• Aneuploidy related transcriptional changes in endometrial cancer link low expression of chromosome 15q genes to poor survival 

      Mauland, Karen Klepsland; Wik, Elisabeth; Høivik, Erling Andre; Kusonmano, Kanthida; Halle, Mari Kyllesø; Berg, Anna; Haugland, Hans Kristian; Øyan, Anne Margrete; Kalland, Karl-Henning; Stefansson, Ingunn Marie; Akslen, Lars A.; Krakstad, Camilla; Trovik, Jone; Werner, Henrica Maria Johanna; Salvesen, Helga Birgitte (Peer reviewed; Journal article, 2017)
      Aneuploidy is a widely studied prognostic marker in endometrial cancer (EC), however, not implemented in clinical decision-making. It lacks validation in large prospective patient cohorts adjusted for currently standard ...
    • ATAD2 overexpression links to enrichment of B-MYBtranslational signatures and development of aggressive endometrial carcinoma 

      Krakstad, Camilla; Tangen, Ingvild Løberg; Høivik, Erling Andre; Halle, Mari Kyllesø; Berg, Anna; Werner, Henrica Maria Johanna; Ræder, Maria B.; Kusonmano, Kanthida; Zou, June; Øyan, Anne Margrete; Stefansson, Ingunn; Trovik, Jone; Kalland, Karl-Henning; Chen, Hong-Wu; Salvesen, Helga Birgitte (Peer reviewed; Journal article, 2015)
      We have explored the potential for clinical implementation of ATAD2 as a biomarker for aggressive endometrial cancer by investigating to what extent immunohistochemical (IHC) staining for ATAD2 is feasible, reflects clinical ...
    • Candidate locus analysis of the TERT–CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk 

      Carvajal-Carmona, Luis G.; O'Mara, Tracy A.; Painter, Jodie N.; Lose, Felicity A.; Dennis, Joe; Michailidou, Kyriaki; Tyrer, Jonathan P; Ahmed, Shahana; Ferguson, Kaltin; Healey, Catherine S.; Pooley, Karen; Beesley, Jonathan; Cheng, Timothy; Jones, Angela; Howarth, Kimberley; Martin, Lynn; Gorman, Maggie; Hodgson, Shirley; Wentzensen, Nicholas; Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.; Renner, Stefan P.; Dörk, Thilo; Hillemanns, Peter; Durst, Matthias; Runnebaum, Ingo; Lambrechts, Dieter; Coenegrachts, Lieve; Schrauwen, Stefanie; Amant, Frederic; Winterhoff, Boris; Dowdy, Sean C.; Goode, Ellen L.; Teoman, Attila; Salvesen, Helga Birgitte; Trovik, Jone; Njølstad, Tormund Salvesen; Werner, Henrica Maria Johanna; Scott, Rodney J.; Ashton, Katie; Proietto, Tony; Otton, Geoffrey; Wersäll, Ofra; Mints, Miriam; Tham, Emma; Hall, Per; Czene, Kamila; Liu, Jianjun; Li, Jingmei; Hopper, John L.; Southey, Melissa C.; Ekici, Arif B.; Ruebner, Matthias; Johnson, Nichola; Peto, Julian; Burwinkel, Barbara; Marme, Frederik; Brenner, Hermann; Dieffenbach, Aida Karina; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Depreeuw, Jeroen; Moisse, Matthieu; Chang-Claude, Jenny; Rudolph, Anja; Couch, Fergus J.; Olson, Janet E.; Giles, Graham G.; Bruinsma, Fiona; Cunningham, Julie M.; Fridley, Brooke L.; Børresen-Dale, Anne-Lise; Kristensen, Vessela N.; Cox, Angela; Swerdlow, Anthony J.; Orr, Nicholas; Bolla, Manjeet K.; Wang, Qin; Weber, Rachel Palmieri; Chen, Zhihua; Shah, Mitul; Pharoah, Paul D.P.; Dunning, Alison M.; Tomlinson, Ian; Easton, Douglas F.; Spurdle, Amanda B.; Thompson, Deborah J. (Peer reviewed; Journal article, 2014-12-09)
      Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with ...
    • DNA ploidy in curettage specimens identifies high-risk patients and lymph node metastasis in endometrial cancer 

