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  • 1.
    Abelsson, J.
    et al.
    NU Hospital Organization, Uddevalla.
    Merup, M.
    Karolinska Universitetssjukhuset, Huddinge.
    Birgegård, G.
    Uppsala University.
    WeisBjerrum, O.
    Rigshospitalet, University of Copenhagen.
    Brinch, L.
    Rikshospitalet, Oslo University Hospital.
    Brune, M.
    Sahlgrenska Universitetssjukhuset, Göteborg.
    Johansson, P.
    NU Hospital Organization, Uddevalla.
    Kauppila, M.
    Turku University Hospital, Finland.
    Lenhoff, S.
    Skåne University Hospital.
    Liljeholm, M.
    Norrlands Universitetssjukhus, Umeå.
    Malm, Claes
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology UHL.
    Remes, K.
    Turku University Hospital, Finland.
    Vindelöv, L.
    Rigshospitalet, University of Copenhagen.
    Andréasson, Björn
    NU Hospital Organization, Uddevalla.
    The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries2012In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 47, no 3, p. 380-386Article in journal (Refereed)
    Abstract [en]

    Between 1982 and 2009 a total of 92 patients with myelofibrosis (MF) in chronic phase underwent allo-SCT in nine Nordic transplant centers. Myeloablative conditioning (MAC) was given to 40 patients, and reduced intensity conditioning (RIC) was used in 52 patients. The mean age in the two groups at transplantation was 46±12 and 55±8 years, respectively (P<0.001). When adjustment for age differences was made, the survival of the patients treated with RIC was significantly better (P=0.003). Among the RIC patients, the survival was significantly (P=0.003) better for the patients with age <60 years (a 10-year survival close to 80%) than for the older patients. The type of stem cell donor did not significantly affect the survival. No significant difference was found in TRM at 100 days between the MAC- and the RIC-treated patients. The probability of survival at 5 years was 49% for the MAC-treated patients and 59% in the RIC group (P=0.125). Patients treated with RIC experienced significantly less aGVHD compared with patients treated with MAC (P<0.001). The OS at 5 years was 70, 59 and 41% for patients with Lille score 0, 1 and 2, respectively (P=0.038, when age adjustment was made). Twenty-one percent of the patients in the RIC group were given donor lymphocyte infusion because of incomplete donor chimerism, compared with none of the MAC-treated patients (P<0.002). Nine percent of the patients needed a second transplant because of graft failure, progressive disease or transformation to AML, with no significant difference between the groups. Our conclusions are (1) allo-SCT performed with RIC gives a better survival compared with MAC. (2) age over 60 years is strongly related to a worse outcome and (3) patients with higher Lille score had a shorter survival.Bone Marrow Transplantation advance online publication, 9 May 2011; doi:10.1038/bmt.2011.91.

  • 2.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Morad, Vivian
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Saarinen, Niina M
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Estradiol, Tamoxifen, and Flaxseed Alter IL-1 beta and IL-1Ra Levels in Normal Human Breast Tissue in Vivo2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 11, p. E2044-E2054Article in journal (Refereed)
    Abstract [en]

    Introduction: Sex steroid exposure increases the risk of breast cancer by unclear mechanisms. Diet modifications may be one breast cancer prevention strategy. The proinflammatory cytokine family of IL-1 is implicated in cancer progression. IL-1Ra is an endogenous inhibitor of the proinflammatory IL-1 alpha and IL-1 beta. less thanbrgreater than less thanbrgreater thanObjective: The objective of this study was to elucidate whether estrogen, tamoxifen, and/or diet modification altered IL-1 levels in normal human breast tissue. less thanbrgreater than less thanbrgreater thanDesign and Methods: Microdialysis was performed in healthy women under various hormone exposures, tamoxifen therapy, and diet modifications and in breast cancers of women before surgery. Breast tissue biopsies from reduction mammoplasties were cultured. less thanbrgreater than less thanbrgreater thanResults: We show a significant positive correlation between estradiol and in vivo levels of IL-1 beta in breast tissue and abdominal sc fat, whereas IL-1Ra exhibited a significant negative correlation with estradiol in breast tissue. Tamoxifen or a dietary addition of 25 g flaxseed per day resulted in significantly increased levels of IL-1Ra in the breast. These results were confirmed in ex vivo culture of breast biopsies. Immunohistochemistry of the biopsies did not reveal any changes in cellular content of the IL-1s, suggesting that mainly the secreted levels were affected. In breast cancer patients, intratumoral levels of IL-1 beta were significantly higher compared with normal adjacent breast tissue. less thanbrgreater than less thanbrgreater thanConclusion: IL-1 may be under the control of estrogen in vivo and may be attenuated by antiestrogen therapy and diet modifications. The increased IL-1 beta in breast cancers of women strongly suggests IL-1 as a potential therapeutic target in breast cancer treatment and prevention.

  • 3.
    Ahnström, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Fornander, Tommy
    Karolinska University Hospital.
    Skoog, Lambert
    Karolinska University Hospital.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Altered expression of cyclin E and the retinoblastoma protein influences the effect of adjuvant therapy in breast cancer2009In: International Journal of Oncology, ISSN 1019-6439, Vol. 34, no 2, p. 441-448Article in journal (Refereed)
    Abstract [en]

    Cyclin E and the retinoblastoma protein (Rb) are both important regulators of the G(1) phase in the cell cycle. Overexpression of cyclin E and lost expression of Rb has previously been observed in breast tumours at frequencies of 10-50% and 20-30%, respectively. We explored the prognostic role of cyclin E and Rb in breast cancer patients randomised for tamoxifen (TAM), CMF (cyclophosphamide, metotrexate, 5-fluorouracil) chemotherapy and radiotherapy (RT) and how their expression affects the patients response to treatment. Protein expression was assessed with immunohistochemistry. We found overexpression of cyclin E in 32.1% (71/221) of the tumours and loss of Rb expression in 25.0% (59/236). Increased expression of cyclin E correlated to dysfunctional p53 (P=0.003) while loss of Rb correlated to normal p53 status (P=0.001). Our results suggest that patients with high cyclin E tumours have less benefit from tamoxifen (ER+, TAM vs. no TAM; RR=0.97; 95% CI, 0.36-2.60) than patients whose tumours show low expression (ER+, TAM vs. no TAM; RR =0.41; 95% CI, 0.24-0.72). Cyclin E also tended to predict the benefit from radiotherapy with a local recurrence rate of 0.31 (RT vs. CMF; 95% CI, 0.12-0.93) for patients with low expression and 0.68 (RT vs. CMF; 95% CI, 0.2-2.32) for patients with high expression of cyclin E. When the p53 status was taken in consideration the results showed that patients with both normal p53 and normal Rb expression had considerably lower locoregional recurrence rate when treated with radiotherapy instead of CMF (RR=0.17; 95% CI, 0.052-0.58) as compared to patients with either altered Rb or p53 or both (RR=0.70; 95% CI, 0.28-1.73).

  • 4.
    Ahnström Waltersson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Cell cycle alterations and 11q13 amplification in breast cancer: prediction of adjuvant treatment response2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The growth and development of the breast is to a large extent regulated by oestrogens through the oestrogen receptor (ER). Activation of the ERα triggers transcription of genes that are important for cell proliferation and stimulates entry into the G1 phase of the cell cycle. In breast cancer the ERα is often upregulated and is therefore a suitable target for adjuvant therapies such as tamoxifen. Although tamoxifen is an effective treatment in most cases, tumours sometimes acquire resistance to the drug. The aim of this thesis was to investigate the impact of G1 phase proteins and 11q13 amplification on prognosis and treatment response in breast cancer. The material used was from a clinical trial in which postmenopausal breast cancer patients were randomised to chemotherapy or radiotherapy and tamoxifen or no adjuvant treatment. We studied the expression of cyclin D1, cyclin E and Rb with immunohisochemistry and amplification of CCND1 and PAK1 with real time PCR. We found that among patients with high tumour expression of cyclin D1, overexpression of ErbB2 was associated with reduced recurrence-free survival. Both cyclin D1 and cyclin E overexpression were associated with reduced tamoxifen response. High expression of cyclin D1 has been found to induce ligand independent activation of ERα in breast cancer cells and might also switch tamoxifen from acting as an antagonist to an agonist. Overexpression of cyclin E has been shown to be associated with expression of low molecular weight isoforms of the protein that possess an increased kinase activity and are insensitive to p21 and p27 inhibition. Furthermore, amplification of 11q13, and in particular the gene PAK1, was a strong predictor of tamoxifen resistance. The pak1 protein is involved in phosphorylation and ligand independent activation of the ERα. We also found that lost expression of either p53 or Rb reduced the patients benefit from radiotherapy compared with patients with normal expression of both proteins. Normally, ionizing radiation upregulates p53 resulting in G1 arrest or apoptosis. If either functional p53 or Rb is missing the cells can proceed from G1 to the S phase despite damaged DNA. The expression of the microRNA, miR-206, was analysed with real time PCR, and the results showed that high expression of miR-206 correlated to low expression of ERα and 11q13 amplification. In vitro studies have shown that miR-206 negatively regulates the expression of ERα. Taken together the G1 regulators and amplification of 11q13 seem to have an important role in predicting the patient’s response to adjuvant therapy.

    List of papers
    1. Role of cyclin D1 in ErbB2-positive breast cancer and tamoxifen resistance.
    Open this publication in new window or tab >>Role of cyclin D1 in ErbB2-positive breast cancer and tamoxifen resistance.
    Show others...
    2005 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 91, no 2, p. 145-151Article in journal (Refereed) Published
    Abstract [en]

    Cyclin D1 plays an important role in the regulation of the G1 phase in the cell cycle. In mammary epithelial cells the expression of cyclin D1 is regulated through the oestrogen receptor and via ErbB2 signalling. Here we investigated the prognostic significance of cyclin D1 among 230 breast cancer patients randomised for tamoxifen, CMF chemotherapy and radiotherapy. The importance of combined cyclin D1 and ErbB2 overexpression was also analysed. Immunohistochemical analysis of the cyclin D1 expression resulted in 69 (29.8%) weakly positive, 107 (46.5%) moderately positive and 54 (23.7%) strongly positive cases. The prognostic importance of ErbB2 was significantly greater for patients whose tumours overexpressed cyclin D1 than for other patients (p = 0.026). In the former group, ErbB2 overexpression was strongly associated with increased risk of recurrence (RR = 4.7; 95% CI, 2.1-10.4) and breast cancer death (RR = 5.4; 95% CI, 2.3-12.6). This result is in accordance with experimental studies demonstrating a link between cyclin D1 and ErbB2 in oncogenesis. Among oestrogen receptor positive patients, those with moderate cyclin D1 expression significantly did benefit from tamoxifen treatment (RR = 0.42; 95% CI, 0.21-0.82) whereas those with weak or strong expression did not. Therefore cyclin D1 might be a predictive marker for tamoxifen resistance.

    Keywords
    Beta, fonder, prediction, OLS, LAD, WLS
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17431 (URN)10.1007/s10549-004-6457-4 (DOI)15868442 (PubMedID)
    Available from: 2009-03-25 Created: 2009-03-24 Last updated: 2017-12-13Bibliographically approved
    2. Altered expression of cyclin E and the retinoblastoma protein influences the effect of adjuvant therapy in breast cancer
    Open this publication in new window or tab >>Altered expression of cyclin E and the retinoblastoma protein influences the effect of adjuvant therapy in breast cancer
    Show others...
    2009 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 34, no 2, p. 441-448Article in journal (Refereed) Published
    Abstract [en]

    Cyclin E and the retinoblastoma protein (Rb) are both important regulators of the G(1) phase in the cell cycle. Overexpression of cyclin E and lost expression of Rb has previously been observed in breast tumours at frequencies of 10-50% and 20-30%, respectively. We explored the prognostic role of cyclin E and Rb in breast cancer patients randomised for tamoxifen (TAM), CMF (cyclophosphamide, metotrexate, 5-fluorouracil) chemotherapy and radiotherapy (RT) and how their expression affects the patients response to treatment. Protein expression was assessed with immunohistochemistry. We found overexpression of cyclin E in 32.1% (71/221) of the tumours and loss of Rb expression in 25.0% (59/236). Increased expression of cyclin E correlated to dysfunctional p53 (P=0.003) while loss of Rb correlated to normal p53 status (P=0.001). Our results suggest that patients with high cyclin E tumours have less benefit from tamoxifen (ER+, TAM vs. no TAM; RR=0.97; 95% CI, 0.36-2.60) than patients whose tumours show low expression (ER+, TAM vs. no TAM; RR =0.41; 95% CI, 0.24-0.72). Cyclin E also tended to predict the benefit from radiotherapy with a local recurrence rate of 0.31 (RT vs. CMF; 95% CI, 0.12-0.93) for patients with low expression and 0.68 (RT vs. CMF; 95% CI, 0.2-2.32) for patients with high expression of cyclin E. When the p53 status was taken in consideration the results showed that patients with both normal p53 and normal Rb expression had considerably lower locoregional recurrence rate when treated with radiotherapy instead of CMF (RR=0.17; 95% CI, 0.052-0.58) as compared to patients with either altered Rb or p53 or both (RR=0.70; 95% CI, 0.28-1.73).

    Keywords
    cell cycle, radiotherapy, chemotherapy, overexpression, Rb, p53
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16619 (URN)10.3892/ijo_00000168 (DOI)
    Available from: 2009-02-07 Created: 2009-02-06 Last updated: 2017-12-14Bibliographically approved
    3. Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer.
    Open this publication in new window or tab >>Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer.
    Show others...
    2007 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 26, no 49, p. 6997-7005Article in journal (Refereed) Published
    Abstract [en]

    The 11q13 region is amplified in approximately 15% of all breast tumors. Situated in this region are the cyclin D1 gene (CCND1) and the p-21-activated kinase 1 (PAK1) gene. Both genes encode proteins shown to activate the estrogen receptor (ER), leading to transcription of CCND1 and other ER-responsive genes. Here, we investigate the prognostic and treatment predictive role of CCND1 and PAK1 gene amplification in postmenopausal breast cancer patients randomized to tamoxifen treatment or no adjuvant treatment. Amplification of CCND1 and PAK1, assessed by real-time PCR, was observed in 12.5 and 9.3%, respectively. Amplification of PAK1 was seen in 37% of the CCND1-amplified tumors, indicating coamplification (P<0.001). In ER-positive patients, amplification of at least one of the genes indicated a reduced recurrence-free survival (P=0.025). When response to tamoxifen treatment was analysed, patients with PAK1 amplification showed decreased benefit from the drug (ER+; relative risk ratio (RR)=1.62; 95% confidence interval (CI), 0.47-5.55) compared to patients without amplification (ER+; RR=0.53; 95% CI, 0.32-0.88). This was not evident for CCND1 amplification. We show that PAK1 may be a predictor of tamoxifen resistance and furthermore, we do not discard PAK1 as a potential candidate oncogene in the 11q13 amplicon. In addition, we show that high pak1 protein levels may predict tamoxifen insensitivity.

