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  • 151.
    Kristensen, Ingrid
    et al.
    Lund University.
    Lindh, Jack
    Umeå University.
    Nilsson, Per
    Lund University Hospital.
    Bergström, Per
    Umeå University.
    Björk-Eriksson, Thomas
    Sahlgrenska University Hospital, Gothenburg.
    Engellau, Jacob
    Lund University Hospital.
    Hjelm-Skog, Anna-Lena
    Karolinska University Hospital, Stockholm.
    Malmer, Beatrice
    Umeå University.
    Martinsson, Ulla
    Uppsala University Hospital.
    Karlsson, Mikael
    Umeå University.
    Agrup, Måns
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Telemedicine as a tool for sharing competence in paediatric radiotherapy - Implementation and initial experiences from a Swedish project2009Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, nr 1, s. 146-152Artikkel i tidsskrift (Annet vitenskapelig)
  • 152. Kronblad, A
    et al.
    Jirström, K
    Rydén, L
    Nordenskjöld, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Landberg, G
    Hypoxia inducible factor-1α is a prognostic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response2006Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 118, nr 10, s. 2609-2616Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hypoxia is common in many solid tumours, including breast cancer. Hypoxia triggers the expression of hypoxia inducible factor-1α (HIF-1α), and HIF-1α has been associated with an impaired prognosis in breast cancer and down-regulation of the oestrogen receptor (ER), potentially affecting the treatment efficiency of antioestrogens. The role of HIF-1α regarding prognostic and treatment predictive information in breast cancer has not been established and we therefore analyzed HIF-1α using immunohistochemistry in a cohort of 377 premenopausal stage II breast cancers arranged in a tissue microarray. The patients were included in a randomized trial with either 2 years of tamoxifen or no adjuvant treatment. The tamoxifen treatment effect could be studied in subgroups of breast cancer and pure prognostic information could be scrutinized for untreated control patients. HIF-1α was scored as positive in 24% of the tumours and correlated positively to tumour size, Nottingham histological grade (NHG), Ki-67, Her2 and cyclin E expression and negatively to lymph node status, cyclin D1, ER and PR (progesterone receptor) expression. Surprisingly, there was no difference in tamoxifen response for patients with high or low HIF-1α expressing tumours. In lymph node-positive patients as well as NHG 1/2 tumours, high HIF-1α protein expression was significantly associated with an impaired recurrence-free survival (p = 0.014, 0.018). When analyzing the subgroup of NHG 1/2 tumours, a high HIF-1α expression was the only independent significant prognostic marker in multivariate analysis, including standard prognostic markers, suggesting that HIF-1α might be a useful prognostic marker in this subgroup of breast cancer, with a rather good but diverse prognosis. © 2005 Wiley-Liss, Inc.

  • 153.
    Kågedal, Bertil
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Lindqvist, Maria
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin.
    Farnebäck, Malin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Lenner, Liselotte
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell hematologi.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Failure of the PAXgene™ Blood RNA System to maintain mRNA stability in whole blood2005Inngår i: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 43, nr 11, s. 1190-1192Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In multicentre studies of malignant and inflammatory diseases, whole blood, cell or tissue samples are often collected for analyses of gene expression to predict or monitor treatment effects. For correct analysis, sample stability during handling and transport is crucial. In developing the logistics for multicentre studies in malignant melanoma and inflammatory bowel disease, we found poor stability of a number of transcripts using the PAXgene™ Blood RNA System, which was advertised to maintain RNA stability for several days at room temperature. The results indicate that general statements on sample stability are not reliable and have to be verified for the specific transcripts of interest. © 2005 by Walter de Gruyter. Berlin.

  • 154. Lacombe, D
    et al.
    Fumoleau, P
    Zwierzina, H
    Twelves, C
    Håkansson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Jayson, G
    Lehmann, F
    Verweij, J
    The EORTC and drug development2002Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 38, s. 19-23Artikkel i tidsskrift (Fagfellevurdert)
  • 155.
    Lewander, Andreas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Arbman, Gunnar
    Dept Surg Ostergotland, Norrkoping, Sweden.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Polymorphism in the promoter region of the NFKBIA gene is rare in Swedish and Chinese colorectal cancer patients and controls2010Inngår i: MOLECULAR MEDICINE REPORTS, ISSN 1791-2997, Vol. 3, nr 1, s. 69-74Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To investigate whether a -708ins/del8 polymorphism in the promoter region of the NFKBIA gene is related to colorectal cancer risk and clinicopathological variables, we, genotyped 92 Swedish and 93 Chinese patients as well as 174 Swedish and 159 Chinese healthy controls by polymerase chain reaction-single stranded conformation polymorphism and DNA sequencing. The -708/del8 polymorphism was found in two Swedish patients and eight Swedish controls, but was absent in the Chinese population. However, among the Chinese population we found other mutations in three patients and in one control. In conclusion, the -708ins/del8 polymorphism is too rare to have a major impact on colorectal cancer incidence in the two populations.

  • 156.
    Lewander, Andreas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gao, Jingfang
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Adell, G.
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Expression of NF-κB p65 phosphorylated at Serine-536 in rectal cancer with or without preoperative radiotherapy2011Inngår i: RADIOLOGY AND ONCOLOGY, ISSN 1318-2099, Vol. 45, nr 4, s. 279-284Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the present study, we investigated NF-κB p65 phosphorylated at Serine-536 (phospho-Ser536-p65) in rectal cancer and its relationship to radiotherapy (RT) and clinicopathological and biological factors. Expression of phospho-Ser536-p65 was examined by using immunohistochemistry in 141 primary rectal cancers, 149 normal mucosa specimens and 48 metastases in the lymph nodes, from rectal cancer patients randomized to received RT or not. The expression of phospho-Ser536-p65 in the cytoplasm increased from normal mucosa to primary tumor (p<0.0001, for both RT and non-RT groups). The expression did not further increased from primary tumor to metastases in the either group (p>0.05). We found that the expression of phospho-Ser536-p65 was positively related to or tended to be positively related to expression of TEM1 (p=0.02), FXYD-3 (p=0.0006), PRL (p=0.02), p73 (p=0.048) and MAC30 (p=0.051) in the RT group but there were no such relationships in the non-RT group (p>0.05). The expression of the phospho-Ser536-p65 was not related to clinicopathological factors including survival (p>0.05). The increased expression of phospho-Ser536-p65 may be involved in rectal cancer development. After RT, the expression of NF-κB seems to be positively related to the biological factors which associated with more malignant features of tumors. However, we did not find that the phospho-Ser536-p65 was directly related to clinical response of RT.