      Njølstad, Tormund Salvesen; Trovik, Jone; Hveem, Tarjei Sveinsgjerd; Kjæreng, Marna Lill; Kildal, Wanja; Pradhan, Manohar; Marcickiewicz, Janusz; Tingulstad, Solveig; Staff, Anne Cathrine; Haugland, Hans Kristian; Eraker, Runar; Oddenes, Klaus; Rokne, Jan Anders; Tjugum, Jostein; Lode, Margaret Sævik; Amant, Frédéric; Werner, Henrica Maria Johanna; Salvesen, Helga Birgitte; Danielsen, Håvard Emil (Peer reviewed; Journal article, 2015-04-21)
      Background: Preoperative risk stratification is essential in tailoring endometrial cancer treatment, and biomarkers predicting lymph node metastasis and aggressive disease are aspired in clinical practice. DNA ploidy ...
    • Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer 

      Shen, Hui; Fridley, BL; Song, HL; Lawrenson, K; Cunningham, JM; Ramus, SJ; Cicek, MS; Tyrer, J; Stram, D; Larson, MC; Kobel, M; Ziogas, A; Zheng, W; Yang, HP; Wu, AH; Wozniak, EL; Woo, YL; Winterhoff, B; Wik, Elisabeth; Whittemore, AS; Wentzensen, N; Weber, RP; Vitonis, AF; Vincent, D; Vierkant, RA; Vergote, I; Van Den Berg, D; Van Altena, AM; Tworoger, SS; Thompson, PJ; Tessier, DC; Terry, KL; Teo, SH; Templeman, C; Stram, DO; Southey, MC; Sieh, W; Siddiqui, N; Shvetsov, YB; Shu, XO; Shridhar, V; Wang-Gohrke, S; Severi, G; Schwaab, I; Salvesen, Helga Birgitte; Rzepecka, IK; Runnebaum, IB; Rossing, MA; Rodriguez-Rodriguez, L; Risch, HA; Renner, SP; Poole, EM; Pike, MC; Phelan, CM; Pelttari, LM; Pejovic, T; Paul, J; Orlow, I; Omar, SZ; Olson, SH; Odunsi, K; Nickels, S; Nevanlinna, H; Ness, RB; Narod, SA; Nakanishi, T; Moysich, KB; Monteiro, ANA; Moes-Sosnowska, J; Modugno, F; Menon, U; McLaughlin, JR; McGuire, V; Matsuo, K; Adenan, NAM; Massuger, LFAG; Lurie, G; Lundvall, L; Lubinski, J; Lissowska, J; Levine, DA; Leminen, A; Lee, AW; Le, ND; Lambrechts, S; Lambrechts, D; Kupryjanczyk, J; Krakstad, Camilla; Konecny, GE; Kjaer, SK; Kiemeney, LA; Kelemen, LE; Keeney, GL; Karlan, BY; Karevan, R; Kalli, KR; Kajiyama, H; Ji, BT; Jensen, A; Jakubowska, A; Iversen, E; Hosono, S; Hogdall, CK; Hogdall, E; Hoatlin, M; Hillemanns, P; Heitz, F; Hein, R; Harter, P; Halle, Mari Kyllesø; Hall, P; Gronwald, J; Gore, M; Goodman, MT; Giles, GG; Gentry-Maharaj, A; Garcia-Closas, M; Flanagan, JM; Fasching, PA; Ekici, AB; Edwards, R; Eccles, D; Easton, DF; Durst, M; du Bois, A; Dork, T; Doherty, JA; Despierre, E; Dansonka-Mieszkowska, A; Cybulski, C; Cramer, DW; Cook, LS; Chen, XQ; Charbonneau, B; Chang-Claude, J; Campbell, I; Butzow, R; Bunker, CH; Brueggmann, D; Brown, R; Brooks-Wilson, A; Brinton, LA; Bogdanova, N; Block, MS; Benjamin, E; Beesley, J; Beckmann, MW; Bandera, EV; Baglietto, L; Bacot, F; Armasu, SM; Antonenkova, N; Anton-Culver, H; Aben, KK; Liang, D; Wu, XF; Lu, KR; Hildebrandt, MAT; Schildkraut, JM; Sellers, TA; Huntsman, D; Berchuck, A; Chenevix-Trench, G; Gayther, SA; Pharoah, PDP; Laird, PW; Goode, EL; Pearce, CL (Peer reviewed; Journal article, 2013-03-27)
      HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with ...
    • HER2 expression patterns in paired primary and metastatic endometrial cancer lesions 