    Keywords
    Cyclin D1, pak1, drug resistance, breast cancer, real-time PCR
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17456 (URN)10.1038/sj.onc.1210506 (DOI)17486065 (PubMedID)
    Available from: 2009-03-25 Created: 2009-03-25 Last updated: 2017-12-13Bibliographically approved
    4. miR-206 expression is downregulated in cyclin D1 amplified breast tumours
    Open this publication in new window or tab >>miR-206 expression is downregulated in cyclin D1 amplified breast tumours
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Amplification in the 11q13 region has been found in around 15% of all breast cancers and is strongly correlated with oestrogen receptor (ER) positive tumours. We have previously found that amplification of at least one of the genes PAK1 or CCND1 is associated with decreased recurrencefree survival among ER+ patients. Other genes in the amplicon might also contribute to this effect and situated close to CCND1 are the FGF-3, -4 and - 19 genes. The FGF-4 protein has been shown to inhibit the expression of the ERα regulator miR-206 in chicken embryo. In this study we analysed 23 tumours with and 27 tumours without previously detected 11q13 amplification to explore if 11q13 amplification is associated with decreased levels of miR-206 and if miR-206 is associated with ER expression. Using real-time PCR, we found that miR-206 expression was inversely correlated to CCND1 and 11q13 amplification (P=0.016 and P=0.022 respectively). Tumours with low miR-206 expression had higher levels of ERα than tumours with intermediate and high expression (P=0.043). We conclude that miR-206 might be an important regulator of the ERα. Our finding that low mir-206 is associated with CCND1 amplification and thereby also FGF-4 amplification points towards the possibility of a miR-206 regulator, FGF-4 or another FGF, present in the amplicon.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-17457 (URN)
    Available from: 2009-03-25 Created: 2009-03-25 Last updated: 2010-01-14Bibliographically approved
  • 5.
    Ahnström Waltersson, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Fornander, Tommy
    Department of Cytology, Karolinska University Hospital, SE-104 01 Stockholm, Sweden.
    Skoog, Lambert
    Department of Cytology, Karolinska University Hospital, SE-104 01 Stockholm, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    miR-206 expression is downregulated in cyclin D1 amplified breast tumoursManuscript (preprint) (Other academic)
    Abstract [en]

    Amplification in the 11q13 region has been found in around 15% of all breast cancers and is strongly correlated with oestrogen receptor (ER) positive tumours. We have previously found that amplification of at least one of the genes PAK1 or CCND1 is associated with decreased recurrencefree survival among ER+ patients. Other genes in the amplicon might also contribute to this effect and situated close to CCND1 are the FGF-3, -4 and - 19 genes. The FGF-4 protein has been shown to inhibit the expression of the ERα regulator miR-206 in chicken embryo. In this study we analysed 23 tumours with and 27 tumours without previously detected 11q13 amplification to explore if 11q13 amplification is associated with decreased levels of miR-206 and if miR-206 is associated with ER expression. Using real-time PCR, we found that miR-206 expression was inversely correlated to CCND1 and 11q13 amplification (P=0.016 and P=0.022 respectively). Tumours with low miR-206 expression had higher levels of ERα than tumours with intermediate and high expression (P=0.043). We conclude that miR-206 might be an important regulator of the ERα. Our finding that low mir-206 is associated with CCND1 amplification and thereby also FGF-4 amplification points towards the possibility of a miR-206 regulator, FGF-4 or another FGF, present in the amplicon.

  • 6.
    Ahnström Waltersson, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Rutqvist, Lars Erik
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden.
    Skoog, Lambert
    Department of Cytology, Karolinska Hospital, Stockholm, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Role of cyclin D1 in ErbB2-positive breast cancer and tamoxifen resistance.2005In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 91, no 2, p. 145-151Article in journal (Refereed)
    Abstract [en]

    Cyclin D1 plays an important role in the regulation of the G1 phase in the cell cycle. In mammary epithelial cells the expression of cyclin D1 is regulated through the oestrogen receptor and via ErbB2 signalling. Here we investigated the prognostic significance of cyclin D1 among 230 breast cancer patients randomised for tamoxifen, CMF chemotherapy and radiotherapy. The importance of combined cyclin D1 and ErbB2 overexpression was also analysed. Immunohistochemical analysis of the cyclin D1 expression resulted in 69 (29.8%) weakly positive, 107 (46.5%) moderately positive and 54 (23.7%) strongly positive cases. The prognostic importance of ErbB2 was significantly greater for patients whose tumours overexpressed cyclin D1 than for other patients (p = 0.026). In the former group, ErbB2 overexpression was strongly associated with increased risk of recurrence (RR = 4.7; 95% CI, 2.1-10.4) and breast cancer death (RR = 5.4; 95% CI, 2.3-12.6). This result is in accordance with experimental studies demonstrating a link between cyclin D1 and ErbB2 in oncogenesis. Among oestrogen receptor positive patients, those with moderate cyclin D1 expression significantly did benefit from tamoxifen treatment (RR = 0.42; 95% CI, 0.21-0.82) whereas those with weak or strong expression did not. Therefore cyclin D1 might be a predictive marker for tamoxifen resistance.

  • 7.
    Alkner, S.
    et al.
    Lund University Hospital.
    Bendahl, P.-O.
    Lund University Hospital.
    Ferno, M.
    Lund University Hospital.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Ryden, L.
    Lund University Hospital.
    Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women: Results from a controlled randomised trial2009In: European Journal of Cancer, ISSN 0959-8049, Vol. 45, no 14, p. 2496-2502Article in journal (Refereed)
    Abstract [en]

    Background: Adjuvant treatment with tamoxifen reduces the risk of contralateral breast cancer in hormone-responsive postmenopausal patients, whereas the effect in premenopausal women has not been fully elucidated. We have therefore studied the effect of tamoxifen on contralateral breast cancer in premenopausal women in a controlled randomised trial. Patients and methods: Premenopausal women (564) with stage II breast cancers were randomised to 2 years of tamoxifen versus control irrespective of oestrogen receptor (ER) and progesterone receptor (PgR) status. The median follow-up for patients not developing a contralateral cancer was 14 years. Results: In the control group 35 women, and in the tamoxifen group 17 women, developed a contralateral breast cancer as a primary event. Tamoxifen significantly reduced the risk of contralateral breast cancer in all women regardless of age (hazard ratio (HR) 0.5, p = 0.02). In subgroup analysis the risk reduction was most pronounced in patients less than40 years of age (HR 0.09, p = 0.02). A risk reduction was also seen in women 40-49 years of age or ≥50 years of age, although in these subgroups this did not reach statistical significance. The reduced risk of contralateral breast cancer was persistent during the whole follow-up time. Conclusion: In this randomised trial, adjuvant treatment using tamoxifen for 2 years reduced the incidence of contralateral breast cancer by 50% in all premenopausal women, and by 90% in women less than40 years of age. The effect of tamoxifen was not significantly dependent on time.

  • 8.
    Alkner, S
    et al.
    Lund University.
    Bendahl, P-O
    Lund University.
    Grabau, D
    Lund University.
    Lovgren, K
    Lund University.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Ryden, L
    Lund University.
    Ferno, M
    Lund University.
    AIB1 is a predictive factor for tamoxifen response in premenopausal women2010In: ANNALS OF ONCOLOGY, ISSN 0923-7534, Vol. 21, no 2, p. 238-244Article in journal (Refereed)
    Abstract [en]

    Background: Clinical trials implicate the estrogen receptor ( ER) coactivator amplified in breast cancer 1 (AIB1) to be a prognostic and a treatment-predictive factor, although results are not unanimous. We have further investigated this using a controlled randomised trial of tamoxifen versus control. Materials and methods: A total of 564 premenopausal women were entered into a randomised study independent of ER status. Using a tissue microarray, AIB1 and ER were analysed by immunohistochemistry. Results: AIB1 scores were obtained from 349 women. High AIB1 correlated to factors of worse prognosis (human epidermal growth factor receptor 2, Nottingham histological grade 3, and lymph node metastases) and to ER negativity. In the control arm, high AIB1 was a negative prognostic factor for recurrence- free survival (RFS) (P = 0.02). However, ER-positive patients with high AIB1 responded significantly to tamoxifen treatment (P = 0.002), increasing RFS to the same level as for systemically untreated patients with low AIB1. Although ER-positive patients with low AIB1 had a better RFS from the beginning, this was not further improved by tamoxifen (P = 0.8). Conclusions: In the control group, high AIB1 was a negative prognostic factor. However, ER-positive patients with high AIB1 responded significantly to tamoxifen. This implicates high AIB1 to be an independent predictive factor of improved response to tamoxifen and not, as has previously been discussed, a factor predicting tamoxifen resistance.

  • 9.
    Andreasson, Hakan
    et al.
    Uppsala University.
    Wanders, Alkwin
    Uppsala University.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Willen, Roger
    Uppsala University.
    Graf, Wilhelm
    Uppsala University.
    Nygren, Peter
    Uppsala University.
    Glimelius, Bengt
    Uppsala University.
    Zhang, Zhi-Yong
    Tangshan Gongren Hospital.
    Mahteme, Haile
    Uppsala University.
    Histopathological Classification of Pseudomyxoma Peritonei and the Prognostic Importance of PINCH Protein2012In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 4, p. 1443-1448Article in journal (Refereed)
    Abstract [en]

    Aim: The aims of this study were i) to assess a new and more detailed histopathological classification and to analyze concordance between pathologists in the histopathological classification of pseudomyxoma peritonei (PMP); ii) to analyze the expression in the stroma of the particularly interesting new cysteine-histidine (PINCH) protein and its prognostic importance in PMP. Materials and Methods: Surgical specimens from 81 patients, classified according to the Ronnett et al histopathological classification were compared to a new system with four groups ranging from indolent to aggressive growth patterns. PINCH protein expression was analyzed and was related to clinical variables. Results: The new four-group classification provided better prognostic information than the classification according to Ronnett et al. (p=0.04). Expression of the PINCH protein in the stroma was found in 83% of the cases and was associated with high tumor burden (p=0.002) and a poor prognosis (p=0.04). Conclusion: The proposed new PMP classification system may provide additional prognostic information. PINCH protein is expressed in PMP and has prognostic information.