  • 157.
    Lewander, Andreas
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gao, Jingfang
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    NF-κB p65 phosphorylated at Serine-536 is an independent prognostic factor in Swedish colorectal cancer patientsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background: NF-κB transcription factor protein family has diverse cellular and biological functions, and post-translational modification is important to regulate these functions. An important site of phosphorylation of p65 subunit is at Serine-536 (phospho-Ser536-p65), and this phosphorylation is involved in regulation of transcriptional activity, nuclear localization and protein stability. In this study, we investigated a phospho-Ser536-p65 in colorectal cancers and its relationship to clinicopathological factors of the patients.

    Materials and Methods: Expression of phospho-Ser536-p65 was examined by using immunohistochemistry in 203 primary colorectal cancers, 156 normal mucosa specimens and 18 metastases in the lymph nodes.

    Results: The expression of phospho-Ser536-p65 increased from normal mucosa to primary tumour (p<0.0001). Further, the increased expression of phospho-Ser536-p65 in the cytoplasm of the primary tumours correlated with worse survival of the patients independent of gender, age, tumor location, stage and differentiation (p=0.04, hazard ratio 1.89, 95% CI 1.03-3.47).

    Conclusion: The NF-κB p65 subunit phosphorylated at Serine-536 is anindependent prognostic factor in colorectal cancer patients.

  • 158.
    Lewander, Andreas
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi.
    Kumar Reddy Butchi, Anil
    Gao, Jingfang
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi.
    He, Lu-Jun
    Lindblom, Annika
    Arbman, Gunnar
    Carstensen, John
    Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutionen för hälsa och samhälle, Tema hälsa och samhälle.
    Zhang, Zhi-Yong
    Sun, Xiao-Feng
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Polymorphism in the promoter region of the NFKB1 gene increases the risk of sporadic colorectal cancer in Swedish but not in Chinese populations2007Inngår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 42, nr 11, s. 1332-1338Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. An insertion/deletion polymorphism (-94ins/delATTG) in the promoter region of the NFKB1 gene correlates to an increased risk of ulcerative colitis, a known risk factor for colorectal cancer, but this polymorphism has not been studied in colorectal cancer patients. The purpose of this study was to investigate whether this polymorphism is related to colorectal cancer risk and clinicopathological variables. Material and methods. Case samples were taken from four groups of Swedish patients: 193 unselected patients, 90 patients with ≥3 affected 1st-degree relatives, 85 patients with 2 affected 1st-degree relatives, and 109 sporadic cancer patients, and one group of 193 unselected Chinese patients. Controls included 439 Swedish and 458 Chinese healthy individuals. Genotypes were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Results. The deletion increased the risk of colorectal cancer among Swedish unselected patients (OR=3.81, 95% CI: 2.17-6.69, p<0.0001 for heterozygote deletion, and OR=4.65, 95% CI: 2.43-8.89, p<0.0001 for homozygote deletion) and sporadic cancer patients (OR=7.73, 95% CI: 3.06-19.57, p<0.0001 for heterozygote deletion, and OR=6.58, 95% CI: 2.35-18.43, p<0.0001 for homozygote deletion) compared to homozygote insertion (wild-type), but not among the other Swedish or Chinese patients (p>0.05). Similar evidence was seen in age-adjusted analyses (p<0.0001). The polymorphism did not correlate to clinicopathological variables (p>0.05). Conclusions. Deletion of the polymorphism was associated with increased susceptibility to sporadic colorectal cancers in the Swedish population, but not in the Swedish patients with a family history of colorectal cancer or in Chinese patients. © 2007 Taylor & Francis.

  • 159.
    Licznerska, Barbara E.
    et al.
    Institution of Clinical and Experimental Medicine Linköping University.
    Wegman, Pia P.
    Institution of Clinical and Experimental Medicine Linköping University.
    Nordenskjöld, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Wingren, Sten
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin.
    In situ levels of oestrogen producing enzymes and its prognostic significance in postmenopausal breast cancer patients2008Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 112, nr 1, s. 15-23Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The risk of developing breast cancer is strongly correlated with the overall exposure to oestrogen and most tumours are more or less dependent on oestrogen for their growth. A great majority of breast cancers occur after menopause when the ovaries have ceased to be functional, yet breast tumours in postmenopausal women maintain high intratumoural oestrogen concentrations, primarily through enzymatic conversion of androgenic precursors. Patients with a hormone dependent tumour generally receive the anti-oestrogen tamoxifen that mediate its anti-tumour effect by competing with oestrogen for binding to the oestrogen-receptor (ER). We therefore propose that the levels of oestrogen producing enzymes may affect the prognosis in postmenopausal breast cancer patients treated with tamoxifen. Methods: We measured the mRNA and protein levels of aromatase and sulfatase by real-time PCR (n = 161) and immunohistochemistry (n = 131) in postmenopausal women with breast cancer. Results: A significant better recurrence-free survival was detected in patients with weak or high protein expression of stromal aromatase (P = 0.0008), as also demonstrated by a decreased relative risk (RR = 0.50, CI = 0.33-0.76, P = 0.003). When we combined patients with weak and high stromal aromatase and selected only ER-positive patients, the improved prognosis was even more evident (P = 0.0000) and was shown to be a significant prognostic factor in a multivariate Cox-model (HR = 0.15, CI = 0.06-0.39, P = 0.000). The mRNA expression of aromatase and sulfatase, as well as the protein expression of sulfatase revealed no prognostic significance. Conclusion: Protein expression of stromal aromatase may serve as a significant prognostic marker in ER-positive patients. © 2007 Springer Science+Business Media, LLC.

