (<4 Gy) total-body radiation in 23% of patients. The median nucleated and CD34 cell dose infused were 9.1 x 10(8)/kg and 5.8 x 10(6)/kg, respectively. Results,. Overall, 2-year leukemia-free survival (LFS) was 41% +/- 4% and it was 46% +/- 5% for patients receiving a higher cell dose (>9.1 x 10(8)/kg) and 37% +/- 5% for the remainders (P = .03). Higher cell doses exclusively benefited patients who received transplantations in CR2 or beyond, with LFS of 47 +/- 8 versus 20 +/- 8, with no detectable effect for patients who received transplants in CR1. In a multivariate analysis of the overall patient population, higher nucleated cell dose cells were associated with higher LFS (P = .04), higher incidence of chronic graft-versus-host disease (P = .01), and there was a trend towards a lower relapse incidence (P = .06). Interestingly, CD34+ cell dose was not associated with any outcomes. Conclusion Nucleated cell dose is an important factor that can be modified to improve results of RIC for patients with AML transplanted later than om CR1.

  • 95.
    Green, Henrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Söderkvist, Peter
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Rosenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Horvath, G.
    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    In response [2]2006Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 12, nr 13, s. 4127-4129Annet (Annet vitenskapelig)
    Abstract [en]

    [No abstract available]

  • 96.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Horvath, György
    Department of Oncology, Sahlgrenska Academy at Göteborg University, Gothenburg, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    β-tubulin mutations in ovarian cancer using single strand conformation analysis – risk of false positive results from paraffin embedded tissues2006Inngår i: Cancer Letters, ISSN 0304-3835, Vol. 236, nr 1, s. 148-154Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in the β-tubulin gene have been proposed as a resistance mechanism to paclitaxel. We therefore investigated the presence of mutations in the β-tubulin M40 gene in 40 ovarian tumours (16 paraffin-embedded and 24 freshly frozen) selected for good or poor response to chemotherapy with paclitaxel or non-tubulin-affecting regimens. The presence of mutations was investigated using single strand conformation analysis followed by sequencing of the products with altered mobility. No sequence variants in the exons of the β-tubulin M40 gene were detected. Non-reproducible shifts were identified, in eight out of 16 paraffin embedded samples. This may explain some of the previously published discrepancies. In conclusion, sequence variants in the β-tubulin M40 gene are rare and are unlikely to be a clinically relevant explanation of resistance to paclitaxel.

  • 97.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bachmeier, K
    Central Hospital, Karlstad.
    Bäcklund, L M
    Karolinska University Hospital, Stockholm.
    Carlsson, L
    District Hospital, Sundsvall.
    Hansen, J
    Central Hospital, Karlstad.
    Lagerlund, M
    District Hospital, Kalmar.
    Norberg, B
    District Hospital, Jönköping.
    Franzén, A
    MSD Sweden, Stockholm.
    Åleskog, A
    MSD Sweden, Stockholm.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, LAH Linköping.
    Pegylated liposomal doxorubicin as first-line monotherapy in elderly women with locally advanced or metastatic breast cancer: Novel treatment predictive factors identified2011Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 313, nr 2, s. 145-153Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We investigated the efficacy and safety of single-agent pegylated liposomal doxorubicin (PLD) as first-line treatment for elderly women with advanced breast cancer and evaluated predictive markers for response and toxicity. Twenty-five women ⩾65years received 40mg/m(2) PLD every 28days. Time to treatment failure (TTF), response rate, time to progression (TTP) and overall survival (OS) was calculated. The ABCB1 single nucleotide polymorphisms (SNP), tumor MRN complex, and TOPOIIα were analyzed. A mean of 7.4 cycles PLD were administered and TTF was 5.5months and OS 20.6months. ABCB1 SNPs were found to correlate to both efficacy and toxicity, while tumor expression of the MRN complex and TOPOIIα correlated to TTP. PLD is a safe and effective treatment for elderly breast cancer patients. Also potential predictive markers were identified.