  • 10.
    Antoniou, Antonis C.
    et al.
    Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Beesley, Jonathan
    Queensland Institute of Medical Research, Brisbane, Australia.
    McGuffog, Lesley
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    M. Sinilnikova, Olga
    Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, Lyon, France.
    Healey, Sue
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    L. Neuhausen, Susan
    Beckman Research Institute City Hope, Department Populat Science, Duarte, CA USA.
    Chun Ding, Yuan
    Beckman Research Institute City Hope, Department Populat Science, Duarte, CA USA.
    R. Rebbeck, Timothy
    University Penn, Sch Med, Abramson Canc Centre, Philadelphia, PA 19104 USA.
    N. Weitzel, Jeffrey
    City Hope Natl Med Centre, Duarte, CA 91010 USA.
    T. Lynch, Henry
    Creighton University, Omaha, NE 68178 USA.
    Isaacs, Claudine
    A. Ganz, Patricia
    University Calif Los Angeles, Jonsson Comprehens Canc Centre, Los Angeles, CA 90024 USA.
    Tomlinson, Gail
    University Texas Hlth Science Centre San Antonio, San Antonio, TX 78229 USA.
    I. Olopade, Olufunmilayo
    University Chicago, Med Centre, Chicago, IL 60637 USA.
    J. Couch, Fergus
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA.
    Wang, Xianshu
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA.
    M. Lindor, Noralane
    Mayo Clin, Department Med Genet, Rochester, MN USA.
    S. Pankratz, Vernon
    Mayo Clin, Department Hlth Science Research, Rochester, MN USA.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Department Expt Oncol and Mol Med, Milan, Italy.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Zaffaroni, Daniela
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Barile, Monica
    IEO, Div Canc Prevent and Genet, Milan, Italy.
    Viel, Alessandra
    IRCCS, CRO, Div Expt Oncol 1, Aviano, PN, Italy.
    Allavena, Anna
    University Turin, Department Genet Biol and Biochem, Turin, Italy.
    DallOlio, Valentina
    Cogentech, Consortium Genom Technology, Milan, Italy.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Department Expt Oncol and Mol Med, Milan, Italy.
    I. Szabo, Csilla
    Mayo Clin, Coll Med, Department Lab Med and Pathol, Rochester, MN USA.
    Zikan, Michal
    Charles University Prague, Fac Med 1, Department Biochem and Expt Oncol, Prague, Czech Republic.
    Claes, Kathleen
    Ghent University Hospital, Centre Med Genet, B-9000 Ghent, Belgium.
    Poppe, Bruce
    Ghent University Hospital, Centre Med Genet, B-9000 Ghent, Belgium.
    Foretova, Lenka
    Masaryk Mem Canc Institute, Department Canc Epidemiol and Genet, Brno, Czech Republic.
    L. Mai, Phuong
    US Natl Canc Institute, Clin Genet Branch, Rockville, MD USA.
    H. Greene, Mark
    US Natl Canc Institute, Clin Genet Branch, Rockville, MD USA.
    Rennert, Gad
    Technion Israel Institute Technology, Carmel Med Centre, Haifa, Israel.
    Lejbkowicz, Flavio
    Technion Israel Institute Technology, Carmel Med Centre, Haifa, Israel.
    Glendon, Gord
    OCGN, Toronto, ON, Canada.
    Ozcelik, Hilmi
    Mt Sinai Hospital, Fred A Litwin Centre Canc Genet, Samuel Lunenfeld Research Institute, New York, NY 10029 USA.
    L. Andrulis, Irene
    OCGN, Toronto, ON, Canada.
    Thomassen, Mads
    Odense University Hospital, Department Clin Genet, DK-5000 Odense, Denmark.
    Gerdes, Anne-Marie
    Rigshosp, Department Clin Genet, Odense, Denmark.
    Sunde, Lone
    Aalborg Hospital, Department Clin Genet, Aalborg, Denmark.
    Cruger, Dorthe
    Vejle Hospital, Department Clin Genet, Velje, Denmark.
    Birk Jensen, Uffe
    Aarhus University Hospital, Department Clin Genet, DK-8000 Aarhus, Denmark.
    Caligo, Maria
    University Pisa, Div Surg Mol and Ultrastruct Pathol, Department Oncol, Pisa, Italy.
    Friedman, Eitan
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Kaufman, Bella
    Sheba Med Centre, Institute Oncol, Tel Hashomer, Israel.
    Laitman, Yael
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Milgrom, Roni
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Dubrovsky, Maya
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Cohen, Shimrit
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Borg, Ake
    Lund University, Department Oncol, Lund, Sweden.
    Jernstroem, Helena
    Lund University, Department Oncol, Lund, Sweden.
    Lindblom, Annika
    Karolinska Institute, Department Mol Med and Surg, Stockholm, Sweden.
    Rantala, Johanna
    Karolinska Institute, Department Mol Med and Surg, Stockholm, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, Beatrice
    Umea University, Department Radiat Science, Umea, Sweden.
    Nathanson, Kate
    University Penn, Philadelphia, PA 19104 USA.
    Domchek, Susan
    University Penn, Philadelphia, PA 19104 USA.
    Jakubowska, Ania
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Lubinski, Jan
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Huzarski, Tomasz
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Osorio, Ana
    Spanish Natl Canc Research Centre, Human Genet Grp, Human Canc Genet Programme, Madrid, Spain.
    Lasa, Adriana
    Hospital Santa Creu and Sant Pau, Genet Serv, Barcelona, Spain.
    Duran, Mercedes
    University Valladolid, Institute Biol and Mol Genet, IBGM UVA, Valladolid, Spain.
    Tejada, Maria-Isabel
    Cruces Hospital Barakaldo, Mol Genet Lab, Department Biochem, Bizkaia, Spain.
    Godino, Javier
    University Lozano Blesa, Hospital Clin, Oncol Serv, Zaragoza, Spain.
    Benitez, Javier
    Spanish Natl Canc Research Centre, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain.
    Hamann, Ute
    Deutsch Krebsforschungszentrum, Mol Genet Breast Canc, D-6900 Heidelberg, Germany.
    Kriege, Mieke
    Daniel Denhoed Canc Centre, Erasmus MC, Department Med Oncol, Family Canc Clin, Rotterdam, Netherlands.
    Hoogerbrugge, Nicoline
    Radboud University Nijmegen, Nijmegen Med Centre, Hereditary Canc Clin, NL-6525 ED Nijmegen, Netherlands.
    B. van der Luijt, Rob
    University Med Centre Utrecht, Department Med Genet, Utrecht, Netherlands.
    J. van Asperen, Christi
    Leiden University, Med Centre, Department Clin Genet, Leiden, Netherlands.
    Devilee, Peter
    Leiden University, Department Human Genet, Med Centre, Department Pathol, NL-2300 RA Leiden, Netherlands.
    J. Meijers-Heijboer, E.
    Vrije University Amsterdam Med Centre, Department Clin Genet, Amsterdam, Netherlands.
    J. Blok, Marinus
    University Med Centre, Department Genet and Cell Biol, Maastricht, Netherlands.
    M. Aalfs, Cora
    University Amsterdam, Acad Med Centre, Department Clin Genet, NL-1105 AZ Amsterdam, Netherlands.
    Hogervorst, Frans
    Netherlands Canc Institute, Family Canc Clin, Amsterdam, Netherlands.
    Rookus, Matti
    Netherlands Canc Institute, Department Epidemiol, Amsterdam, Netherlands.
    Cook, Margaret
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Oliver, Clare
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Frost, Debra
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Conroy, Don
    University Cambridge, Department Oncol, Cambridge, England.
    Gareth Evans, D.
    Cent Manchester University Hospital NHS Fdn Trust, Manchester Acad Hlth Science Centre, Manchester, Lancs, England.
    Lalloo, Fiona
    Cent Manchester University Hospital NHS Fdn Trust, Manchester Acad Hlth Science Centre, Manchester, Lancs, England.
    Pichert, Gabriella
    Guys and St Thomas NHS Fdn Trust, London, England.
    Davidson, Rosemarie
    Ferguson Smith Centre Clin Genet, Glasgow, Lanark, Scotland.
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, W Midlands Reg Genet Serv, Birmingham, W Midlands, England.
    Cook, Jackie
    Sheffield Childrens Hospital, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England.
    Paterson, Joan
    Addenbrookes Hospital, Department Clin Genet, E Anglian Reg Genet Serv, Cambridge, England.
    Hodgson, Shirley
    University London, Department Clin Genet, St Georges Hospital, London, England.
    J. Morrison, Patrick
    Belfast City Hospital, Northern Ireland Reg Genet Centre, Belfast BT9 7AD, Antrim, North Ireland.
    E. Porteous, Mary
    Western Gen Hospital, SE Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland.
    Walker, Lisa
    Churchill Hospital, Oxford Reg Genet Serv, Oxford OX3 7LJ, England.
    John Kennedy, M.
    St James Hospital, Canc Genet Program, Hope Directorate, Dublin, Ireland.
    Dorkins, Huw
    Kennedy Galton Centre, NW Thames Reg Genet Serv, Harrow, Middx, England.
    Peock, Susan
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    K. Godwin, Andrew
    Fox Chase Canc Centre, Department Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA.
    Stoppa-Lyonnet, Dominique
    University Paris 05, INSERM, U509, Serv Genet Oncol,Institute Curie, Paris, France.
    de Pauw, Antoine
    University Paris 05, INSERM, U509, Serv Genet Oncol,Institute Curie, Paris, France.
    Mazoyer, Sylvie
    University Lyon 1, CNRS, Centre Leon Berard, Equipe Labellisee LIGUE 2008,UMR5201, F-69365 Lyon, France.
    Bonadona, Valerie
    University Lyon 1, CNRS, UMR5558, F-69365 Lyon, France.
    Lasset, Christine
    University Lyon 1, CNRS, UMR5558, F-69365 Lyon, France.
    Dreyfus, Helene
    CHU Grenoble, Department Genet, F-38043 Grenoble, France.
    Leroux, Dominique
    CHU Grenoble, Department Genet, F-38043 Grenoble, France.
    Hardouin, Agnes
    Centre Francois Baclesse, F-14021 Caen, France.
    Berthet, Pascaline
    Centre Francois Baclesse, F-14021 Caen, France.
    Faivre, Laurence
    Centre Hospital University Dijon, Centre Genet, Dijon, France.
    Loustalot, Catherine
    Centre Lutte Canc Georges Francois Leclerc, Dijon, France.
    Noguchi, Tetsuro
    INSERM, Institute Paoli Calmettes, UMR599, Department Oncol Genet, F-13258 Marseille, France.
    Sobol, Hagay
    INSERM, Institute Paoli Calmettes, UMR599, Department Oncol Genet, F-13258 Marseille, France.
    Rouleau, Etienne
    Centre Rene Huguenin, INSERM, U735, St Cloud, France.
    Nogues, Catherine
    Frenay, Marc
    Centre Antoine Lacassagne, F-06054 Nice, France.
    Venat-Bouvet, Laurence
    Centre Hospital University Limoges, Department Oncol, Limoges, France.
    L. Hopper, John
    University Melbourne, Melbourne, Vic, Australia.
    B. Daly, Mary
    Fox Chase Canc Centre, Department Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA.
    B. Terry, Mary
    Columbia University, New York, NY USA.
    M. John, Esther
    Canc Prevent Institute Calif, Fremont, CA USA.
    S. Buys, Saundra
    University Utah, Hlth Science Centre, Huntsman Canc Institute, Salt Lake City, UT USA.
    Yassin, Yosuf
    Dana Farber Canc Institute, Boston, MA 02115 USA.
    Miron, Alexander
    Dana Farber Canc Institute, Boston, MA 02115 USA.
    Goldgar, David
    University Utah, Department Dermatol, Salt Lake City, UT USA.
    F. Singer, Christian
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Catharina Dressler, Anne
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Gschwantler-Kaulich, Daphne
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Pfeiler, Georg
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    V. O. Hansen, Thomas
    University Copenhagen, Rigshosp, Department Clin Biochem, DK-2100 Copenhagen, Denmark.
    Jnson, Lars
    University Copenhagen, Rigshosp, Department Clin Biochem, DK-2100 Copenhagen, Denmark.
    A. Agnarsson, Bjarni
    University Hospital, Department Pathol, Reykjavik, Iceland.
    Kirchhoff, Tomas
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Offit, Kenneth
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Devlin, Vincent
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Dutra-Clarke, Ana
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Piedmonte, Marion
    Roswell Pk Canc Institute, GOG Stat and Data Centre, Buffalo, NY 14263 USA.
    C. Rodriguez, Gustavo
    NorthShore University Hlth Syst, Evanston NW Healthcare, Evanston, IL USA.
    Wakeley, Katie
    Tufts University, New England Med Centre, Boston, MA 02111 USA.
    F. Boggess, John
    University N Carolina, Chapel Hill, NC USA.
    Basil, Jack
    St Elizabeth Hospital, Edgewood, KY USA.
    E. Schwartz, Peter
    Yale University, Sch Med, New Haven, CT USA.
    V. Blank, Stephanie
    NYU, Sch Med, New York, NY USA.
    Ewart Toland, Amanda
    Ohio State University, Centre Comprehens Canc, Department Internal Med and Mol Virol, Div Human Canc Genet, Columbus, OH 43210 USA.
    Montagna, Marco
    IRCCS, Ist Oncol Veneto, Immunol and Mol Oncol Unit, Padua, Italy.
    Casella, Cinzia
    IRCCS, Ist Oncol Veneto, Immunol and Mol Oncol Unit, Padua, Italy.
    Imyanitov, Evgeny
    NN Petrov Institute Oncol, St Petersburg, Russia.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Riga, Latvia.
    Blanco, Ignacio
    Catalan Institute Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain.
    Lazaro, Conxi
    Catalan Institute Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain.
    J. Ramus, Susan
    University London Imperial Coll Science Technology and Med, Gynaecol Oncol Unit, UCL EGA Institute Womens Hlth, London, England.
    Sucheston, Lara
    Roswell Pk Canc Institute, Department Canc Prevent and Control, Buffalo, NY 14263 USA.
    Y. Karlan, Beth
    Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA 90048 USA.
    Gross, Jenny
    Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA 90048 USA.
    Schmutzler, Rita
    University Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany.
    Wappenschmidt, Barbara
    University Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany.
    Engel, Christoph
    University Leipzig, Institute Med Informat Stat and Epidemiol, Leipzig, Germany.
    Meindl, Alfons
    Tech University Munich, Klinikum Rechts Isar, Department Obstet and Gynaecol, Div Tumor Genet, D-8000 Munich, Germany.
    Lochmann, Magdalena
    Tech University Munich, Klinikum Rechts Isar, Department Obstet and Gynaecol, Div Tumor Genet, D-8000 Munich, Germany.
    Arnold, Norbert
    University Kiel, Department Obstet and Gynaecol, University Hospital Schleswig Holstein, Kiel, Germany.
    Heidemann, Simone
    University Kiel, Institute Human Genet, University Hospital Schleswig Holstein, Kiel, Germany.
    Varon-Mateeva, Raymonda
    Campus Virchow Klinikum, Charite Berlin, Institute Human Genet, Berlin, Germany.
    Niederacher, Dieter
    University Dusseldorf, Department Obstet and Gynaecol, Div Mol Genet, University Hospital Dusseldorf, Dusseldorf, Germany.
    Sutter, Christian
    University Heidelberg, Institute Human Genet, Div Mol Diagnost, Heidelberg, Germany.
    Deissler, Helmut
    University Hospital Ulm, Department Obstet and Gynaecol, Ulm, Germany.
    Gadzicki, Dorothea
    Hannover Med Sch, Institute Cell and Mol Pathol, D-3000 Hannover, Germany.
    Preisler-Adams, Sabine
    University Hospital Muenster, Institute Human Genet, Munster, Germany.
    Kast, Karin
    Tech University Dresden, Department Obstet and Gynaecol, University Hospital Carl Gustav Carus, Dresden, Germany.
    Schoenbuchner, Ines
    University Wurzburg, Institute Human Genet, Div Med Genet, Wurzburg, Germany.
    Caldes, Trinidad
    Hospital Clin San Carlos, Mol Oncol Lab, Madrid, Spain.
    de la Hoya, Miguel
    Hospital Clin San Carlos, Mol Oncol Lab, Madrid, Spain.
    Aittomaeki, Kristiina
    University Helsinki, Cent Hospital, Department Clin Genet, Helsinki, Finland.
    Nevanlinna, Heli
    University Helsinki, Cent Hospital, Department Obstet and Gynecol, FIN-00290 Helsinki, Finland.
    Simard, Jacques
    Centre Hospital University Quebec, Canada Research Chair Oncogenet, Canc Genom Lab, Quebec City, PQ, Canada.
    B. Spurdle, Amanda
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Holland, Helene
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Chen, Xiaoqing
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Platte, Radka
    Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Chenevix-Trench, Georgia
    Queensland Institute of Medical Research, Brisbane, Australia.
    F. Easton, Douglas
    University Chicago, Med Centre, Chicago, IL 60637 USA.
    Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 23, p. 9742-9754Article in journal (Refereed)
    Abstract [en]

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03–1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01–1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10−11 − 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers. Cancer Res; 70(23); 9742–54. ©2010 AACR.

  • 11. Arlehag, L
    et al.
    Adell, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Knutsen Holmqvist, Annica
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Thorstenson, Sten
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology.
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    ATM expression in rectal cancers with or without preoperative radiotherapy2005In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 14, no 2, p. 313-317Article in journal (Refereed)
    Abstract [en]

    Patients with ATM (Ataxia-Telangiectasia mutated) mutation show increased sensitivity to radiation and have a higher risk of developing malignancies. The present study aimed to investigate whether ATM expression was related to radiotherapy, and clinicopathological and biological variables in rectal cancers. ATM expression was immunohistochemically examined in 78 rectal cancers from patients who participated in a Swedish rectal cancer trial of preoperative radiotherapy. Of 78 patients, 44 underwent surgery alone, and 34 underwent both preoperative radiotherapy and surgery. Fifty-eight cases had normal rectal mucosa adjacent to the tumour. The results showed that, compared to normal mucosa, tumours had less nuclear (p=0.03) but more cytoplasmic expression of ATM (p=0.004). In tumours, less expression of ATM, either in the nucleus (p=0.07) or in the cytoplasm (p=0.02 for staining intensity, and p=0.07 for staining percentage), tended to be correlated with male patients. Also, ATM expression was not related to radiotherapy or other clinicopathological and biological variables (p > 0.05). In conclusion, the pattern of ATM expression was changed from normal mucosa to tumour. Less expression of ATM may be related to males.

  • 12.
    Arver, Brita
    et al.
    Karolinska Institute.
    Isaksson, Karin
    Karolinska Institute.
    Atterhem, Hans
    Umea University Hospital.
    Baan, Annika
    Sahlgrens University Hospital.
    Bergkvist, Leif
    Uppsala University.
    Brandberg, Yvonne
    Karolinska Institute.
    Ehrencrona, Hans
    Uppsala University.
    Emanuelsson, Monica
    Umea University.
    Hellborg, Henrik
    Karolinska University Hospital.
    Henriksson, Karin
    Skane University Hospital.
    Karlsson, Per
    Sahlgrens University Hospital.
    Loman, Niklas
    Skane University Hospital.
    Lundberg, Jonas
    Sahlgrens University Hospital.
    Ringberg, Anita
    Skane University Hospital.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Wickman, Marie
    Karolinska Institute.
    Sandelin, Kerstin
    Karolinska Institute.
    Bilateral Prophylactic Mastectomy in Swedish Women at High Risk of Breast Cancer: A National Survey2011In: ANNALS OF SURGERY, ISSN 0003-4932, Vol. 253, no 6, p. 1147-1154Article in journal (Refereed)
    Abstract [en]

    Background/Objective: This study attempted a national inventory of all bilateral prophylactic mastectomies performed in Sweden between 1995 and 2005 in high-risk women without a previous breast malignancy. The primary aim was to investigate the breast cancer incidence after surgery. Secondary aims were to describe the preoperative risk assessment, operation techniques, complications, histopathological findings, and regional differences. Methods: Geneticists, oncologists and surgeons performing prophylactic breast surgery were asked to identify all women eligible for inclusion in their region. The medical records were reviewed in each region and the data were analyzed centrally. The BOADICEA risk assessment model was used to calculate the number of expected/prevented breast cancers during the follow-up period. Results: A total of 223 women operated on in 8 hospitals were identified. During a mean follow-up of 6.6 years, no primary breast cancer was observed compared with 12 expected cases. However, 1 woman succumbed 9 years post mastectomy to widespread adenocarcinoma of uncertain origin. Median age at operation was 40 years. A total of 58% were BRCA1/2 mutation carriers. All but 3 women underwent breast reconstruction, 208 with implants and 12 with autologous tissue. Four small, unifocal, invasive cancers and 4 ductal carcinoma in situ were found in the mastectomy specimens. The incidence of nonbreast related complications was low(3%). Implant loss due to infection/necrosis occurred in 21 women (10%) but a majority received a new implant later. In total, 64% of the women underwent at least 1 unanticipated secondary operation.