  • 160.
    Lindahl, Gabriel
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Saarinen, Niina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Tamoxifen, Flaxseed, and the Lignan Enterolactone Increase Stroma- and Cancer Cell-Derived IL-1Ra and Decrease Tumor Angiogenesis in Estrogen-Dependent Breast Cancer2011Inngår i: CANCER RESEARCH, ISSN 0008-5472, Vol. 71, nr 1, s. 51-60Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The proinflammatory cytokines IL-1 alpha and IL-1 beta promote tumor angiogenesis that might be counteracted by the IL-1 receptor antagonist (IL-1Ra), anakinra, a clinically approved agent. A diet with high amounts of phytoestrogens, such as flaxseed (Flax), genistein (GEN), and the mammalian lignan enterolactone (ENL), may affect breast cancer progression in a similar fashion as the antiestrogen tamoxifen. Both cancer cells and tumor stroma may be targets for cancer therapy. By using microdialysis in a model of human breast cancers in nude mice, we could perform species-specific analyses of released proteins in the microenvironment. We show that tumors treated with tamoxifen and fed Flax or ENL exhibited decreased in vivo release of IL-1 beta derived from the murine stroma and decreased microvessel density whereas dietary GEN had no effects. Cancer cell-released IL-1Ra were approximately 5 times higher than stroma-derived IL-1Ra. Tamoxifen, Flax, and ENL increased IL-1Ra levels significantly whereas GEN did not. The tumor stroma contained macrophages, which expressed the estrogen receptor. In vitro, estradiol decreased IL-1Ra released from breast cancer cells and from cultured macrophages. IL-1Ra decreased endothelial cell proliferation significantly in vitro whereas breast cancer cell proliferation was unaffected in presence of estradiol. Finally, IL-1Ra therapy of tumor-bearing mice opposed estrogen-dependent breast cancer growth and decreased angiogenesis. We conclude that the release of IL-1s both by cancer cells and the stroma, where macrophages are a key component, may offer feasible targets for antiestrogen therapy and dietary interventions against breast cancer.

  • 161.
    Linderholm, B
    et al.
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Bergqvist, J
    Karolinska Institute.
    Hellborg, H
    Karolinska Institute.
    Johansson, U
    Karolinska Institute.
    Linderholm, M
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Elmberger, G
    Karolinska Institute.
    Skoog, L
    Karolinska Institute.
    Bergh, J
    Karolinska Institute.
    Shorter survival-times following adjuvant endocrine therapy in oestrogen- and progesterone-receptor positive breast cancer overexpressing HER2 and/or with an increased expression of vascular endothelial growth factor2009Inngår i: MEDICAL ONCOLOGY, ISSN 1357-0560, Vol. 26, nr 4, s. 480-490Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To investigate the possible correlation between expression of HER2 and vascular endothelial growth factor (VEGF), and to determine the predictive value of these factors in patients receiving adjuvant endocrine therapy including the group with a breast cancer (BC) positive for both oestrogen receptor (ER) and progesterone receptor (PgR). Material and methods: By enzyme immuno-sorbent assays (ELISA) tumour levels of HER2 and VEGF proteins were determined in 679 consecutive primary BC patients, median age 63 years, median follow-up time 92 months. A total of 404 patients received adjuvant endocrine therapy, mainly tamoxifen, out of them 295 had an ER and PgR positive BC. In 160 patients, HER2 status was also determined by immunohistochemistry (IHC) using the monoclonal antibody CB11. Results: Overexpression of HER2 by IHC was found in 15% of the patients. Overexpression of HER2 by ELISA correlated with HER2 by IHC (P andlt; 0.001) and a higher VEGF expression (P = 0.004). Patients receiving adjuvant endocrine therapy with high VEGF (RFS P = 0.0087, BCCS P = 0.0012) or over-expressing HER2 (RFS P = 0.0116, BCCS P = 0.0036) had significantly shorter survival. Factors retaining statistical significance in multivariate analyses for recurrence-free survival (RFS) were nodal status (P andlt; 0.001), tumour size (P = 0.005) and VEGF (P = 0.032) and for breast cancer corrected survival (BCCS) nodal status (P andlt; 0.001), tumour size (P = 0.001), ER status (P = 0.022), and VEGF (P = 0.016). Both factors were significantly correlated with survival in the group with a BC positive for both ER and PgR; VEGF (RFS P = 0.0177, BCCS P = 0.0321) and HER2 (RFS P = 0.0143, BCCS P = 0.0311). In multivariate analyses, nodal status (P andlt; 0.001) and VEGF (P = 0.021) were independent factors for RFS. Nodal status (P andlt; 0.001) and tumour size (P = 0.016) retained independent factors for BCCS. Combined analysis identified a high-risk group (HER2 positive and high VEGF) with significantly reduced survival. Conclusion: The results from this retrospective analysis suggest that overexpression of HER2 and higher VEGF expression may add information on patients outcome after adjuvant endocrine therapy in ER and PgR positive BC.

  • 162.
    Linderholm, B K
    et al.
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Klintman, M.
    Lund University Hospital.
    Grabau, A.
    Lund University Hospital.
    Bendahl, P-O
    Lund University Hospital.
    Ferno, M.
    Lund University Hospital.
    Per, M.
    Lund University Hospital.
    Significantly higher expression of vascular endothelial growth factor (VEGF) and shorter survival after recurrences in premenopausal node negative patients with triple negative breast cancer in CANCER RESEARCH, vol 69, issue 2, pp 128S-129S2009Inngår i: CANCER RESEARCH, 2009, Vol. 69, nr 2, s. 128S-129SKonferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 163.
    Linderholm, B.K.
    et al.
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gruvbreger-Saal, S.
    Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
    Ferno, M.
    Fernö, M., Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
    Bendahl, P.-O.
    Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
    Malmstrom, P.
    Malmström, P., Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
    Vascular endothelial growth factor is a strong predictor of early distant recurrences in a prospective study of premenopausal women with lymph-node negative breast cancer2008Inngår i: Breast, ISSN 0960-9776, E-ISSN 1532-3080, Vol. 17, nr 5, s. 484-491Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We investigate the prognostic significance of the pro-angiogenic cytokine vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), and S-phase fraction (SPF) for distant disease free survival (DDFS) in 219 premenopausal patients with node-negative breast cancer (NNBC). In univariate analysis significantly shorter DDFS was observed for patients with high VEGF (p = 0.006), high uPA (p = 0.001), and high SPF (p < 0.001). The prognostic significance of VEGF varied over time being very strong for early relapses (0-2.25 years follow-up) (HR = 7.9, p = 0.006) while no difference was seen in the subsequent follow-up period (HR = 1.3, p = 0.62). In a series of bivariate analyses VEGF provided prognostic information during the whole observation period (0-72 months) in addition to age, tumour size, oestrogen receptor (ER), progesterone receptor (PgR), and uPA. Also this effect was more pronounced during the first follow-up period suggesting VEGF as a marker of early recurrences. © 2008 Elsevier Ltd. All rights reserved.