      Halle, Mari Kyllesø; Tangen, Ingvild Løberg; Berg, Hege Fredriksen; Hoivik, Erling A; Mauland, Karen Klepsland; Kusonmano, Kanthida; Berg, Anna; Hurtado, Antoni; Kalland, Karl-Henning; Øyan, Anne Margrete; Stefansson, Ingunn; Vintermyr, Olav Karsten; Werner, Henrica Maria Johanna; Haldorsen, Ingfrid S.; Trovik, Jone; Salvesen, Helga Birgitte; Krakstad, Camilla (Peer reviewed; Journal article, 2017-11-23)
      Background: Despite successful implementation of drugs targeting the human epidermal growth factor receptor 2 (HER2) receptor in breast and gastric cancers, the potential of HER2 as a therapeutic target in other cancers ...
    • High BMI is significantly associated with positive progesterone receptor status and clinico-pathological markers for non-aggressive disease in endometrial cancer 

      Mauland, Karen Klepsland; Trovik, Jone; Wik, Elisabeth; Ræder, Maria B.; Njølstad, Tormund Salvesen; Stefansson, Ingunn Marie; Øyan, Anne Margrete; Kalland, Karl-Henning; Bjørge, Tone; Akslen, Lars A.; Salvesen, Helga Birgitte (Peer reviewed; Journal article, 2011)
      Background: Endometrial cancer incidence is increasing in industrialised countries. High body mass index (BMI, kg m−2) is associated with higher risk for disease. We wanted to investigate if BMI is related to clinico-pathological ...
    • HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer 

      Teschendorff, Andrew E.; Lee, Shih-Han; Jones, Allison; Fiegl, Heidi; Kalwa, Marie; Wagner, Wolfgang; Chindera, Kantaraja; Evans, Iona; Dubeau, Louis; Orjalo, Arturo; Horlings, Hugo M.; Niederreiter, Lukas; Kaser, Arthur; Yang, Winnie; Goode, Ellen L.; Fridley, Brooke L.; Jenner, Richard G.; Berns, Els M.; Wik, Elisabeth; Salvesen, Helga Birgitte; Wisman, G. B. A.; van der Zee, Ate G.; Davidson, Ben; Trope, Claes Gøran; Lambrechts, Sandrina; Vergote, Ignace; Calvert, Hilary; Jacobs, Ian J.; Widschwendter, Martin (Peer reviewed; Journal article, 2015-10-24)
      Background: Understanding carboplatin resistance in ovarian cancer is critical for the improvement of patients’ lives. Multipotent mesenchymal stem cells or an aggravated epithelial to mesenchymal transition phenotype of ...
    • Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31 