  • 13.
    Aspenberg, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology. Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Editorial: Bisphosphonate-induced fractures: Nature strikes back?2008In: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 79, no 4, p. 459-460Article in journal (Other academic)
  • 14.
    Auner, H W.
    et al.
    University of London Imperial Coll Science Technology and Med, England .
    Szydlo, R
    University of London Imperial Coll Science Technology and Med, England .
    van Biezen, A
    Leiden University, Netherlands .
    Iacobelli, S
    University of Roma Tor Vergata, Italy .
    Gahrton, G
    Karolinska Institute, Sweden .
    Milpied, N
    Hop Haut Leveque, France .
    Volin, L
    University of Helsinki, Finland .
    Janssen, J
    Vrije University of Amsterdam, Netherlands .
    Nguyen Quoc, S
    Grp Hospital Pitie Salpetriere, France .
    Michallet, M
    Hop Edouard Herriot, France .
    Schoemans, H
    University Hospital Gasthuisberg, Belgium .
    el Cheikh, J
    Institute J Paoli I Calmettes, France .
    Petersen, E
    University of Medical Centre, Netherlands .
    Guilhot, F
    Hop La Miletrie, France .
    Schoenland, S
    Heidelberg University, Germany .
    Ahlberg, Lucia
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Morris, C
    Queens University of Belfast, North Ireland .
    Garderet, L
    Hop St Antoine, France .
    de Witte, T
    Radboud University of Nijmegen, Netherlands .
    Kroeger, N
    University Hospital Eppendorf, Germany .
    Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation2013In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 48, no 11, p. 1395-1400Article in journal (Refereed)
    Abstract [en]

    Outcomes and prognostic factors of reduced intensity-conditioned allo-SCT (RIC allo-SCT) for multiple myeloma (MM) relapsing or progressing after prior autologous (auto)-SCT are not well defined. We performed an analysis of 413 MM patients who received a related or unrelated RIC allo-SCT for the treatment of relapse/progression after prior auto-SCT. Median age at RIC allo-SCT was 54.1 years, and 44.6% of patients had undergone two or more prior auto-SCTs. Median OS and PFS from the time of RIC allo-SCT for the entire population were 24.7 and 9.6 months, respectively. Cumulative non-relapse mortality (NRM) at 1 year was 21.5%. In multivariate analysis, CMV seronegativity of both patient and donor was associated with significantly better PFS, OS and NRM. Patient-donor gender mismatch was associated with better PFS, fewer than two prior auto-SCT was associated with better OS, and shorter time from the first auto-SCT to the RIC allo-SCT was associated with lower NRM. The results of this study identify patient and donor CMV seronegativity as the key prognostic factor for outcome after RIC allo-SCT for MM relapsing or progressing after prior auto-SCT.

  • 15.
    Aus, Gunnar
    et al.
    Department of Urology, Sahlgrens University Hospital, 413 45, Göteborg, Sweden.
    Nordenskjöld, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Robinson, David
    Department of Surgery, Höglandssjukhuset, Eksjö, Sweden.
    Rosell, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Varenhorst, Eberhard
    Department of Urology and Surgery, Vrinnevisjukhuset, Norrköping, Sweden.
    Prognostic Factors and Survival in Node-Positive (N1) Prostate Cancer: A Prospective Study Based on Data from a Swedish Population-Based Cohort2003In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 43, no 6, p. 627-631Article in journal (Refereed)
    Abstract [en]

    Objective: At presentation of prostate cancer, patients with proven lymph node metastasis (N1) are comparatively rare. It is difficult to give prognostic information based on the present literature. The aim of this study was to evaluate the impact of known risk factors in patients with pelvic node involvement and without distant metastasis.

    Methods: From the population-based, prospective prostate cancer tumour registry of the South–East Region in Sweden, we collected data on all 181 patients with N1, M0 prostate cancer diagnosed from January 1987 to October 2000 with a follow-up to December 2001. Mean follow-up was 62 months. Pre-operative risk factors as age, T-category, serum PSA, tumour grade and also primary treatment given was correlated to the outcome.

    Results: Median age at diagnosis was 65 years. Cancer-specific survival was highly variable with 5-year survival of 72%, a median of 8 years and the projected 13-year figure was 31%. T-category, age, PSA or treatment did not affect the outcome while poorly differentiated tumours had a tendency towards lower cancer-specific survival (p=0.0523) when compared to well and moderately differentiated tumours.

    Conclusions: This population-based cohort of prostate cancer patients with pelvic node involvement treated principally with non-curative intent had a median cancer-specific survival of 8 years. Preoperatively known risk factors seem to have but a modest impact on the prognosis for patients in this stage of the disease.

  • 16.
    Aus, Gunnar
    et al.
    Department of Urology, Sahlgrens University Hospital, Go¨ teborg, Sweden.
    Robinson, David
    Section of Urology, Ryhov County Hospital, Jönköping, Sweden.
    Rosell, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Sandblom, Gabriel
    Department of Surgery, Akademiska Hospital, Uppsala, Sweden.
    Varenhorst, Eberhard
    Department of Surgery and Urology, Vrinnevi Hospital, Norrköping, Sweden..
    Survival in prostate carcinoma - Outcomes from a prospective, population-based cohort of 8887 men with up to 15 years of follow-up: Results from three counties in the population-based National Prostate Cancer Registry of Sweden2005In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 103, no 5, p. 943- 951Article in journal (Refereed)
    Abstract [en]

    BACKGROUND To decide on screening strategies and curative treatments for prostate carcinoma, it is necessary to determine the incidence and survival in a population that is not screened.

    METHODS The 15-year projected survival data were analyzed from a prospective, complete, population-based registry of 8887 patients with newly diagnosed prostate carcinoma from 1987 to 1999.

    RESULTS The median patient age at diagnosis was 75 years (range, 40-96 years), and 12% of patients were diagnosed before the age 65 years. The median follow-up was 80 months for patients who remained alive. In total, 5873 of 8887 patients (66.1%) had died, and 2595 of those patients (44.2%) died directly due to prostate carcinoma. The overall median age at death was 80 years (range, 41-100 years). The projected 15-year disease-specific survival rate was 44% for the whole population. In total, 18% of patients had metastases at diagnosis (M1), and their median survival was 2.5 years. Patients with nonmetastatic T1-T3 prostate carcinoma (age < 75 years at diagnosis; n = 2098 patients) had a 15-year projected disease-specific survival rate of 66%. Patients who underwent radical prostatectomy had a significantly lower risk of dying from prostate carcinoma (relative risk, 0.40) compared with patients who were treated with noncurative therapies or radiotherapy.

    CONCLUSIONS The disease-specific mortality was comparatively high, but it took 15 years to reach a disease-specific mortality rate of 56%. These data form a truly population-based baseline on how prostate carcinoma will affect a population when screening is not applied and can be used for comparison with other health care strategies. Cancer 2005. © 2005 American Cancer Society.

  • 17. Bagwell, CB
    et al.
    Clark, GM
    Chassevent, A
    Bendahl, PO
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Killander, D
    Jourdan, ML
    Romain, S
    Hunsberger, B
    Wright, S
    Baldetorp, B
    DNA and cell cycle analysis as prognostic indicators in breast tumors revisited2001In: Clinics in Laboratory Medicine, ISSN 0272-2712, E-ISSN 1557-9832, Vol. 21, no 4, p. 875-+Article in journal (Refereed)
    Abstract [en]

    Both DNA ploidy and S-phase ploidy are promising prognostic factors for node-negative breast cancer patients. Based largely on the analysis of one large study, much of the reported problems with these factors have been caused by some unappreciated complexities in categorizing DNA ploidy into low- and high-risk groups and the lack of some necessary adjustments to eliminate unwanted correlations between DNA S-phase and ploidy. When both DNA ploidy and S-phase are compensated properly, they become independent prognostic markers, forming a powerful prognostic model.

  • 18. Bagwell, CB
    et al.
    Clark, GM
    Spyratos, F
    Chassevent, A
    Bendahl, PO
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Killander, D
    Jourdan, ML
    Romain, S
    Hunsberger, CB
    Wright, S
    Baldetorp, B
    Multivariate analyses of flow cytometric S-phase and ploidy as node-negative breast cancer prognostic factors: an international and multi-center study2001In: Abstract Issue, 24th Annual San Antonio, Breast Cancer Symposium. December 10-13, 2001 San Antonio Marriott Rivercenter, Texas, USA.: Breast Cancer Research and Treatment, ISSN 0167-6806, Vol 69, Issue 3, 2001, Vol. 69, no 3, p. 260-260Conference paper (Refereed)
    Abstract [en]

    Recently a set of ten adjustments that optimizes the prognostic strength of both DNA ploidy (P) and S-phase (S) was published (Cytometry, 46(3), 2001). Also presented was an optimal method of combining P and S (P+S) that stratifies node-negative patients into highly significant risk groups. The adjustments compensate for many unappreciated complexities in categorizing P into low and high risk groups and eliminate unwanted correlation between P and S. The purpose of this study is to examine P+S in the context of other well-known prognostic factors such as primary size (pT), estrogen and progesterone receptor (ER,PR) and menopausal status (MS). Methods: DNA histograms derived from frozen primary tumors and clinical databases were provided by Baylor College, n=935; Sweden, n=210 (Lund, Linkoping, Stockholm) and France, n=220 (Angers, Marseille, Saint Cloud, Tours). Time to metastasis was the tested clinical outcome. Results: Cox proportional hazards analysis of theBaylor data revealed P+S, p<0.000002, and pT, p<0.003, as independent significant prognostic factors. The Sweden study also showed P+S the mostsignificant prognostic factor, p<0.002, as well as MS, p<0.004 and ER, p<0.007. The French study results were MS, p<0.0005, P+S, p<0.002 and pT, p<0.007.A P+S, MS and pT prognostic model stratified patients in all studies into highly significant categories, Baylor, p<0.000005, Sweden, p<0.00001, and French, p<0.000005, with low and high risk 10-year relapse-free survival fractions of 0.92-0.69, 0.95-0.58 and 0.96-0.60 respectively. Conclusion: A combined P+S, MS and pT prognostic model is a powerful and reliable method of stratifying node-negative breast cancer patients into highly significant prognostic groups.

  • 19.
    Baker, Ann-Marie
    et al.
    University of Aberdeen.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Southall, Stacey M
    Institute for Cancer Research.
    Wilson, Jon R
    Institute for Cancer Research.
    Erler, Janine T
    Institute for Cancer Research.
    The Role of Lysyl Oxidase in SRC-Dependent Proliferation and Metastasis of Colorectal Cancer2011In: JOURNAL OF THE NATIONAL CANCER INSTITUTE, ISSN 0027-8874, Vol. 103, no 5, p. 407-424Article in journal (Refereed)
    Abstract [en]

    Background Emerging evidence implicates lysyl oxidase (LOX), an extracellular matrix-modifying enzyme, in promoting metastasis of solid tumors. We investigated whether LOX plays an important role in the metastasis of colorectal cancer (CRC). Methods We analyzed LOX expression in a patient CRC tissue microarray consisting of normal colon mucosa (n = 49), primary (n = 510), and metastatic (n = 198) tissues. LOX was overexpressed in CRC cell line SW480 (SW480+LOX), and the expression was knocked down in CRC cell line SW620 using LOX-specific short hairpin RNA (SW620+shLOX). Effect of LOX manipulation on three-dimensional cell proliferation and invasion was characterized in vitro. Effect of LOX manipulation on tumor proliferation and metastasis was investigated in a subcutaneous tumor mouse model (n = 3 mice per group) and in an intrasplenic metastatic mouse model (n = 3 mice per group). The mechanism of LOX-mediated effects via v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian) (SRC) was investigated using dasatinib, an inhibitor of SRC activation. All statistical tests were two-sided. Results Compared with normal colon tissue (n = 49), LOX expression was statistically significantly increased in tumor tissues (n = 510) of CRC patients (P andlt; .001), and a greater increase was observed in metastatic tissue (n = 198). SW480+LOX cells showed a statistically significantly increased three-dimensional proliferation (P = .037) and invasion (P = .015), whereas SW620+shLOX cells showed reduced proliferation (P = .011) and invasion (P = .013) compared with controls. Subcutaneous tumor growth in mice was statistically significantly increased in SW480+LOX tumors (P = .036) and decreased in SW620+shLOX tumors (P = .048), and metastasis was statistically significantly increased in SW480+LOX tumors (P = .044) and decreased in SW620+shLOX tumors (SW620 control vs SW620+shLOX, mean = 1.0 luminescent signal, 95% confidence interval = 0.3 to 1.7 luminescent signal, vs mean = 0.3 luminescent signal, 95% confidence interval = 0.1 to 0.5 luminescent signal; P = .035) compared with controls. LOX-mediated effects on tumor progression were associated with SRC activation, and these effects were inhibited by dasatinib. Conclusions LOX showed an important role in CRC cell proliferation and metastasis and was dependent on the activation of SRC. These results have the potential to identify patients with high SRC activity, who may benefit from dasatinib treatment.

  • 20.
    Baldetorp, Bo
    et al.
    Department of Oncology, University Hospital, Lund, Sweden.
    Bendahl, Pär-Ola
    Department of Oncology, University Hospital, Lund, Sweden.
    Ferno, Mårten
    Department of Oncology, University Hospital, Lund, Sweden.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Improved DNA flow cytometric, DNA ploidy, and S-phase reproducibility between 15 laboratories in analysis of breast cancer using generalized guidelines2003In: Cytometry, ISSN 0196-4763, E-ISSN 1097-0320, Vol. 56A, no 1, p. 1-7Article in journal (Refereed)
    Abstract [en]

    Background

    Lack of generalized guidelines for DNA flow cytometric analysis (FCM) may be the main reason for its limited use in the clinical management of breast cancer.

    Methods

    After an initial interlaboratory reproducibility study (Round I), we concluded that it was the evaluation of the DNA histograms rather than the technical performance of the analysis that was the main reason for discordant results between laboratories. Guidelines for the interpretation of DNA histograms were therefore drawn up. We present here data from a new reproducibility study (Round II) using these guidelines.

    Results

    For 10 laboratories also participating in Round I, use of the guidelines increased the concordance in DNA ploidy status from 89% to 100% for the 46 samples used in both rounds. The concordance rate for SPF also increased; mean rs-value increased from 0.81 to 0.88, and mean kappa value (lower two-thirds versus upper third versus not reported) increased from 0.55 to 0.71. Five new laboratories, participating only in Round II, also agreed with the 10 original laboratories regarding DNA ploidy status. With the inclusion of all 15 laboratories, we obtained a mean rs-value of 0.81 and a mean kappa value of 0.72 for SPF.

    Conclusions

    Generalized guidelines for DNA FCM increase interlaboratory agreement, which is highly important in clinical routines and in multicenter studies. Furthermore, inexperienced FCM laboratories using generalized guidelines can produce and interpret DNA FCM data equally as well as experienced laboratories.

  • 21.
    Baron, Frederic
    et al.
    ULg, Liege, Belgium .
    Labopin, Myriam
    University of Paris 06.
    Mohty, Mohamad
    CHU Hotel Dieu, Nantes, France .
    Basara, Nadezda
    University of Leipzig.
    Niederwieser, Dietger
    University of Leipzig.
    Milpied, Noel-Jean
    CHU Bordeaux.
    Cornelissen, J J
    Erasmus University.
    Malm, Claes
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Sengeloev, Henrik
    Rigshosp, Copenhagen, Denmark .
    Blaise, Didier
    CHU Marseille.
    Janssen, Jeroen J W M
    Vrije University Amsterdam.
    Petersen, Eefke
    University Medical Centre Utrecht.
    Socie, Gerard
    St Louis Hospital, Paris, France .
    Rocha, Vanderson
    St Louis Hospital, Paris, France .
    Graft-Versus-Leukemia (GVL) Effect After Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) as Treatment for Acute Myeloid Leukemia (AML): a Survey From the Acute Leukemia Working Party of the EBMT in BLOOD, vol 114, issue 22, pp 1284-12852009In: BLOOD, American Society of Hematology , 2009, Vol. 114, no 22, p. 1284-1285Conference paper (Refereed)
    Abstract [en]

    n/a

  • 22.
    Bastami, Salumeh
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Norling, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Trinks, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Holmlund, Birgitta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Walz, Thomas M
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Uppugunduri, Srinivas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    Inhibitory effect of opiates on LPS mediated release of TNF and IL-82013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 5, p. 1022-1033Article in journal (Refereed)
    Abstract [en]

    Most patients with advanced cancer experience severe pain and are often treated with opiates. Cancer patients are especially susceptible to opportunistic infections due to treatment with immunosuppressive and cytostatic drugs. Since opiates have been demonstrated to have immunomodulatory effects, it is of clinical importance to evaluate potential differences between commonly used opiates with regard to their effect on the immune system. The aim of this study was to evaluate the effect of morphine, tramadol, fentanyl and ketobemidone on the functioning of the immune system with special reference to TNF and IL-8 release. Method. U-937 cells were preincubated with different concentrations of opioids followed by stimulation with LPS 100 μg/ml for three hours. The effect of opioids on the levels of cytokine mRNA was studied using RT-PCR. Erk and Akt phosphorylation was also measured by Western blot. Results. All opioids with the exception of fentanyl were capable of inhibiting TNF release from U-937 cells. Morphine had no effect on IL-8 release but the effect of other opiates was almost the same as the effect on TNF. All opioids with the exception of fentanyl were capable of inhibiting production of mRNA for TNF and IL-8. The observed effects of opiates were not always reversible by naloxone, suggesting that the effects might be mediated by other receptors or through a non-receptor mediated direct effect. Although preliminary evidence suggests the involvement of Erk and Akt pathways, further studies are needed to unravel the intracellular pathways involved in mediating the effects of opiates. Our data suggests that the order of potency with regard to inhibition of cytokine release is as follows: tramadol > ketobemidone > morphine > fentanyl. Conclusion. Further studies are needed to understand the clinical implications of the observed immunosuppressive effects of tramadol and ketobemidone and to improve opioid treatment strategies in patients with cancer.