  • 164.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Wennerstrand, Patricia
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Hertervig, Erik
    Department of Gastroenterology, Lund University.
    Mårtensson, Lars-Göran
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biokemi. Linköpings universitet, Tekniska högskolan.
    Characterization of a novel sequence variant, TPMT*28, in the human thiopurine methyltransferase gene2010Inngår i: Pharmacogenetics and genomics, ISSN 1744-6880, Vol. 20, nr 11, s. 700-707Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The activity of the human enzyme thiopurine methyltransferase (TPMT) varies greatly between individuals because of genetic polymorphism. TPMT is involved in the detoxification and activation of thiopurines such as 6-mercaptopurine, 6-thioguanine, and azathioprine. These drugs are used in the treatment of acute lymphoblastic leukemia and inflammatory bowel disease. A total of 29 sequence variants have been identified so far in the TPMT gene. However, most of these variants are rare and not fully characterized. METHODS AND RESULTS: In this study, we describe the identification and characterization of a novel TPMT sequence variant, originally found in a Swedish man of Italian origin. Sequencing of the variable number tandem repeats region of the TPMT promoter and exons III-X revealed a T-to-C transition at nucleotide 611, causing an amino acid substitution from isoleucine to threonine at amino acid 204, positioned in an α-helix, approximately 16 Å from the active site. This new variant was found in the patient and in his son. Both had intermediate enzyme activity (8.1 U/ml packed red blood cells and 8.8 U/ml packed red blood cells, respectively) and neither carried other variants in the coding region of the gene. To be able to study this variant in more detail, the TPMT*28 variant was expressed in Escherichia coli, and an in-vitro characterization of the variant revealed that the protein was destabilized and showed a stronger tendency towards degradation at 37°C than the wild-type protein. The individuals carrying the TPMT*28 variant had less TPMT protein and lower TPMT activity in both red and white blood cells compared with a wild-type control. CONCLUSIONS: We present a detailed in-vivo and in-vitro characterization of a novel TPMT sequence variant (TPMT*28) causing decreased TPMT activity. Individuals carrying TPMT*28 might have an increased risk for developing severe side effects if treated with conventional doses of thiopurines.

  • 165.
    Lindqvist Appell, Malin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Wennerstrand, Patricia
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Skoglund, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lars-Göran, Mårtensson
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Hertervig, Erik
    Lund University Hospital, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Explaining TPMT genotype/phenotype discrepancy by identification of a novel sequence variant, TPMT*272009Inngår i: 13th International Symposium on Purine and Pyrimidine metabolism in man, 2009Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Thiopurine methyltransferase (TPMT) is a polymorphic enzyme involved in the metabolism of thiopurine drugs. Owing to polymorphisms in the TPMT gene (TPMT*2-*22), the enzyme activity varies interindividually. Patients with reduced TPMT activity may develop adverse reactions when treated with standard doses of thiopurines. This work focuses on a TPMT genotype/phenotype discrepancy found in a patient during routine testing. The patient displayed very low TPMT enzyme activity and she was genotyped by pyrosequencing as being heterozygous for the 460G>A and 719A>G polymorphisms (TPMT*3A). Complete sequencing in combination with haplotyping of the TPMT gene revealed a novel sequence variant, 500C>G, on one allele and TPMT*3A on the other allele, giving rise to the novel genotype TPMT*3A/*23. When investigating the patient's relatives, they too had the TPMT*3A/*23 genotype in combination with low enzyme activity. We conclude that this novel variant allele affects enzyme activity, as the individuals carrying it had almost undetectable TPMT activity.

  • 166.
    Liu, H.-Y.
    et al.
    Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China, Shanxi Cancer Hospital, Taiyuan, China.
    Zhou, B.
    Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
    Wang, L.
    Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
    Li, Y.
    Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
    Zhou, Z.-G.
    Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China, National Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China, Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 37 Guo Xue Xiang, Chengdu 610041, Sichuan Province, China.
    Sun, Xiao-Feng
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Xu, B.
    Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
    Zeng, Y.-J.
    Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
    Song, J.-M.
    Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
    Luo, H.-Z.
    Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
    Yang, L.
    Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
    Association of E1AF mRNA expression with tumor progression and matrilysin in human rectal cancer2007Inngår i: Oncology, ISSN 0030-2414, E-ISSN 1423-0232, Vol. 73, nr 5-6, s. 384-388Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: To examine E1AF mRNA expression and to determine whether it is correlated with tumor progression and matrilysin in human rectal cancer. Methods: Real-time RT-PCR was used to determine E1AF and matrilysin expression in 100 matched rectal cancers and normal tissues. Results: Among the 100 rectal cancers, 69 cases of E1AF mRNA overexpression were observed. E1AF mRNA overexpression correlated well with matrilysin. In carcinomas, E1AF mRNA overexpression correlated significantly with depth of invasion, lymph node metastasis, venous involvement and advanced pTNM stage. Conclusions: E1AF was correlated significantly with tumor progression of human rectal cancer and may be an important factor in rectal cancer progression. Copyright © 2008 S. Karger AG.