  • 98.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Horvath, Grörgy
    Department of Oncology Sahlgrenska Academy at Göteborg University, Gothenburg.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    ABCB1 G1199A polymorphism and ovarian cancer response to paclitaxel2008Inngår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, nr 6, s. 2045-2048Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    P-glycoprotein (P-gp), encoded by the ABCB1 gene, confers multi-drug resistance to a variety of antineoplastic agents, for example, paclitaxel. Recently, the G1199T/A polymorphism in the ABCB1 gene was shown to be important for the function of P-gp as well as for the resistance to several chemotherapeutic agents in vitro. We analyzed the allelic distribution of the G1199T/A and other polymorphisms in exons 11 and 12 of the ABCB1 gene in ovarian cancer patients treated with paclitaxel and carboplatin in order to evaluate their predictive value in vivo. The SNPs C1236T, G1199T/A, and A1308G were determined using Pyrosequencing in 51 patients with advanced ovarian cancer and correlated to the progression free survival. The G1199T/A SNP was found to affect the progression free survival. Although only two heterozygous (G/A) patients were found their mean progression free survival was only 2 months as compared to 19 months for the wild-type patients. This is in accordance with the higher resistance for the 1199A genetic variant found in vitro. Genotyping of the ABCB1 gene may be important for determining the tumor resistance to paclitaxel and provide useful information for individualized therapy.  

  • 99.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Horvath, György
    Department of Oncology, Sahlgrenska Academy at Göteborg University, Gothenburg, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    mdr-1 single nucleotide polymorphisms in ovarian cancer tissue – G2677T/A correlates with response to paclitaxel chemotherapy2006Inngår i: Clinical Cancer Research, ISSN 1078-0432, Vol. 12, nr 3 pt 1, s. 854-859Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: P-glycoprotein, encoded by the mdr-1 gene, confers multidrug resistance to a variety of antineoplastic agents, e.g., paclitaxel. Recently, different polymorphisms in the mdr-1 gene have been identified and their consequences for the function of P-glycoprotein, as well as for the treatment response to P-glycoprotein substrates, are being clarified. We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435T in ovarian cancer patients with good or poor response to treatment with paclitaxel in combination with carboplatin in order to evaluate their predictive values.

    Experimental Design: Fifty-three patients were included in the study; 28 of them had been relapse-free for at least 1 year and 25 had progressive disease or relapsed within 12 months. A reference material consisting of 200 individuals was also analyzed. The genotypes of each single nucleotide polymorphism (SNP) were determined using Pyrosequencing.

    Results: The G2677T/A SNP was found to significantly correlate with treatment outcome. The probability of responding to paclitaxel treatment was higher in homozygously mutated patients (T/T or T/A; Fisher's exact test; P < 0.05). The frequency of the T or A alleles was also higher in the group of patients who had a good response (P < 0.05). There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment (Χ2 test for linear-by-linear association; P = 0.03). However, the C3435T SNP was not found to correlate to treatment outcome.

    Conclusions: The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in ovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy.

  • 100.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Mirghani, Rajaa A
    Karolinska University .
    Rymark, Per
    Västerås Hospital.
    Åvall Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Karolinska University Hospital.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Tekniska högskolan. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer2009Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 104, nr 2, s. 130-137Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The purpose of this study was to evaluate the role of sequence variants in the CYP2C8, ABCB1 and CYP3A4 genes and the CYP3A4 phenotype for the pharmacokinetics and toxicity of paclitaxel in ovarian cancer patients. Thirty-eight patients were treated with paclitaxel and carboplatin. The genotypes of CYP2C8*1B, *1C, *2, *3, *4, *5, *6, *7, *8 and P404A, ABCB1 G2677T/A and C3435T, as well as CYP3A4*1B, were determined by pyrosequencing. Phenotyping of CYP3A4 was performed in vivo with quinine as a probe. The patients were monitored for toxicity and 23 patients underwent a more extensive neurotoxicity evaluation. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants. A lower clearance of paclitaxel was found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. In addition, the CYP3A4 enzyme activity in vivo affected which metabolic pathway was dominant in each patient, but not the total clearance of paclitaxel. The exposure to paclitaxel correlated to the degree of neurotoxicity. Our findings suggest that interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.

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