  • 23.
    Bendrik, Christina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    MMP-3 and MMP-9 Gene Transfer Decrease Growth and Angiogenesis in Breast Cancer Xenografts In Vivo2009Manuscript (preprint) (Other academic)
    Abstract [en]

    Matrix metalloproteinases (MMPs) are largely implicated in tumor behaviour due to their extracellular matrix (ECM) remodelling capacities. Although MMP activity generally is discussed in terms of facilitating tumor invasion, MMP inhibition in clinical trials has failed. Increasing amounts of data show that MMPs may inhibit tumor progression by generating anti-angiogenic factors such as endostatin from the tumoral stroma. We have previously shown that intratumoral gene transfer of MMP-9 induced tumor regression and reduced angiogenesis of breast cancer in vivo. Whether MMP activities induce tumor progression or regression may depend on type of MMP and the expression level in the tumor tissue. In this study we treated established breast cancers in nude mice with adenovirus vectors carrying the human genes of MMP-3 or MMP-9 in low or high dose. Microdialysis was used to sample endostatin in situ and tumor growth was monitored for 35 days. Tumors in mice treated with low-dose of either MMP-3 or MMP-9 vectors exhibited tumor stasis throughout the experiment whereas high-dose gene transfer of either MMP-3 or MMP-9 induced significant tumor regression compared to controls treated with empty vectors. The extracellular in vivo levels of endostatin were increased in tumors that received either high or low MMP-3 or MMP-9 gene transfer and these tumors exhibited decreased microvessel area compared to controls. Our results propose that increased expression of MMP-3 and MMP-9 have therapeutic effects of established breast cancer in a dose dependent manner where a slight increase of MMP expression results in tumor stasis and a high expression of either MMP-3 or MMP-9 by gene transfer results in a potent tumor regression.

  • 24.
    Bendrik, Christina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    MMP-3 and MMP-9 Gene Transfer Decrease Growth and Angiogenesis in Breast Cancer Xenografts In Vivo in CANCER RESEARCH, vol 69, issue 24, pp 761S-761S2009In: CANCER RESEARCH, 2009, Vol. 69, no 24, p. 761S-761SConference paper (Refereed)
    Abstract [en]

    n/a

  • 25.
    Bendrik, Christina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Karlsson, Lisa
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Dabrosin, Charlotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Increased endostatin generation and decreased angiogenesis via MMP-9 by tamoxifen in hormone dependent ovarian cancer2010In: CANCER LETTERS, ISSN 0304-3835, Vol. 292, no 1, p. 32-40Article in journal (Refereed)
    Abstract [en]

    There are several similarities between breast and ovarian cancer but anti-estrogen treatment is rarely used in ovarian cancer. We have previously shown that the most widely used anti-estrogen tamoxifen increased MMP-9 activity and endostatin generation in breast cancer. Here, we show that tamoxifen exposure of highly hormone responsive ovarian cancer cells decreased proliferation, and increased MMP-9 activity leading to increased levels of endostatin both in cell culture in vitro and in solid tumors of nude mice. Tamoxifen exposed tumors also exhibited significantly decreased tumor growth and vascularisation. Moreover, in ascites from ovarian cancer patients, MMP-9 was undetectable in majority of cases but a significant correlation of MMP-2 and endostatin was found. The effects on MMPs and endostatin generation are previously unknown mechanisms of estradiol and tamoxifen in ovarian cancer, which may have therapeutic implications in future anti-cancer options of hormone dependent ovarian cancer.

  • 26.
    Bendrik, Christina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Robertson, Jennifer
    Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics McMaster University, Hamilton, Ontario, Canada.
    Gauldie, Jack
    Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics McMaster University, Hamilton, Ontario, Canada.
    Dabrosin, Charlotta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo2008In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 68, no 9, p. 3405-3412Article in journal (Refereed)
    Abstract [en]

    Matrix metalloproteinases (MMP) are important regulators of angiogenesis and tumor progression by degradation of extracellular matrix. Clinical trials using MMP inhibitors have failed and recent studies suggest that MMPs may in contrast suppress tumor growth. It is not known, however, if MMPs or their inhibitors, tissue inhibitor of metalloproteinases (TIMP), can be used as therapy of established cancer. Here, adenovirus vectors carrying the human genes for MMP-9, TIMP-1, or empty controls were injected intratumorally in breast cancers established in mice supplemented with estradiol and treated with tamoxifen. Microdialysis was used to quantify MMP activity and sampling of endostatin and vascular endothelial growth factor (VEGF) in situ. We show that AdMMP-9 increased MMP activity in vivo, decreased tumor growth rate, and decreased microvessel area significantly. AdMMP-9 therapy resulted in significantly increased levels of endostatin in vivo, whereas VEGF levels were unaffected. As previously shown, tamoxifen exposure by itself increased MMP activity in all treatment groups. Moreover, the combined therapy with AdMMP-9 and tamoxifen further reduced tumor growth and increased the endostatin levels compared with either treatment alone. Gene transfer of TIMP-1 had no effects on tumor progression and counteracted the therapeutic effect of tamoxifen in our breast cancer model. This is the first report showing that overexpression of MMP-9 results in increased generation of antiangiogenic fragments, decreased angiogenesis, and therapeutic effects of established breast cancer.

  • 27. Berglund, P
    et al.
    Stighall, M
    Jirström, K
    Rydén, L
    Ferno, M
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Landberg, G
    Cyclin E confers a prognostic value in premenopausal breast cancer patients with tumours exhibiting an infiltrative growth pattern2008In: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 61, no 2, p. 184-191Article in journal (Refereed)
    Abstract [en]

    Aims: To investigate the prognostic value of cyclin E in relation to tumour growth pattern by analysing stage II primary breast cancers from premenopausal women not subjected to any further adjuvant treatment. To analyse the value of cyclin E as a predictor of tamoxifen response, by comparing untreated and treated patients with oestrogen receptor positive tumours. Methods: Breast cancer samples, assembled in tissue microarrays, were immunohistochemically stained for cyclin E and evaluated regarding the presence of nuclear staining. The overall growth characteristics of each tumour were assessed using whole tissue sections. Results: Tumours displaying a pushing margin phenotype were strongly associated with high cyclin E levels, lymph node negative disease, a high histological grade and oestrogen receptor negativity, and exhibited a better prognosis compared to tumours with an infiltrative growth pattern. In the total cohort of non-treated patients (n = 187), cyclin E was not associated with recurrence free survival (RFS). However, when analysing the subgroup of tumours lacking a pushing growth pattern (n = 141), cyclin E was significantly associated with RFS, independent of histological grade and node status. There was no significant difference in tamoxifen response with regard to different cyclin E levels. Conclusion: The prognostic value of cyclin E in premenopausal breast cancer is limited to patients with breast carcinomas exhibiting an exclusively infiltrative growth pattern. This limitation could be explained by the presence of a small but distinct subgroup of cyclin E-high breast cancers with a pushing margin phenotype and a more favourable outcome.

  • 28.
    Bjorkholm, M.
    et al.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden, Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Derolf, A.R.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
    Hultcrantz, M.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden, Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Kristinsson, S.Y.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
    Ekstrand, C.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
    Goldin, L.R.
    National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
    Andreasson, B.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Birgegard, G.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Linder, O.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Malm, Claes
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology UHL.
    Markevarn, B.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Nilsson, L.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Samuelsson, J.
    Swedish Chronic Myeloproliferative Neoplasm Study Group, Stockholm, Sweden.
    Granath, F.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
    Landgren, O.
    Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
    Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms2011In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 29, no 17, p. 2410-2415Article in journal (Refereed)
    Abstract [en]

    Purpose: Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU). Methods: On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk. Results: Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P32), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P32 greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation. Conclusion: The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P32 and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors. © 2011 by American Society of Clinical Oncology.

  • 29.
    Blom, René
    et al.
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Guerrieri, C.
    Department of Pathology, St. Vincent's Hospital, New York, New York, USA.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Malmström, Helena
    Linköping University, Department of Molecular and Clinical Medicine.
    Simonsen, E.
    Leiomyosarcoma of the uterus: A clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 49 cases1998In: Gynecologic Oncology, ISSN 0090-8258, Vol. 68, no 1, p. 54-61Article in journal (Refereed)
    Abstract [en]

    AIM: The authors analyzed in a retrospective manner the prognostic significance of p53 and mdm-2 expression, DNA ploidy, S-phase fraction (SPF), and traditional clinical and pathological prognostic factors in patients with uterine leiomyosarcomas. MATERIAL: Forty-nine patients were diagnosed with uterine leiomyosarcoma (25 stage I, 4 stage II, 8 stage III, and 12 stage IV). DNA flow cytometric analysis and immunohistochemical staining for p53 and mdm-2 were performed on paraffin-embedded archival tissue from the uterine tumors. RESULTS: Of the 49 patients, 35 (71%) died of disease and 2 died of intercurrent disease. The 5-year survival rate was 33%. FIGO surgical stage, DNA ploidy, SPF, mitotic index, cellular atypia, and tumor grade obtained significance (P < 0.05) in a univariate survival analysis of the leiomyosarcomas. In a multivariate analysis with survival as the end point, stage was found to be the most important factor (P = 0.007); DNA ploidy (P = 0. 045) and SPF (P = 0.041) also had independent prognostic significance. For FIGO stage I tumors, DNA ploidy (P = 0.04) and tumor grade (P = 0.01) were statistically significant in a univariate analysis, while only grade had independent prognostic significance (P = 0.01) in a multivariate analysis. In a univariate analysis including only FIGO stage I and II tumors with disease-free survival as the end point, p53 overexpression (P = 0.0016), DNA ploidy (P = 0.042), and tumor grade (P = 0.008) obtained significance. In a multivariate analysis, only p53 had independent statistical significance (P = 0.01). All p53 immunopositive stage I-II tumors recurred within 28 months from diagnosis. CONCLUSION: This study found that stage represents the most important prognostic factor for uterine leiomyosarcomas. DNA ploidy and SPF had independent prognostic value. DNA flow cytometry is useful in gaining additional prognostic information. In stage I patients, tumor grade gives significant information regarding clinical outcome. In addition, p53 overexpression may predict a higher risk of recurrence in early stage leiomyosarcomas.

  • 30.
    Blom, René
    et al.
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Guerrieri, C.
    Department of Pathology, St. Vincent's Hospital, New York, New York, USA.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Malmström, Helena
    Linköping University, Department of Molecular and Clinical Medicine.
    Sullivan, S.
    Simonsen, E.
    Malignant mixed Mullerian tumors of the uterus: a clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 44 cases1998In: Gynecologic Oncology, ISSN 0090-8258, Vol. 68, no 1, p. 18-24Article in journal (Refereed)
    Abstract [en]

    AIM: The authors retrospectively analyzed the prognostic significance of p53, mdm-2, DNA ploidy, S-phase fraction (SPF), and traditional clinical and pathologic factors in patients with malignant mixed Müllerian tumors (MMMT) of the uterus. METHODS: Between 1970 and 1995, 44 uterine tumors were diagnosed as MMMT (21 stage I, 2 stage II, 10 stage III, and 11 stage IV). Thirty-two were homologous type and 12 were heterologous type. DNA flow cytometry and immunohistochemical analysis for p53 and mdm-2 overexpression were performed on paraffin-embedded archival tissue. RESULTS: 68% of the tumors were nondiploid and 61% had an SPF greater than 10%. Sixty-one percent overexpressed p53 and 25% were mdm-2-positive. Furthermore, 91% of the tumors had a mitotic count greater than 10/10 hpf and 95% had high-grade cytologic atypia. Twenty-seven (61%) patients died of tumor and 6 (14%) died of intercurrent disease. Eleven (25%) patients are alive with no evidence of disease. The median follow-up for patients still alive was 59 months (range, 28-178 months). The overall 5-year survival rate was 38%. In a univariate analysis that included stage, histologic type, DNA ploidy, SPF, p53, mdm-2, mitotic index, and age, and with survival as the end point, only stage reached statistically prognostic significance. CONCLUSION: The majority of the tumors had obvious signs of aggressiveness such as high grade, high mitotic count, nondiploid pattern, high SPF, and overexpression of p53. This study found that stage is the most important prognostic factor for survival in MMMTs of the uterus.

  • 31.
    Bojmar, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Ellegard, Sander
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Björnsson, Bergthor
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Hallböök, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    The Role of MicroRNA-200 in Progression of Human Colorectal and Breast Cancer2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. 84815-Article in journal (Refereed)
    Abstract [en]

    The role of the epithelial-mesenchymal transition (EMT) in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200 ZEB E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMTmarkers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200 - ZEB - E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.

  • 32.
    Bostner, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Ahnström Waltersson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Fornander, T
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Skoog, L
    Department of Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer.2007In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 26, no 49, p. 6997-7005Article in journal (Refereed)
    Abstract [en]

    The 11q13 region is amplified in approximately 15% of all breast tumors. Situated in this region are the cyclin D1 gene (CCND1) and the p-21-activated kinase 1 (PAK1) gene. Both genes encode proteins shown to activate the estrogen receptor (ER), leading to transcription of CCND1 and other ER-responsive genes. Here, we investigate the prognostic and treatment predictive role of CCND1 and PAK1 gene amplification in postmenopausal breast cancer patients randomized to tamoxifen treatment or no adjuvant treatment. Amplification of CCND1 and PAK1, assessed by real-time PCR, was observed in 12.5 and 9.3%, respectively. Amplification of PAK1 was seen in 37% of the CCND1-amplified tumors, indicating coamplification (P<0.001). In ER-positive patients, amplification of at least one of the genes indicated a reduced recurrence-free survival (P=0.025). When response to tamoxifen treatment was analysed, patients with PAK1 amplification showed decreased benefit from the drug (ER+; relative risk ratio (RR)=1.62; 95% confidence interval (CI), 0.47-5.55) compared to patients without amplification (ER+; RR=0.53; 95% CI, 0.32-0.88). This was not evident for CCND1 amplification. We show that PAK1 may be a predictor of tamoxifen resistance and furthermore, we do not discard PAK1 as a potential candidate oncogene in the 11q13 amplicon. In addition, we show that high pak1 protein levels may predict tamoxifen insensitivity.