  • 167.
    Lof-Ohlin, Zarah M
    et al.
    Orebro University Hospital.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Nilsson, Torbjorn K
    Orebro University Hospital.
    DNA methylation of the p14(ARF), RASSFIA and APCIA genes define a poor prognosis subset of colorectal cancer patients independently of tumor stage and tumor differentiation in INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, vol 26, issue , pp S5-S52010Inngår i: INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, Spandidos Publications , 2010, Vol. 26, s. S5-S5Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 168.
    Loftas, Per
    et al.
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Önnesjö, Sofia
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Widegren, Emma
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Adell, Gunnar
    Karolinska University Hospital.
    Kayed, Hany
    University of Heidelberg.
    Kleeff, Joerg
    Tech University of Munich.
    Zentgraf, Hanswalter
    University of Heidelberg.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    EXPRESSION OF FXYD-3 IS AN INDEPENDENT PROGNOSTIC FACTOR IN RECTAL CANCER PATIENTS WITH PREOPERATIVE RADIOTHERAPY2009Inngår i: INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, ISSN 0360-3016, Vol. 75, nr 1, s. 137-142Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: FXYD-3 (MAT-8) is overexpressed in several types of cancers; however, its clinical relevance in rectal cancers has not been studied. Therefore, we examined FXYD-3 expression in rectal cancers from the patients who participated in a Swedish clinical trial of preoperative radiotherapy (RT) to determine whether FXYD-3 was overexpressed in rectal cancers and correlated with RT, survival, and other clinicopathologic variables. Methods and Materials: The study included 140 rectal cancer patients who participated in a clinical trial of preoperative RT, 65 with and 75 without RT before surgery. FXYD-3 expression was immumohistochemically examined in distant (n = 70) and adjacent (n = 101) normal mucosa, primary tumors (n = 140), and lymph node metastasis (n = 36). Results: In the whole cohort, strong FXYD-3 expression was correlated with infiltrative tumor growth (p = 0.02). In the RT group, strong FXYD-3 expression alone (p = 0.02) or combined with phosphatase of regenerating liver was associated with an unfavorable prognosis (p = 0.02), independent of both TNM stage and tumor differentiation. In tumors with strong FXYD-3 expression, there was less tumor necrosis (p = 0.02) and a trend toward increased incidence of distant metastasis (p = 0.08) after RT. None of these effects was seen in the non-RT group. FXYD-3 expression in the primary tumors tended to he increased compared with normal mucosa regardless of RT. Conclusion: FXYD-3 expression was a prognostic factor independent of tumor stage and differentiation in patients receiving preoperative RT for rectal cancer.

  • 169. Lofti, K.
    et al.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Juliusson, G.
    Lund Strategic Centre for Stem Cell Biology and Therapy, Department of Hematology, Lund University Hospital, Lund, Sweden.
    Monitoring oral cyclosporine therapy [1]2005Inngår i: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 36, nr 4, s. 367Annet (Annet vitenskapelig)
    Abstract [en]

    [No abstract available]

  • 170.
    Loof, Jasmine
    et al.
    University of Skovde.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Bratthall, Charlotte
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Doré, Siv
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Starkhammar, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Zhang, Hong
    University of Skovde.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Impact of PINCH expression on survival in colorectal cancer patients2011Inngår i: BMC CANCER, ISSN 1471-2407, Vol. 11, nr 103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The adaptor protein PINCH is overexpressed in the stroma of several types of cancer, and is an independent prognostic marker in colorectal cancer. In this study we further investigate the relationship of PINCH and survival regarding the response to chemotherapy in colorectal cancer. Results: Paraffin-embedded tissue sections from 251 primary adenocarcinomas, 149 samples of adjacent normal mucosa, 57 samples of distant normal mucosa and 75 lymph node metastases were used for immunohistochemical staining. Stromal staining for PINCH increased from normal mucosa to primary tumour to metastasis. Strong staining in adjacent normal mucosa was related to worse survival independently of sex, age, tumour location, differentiation and stage (p = 0.044, HR, 1.60, 95% Cl, 1.01-2.52). PINCH staining at the invasive margin tended to be related to survival (p = 0.051). In poorly differentiated tumours PINCH staining at the invasive margin was related to survival independently of sex, age and stage (p = 0.013, HR, 1.90, 95% Cl, 1.14-3.16), while in better differentiated tumours it was not. In patients with weak staining, adjuvant chemotherapy was related to survival (p = 0.010, 0.013 and 0.013 in entire tumour area, invasive margin and inner tumour area, respectively), but not in patients with strong staining. However, in the multivariate analysis no such relationship was seen. Conclusions: PINCH staining in normal adjacent mucosa was related to survival. Further, PINCH staining at the tumour invasive margin was related to survival in poorly differentiated tumours but not in better differentiated tumours, indicating that the impact of PINCH on prognosis was dependent on differentiation status.

  • 171.
    Lundgren, K
    et al.
    University Manchester.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Landberg, G
    University Manchester.
    Hypoxia, Snail and incomplete epithelial-mesenchymal transition in breast cancer2009Inngår i: BRITISH JOURNAL OF CANCER, ISSN 0007-0920, Vol. 101, nr 10, s. 1769-1781Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Hypoxia is an element of the tumour microenvironment that impacts upon numerous cellular factors linked to clinical aggressiveness in cancer. One such factor, Snail, a master regulator of the epithelial-mesenchymal transition (EMT), has been implicated in key tumour biological processes such as invasion and metastasis. In this study we set out to investigate regulation of EMT in hypoxia, and the importance of Snail in cell migration and clinical outcome in breast cancer. METHODS: Four breast cancer cell lines were exposed to 0.1% oxygen and expression of EMT markers was monitored. The migratory ability was analysed following Snail overexpression and silencing. Snail expression was assessed in 500 tumour samples from premenopausal breast cancer patients, randomised to either 2 years of tamoxifen or no adjuvant treatment. RESULTS: Exposure to 0.1% oxygen resulted in elevated levels of Snail protein, along with changes in vimentin and E-cadherin expression, and in addition increased migration of MDA-MB-468 cells. Overexpression of Snail increased the motility of MCF-7, T-47D and MDA-MB-231 cells, whereas silencing of the protein resulted in decreased migratory propensity of MCF-7, MDA-MB-468 and MDA-MB-231 cells. Moreover, nuclear Snail expression was associated with tumours of higher grade and proliferation rate, but not with disease recurrence. Interestingly, Snail negativity was associated with impaired tamoxifen response (P = 0.048). CONCLUSIONS: Our results demonstrate that hypoxia induces Snail expression but generally not a migratory phenotype, suggesting that hypoxic cells are only partially pushed towards EMT. Furthermore, our study supports the link between Snail and clinically relevant features and treatment response.

  • 172.
    Lundgren, Katja
    et al.
    Lund University.
    Holm, Karolina
    Lund University.
    Nordenskjöld, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Borg, Ake
    Lund University.
    Landberg, Goran
    Lund University.
    Gene products of chromosome 11q and their association with CCND1 gene amplification and tamoxifen resistance in premenopausal breast cancer2008Inngår i: Breast cancer research, ISSN 1465-5411, Vol. 10, nr 5, s. R81-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: The amplification event occurring at chromosome locus 11q13, reported in several different cancers, includes a number of potential oncogenes. We have previously reported amplification of one such oncogene, namely CCND1, to be correlated with an adverse effect of tamoxifen in premenopausal breast cancer patients. Over-expression of cyclin D-1 protein, however, confers tamoxifen resistance but not a tamoxifen-induced adverse effect. Potentially, co-amplification of an additional 11q13 gene, with a resulting protein over-expression, is required to cause an agonistic effect. Moreover, during 11q13 amplification a deletion of the distal 11q region has been described. In order to assess the potential impact of the deletion we examined a selected marker for this event.