      Permuth-Wey, Jennifer; Lawrenson, K; Shen, HC; Velkova, A; Tyrer, JP; Chen, ZH; Lin, HY; Chen, YA; Tsai, YY; Qu, XT; Ramus, SJ; Karevan, R; Lee, J; Lee, N; Larson, MC; Aben, KK; Anton-Culver, H; Antonenkova, N; Antoniou, AC; Armasu, SM; Bacot, F; Baglietto, L; Bandera, EV; Barnholtz-Sloan, J; Beckmann, MW; Birrer, MJ; Bloom, G; Bogdanova, N; Brinton, LA; Brooks-Wilson, A; Brown, R; Butzow, R; Cai, QY; Campbell, I; Chang-Claude, J; Chanock, S; Chenevix-Trench, G; Cheng, JQ; Cicek, MS; Coetzee, GA; Cook, LS; Couch, FJ; Cramer, DW; Cunningham, JM; Dansonka-Mieszkowska, A; Despierre, E; Doherty, JA; Dork, T; du Bois, A; Durst, M; Easton, DF; Eccles, D; Edwards, R; Ekici, AB; Fasching, PA; Fenstermacher, DA; Flanagan, JM; Garcia-Closas, M; Gentry-Maharaj, A; Giles, GG; Glasspool, RM; Gonzalez-Bosquet, J; Goodman, MT; Gore, M; Gorski, B; Gronwald, J; Hall, P; Halle, Mari Kyllesø; Harter, P; Heitz, F; Hillemanns, P; Hoatlin, M; Hogdall, CK; Hogdall, E; Hosono, S; Jakubowska, A; Jensen, A; Jim, H; Kalli, KR; Karlan, BY; Kaye, SB; Kelemen, LE; Kiemeney, LA; Kikkawa, F; Konecny, GE; Krakstad, Camilla; Kjaer, SK; Kupryjanczyk, J; Lambrechts, D; Lambrechts, S; Lancaster, JM; Le, ND; Leminen, A; Levine, DA; Liang, D; Lim, BK; Lin, J; Lissowska, J; Lu, KH; Lubinski, J; Lurie, G; Massuger, LFAG; Matsuo, K; McGuire, V; McLaughlin, JR; Menon, U; Modugno, F; Moysich, KB; Nakanishi, T; Narod, SA; Nedergaard, L; Ness, RB; Nevanlinna, H; Nickels, S; Noushmehr, H; Odunsi, K; Olson, SH; Orlow, I; Paul, J; Pearce, CL; Pejovic, T; Pelttari, LM; Pike, MC; Poole, EM; Raska, P; Renner, SP; Risch, HA; Rodriguez-Rodriguez, L; Rossing, MA; Rudolph, A; Runnebaum, IB; Rzepecka, IK; Salvesen, Helga Birgitte; Schwaab, I; Severi, G; Shridhar, V; Shu, XO; Shvetsov, YB; Sieh, W; Song, HL; Southey, MC; Spiewankiewicz, B; Stram, D; Sutphen, R; Teo, SH; Terry, KL; Tessier, DC; Thompson, PJ; Tworoger, SS; van Altena, AM; Vergote, I; Vierkant, RA; Vincent, D; Vitonis, AF; Wang-Gohrke, S; Weber, RP; Wentzensen, N; Whittemore, AS; Wik, Elisabeth; Wilkens, LR; Winterhoff, B; Woo, YL; Wu, AH; Xiang, YB; Yang, HP; Zheng, W; Ziogas, A; Zulkifli, F; Phelan, CM; Iversen, E; Schildkraut, JM; Berchuck, A; Fridley, BL; Goode, EL; Pharoah, PDP; Monteiro, ANA; Sellers, TA; Gayther, SA (Peer reviewed; Journal article, 2013-03-27)
      Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ ...
    • Increased microvascular proliferation is negatively correlated to tumour blood flow and is associated with unfavourable outcome in endometrial carcinomas 

      Haldorsen, Ingfrid S.; Stefansson, Ingunn; Grüner, Renate; Husby, Jenny Hild Aase; Magnussen, Inger Johanne; Werner, Henrica Maria Johanna; Salvesen, Øyvind; Bjørge, Line; Trovik, Jone; Taxt, Torfinn; Akslen, Lars A.; Salvesen, Helga Birgitte (Peer reviewed; Journal article, 2014)
      Background: We aimed to study the angiogenic profile based on histomorphological markers in endometrial carcinomas in relation to imaging parameters obtained from preoperative dynamic contrast-enhanced magnetic resonance ...
    • MDM2 Promoter SNP344T>A (rs1196333) Status Does Not Affect Cancer Risk 