  • 33.
    Bostner, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Fornander, T
    Karolinska Instititute.
    Skoog, L
    Karolinska Instititute.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Stal, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Estrogen Receptor alpha Phosphorylation on Serine 305, p21-Activated Kinase 1 and Tamoxifen Response in Postmenopausal Breast Cancer in CANCER RESEARCH, vol 69, issue 24, pp 596S-596S2009In: CANCER RESEARCH, 2009, Vol. 69, no 24, p. 596S-596SConference paper (Refereed)
    Abstract [en]

    n/a

  • 34.
    Bostner, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Bivik, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Perez-Tenorio, Gizeh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Franzén, Hanna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Konstantinell, Aelita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    S6 kinase signaling and tamoxifen response in breast cancer cells and in two randomized breast cancer cohorts2013Manuscript (preprint) (Other academic)
    Abstract [en]

    Detecting signals in the mammalian target of rapamycin (mTOR), and the estrogen receptor (ER) pathways for prediction of treatment response may be a future clinical tool in primary breast cancer. Here, we investigated the validity and value of the mTOR targets p70-S6 kinase (S6K) 1 and 2 as biomarkers for tamoxifen sensitivity in vitro and in two independent tamoxifen randomized postmenopausal breast cancer cohorts. In addition, the prognostic value of the S6Ks was evaluated. A simultaneous knockdown of the S6Ks in ER-positive breast cancer cells resulted in G1 arrest, and tamoxifen-induced G1 arrest was in part S6K1+S6K2 dependent, suggesting separate roles in proliferation and in tamoxifen response. We found S6K1 to correlate with HER2 and cytoplasmic Akt activity, whereas S6K2 and phosphorylated S6K were closer connected with ER positivity, low proliferation and nucleic p-Akt. Treatment prediction and prognosis were evaluated by immunohistochemical staining. Nuclear accumulation of S6K1 was indicative of a reduced tamoxifen treatment effect, compared with a significant benefit from tamoxifen treatment in patients without tumor S6K1 nuclear accumulation. Patients with a combination of S6K1 nuclear accumulation and S6K2 cytoplasmic accumulation in the tumor cells had no tamoxifen benefit. Also, S6K1 and S6K2 activation, indicated by p-S6K-t389 expression, was associated with low benefit from tamoxifen compared with untreated patients. In addition, high protein expression of S6K1, independent of localization, predicted worse prognosis. This was not evident for variations in S6K2 or p-S6K-t389 expression.

    In conclusion, the mTOR targeted kinases S6K1 and S6K2 interfere with proliferation and response to tamoxifen. Monitoring their activity andintracellular localization may provide biomarkers for breast cancer treatment, allowing for identification of a group of patients less likely tobenefit from tamoxifen and thus in need of an alternative or additional treatment.

  • 35.
    Bostner, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Pandiyan, Muneeswaran J.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Westman, Hanna
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Stockholm S Gen Hospital, Sweden .
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit2013In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 137, no 2, p. 397-406Article in journal (Refereed)
    Abstract [en]

    The frequent alterations of the PI3K/Akt/mTOR-growth signaling pathway are proposed mechanisms for resistance to endocrine therapy in breast cancer, partly through regulation of estrogen receptor alpha (ER) activity. Reliable biomarkers for treatment prediction are required for improved individualized treatment. We performed a retrospective immunohistochemical analysis of primary tumors from 912 postmenopausal patients with node-negative breast cancer, randomized to either tamoxifen or no adjuvant treatment. Phosphorylated (p) Akt-serine (s) 473, p-mTOR-s2448, and ER phosphorylations-s167 and -s305 were evaluated as potential biomarkers of prognosis and tamoxifen treatment efficacy. High expression of p-mTOR indicated a reduced response to tamoxifen, most pronounced in the ER+/progesterone receptor (PgR) + subgroup (tamoxifen vs. no tamoxifen: hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.31-2.38; P = 0.78), whereas low p-mTOR expression predicted tamoxifen benefit (HR, 0.29; 95 % CI, 0.18-0.49; P = 0.000002). In addition, nuclear p-Akt-s473 as well as p-ER at -s167 and/or -s305 showed interaction with tamoxifen efficacy with borderline statistical significance. A combination score of positive pathway markers including p-Akt, p-mTOR, and p-ER showed significant association with tamoxifen benefit (test for interaction; P = 0.029). Cross-talk between growth signaling pathways and ER-signaling has been proposed to affect tamoxifen response in hormone receptor-positive breast cancer. The results support this hypothesis, as an overactive pathway was significantly associated with reduced response to tamoxifen. A clinical pre-treatment test for cross-talk markers would be a step toward individualized adjuvant endocrine treatment with or without the addition of PI3K/Akt/mTOR pathway inhibitors.

  • 36.
    Bostner, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Skoog, Lambert
    Karolinska University Hospital.
    Fornander, Tommy
    Karolinska University Hospital.
    Nordenskjöld, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Estrogen Receptor-alpha Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer2010In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 5, p. 1624-1633Article in journal (Refereed)
    Abstract [en]

    Purpose: In vitro, p21-activated kinase 1 (Pak1) phosphorylates the serine 305 residue of the estrogen receptor alpha (ER alpha) and influences the response of breast cancer cells to tamoxifen. We investigated the influence of Pak1 and pER alpha(ser305) on breast cancer prognosis and results of tamoxifen therapy. Experimental Design: We examined Pak1 and pER alpha(ser305) protein by immunohistochemistry in a series of 912 tumors from node-negative breast cancer patients randomized to tamoxifen or no adjuvant endocrine treatment. Results: Cytoplasmic Pak1 correlated to large tumors and ER negativity, whereas nuclear Pak1 and pER alpha(ser305) correlated to small tumors and ER positivity. Nuclear expression of Pak1 and pER alpha(ser305) predicted reduced response to tamoxifen in patients with ER alpha-positive tumors (tamoxifen versus no tamoxifen: hazard ratio (HR), 1.33; 95% confidence interval (95% CI), 0.42-4.2; P = 0.63), whereas patients lacking this combination benefitted significantly from tamoxifen (HR, 0.43; 95% CI, 0.30-0.62; P less than 0.0001). Similar nonsignificant trends were detected in analyses of the proteins separately. Pak1 in the cytoplasm was an independent prognostic marker, indicating increased recurrence rate (HR, 1.79; 95% CI, 1.17-2.74; P = 0.0068) and breast cancer mortality (HR, 1.98; 95% CI, 1.14-3.46; P = 0.016) for patients randomized to no adjuvant treatment. Conclusion: Our results suggest that patients with tumors expressing Pak1 and pER alpha(ser305) in combination are a group in which tamoxifen treatment is insufficient. In addition, the pathway may be of interest as a drug target in breast cancer. Furthermore, the findings support previous studies showing that Pak1 has differential roles in the cytoplasm and the nucleus.

  • 37.
    Bu, Huajie
    et al.
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Rosdahl, Inger
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Dermatology and Venerology in Östergötland.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Holmdahl-Källenand, Katarina
    Zhang, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences.
    Importance of polymorphisms at NF-κB1 and NF-κBIα genes in melanoma risk, clinicopathological features and tumor progression in Swedish melanoma patients2007In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 133, no 11, p. 859-866Article in journal (Refereed)
    Abstract [en]

    In this study, functional polymorphisms of NF-κB1 and NF-κBIα genes were examined in 185 melanoma patients and 438 tumor-free individuals. Associations of the polymorphisms with melanoma risk, age and pigment phenotypes of the patients and clinico-pathological tumor characteristics were analyzed. DNAs were isolated from mononuclear cells of venous blood. Polymorphisms of the genes were genotyped by a PCR-RFLP technique, and transcription level of NF-κBIα was examined by a quantitative real-time reverse transcription PCR. Results showed that both ATTG insertion polymorphism of NF-κB1 and A to G polymorphism of NF-κBIα genes were correlated with melanoma risk, especially, in a combination of ATTG2/ATTGT2 and GG. NF-κB1 ATTG2/ATTG2 and NF-κBIα GG genotypes were associated with male gender and age > 65 years (at diagnosis). Patients with ATTG1/ATTG1 genotype had thinner tumors and lower Clark levels at diagnosis. Frequency of ATTG1/ATTG1 genotype was higher in patients with melanomas on intermittently sun-exposed pattern of the body and NF-κBIα GG was more frequent in the patients with melanomas at rarely exposed sites. There were no differences in the gene transcription level between patients with different NF-κBIα genotypes. These data suggest that NF-κB1 and NF-κBIα genes might be susceptible genes for melanoma risk and functional polymorphisms of these genes might be biological predictors for melanoma progression.

  • 38.
    Bu, Huajie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences.
    Rosdahl, Inger
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Dermatology and Venerology in Östergötland.
    Sun, Xiao-Feng
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Zhang, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology. Linköping University, Faculty of Health Sciences.
    Genotype < 21CAs/>= 21CAs and allele < 21CAs of the MANBA gene in melanoma risk and progression in a Swedish population2009In: Molecular medicine reports, ISSN 1791-2997, Vol. 2, no 2, p. 259-263Article in journal (Refereed)
    Abstract [en]

    Cutaneous melanoma is characterized by poor patient outcome in its later stages. The search for genetic markers is therefore crucial for the identification of populations at risk for melanoma. Highly polymorphic CA repeats in 3 proximity in the MANBA gene were examined by PCR-capillary electrophoresis in 185 Swedish melanoma patients and 441 tumor-free age- and gender-matched individuals. The associations of the polymorphisms with melanoma risk, the pigment phenotypes of the patients and tumor characteristics were analyzed. A significant difference in allelic distribution between melanoma patients and tumor-free individuals was observed. The frequency of the MANBA genotype <21CAs/>= 21CAs was significantly higher in melanoma patients than in the controls. When comparing allele distribution in patients and their matched controls, the allele <21 CAs was found to be associated with the female gender (39.8 vs. 31.2%, P=0.041, OR=1.46, 95% Cl 1.02-2.10), but not with male gender (34.4 vs. 30.9%, P=0.39). Within the melanoma group, there were no differences in the distribution of the MANBA alleles associated with patient gender or age before or after 55 years at diagnosis, nor was there any association between the MANBA genotype and pigment phenotype or tumor sites. The MANBA allele <21CAs was, however, associated with thin melanomas at diagnosis (Breslow thickness <= 1.5 mm and Clark levels I and II). In conclusion, these data suggest that MANBA polymorphisms might be an indicator of tumor growth and progression and, together with other markers, could be used to identify individuals at increased risk of melanoma.

  • 39.
    Busch, Susann
    et al.
    University of Manchester, England .
    Ryden, Lisa
    University of Lund Hospital, Sweden .
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Jirstrom, Karin
    Lund University, Sweden .
    Landberg, Goran
    University of Manchester, England Lund University, Sweden Gothenburg University, Sweden .
    Low ERK Phosphorylation in Cancer-Associated Fibroblasts Is Associated with Tamoxifen Resistance in Pre-Menopausal Breast Cancer2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9Article in journal (Refereed)
    Abstract [en]

    Purpose: The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial. less thanbrgreater than less thanbrgreater thanPatients and Methods: Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK) and smooth muscle actin-alpha expression (SMA alpha) in cancer-associated fibroblasts (CAFs) and links to clinico-pathological data and treatment-predictive values were delineated. less thanbrgreater than less thanbrgreater thanResults: By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not respond to tamoxifen treatment despite having estrogen-receptor alpha (ER alpha-positive tumors compared to patients with high pERK levels in CAFs (P = 0.015, multivariate Cox regression interaction analysis). In both clinical materials we further show a significant association between pERK and SMA alpha, a characteristic marker for activated fibroblasts. SMA alpha expression however was not linked to treatment-predictive information but instead had prognostic qualities. less thanbrgreater than less thanbrgreater thanConclusion: The data suggests that the presence of a subpopulation of CAFs, defined by minimal activated ERK signaling, is linked to an impaired tamoxifen response. Thus, this report illustrates the importance of the stroma for monitoring treatment effects in pre-menopausal breast cancer.

  • 40.
    Börjeson, Sussanne
    et al.
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Starkhammar, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Berterö, Carina
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Common symptoms experienced among patients with colorectal cancer, and barriers to reporting symptoms or distress; the staff perspective2011In: Austral-Asian Journal of Cancer, ISSN 0972-2556, Vol. 10, no 1, p. 12-20Article in journal (Refereed)
  • 41.
    Börjeson, Sussanne
    et al.
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Starkhammar, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Unosson, Mitra
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Health Sciences.
    Berterö, Carina
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Common Symptoms and Distress Experienced Among Patients with Colorectal Cancer: A Qualitative part of Mixed Method Design2012In: Open Nursing Journal, ISSN 1874-4346, E-ISSN 1874-4346, Vol. 6, no 1, p. 100-107Article in journal (Refereed)
    Abstract [en]

    Background :

    Colorectal cancer is one of the most common types of tumour in the world. Treatment side effects, together with the tumour symptoms, can result in a ‘symptom burden’. To understand the patient’s burden during chemotherapy treatment and plan effective symptom relief there is a need for more knowledge about the experience of symptoms from the patients’ perspective.

    Objectives :

    The study was designed to qualitatively identify and describe the most common symptoms among patients treated for colorectal cancer, and discover whether there are barriers to reporting symptoms.

    Methods :

    Thirteen Swedish patients diagnosed with colorectal cancer and treated with chemotherapy were interviewed face-to-face. The interviews were audio-taped and transcribed verbatim. The transcripts were analysed by following the principles of qualitative content analysis.

    Results :

    Nine symptoms/forms of distress were identified. Those most frequently expressed were fatigue, changed bowel habits, and affected mental well-being, closely followed by nausea, loss of appetite and neurological problems. Of particular note were the affected mental well-being, the magnitude of the neurological problems described, the symptoms related to skin and mucous membrane problems, and the reports of distressing pain. Barriers to symptom control were only expressed by the patients in passing and very vaguely.

    Conclusion :

    This study confirms other reports on most common symptoms in colorectal cancer. It also highlights the early onset of symptoms and provides data on less well-studied issues that warrant further study, namely affected mental well-being, the magnitude of the neurological problems and symptoms related to the skin and mucous membranes. Nurses need to be sensitive to the patients’ need presented and not only noting symptoms/distresses they have guidelines for.

  • 42.
    Carlsson, Björn
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Olsson, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Reis, Margareta
    Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
    Wålinder, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Nordin, Conny
    Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Lundmark, Jöns
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Scordo, M. G.
    Dahl, M-L.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Enantioselective Analysis of Citalopram and Metabolites in Adolescents2001In: Therapeutic drug monitoring, ISSN 0163-4356, Vol. 23, no 6, p. 658-664Article in journal (Refereed)
    Abstract [en]

    Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent despite its increasing use in these age groups. The aim of this study was to investigate a group of adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites desmethylcitalopram and didesmethylcitalopram. Moreover, the authors studied the genotypes for the polymorphic cytochrome P450 enzymes CYP2D6 and CYP2C19 in relation to the different enantiomers. The S/R ratios of citalopram and desmethylcitalopram found in this study of 19 adolescents were similar to studies involving older patients. The concentrations of the R-(-)- and S-(+)-enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies, the R-(-)-enantiomer (distomer) being the major enantiomer. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the CYP2C19 enzyme.

  • 43. Carlsson, L
    et al.
    Håkansson, Annika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Common cancer-related symptoms among GP patients - Opportunistic screening in primary health care2001In: Scandinavian Journal of Primary Health Care, ISSN 0281-3432, E-ISSN 1502-7724, Vol. 19, no 3, p. 199-203Article in journal (Refereed)
    Abstract [en]

    Objective-To study the occurrence of symptoms related to the five most common forms of cancer among patients regularly visiting primary care. To estimate the proportion of symptoms needing GP examination, and the number of tumours thus diagnosed. Design-Patients with some form of non-malignant chronic disease received a letter with information about cancer-related symptoms along with an invitation to regular check-up. The letter described the most common symptoms of breast, colorectal, lung, prostate and skin cancers. Setting-12 health centres in Kalmar County, Sweden. Subjects-5200 patients aged over 40 years. Results-One patient in 13 reported cancer-related symptoms to the GP. Women reported more symptoms than men, and almost half of them had had symptoms at previous check-ups. The GP was able to explain 7 out of 10 patients' symptoms directly. When other symptoms were examined, 8 cancers were diagnosed as well as 6 pre-malignant tumours, corresponding to 3 tumour diagnoses per 1000 check-ups. Conclusion-While attending regular check-ups, patients may not report symptoms which cause anxiety and sometimes indicate serious diseases. It is possible to widen the perspective and link both primary and secondary prevention of certain cancers to the check-up.