    Method: Array comparative genomic hybridization analysis was employed to identify and confirm changes in the gene expression of a number of different genes mapping to the 11q chromosomal region, associated with CCND1 amplification. The subsequent protein expression of these candidate genes was then examined in a clinical material of 500 primary breast cancers from premenopausal patients who were randomly assigned to either tamoxifen or no adjuvant treatment. The protein expression was also compared with gene expression data in a subset of 56 breast cancer samples.

    Results: Cortactin and FADD (Fas-associated death domain) over-expression was linked to CCND1 amplification, determined by fluorescence in situ hybridization, but was not associated with a diminished effect of tamoxifen. However, deletion of distal chromosome 11q, defined as downregulation of the marker Chk1 (checkpoint kinase 1), was associated with an impaired tamoxifen response, and interestingly with low proliferative breast cancer of low grade. For Pak1 (p21-activated kinase 1) and cyclin D-1 the protein expression corresponded to the gene expression data.

    Conclusions: The results indicate that many 11q13 associated gene products are over-expressed in conjunction with cyclin D-1 but not linked to an agonistic effect of tamoxifen. Finally, the deletion of distal 11q, linked to 11q13 amplification, might be an important event affecting breast cancer outcome and tamoxifen response.

  • 173.
    Lyth, Johan
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Börjeson, Sussanne
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Frodin, U
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Pain assessments during autologous stem cell transplantation in BONE MARROW TRANSPLANTATION, vol 46, issue , pp S450-S4512011Inngår i: BONE MARROW TRANSPLANTATION, Nature Publishing Group , 2011, Vol. 46, s. S450-S451Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 174.
    Lööf, Jasmine
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Pfeifer, Daniella
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Adell, Gunnar
    Karolinska University Hospital.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Significance of an exon 2 G4C14-to-A4T14 polymorphism in the p73 gene on survival in rectal cancer patients with or without preoperative radiotherapy2009Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 92, nr 2, s. 215-220Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and Purpose: An exon 2 G4C14→A4T14 polymorphism in the p73 gene was shown to be related to survival in several types of cancers, including colorectal cancer. The purpose was to investigate if this polymorphism was related to survival in rectal cancer patients with or without preoperative radiotherapy.

    Material and Methods: DNA extracted from tissue of 138 rectal cancer patients that received preoperative radiotherapy or had surgery alone was typed for the polymorphism by PCR using confronting two-pair primers.

    Results: Among patients, 69% had GC/GC genotype, 27% GC/AT and 4% AT/AT. In the radiotherapy group, patients carrying the AT (GC/AT+AT/AT) allele had stronger expression of p53 (p=0.001) and survivin protein (p=0.03) than those carrying the GC/GC genotype. Further, among patients receiving preoperative radiotherapy the GC/GC genotype tended to be related to better survival (p=0.20). Patients with GC/GC genotype, along with negative p53 and weak survivin expression showed better survival than the other patients (p=0.03), even after adjusting for TNM stage and tumor differentiation (p=0.01, RR, 7.63, 95% CI, 1.50-38.74). In the non-radiotherapy group, the polymorphism was not related to survival (p=0.74).

    Conclusions: Results suggest that the p73 G4C14→A4T14 polymorphism could be one factor influencing outcome of preoperative radiotherapy in rectal cancer patients.

  • 175.
    M Del Campo, J
    et al.
    Vall Hebron University Hospital.
    Roszak, A
    Wielkopolska Oncol Centre.
    Bidzinski, M
    Maria Sklodowska Curie Mem Canc Centre.
    Ciuleanu, T E
    Ion Chiricuta Canc Institute.
    Högberg, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Wojtukiewicz, M Z
    Med University, Comprehens Canc Centre Bialystok.
    Poveda, A
    Valencian Institute Oncol.
    Boman, K
    Umeå University Hospital.
    Westermann, A M
    University of Amsterdam.
    Lebedinsky, C
    PharmaMar Clin R&D.
    Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m(2) 24 h or 1.3 mg/m(2) 3 h) to patients with relapsed, platinum-sensitive, advanced ovarian cancer2009Inngår i: ANNALS OF ONCOLOGY, ISSN 0923-7534, Vol. 20, nr 11, s. 1794-1802Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Patients and methods: Patients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m(2) 24 h (arm A, n = 54) or 1.3 mg/m(2) 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute-Common Toxicity Criteria v. 2.0. Results: ORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3-8.6 months; arm A) and 6.8 months (95% CI 4.6-7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B). Conclusions: Both every-3-weeks trabectedin regimes, 1.5 mg/m(2) 24 h and 1.3 mg/m(2) 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.

  • 176.
    Maguire, P.
    et al.
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Margolin, S.
    Department of Oncology, Karolinska University Hospital, Södersjukhuset, Stockholm, Sweden.
    Skoglund, J.
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Sun, Xiao-Feng
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gustafsson, J.-A.
    Gustafsson, J.-Å., Department of Medical Nutrition, Karolinska Institute, Novum, Huddinge, Sweden.
    Borresen-Dale, A.-L.
    Børresen-Dale, A.-L., Department of Genetics, Norwegian Radium Hospital, University of Oslo, Montebello, Oslo, Norway.
    Lindblom, A.
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden, Department of Molecular Medicine, CMM L8:02, Karolinska Institute, S-171 76 Stockholm, Sweden.
    Estrogen receptor beta (ESR2) polymorphisms in familial and sporadic breast cancer2005Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 94, nr 2, s. 145-152Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Estrogen is involved in both normal mammary development and in breast carcinogenesis. A family history of disease and exposure to estrogen are major risk factors for developing breast cancer. Estrogen exerts its biological effects through binding to the estrogen receptors, estrogen receptor alpha (ESR1) and the more recently discovered estrogen receptor beta (ESR2). Genetic variation in genes involved in estrogen biosynthesis, metabolism and signal transduction have been suggested to play a role in breast cancer risk. We therefore tested the hypothesis that common genetic variants of the ESR2 gene may be associated with increased risk for breast cancer and this risk may vary between breast cancer groups. We investigated three common ESR2 polymorphisms, rs1256049 (G1082A), rs4986938 (G1730A) and rs928554 (Cx+56 A?G) for association to breast cancer risk. A total of 723 breast cancer cases and 480 controls were included in the study. Of the breast cancer cases, 323 were sporadic and 400 were familial, the familial cases were further divided into familial high-risk and familial low-risk breast cancer cases. We found no overall statistically significant association for any of the single polymorphisms studied. Haplotype analysis suggested one haplotype associated with increased risk in sporadic breast cancer patients (OR = 3.0, p = 0.03). Further analysis is needed to elucidate the role of estrogen receptor beta in breast cancer susceptibility. © Springer 2005.