      Knappskog, Stian; Gansmo, Liv B.; Romundstad, Pål; Bjørnslett, Merete; Trovik, Jone; Lønning, Per Eystein; Salvesen, Helga Birgitte (Peer reviewed; Journal article, 2012-04-30)
      The MDM2 proto-oncogene plays a key role in central cellular processes like growth control and apoptosis, and the gene locus is frequently amplified in sarcomas. Two polymorphisms located in the MDM2 promoter P2 have been ...
    • Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1 

      Cheng, Timothy H.T.; Thompson, Deborah; Painter, Jodie; Omara, Tracy; Gorman, Maggie; Martin, Lynn; Palles, Claire; Jones, Angela; Buchanan, Daniel D.; Ko Win, Aung; Hopper, John; Jenkins, Mark; Lindor, Noralane M.; Newcomb, Polly A.; Gallinger, Steve; Conti, David; Schumacher, Fred; Casey, Graham; Giles, Graham G.; Pharoah, Paul; Peto, Julian; Cox, Angela; Swerdlow, Anthony; Couch, Fergus; Cunningham, Julie M.; Goode, Ellen L.; Winham, Stacey J.; Lambrechts, Diether; Fasching, Peter; Burwinkel, Barbara; Brenner, Hermann; Brauch, Hiltrud; Chang-Claude, Jenny; Salvesen, Helga Birgitte; Kristensen, Vessela N.; Darabi, Hatef; Li, Jingmei; Liu, Tao; Lindblom, Annika; Hall, Per; De Polanco, Magdalena Echeverry; Sans, Monica; Carracedo, Angel; Castellvi-Bel, Sergi; Rojas-Martinez, Augusto; Aguiar Jnr, Samuel; Teixeira, Manuel R.; Dunning, Alison M.; Dennis, Joe; Otton, Geoffrey; Proietto, Tony; Holliday, Elizabeth; Attia, John; Ashton, Katie; Scott, Rodney J.; McEvoy, Mark; Dowdy, Sean C.; Fridley, Brooke L.; Werner, Henrica Maria Johanna; Trovik, Jone; Njølstad, Tormund Salvesen; Tham, Emma; Mints, Miriam; Runnebaum, Ingo; Hillemanns, Peter; Dörk, Thilo; Amant, Frederic; Schrauwen, Stefanie; Hein, Alexander; Beckmann, Matthias W.; Ekici, Arif; Czene, Kamila; Meindl, Alfons; Bolla, Manjeet K.; Michailidou, Kyriaki; Tyrer, Jonathan P.; Wang, Qin; Ahmed, Shahana; Healey, Catherine S.; Shah, Mitul; Annibali, Daniela; Depreeuw, Jeroen; Al-Tassan, Nada A.; Harris, Rebecca; Meyer, Brian F; Whiffin, Nicola; Hosking, Fay J.; Kinnersley, Ben; Farrington, Susan M; Timofeeva, Maria; Tenesa, Albert; Campbell, Harry; Haile, Robert W.; Hodgson, Shirley; Carvajal-Carmona, Luis; Cheadle, Jeremy P.; Easton, Douglas; Dunlop, Malcolm; Houlston, Richard; Spurdle, Amanda; Tomlinson, Ian (Peer reviewed; Journal article, 2015-12-01)
      High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using ...
    • Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer 