  • 44.
    Celik, Betul
    et al.
    Antalya Education and Research Hospital, Turkey.
    Didem Yalcin, Arzu
    Antalya Education and Research Hospital, Turkey.
    Bisgin, Atil
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Dimitrakopoulou-Strauss, Antonia
    German Cancer Research Centre, Heidelberg, Germany.
    Kargi, Aysegül
    Antalya Education and Research Hospital, Turkey.
    Strauss, Ludwig G.
    German Cancer Research Centre, Heidelberg, Germany.
    Level of TNF-related apoptosis-inducing-ligand and CXCL8 correlated with 2-[18F]Fluoro-2-deoxy-D-glucose uptake in anti-VEGF treated colon cancers2013In: Medical Science Monitor, ISSN 1234-1010, E-ISSN 1643-3750, Vol. 19, p. 875-882Article in journal (Refereed)
    Abstract [en]

    Background

    The changes and correlations of TRAIL (TNF-related apoptosis-inducing-ligand) and CXCL8 (IL8) prior to treatment and three months following therapy as well as the corresponding Positron emission tomography (PET/CT) (SUVmax: standardized uptake maximum values) results were evaluated.

    Material/Methods

    The measurements were taken before and after treatment for comparison purposes. The study population comprised 29 patients with Metastatic Colorectal cancer (MCRC), undergoing PET/CT scanning prior to treatment.

    Results

    There were significant changes prior to treatment and three months later for sTRAIL (p=0.0080) and CXCL8 (p=0.0001)values. Generally, sTRAIL values were increasing during therapy, while a decrease was observed for CXCL8. Correlation analysis was applied to the data and revealed significant correlations for the SUVmax in the primary tumor prior to treatment and CXCL8 prior to therapy (p=0.0303). Furthermore, significant correlations were observed for the SUVmax and sTRAIL (p=0.0237) as well as CXCL8 (p=0.0002) three months after treatment initiation. CXCL8 prior to treatment was also correlated with the SUV three months after onset of treatment (p=0.0072). A significant correlation was noted for one combination of two variables, the SUVmax in the metastases and CXCL8 prior to treatment (p=0.0175). These results are supported when we group the SUVmax in the metastases following treatment into two groups with SUVmax <5 and SUVmax >5.

    Conclusions

    This study provides evidence that proteomics patterns of sTRAIL and CXCL8 predict tumor response und survival in MCRC patients treated with bevacizumab and within a high concordance of FDG-PET/CT findings.

  • 45.
    Chavez Sanchez, B
    et al.
    Karolinska Institute & University Hospital.
    Sundqvist, M
    Kalmar Hospital.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Linderholm, B
    PROLONGED TAMOXIFEN TREATMENT INCREASES SURVIVAL FOR PATIENTS WITH PRIMARY BREAST CANCERS EXPRESSING HIGH LEVELS OF VEGF2009In: in ANNALS OF ONCOLOGY, vol 20, 2009, Vol. 20, p. 47-47Conference paper (Refereed)
  • 46.
    Couch, Fergus J.
    et al.
    Mayo Clin, MN USA.
    Wang, Xianshu
    Mayo Clin, MN USA.
    McGuffog, Lesley
    University of Cambridge, England.
    Lee, Andrew
    University of Cambridge, England Mayo Clin, MN USA.
    Olswold, Curtis
    Mayo Clin, MN USA.
    Kuchenbaecker, Karoline B.
    University of Cambridge, England.
    Soucy, Penny
    Centre Hospital University of Quebec, Canada University of Laval, Canada.
    Fredericksen, Zachary
    Mayo Clin, MN USA.
    Barrowdale, Daniel
    University of Cambridge, England.
    Dennis, Joe
    University of Cambridge, England.
    Gaudet, Mia M.
    Amer Cancer Soc, GA USA.
    Dicks, Ed
    University of Cambridge, England.
    Kosel, Matthew
    Mayo Clin, MN USA.
    Healey, Sue
    Queensland Institute Medical Research, Australia.
    Sinilnikova, Olga M.
    Hospital Civils Lyon, France University of Lyon 1, France.
    Lee, Adam
    University of Cambridge, England Mayo Clin, MN USA.
    Bacot, Francois
    Centre Innovat Genome Quebec, Canada McGill University, Canada.
    Vincent, Daniel
    Centre Innovat Genome Quebec, Canada McGill University, Canada.
    Hogervorst, Frans B. L.
    Netherlands Cancer Institute, Netherlands.
    Peock, Susan
    University of Cambridge, England.
    Stoppa-Lyonnet, Dominique
    Institute Curie, France University of Paris 05, France.
    Jakubowska, Anna
    Pomeranian Medical University, Poland.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy.
    Schmutzler, Rita Katharina
    University Hospital Cologne, Germany.
    Domchek, Susan M.
    University of Penn, PA USA.
    Piedmonte, Marion
    Roswell Pk Cancer Institute, NY USA.
    Singer, Christian F.
    Medical University of Vienna, Austria.
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel.
    Thomassen, Mads
    Odense University Hospital, Denmark.
    Hansen, Thomas V. O.
    Copenhagen University Hospital, Denmark.
    Neuhausen, Susan L.
    City Hope National Medical Centre, CA USA.
    Szabo, Csilla I.
    University of Delaware, DE USA.
    Blanco, Ignacio
    IDIBELL Catalan Institute Oncol, Spain.
    Greene, Mark H.
    NCI, MD USA.
    Karlan, Beth Y.
    Cedars Sinai Medical Centre, CA USA.
    Garber, Judy
    Dana Farber Cancer Institute, MA USA.
    Phelan, Catherine M.
    University of S Florida, FL USA.
    Weitzel, Jeffrey N.
    City Hope National Medical Centre, CA USA.
    Montagna, Marco
    Ist Oncology Veneto IOV IRCCS, Italy.
    Olah, Edith
    National Institute Oncol, Hungary.
    Andrulis, Irene L.
    Mt Sinai Hospital, Canada.
    Godwin, Andrew K.
    University of Kansas, KS USA.
    Yannoukakos, Drakoulis
    National Centre Science Research Demokritos, Greece .
    Goldgar, David E.
    University of Utah, UT USA .
    Caldes, Trinidad
    Hospital Clin San Carlos, Spain .
    Nevanlinna, Heli
    University of Helsinki, Finland .
    Osorio, Ana
    Spanish National Cancer Centre CNIO, Spain Biomed Network Rare Disease CIBERER, Spain .
    Terry, Mary Beth
    Columbia University, NY USA .
    Daly, Mary B.
    Fox Chase Cancer Centre, PA USA .
    van Rensburg, Elizabeth J.
    University of Pretoria, South Africa.
    Hamann, Ute
    Deutsch Krebsforschungszentrum DKFZ, Germany .
    Ramus, Susan J.
    University of So Calif, CA USA .
    Ewart Toland, Amanda
    Ohio State University, OH USA .
    Caligo, Maria A.
    University of Pisa, Italy.
    Olopade, Olufunmilayo I.
    University of Chicago, IL USA .
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA USA .
    Claes, Kathleen
    Ghent University Hospital, Belgium .
    Beattie, Mary S.
    University of Calif San Francisco, CA USA .
    Southey, Melissa C.
    University of Melbourne, Australia .
    Imyanitov, Evgeny N.
    NN Petrov Oncology Research Institute, Russia .
    Tischkowitz, Marc
    McGill University, Canada .
    Janavicius, Ramunas
    Vilnius University Hospital Santariskiu Clin, Lithuania .
    John, Esther M.
    Cancer Prevent Institute Calif, CA USA .
    Kwong, Ava
    Hong Kong Sanat and Hospital, Peoples R China .
    Diez, Orland
    University Hospital Vall dHebron, Spain Vall dHebron Institute Oncology VHIO, Spain .
    Balmana, Judith
    University Hospital, Spain .
    Barkardottir, Rosa B.
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
    Arun, Banu K.
    University of Texas MD Anderson Cancer Centre, TX USA .
    Rennert, Gad
    Clalit National Israeli Cancer Control Centre, Israel Carmel Hospital, Israel B Rappaport Fac Med, Israel .
    Teo, Soo-Hwang
    University of Malaya, Malaysia .
    Ganz, Patricia A.
    University of Calif Los Angeles, CA USA .
    Campbell, Ian
    Peter MacCallum Cancer Centre, Australia .
    van der Hout, Annemarie H.
    University of Groningen, Netherlands .
    van Deurzen, Carolien H. M.
    Erasmus University, Netherlands .
    Seynaeve, Caroline
    Erasmus University, Netherlands .
    Gomez Garcia, Encarna B.
    MUMC, Netherlands .
    van Leeuwen, Flora E.
    Netherlands Cancer Institute, Netherlands .
    Meijers-Heijboer, Hanne E. J.
    Vrije University of Amsterdam Medical Centre, Netherlands .
    Gille, Johannes
    Vrije University of Amsterdam Medical Centre, Netherlands .
    Ausems, Margreet G. E. M.
    University of Medical Centre Utrecht, Netherlands .
    Blok, Marinus J.
    Maastricht University of Medical Centre, Netherlands .
    Ligtenberg, Marjolijn J. L.
    Radboud University of Nijmegen, Netherlands.
    Rookus, Matti A.
    Netherlands Cancer Institute, Netherlands .
    Devilee, Peter
    Leiden University, Netherlands .
    Verhoef, Senno
    Netherlands Cancer Institute, Netherlands .
    van Os, Theo A. M.
    University of Amsterdam, Netherlands .
    Wijnen, Juul T.
    Leiden University, Netherlands .
    Frost, Debra
    University of Cambridge, England .
    Ellis, Steve
    University of Cambridge, UK.
    Fineberg, Elena
    University of Cambridge, England .
    Platte, Radka
    University of Cambridge, England .
    Evans, Gareth D.
    Central Manchester University Hospital NHS Fdn Trust, England .
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust, England .
    Eeles, Rosalind A.
    Institute Cancer Research, England Royal Marsden NHS Fdn Trust, England .
    Adlard, Julian
    Yorkshire Regional Genet Serv, England .
    Eccles, Diana M.
    University of Southampton, England .
    Cook, Jackie
    Sheffield Childrens Hospital, England .
    Brewer, Carole
    Royal Devon and Exeter Hospital, England .
    Douglas, Fiona
    Newcastle Upon Tyne Hospital NHS Trust, England .
    Hodgson, Shirley
    St Georges University of London, England .
    Morrison, Patrick J.
    Belfast Health and Social Care Trust, North Ireland Queens University of Belfast, North Ireland .
    Side, Lucy E.
    Great Ormond St Hospital Sick Children, England UCL, England .
    Donaldson, Alan
    St Michaels Hospital, England .
    Houghton, Catherine
    Liverpool Womens NHS Fdn Trust, England .
    Rogers, Mark T.
    University of Wales Hospital, Wales .
    Dorkins, Huw
    Kennedy Galton Centre, England .
    Eason, Jacqueline
    Nottingham University Hospital NHS Trust, England .
    Gregory, Helen
    NHS Grampian, Scotland University of Aberdeen, Scotland .
    McCann, Emma
    Glan Clwyd Hospital, Rhyl, UK.
    Murray, Alex
    Singleton Hospital, Wales .
    Calender, Alain
    Hospital Civils Lyon, France .
    Hardouin, Agnes
    Centre Francois Baclesse, France .
    Berthet, Pascaline
    Centre Francois Baclesse, France .
    Delnatte, Capucine
    Centre Rene Gauducheau, France .
    Nogues, Catherine
    Hop Rene Huguenin, France .
    Lasset, Christine
    Centre Leon Berard, France University of Lyon 1, France .
    Houdayer, Claude
    Institute Curie, France University of Paris 05, France .
    Leroux, Dominique
    CHU Grenoble, France University of Grenoble, France .
    Rouleau, Etienne
    Hop Rene Huguenin, France .
    Prieur, Fabienne
    Centre Hospital University of St Etienne, France .
    Damiola, Francesca
    University of Lyon 1, France .
    Sobol, Hagay
    University of Aix Marseille 2, France .
    Coupier, Isabelle
    CHU Arnaud de Villeneuve, France CRLCC Val dAurelle, France .
    Venat-Bouvet, Laurence
    Centre Hospital University of Dupuytren, France .
    Castera, Laurent
    Institute Curie, France .
    Gauthier-Villars, Marion
    Institute Curie, France .
    Leone, Melanie
    Hospital Civils Lyon, France .
    Pujol, Pascal
    CHU Arnaud de Villeneuve, France CRCM Val dAurelle, France .
    Mazoyer, Sylvie
    University of Lyon 1, France .
    Bignon, Yves-Jean
    University of Clermont Ferrand, France .
    Zlowocka-Perlowska, Elzbieta
    Pomeranian Medical University, Poland .
    Gronwald, Jacek
    Pomeranian Medical University, Poland .
    Lubinski, Jan
    Pomeranian Medical University, Poland .
    Durda, Katarzyna
    Pomeranian Medical University, Poland .
    Jaworska, Katarzyna
    Pomeranian Medical University, Poland Warsaw Medical University, Poland .
    Huzarski, Tomasz
    Pomeranian Medical University, Poland .
    Spurdle, Amanda B.
    Queensland Institute Medical Research, Australia .
    Viel, Alessandra
    IRCCS, Italy .
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Italy .
    Bonanni, Bernardo
    Ist Europeo Oncol, Italy .
    Melloni, Giulia
    Fdn IRCCS Ist Nazl Tumori INT, Italy .
    Ottini, Laura
    University of Roma La Sapienza, Italy .
    Papi, Laura
    University of Florence, Italy .
    Varesco, Liliana
    IRCCS AOU San Martino IST Ist Nazl Ric Canc, Italy .
    Grazia Tibiletti, Maria
    Osped Circolo University of Insubria, Italy .
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Volorio, Sara
    Fdn Ist FIRC Oncology Mol, Italy Cogentech Cancer Genet Test Lab, Italy .
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Italy .
    Pensotti, Valeria
    Fdn Ist FIRC Oncology Mol, Italy Cogentech Cancer Genet Test Lab, Italy .
    Arnold, Norbert
    University of Kiel, Germany .
    Engel, Christoph
    University of Leipzig, Germany .
    Deissler, Helmut
    University Hospital Ulm, Germany .
    Gadzicki, Dorothea
    Hannover Medical Sch, Germany .
    Gehrig, Andrea
    University of Wurzburg, Germany .
    Kast, Karin
    Technical University of Dresden, Germany .
    Rhiem, Kerstin
    University Hospital Cologne, Germany .
    Meindl, Alfons
    Technical University of Munich, Germany .
    Niederacher, Dieter
    University of Dusseldorf, Germany .
    Ditsch, Nina
    University of Munich, Germany .
    Plendl, Hansjoerg
    University of Kiel, Germany .
    Preisler-Adams, Sabine
    University of Munster, Germany .
    Engert, Stefanie
    Technical University of Munich, Germany .
    Sutter, Christian
    Heidelberg University, Germany .
    Varon-Mateeva, Raymonda
    Institute Medical and Human Genet, Germany .
    Wappenschmidt, Barbara
    University Hospital Cologne, Germany.
    Weber, Bernhard H. F.
    University of Regensburg, Germany .
    Arver, Brita
    Karolinska University Hospital, Sweden .
    Stenmark-Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Loman, Niklas
    University of Lund Hospital, Sweden .
    Rosenquist, Richard
    Uppsala University, Sweden .
    Einbeigi, Zakaria
    Sahlgrens University Hospital, Sweden .
    Nathanson, Katherine L.
    University of Penn, PA USA .
    Rebbeck, Timothy R.
    University of Penn, PA USA .
    Blank, Stephanie V.
    NYU, NY USA .
    Cohn, David E.
    Ohio State University, OH USA .
    Rodriguez, Gustavo C.
    University of Chicago, IL USA .
    Small, Laurie
    Maine Womens Surg and Cancer Centre, ME USA .
    Friedlander, Michael
    Australia New Zealand GOG, Australia .
    Bae-Jump, Victoria L.
    University of N Carolina, NC USA .
    Fink-Retter, Anneliese
    Medical University of Vienna, Austria .
    Rappaport, Christine
    Medical University of Vienna, Austria.
    Gschwantler-Kaulich, Daphne
    Medical University of Vienna, Austria .
    Pfeiler, Georg
    Medical University of Vienna, Austria.
    Tea, Muy-Kheng
    Medical University of Vienna, Austria .
    Lindor, Noralane M.
    Mayo Clin Arizona, AZ USA .
    Kaufman, Bella
    Chaim Sheba Medical Centre, Israel .
    Shimon Paluch, Shani
    Chaim Sheba Medical Centre, Israel .
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel .
    Skytte, Anne-Bine
    Vejle Hospital, Denmark .
    Gerdes, Anne-Marie
    Rigshosp, Denmark .
    Sokilde Pedersen, Inge
    Aalborg University Hospital, Denmark .
    Traasdahl Moeller, Sanne
    Odense University Hospital, Denmark .
    Kruse, Torben A.
    Odense University Hospital, Denmark .
    Birk Jensen, Uffe
    Aarhus University Hospital, Denmark .
    Vijai, Joseph
    Mem Sloan Kettering Cancer Centre, NY USA .
    Sarrel, Kara
    Mem Sloan Kettering Cancer Centre, NY USA .
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY USA .
    Kauff, Noah
    Mem Sloan Kettering Cancer Centre, NY USA .
    Mulligan, Anna Marie
    University of Toronto, Canada St Michaels Hospital, Canada.
    Glendon, Gord
    Mt Sinai Hospital, Canada .
    Ozcelik, Hilmi
    Mt Sinai Hospital, Canada University of Toronto, Canada .
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark .
    Nielsen, Finn C.
    Copenhagen University Hospital, Denmark .
    Jonson, Lars
    Copenhagen University Hospital, Denmark .
    Andersen, Mette K.
    Copenhagen University Hospital, Denmark .
    Chun Ding, Yuan
    City Hope National Medical Centre, CA USA .
    Steele, Linda
    City Hope National Medical Centre, CA USA .
    Foretova, Lenka
    Masaryk Mem Cancer Institute, Czech Republic .
    Teule, Alex
    IDIBELL Catalan Institute Oncol, Spain .
    Lazaro, Conxi
    IDIBELL Catalan Institute Oncol, Spain .
    Brunet, Joan
    IDIBGI Catalan Institute Oncol, Spain .
    Angel Pujana, Miquel
    IDIBELL Catalan Institute Oncol, Spain .
    Mai, Phuong L.
    NCI, MD USA .
    Loud, Jennifer T.
    NCI, MD USA .
    Walsh, Christine
    Cedars Sinai Medical Centre, CA USA .
    Lester, Jenny
    Cedars Sinai Medical Centre, CA USA .
    Orsulic, Sandra
    Cedars Sinai Medical Centre, CA USA .
    Narod, Steven A.
    University of Toronto, Canada .
    Herzog, Josef
    City Hope National Medical Centre, CA USA .
    Sand, Sharon r.
    City Hope National Medical Centre, CA USA .
    Tognazzo, Silvia
    Ist Oncology Veneto IOV IRCCS, Italy .
    Agata, Simona
    Ist Oncology Veneto IOV IRCCS, Italy .
    Vaszko, Tibor
    National Institute Oncol, Hungary .
    Weaver, Joellen
    Fox Chase Cancer Centre, PA USA .
    Stavropoulou, Alexandra V.
    National Centre Science Research Demokritos, Greece .
    Buys, Saundra S.
    University of Utah, UT USA .
    Romero, Atocha
    Hospital Clin San Carlos, Spain .
    de la Hoya, Miguel
    Hospital Clin San Carlos, Spain .
    Aittomaki, Kristiina
    University of Helsinki, Finland .
    Muranen, Taru A.
    University of Helsinki, Finland .
    Duran, Mercedes
    University of Valladolid IBGM UVA, Spain .
    Chung, Wendy K.
    Columbia University, NY USA.
    Lasa, Adriana
    Hospital Santa Creu and Sant Pau, Spain .
    Dorfling, Cecilia M.
    University of Pretoria, South Africa .
    Miron, Alexander
    Dana Farber Cancer Institute, MA USA .
    Benitez, Javier
    Spanish National Cancer Centre CNIO, Spain Biomed Network Rare Disease CIBERER, Spain .
    Senter, Leigha
    Ohio State University, OH USA .
    Huo, Dezheng
    University of Chicago, IL USA .
    Chan, Salina B.
    University of Calif San Francisco, CA USA .
    Sokolenko, Anna P.
    NN Petrov Oncology Research Institute, Russia .
    Chiquette, Jocelyne
    University of Quebec, Canada .
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Latvia .
    Friebel, Tara M.
    University of Penn, PA USA .
    Agnarsson, Bjarni A.
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
    Lu, Karen H.
    University of Texas MD Anderson Cancer Centre, TX USA .
    Lejbkowicz, Flavio
    Clalit National Israeli Cancer Control Centre, Israel Carmel Hospital, Israel .
    James, Paul A.
    Peter MacCallum Cancer Centre, Australia .
    Hall, Per
    Karolinska Institute, Sweden .
    Dunning, Alison M.
    University of Cambridge, England .
    Tessier, Daniel
    Centre Innovat Genome Quebec, Canada McGill University, Canada .
    Cunningham, Julie
    Mayo Clin, MN USA.
    Slager, Susan L.
    Mayo Clin, MN USA .
    Wang, Chen
    Mayo Clin, MN USA .
    Hart, Steven
    Mayo Clin, MN USA .
    Stevens, Kristen
    Mayo Clin, MN USA .
    Simard, Jacques
    Centre Hospital University of Quebec, Canada University of Laval, Canada .
    Pastinen, Tomi
    McGill University, Canada.
    Pankratz, Vernon S.
    Mayo Clin, MN USA .
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY USA .
    Easton, Douglas F.
    University of Cambridge, England .
    Chenevix-Trench, Georgia
    Queensland Institute Medical Research, Australia .
    Antoniou, Antonis C.
    University of Cambridge, England.
    Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 3Article in journal (Refereed)
    Abstract [en]