  • 177. Marchand, M
    et al.
    Punt, CJA
    Aamdal, S
    Escudier, B
    Kruit, WHJ
    Keilholz, U
    Håkansson, Leif
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    van Baren, N
    Humblet, Y
    Mulders, P
    Avril, M-F
    Eggermont, AMM
    Scheibenbogen, C
    Uiters, J
    Wanders, J
    Delire, M
    Boon, T
    Stoter, G
    Immunisation of metastatic cancer patients with MAGE-3 protein combined with adjuvant SBAS-2: A clinical report2003Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 39, nr 1, s. 70-77Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Fifty-seven patients with MAGE-3-positive measurable metastatic cancer, most of them with melanoma, were vaccinated with escalating doses of a recombinant MAGE-3 protein combined with a fixed dose of the immunological adjuvant SBAS-2, which contained MPL and QS21. The immunisation schedule included 4 intramuscular (i.m.) injections at 3-week intervals. Patients whose tumour stabilised or regressed after 4 vaccinations received 2 additional vaccinations at 6-week intervals. The vaccine was generally well tolerated. Among the 33 melanoma patients who were evaluable for tumour response, we observed 2 partial responses, 2 mixed responses and 1 stabilisation. Time to progression in these 5 patients varied from 4 to 29 months. In addition, a partial response lasting 10 months was observed in 1 of the 3 metastatic bladder cancer patients included. None of the tumour responses described above involved visceral metastases. Immunological responses to the vaccine will be reported separately. ⌐ 2002 Elsevier Science Ltd. All rights reserved.

  • 178.
    Margolin, Sara
    et al.
    Karolinska Institute.
    Bengtsson, Nils-Olof
    Umea University Hospital.
    Carlsson, Lena
    Sundsvall Hospital.
    Edlund, Per
    Gavle Hopsital.
    Hellstrom, Mats
    Karolinska Institute.
    Karlsson, Per
    Sahlgrens University Hospital.
    Lidbrink, Elisabet
    Karolinska Institute.
    Linderholm, Barbro
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Lindman, Henrik
    University Uppsala Hospital.
    Malmstrom, Per
    University Lund Hospital.
    Pettersson Skold, Dagny
    Karolinska Institute.
    Soderberg, Martin
    Malmo University Hospital.
    Villman, Kenneth
    Orebro University Hospital.
    Bergh, Jonas
    Karolinska Institute.
    A randomised feasibility/phase II study (SBG 2004-1) with dose-dense/tailored epirubicin, cyclophoshamide (EC) followed by docetaxel (T) or fixed dosed dose-dense EC/T versus T, doxorubicin and C (TAC) in node-positive breast cancer2011Inngår i: ACTA ONCOLOGICA, ISSN 0284-186X, Vol. 50, nr 1, s. 35-41Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of the study was to evaluate the feasibility of tailored and dose-dense epirubicin and cyclophosphamide followed by docetaxel as adjuvant breast cancer therapy. Material and methods. Patients with node-positive breast cancer received either four cycles of biweekly and tailored EC (epirubicin 38-60-75-90-105-120 mg/m(2), cyclophosphamide 450-600-900-1200 mg/m(2)) followed by four cycles of docetaxel (60-75-85-100 mg/m(2)) (arm A) or the same regimen with fixed doses (E90C600 x 4 -andgt; T-75 x 4) (arm B) or docetaxel, doxorubicin and cyclophosphamide (T(75)A(50)C(500)) every three weeks for six cycles (arm C). All patients received G-CSF support and prophylactic ciprofloxacin. Results. One-hundred and twenty-four patients were randomised in the study. In the A, B and C arm, 17% 19% and 3% of the patients had one or more cycles delayed due to side-effects whereas 24%, 5% and 15% experienced a grade 3 infection or febrile neutropenia. After the introduction of an extra week between the EC and T parts in the A and B arms, grade 3 hand-foot-skin reactions were reduced from 5 to 0.2%. Twenty-nine percent (A and B) and 20% (C) of the patients were hospitalised due to side-effects. Discussion. Dose-dense and tailored EC/T can be given with manageable toxicity and is after adjustment presently studied in the phase III Panther trial.

  • 179.
    Masquelier, M
    et al.
    Karolinska Hosp & Inst, Div Clin Pharmacol, Dept Med, S-17176 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, Dept Clin Pharmacol, S-58185 Linkoping, Sweden Uppsala Univ, Div Toxicol, S-75124 Uppsala, Sweden.
    Vitols, S
    Karolinska Hosp & Inst, Div Clin Pharmacol, Dept Med, S-17176 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, Dept Clin Pharmacol, S-58185 Linkoping, Sweden Uppsala Univ, Div Toxicol, S-75124 Uppsala, Sweden.
    Palsson, M
    Karolinska Hosp & Inst, Div Clin Pharmacol, Dept Med, S-17176 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, Dept Clin Pharmacol, S-58185 Linkoping, Sweden Uppsala Univ, Div Toxicol, S-75124 Uppsala, Sweden.
    Mars, U
    Karolinska Hosp & Inst, Div Clin Pharmacol, Dept Med, S-17176 Stockholm, Sweden Linkoping Univ, Fac Hlth Sci, Dept Clin Pharmacol, S-58185 Linkoping, Sweden Uppsala Univ, Div Toxicol, S-75124 Uppsala, Sweden.
    Larsson, BS
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Low density lipoprotein as a carrier of cytostatics in cancer chemotherapy: Study of stability of drug-carrier complexes in blood2000Inngår i: Journal of drug targeting (Print), ISSN 1061-186X, E-ISSN 1029-2330, Vol. 8, nr 3, s. 155-164Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several solid tumour and leukemia cell types have a higher low density lipoprotein (LDL) uptake than the corresponding normal cells. We are investigating the possibilities to use LDL as a drug carrier to increase the selectivity of antineoplastic drugs in cancer chemotherapy. We have developed a method to incorporate lipophilic cytotoxic agents without interfering with the in vitro and in vivo properties of LDL, In this study, we examined the stability of some drug-LDL complexes in blood and plasma as this is an important prerequisite to achieve a selective therapy. The in vitro dialysis of N-trifluoroacetyl-adriamycin-14-valerat-LDL (AD-32-LDL) against plasma revealed a slow dissociation of the complex. The same method showed a fast and total leakage of paclitaxel from paclitaxel-LDL into the plasma chamber. The dissociation of paclitaxel was confirmed by an autoradiographic study of the distribution of paclitaxel-LDL in tumour-bearing mice. In patients with leukemia the rapid plasma dissociation of AD-32 from LDL illustrated a much higher in vivo instability of this complex. With this method, cholesteryl-linoleate only could be incorporated into LDL in a stable manner as shown by dialysis and autoradiography results. The incorporation of cytotoxic drug derivatives, containing lipophilic anchors, is now under study in order to obtain LDL complexes with better plasma stability.