      Alonso-Alconada, Lorena; Muinelo-Romay, Laura; Madissoo, Kadri; Diaz-Lopez, Antonio; Krakstad, Camilla; Trovik, Jone; Wik, Elisabeth; Hapangama, Dharani; Coenegrachts, Lieve; Cano, Amparo; Gil-Moreno, Antonio; Chiva, Luis; Cueva, Juan; Vieito, Maria; Ortega, Eugenia; Mariscal, Javier; Colas, Eva; Castellvi, Josep; Cusido, Maite; Dolcet, Xavier; Nijman, Hans W.; Bosse, Tjalling; Green, John A.; Romano, Andrea; Reventos, Jaume; Lopez-Lopez, Rafael; Salvesen, Helga Birgitte; Amant, Frederic; Matias-Guiu, Xavier; Moreno-Bueno, Gema; Abal, Miguel; on behalf of ENITEC Consortium (Peer reviewed; Journal article, 2014-09-27)
      Background: About 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we ...
    • Multimodal Imaging of Orthotopic Mouse Model of Endometrial Carcinoma 

      Haldorsen, Ingfrid S.; Popa, Mihaela Lucia; Fonnes, Tina; Brekke, Njål; Kopperud, Reidun Kristin; Visser, Nicole C.; Rygh, Cecilie Brekke; Pavlin, Tina; Salvesen, Helga Birgitte; McCormack, Emmet; Krakstad, Camilla (Peer reviewed; Journal article, 2015-08-07)
      Background: Orthotopic endometrial cancer models provide a unique tool for studies of tumour growth and metastatic spread. Novel preclinical imaging methods also have the potential to quantify functional tumour characteristics ...
    • Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth 

      Holst, Frederik; Høivik, Erling Andre; Gibson, William J.; Taylor-Weiner, Amaro; Schumacher, Steven E.; Asmann, Yan W.; Grossmann, Patrick; Trovik, Jone; Necela, Brian M.; Thompson, E. Aubrey; Meyerson, Matthew; Beroukhim, Rameen; Salvesen, Helga Birgitte; Cherniack, Andrew D. (Peer reviewed; Journal article, 2016-05-10)
      The estrogen receptor alpha (ERα) is highly expressed in both endometrial and breast cancers, and represents the most prevalent therapeutic target in breast cancer. However, anti-estrogen therapy has not been shown to be ...
    • Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development 

      Jones, Allison; Teschendorff, Andrew E.; Li, Quanxi; Hayward, Jane D.; Kannan, Athilakshmi; Mould, Tim; West, James; Zikan, Michal; Cibula, David; Fiegl, Heidi; Lee, Shih-Han; Wik, Elisabeth; Hadwin, Richard; Arora, Rupali; Lemech, Charlotte; Turunen, Henna; Pakarinen, Päivi; Jacobs, Ian J.; Salvesen, Helga Birgitte; Bagchi, Milan K.; Bagchi, Indrani C.; Widschwendter, Martin (Peer reviewed; Journal article, 2013-11-12)
      Background: Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. ...
    • Stathmin Protein Level, a Potential Predictive Marker for Taxane Treatment Response in Endometrial Cancer 

      Werner, Henrica Maria Johanna; Trovik, Jone; Halle, Mari Kyllesø; Wik, Elisabeth; Akslen, Lars A.; Birkeland, Even; Bredholt, Therese; Tangen, Ingvild Løberg; Krakstad, Camilla; Salvesen, Helga Birgitte (Peer reviewed; Journal article, 2014-02-25)
      Stathmin is a prognostic marker in many cancers, including endometrial cancer. Preclinical studies, predominantly in breast cancer, have suggested that stathmin may additionally be a predictive marker for response to ...
    • Switch in FOXA1 status associates with endometrial cancer progression 

      Tangen, Ingvild Løberg; Krakstad, Camilla; Halle, Mari Kyllesø; Werner, Henrica Maria Johanna; Øyan, Anne Margrete; Kusonmano, Kanthida; Petersen, Kjell; Kalland, Karl-Henning; Akslen, Lars A.; Trovik, Jone; Rodriguez, Antoni Hurtado; Salvesen, Helga Birgitte (Peer reviewed; Journal article, 2014-05-21)
      Background: The transcription factor Forkhead box A1 (FOXA1) is suggested to be important in hormone dependent cancers, although with little data for endometrial cancer. We investigated expression levels of FOXA1 in primary ...