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

  • 47.
    Cox, DavidG
    et al.
    University of Lyon 1.
    Simard, Jacques
    Centre Hospital University of Quebec.
    Sinnett, Daniel
    St Justine University of Health Centre.
    Hamdi, Yosr
    Centre Hospital University of Quebec.
    Soucy, Penny
    Centre Hospital University of Quebec.
    Ouimet, Manon
    St Justine University of Health Centre.
    Barjhoux, Laure
    University of Lyon 1.
    Verny-Pierre, Carole
    University of Lyon 1.
    McGuffog, Lesley
    University of Cambridge.
    Healey, Sue
    Queensland Institute Medical Research.
    Szabo, Csilla
    University of Delaware.
    H Greene, Mark
    US National Cancer Institute.
    Mai, Phuong L
    US National Cancer Institute.
    Andrulis, Irene L
    University of Toronto.
    Thomassen, Mads
    Odense University Hospital.
    Gerdes, Anne-Marie
    Copenhagen University Hospital.
    Caligo, Maria A
    University Hospital Pisa.
    Friedman, Eitan
    Chaim Sheba Medical Centre.
    Laitman, Yael
    Chaim Sheba Medical Centre.
    Kaufman, Bella
    Chaim Sheba Medical Centre.
    S Paluch, Shani
    Tel Aviv University.
    Borg, Ake
    University of Lund Hospital.
    Karlsson, Per
    Sahlgrens University Hospital.
    Askmalm Stenmark, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Barbany Bustinza, Gisela
    Karolinska University Hospital.
    Nathanson, KatherineL
    University of Penn.
    Domchek, Susan M
    University of Penn.
    Rebbeck, Timothy R
    University of Penn.
    Benitez, Javier
    Spanish National Cancer Research Centre.
    Hamann, Ute
    Deutsch Krebsforschungszentrum.
    Rookus, Matti A
    Netherlands Cancer Institute.
    van den Ouweland, AnsM W
    Erasmus University.
    Ausems, Margreet G E M
    University of Medical Centre Utrecht.
    Aalfs, CoraM
    University of Amsterdam.
    van Asperen, Christi J
    Leiden University.
    Devilee, Peter
    Leiden University.
    Gille, Hans J J P
    Vrije University of Amsterdam Medical Centre.
    Peock, Susan
    University of Cambridge.
    Frost, Debra
    University of Cambridge.
    Evans, DGareth
    Central Manchester University Hospital NHS Fdn Trust.
    Eeles, Ros
    Institute Cancer Research, Surrey.
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust.
    Adlard, Julian
    Yorkshire Regional Genet Serv.
    Paterson, Joan
    Addenbrookes Hospital.
    Eason, Jacqueline
    Nottingham University Hospital NHS Trust.
    Godwin, Andrew K
    Fox Chase Cancer Centre.
    Remon, Marie-Alice
    Institute Curie.
    Moncoutier, Virginie
    Institute Curie.
    Gauthier-Villars, Marion
    Institute Curie.
    Lasset, Christine
    University of Lyon 1.
    Giraud, Sophie
    Centre Leon Berard.
    Hardouin, Agnes
    Centre Francois Baclesse.
    Berthet, Pascaline
    Centre Francois Baclesse.
    Sobol, Hagay
    University of Aix Marseille 2.
    Eisinger, Francois
    Institute Paoli Calmettes.
    Bressac de Paillerets, Brigitte
    Institute Cancerol Gustave Roussy.
    Caron, Olivier
    Institute Cancerol Gustave Roussy.
    Delnatte, Capucine
    Centre Rene Gauducheau.
    Goldgar, David
    University of Utah.
    Miron, Alex
    Dana Farber Cancer Institute.
    Ozcelik, Hilmi
    Mt Sinai Hospital.
    Buys, Saundra
    University of Utah.
    Southey, Melissa C
    University of Melbourne.
    Terry, MaryBeth
    Columbia University.
    Singer, ChristianF
    Medical University of Vienna.
    Dressler, Anne-Catharina
    Medical University of Vienna.
    Tea, Muy-Kheng
    Medical University of Vienna.
    Hansen, ThomasV O
    Copenhagen University Hospital.
    Johannsson, Oskar
    University of Iceland.
    Piedmonte, Marion
    Roswell Pk Cancer Institute.
    C Rodriguez, Gustavo
    University of Chicago.
    Basil, Jack B
    Good Samaritan Hospital.
    Blank, Stephanie
    NYU.
    Toland, Amanda E
    Ohio State University.
    Montagna, Marco
    Institute Oncology Veneto IOV IRCCS.
    Isaacs, Claudine
    Georgetown University.
    Blanco, Ignacio
    Catalan Institute Oncol.
    Gayther, Simon A
    University of So Calif.
    Moysich, KirstenB
    Roswell Pk Cancer Institute.
    Schmutzler, Rita K
    University Hospital Cologne.
    Wappenschmidt, Barbara
    University Hospital Cologne.
    Engel, Christoph
    University of Leipzig.
    Meindl, Alfons
    Technical University of Munich.
    Ditsch, Nina
    University of Munich.
    Arnold, Norbert
    University of Kiel.
    Niederacher, Dieter
    University of Dusseldorf.
    Sutter, Christian
    University of Heidelberg.
    Gadzicki, Dorothea
    Hannover Medical Sch.
    Fiebig, Britta
    University of Regensburg.
    Caldes, Trinidad
    Hospital Clin San Carlos.
    Laframboise, Rachel
    University of Laval.
    Nevanlinna, Heli
    Helsinki University Central Hospital.
    Chen, Xiaoqing
    Queensland Institute Medical Research.
    Beesley, Jonathan
    Queensland Institute Medical Research.
    Spurdle, Amanda B
    Queensland Institute Medical Research.
    Neuhausen, Susan L
    Beckman Research Institute City Hope.
    Ding, Yuan C
    Beckman Research Institute City Hope.
    Couch, FergusJ
    Mayo Clin.
    Wang, Xianshu
    Mayo Clin.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT.
    Bernard, Loris
    Ist Europeo Oncology IEO.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT.
    Easton, Douglas F
    University of Cambridge.
    Chenevix-Trench, Georgia
    Queensland Institute Medical Research.
    Antoniou, Antonis C
    University of Cambridge.
    Stoppa-Lyonnet, Dominique
    Institute Curie.
    Mazoyer, Sylvie
    University of Lyon 1.
    Sinilnikova, Olga M
    University of Lyon 1.
    Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers2011In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, no 23, p. 4732-4747Article in journal (Refereed)
    Abstract [en]

    Mutations in the BRCA1 gene substantially increase a womans lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

  • 48. Crawley, C
    et al.
    Lalanacette, M
    Szydlo, R
    Gilleece, M
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Michallet, M
    Mackinnon, S
    Einsele, H
    Reiffers, J
    Zander, AR
    Carreras, E
    Carella, A
    Gratwohl, A
    Sotto, JJ
    Cavenagh, JD
    Niederweiser, D
    Ciceri, F
    Apperley, JF
    Reduced intensity conditioned allografts for myeloma: A study from the Chronic Leukaemia Working Party of the EBMT.2002In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 100, no 11, p. 542-Conference paper (Other academic)
  • 49. Crawley, C
    et al.
    Lalancette, M
    Szydlo, R
    Gilleece, M
    Peggs, K
    Mackinnon, S
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Ahlberg, Lucia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Nagler, A
    Shimoni, A
    Sureda, A
    Boiron, JM
    Einsele, H
    Chopra, R
    Carella, A
    Cavenagh, J
    Gratwohl, A
    Garban, F
    Zander, A
    Bjorkstrand, B
    Outcomes for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukaemia Working Party of the EBMT2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, no 11, p. 4532-4539Article in journal (Refereed)
    Abstract [en]

    We report the outcome of 229 patients who received an allograft for myeloma with reduced-intensity conditioning (RIC) regimens from 33 centers within the European Group for Blood and Marrow Transplantation (EBMT). The median age was 52 years and 64% were male. Conditioning regimens were heterogeneous, but most were fludarabine based and T cell depleted with antithymocyte globulin or alemtuzumab. Transplantation-related mortality (TRIM) at 1 year was 22%. The 3-year overall survival (OS) and progression-free survival (PFS) were 41% and 21 %, respectively. Adverse OS was associated with chemoresistant disease (relative risk [RR], 2.9), more than 1 prior transplantation (RR, 2.0), and male patients with female donors (FIR, 1.45). Adverse PFS was associated with chemoresistance (RR, 2.4) and alemtuzumab (RR, 1.8). TRM was increased with female-to-male donation (RR, 2.5) and transplantation more than 1 year from diagnosis (RR, 2.3). Grades II to IV acute graft-versus-host disease (aGvHD) occurred in 31%. Chronic GvHD was associated with better OS and PFS and were 84% and 46% for limited, 58% and 30% for extensive, and 29% and 12% in its absence suggesting that a graft-versus-myeloma effect is important. While RIC is feasible, heavily pretreated patients and patients with progressive disease do not benefit.

  • 50. Crawley, CR
    et al.
    Lalancette, M
    Szydlo, R
    Bacigalupo, A
    Lange, A
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Ringden, O
    Gratwohl, A
    Mayer, J
    Hansz, J
    Zander, AR
    Vitek, A
    Brune, ML
    Urbano-Ispizua, A
    Niederwieser, D
    Mufti, G
    Apperley, JF
    Reduced intensity conditioned allografts for chronic myeloid leukaemia: A study from the chronic leukaemia working party of the EBMT.2002In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 100, no 11, p. 3089-Conference paper (Other academic)
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