  • 180.
    Matthiesen, Leif
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Obstetrik och gynekologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Berg, Göran
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Obstetrik och gynekologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Ernerudh, Jan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för molekylär och klinisk medicin, Klinisk immunologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk immunologi och transfusionsmedicin.
    Håkansson, L
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Lymphocyte subsets and mitogen stimulation of blood lymphocytes in preeclampsia.1999Inngår i: American Journal of Reproductive Immunology and Microbiology, ISSN 8755-8920, Vol. 41, s. 192-203Artikkel i tidsskrift (Fagfellevurdert)
  • 181. Mattsson, Sören
    et al.
    Brahme, Anders
    Carlsson, Jörgen
    Denekamp, Juliana
    Forssell-Aronsson, Eva
    Hellström, Mikael
    Johansson, Karl-Axel
    Kjellén, Elisabeth
    Littbrand, Bo
    Nordenskjöld, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Stenerlöw, Bo
    Turesson, Ingela
    Zackrisson, Björn
    Glimelius, Bengt
    Swedish Cancer Society radiation therapy research investigation2002Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 41, nr 7-8, s. 596-603Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In an investigation by the Swedish Cancer Society, the present status, critical issues and future aspects and prospects were described by an expert group for each of nine major areas of radiation research. A summary of the investigation is presented in this report. A more extensive summary (in Swedish) can be found at www.Cancerfonden.se. It is concluded that radiation therapy plays an increasingly important role in curative and palliative tumour treatment and presents a considerable challenge to research. Several suggestions are made that could improve the possibilities for high-quality radiation therapy research in Sweden.

  • 182.
    Meng, N.
    et al.
    Department of Surgery The Forth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.
    Li, Y.
    Department of Surgery The Forth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.
    Zhang, H.
    Division of Biomedicine School of Life Science, University of Skövde, Skövde,.
    Sun, Xiao-Feng
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    RECK, a novel matrix metalloproteinase regulator2008Inngår i: Histology and Histopathology, ISSN 0213-3911, E-ISSN 1699-5848, Vol. 23, nr 7-9, s. 1003-1010Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Extracellular matrix (ECM) macromolecules are important for creating the cellular environments required during development and morphogenesis of tissues. Matrix metalloproteinases (MMPs) are a family of Zn-dependent endopeptidases that collectively are capable of cleaving virtually all ECM substrates, and play an important role in some physiological and pathological processes. MMP activity can be inhibited by some natural and artificial inhibitors. A newly found membrane-anchored regulator of MMPs, the reversion-inducing-cysteine-rich protein with kazal motifs (RECK), is downregulated when the cells undergo a process of malignant transformation, and is currently the subject of considerable research activity because of its specific structure and function. In this review, we have chosen to concentrate our efforts on the structure, function, regulation, and future prospect of RECK in order to provide a new target for prevention and treatment of tumours.

  • 183. Meng, Wen-Jian
    et al.
    Sun, Xiao-Feng
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Tian, Chao
    Wang, Ling
    Yu, Yong-Yang
    Zhou, Bing
    Gu, Jun
    Xia, Qing-Jie
    Li, Yuan
    Wang, Rong
    Zheng, Xue-Lian
    Zhou, Zong-Guang
    Microsatellite instability did not predict individual survival in sporadic stage II and III rectal cancer patients2007Inngår i: Oncology, ISSN 0890-9091, Vol. 72, nr 1-2, s. 82-88Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: Tumors with high-frequency microsatellite instability (MSI-H) have unique biological behavior and the predictive role of microsatellite instability (MSI) status on survival of colorectal cancer is still debated. The prognostic significance of MSI status in sporadic stage II and III rectal cancer patients needs to be more precisely defined. So we investigated the relationship between MSI status and clinicopathological features and prognosis in these patients. Methods: DNAs from fresh-frozen paired samples of tumors and corresponding normal tissue from 128 stage II and III rectal cancer patients were analyzed for MSI by PCR amplification using markers recommended by a National Cancer Institute workshop on MSI. To assess prognostic significance, Cox proportional hazards modeling was used. Results: Twelve (9.3%) tumors in our study were MSI-H, 28 (21.9%) were low-frequency MSI (MSI-L) and 88 (68.8%) were microsatellite stable (MSS). Most of the MSI-H tumors compared with MSI-L and MSS tumors were found in female patients (p = 0.031), had mucinous histology (p = 0.023), high grade of differentiation (p = 0.002) and high level of preoperative serum carcinoembryonic antigen (p = 0.005). Rectal cancer patients with MSI-H did not show a better clinical outcome than those with MSI-L/MSS, neither in all cases (p = 0.986) nor in stage II and stage III disease analyzed separately (p = 0.705 and p = 0.664, respectively). Conclusions: Data provided here demonstrated there was high incidence of MSI-H and MSI was not a prognostic factor in sporadic stage II and III rectal cancers from the Chinese Han population included in this study. Tumor stage is more suitable than MSI status for prediction of individual survival in sporadic stage II and III rectal cancer patients. Copyright © 2007 S. Karger AG.

  • 184. Meng, Wen-Jian
    et al.
    Wang, Ling
    Tian, Chao
    Yu, Yong-Yang
    Zhou, Beng
    Gu, Yun
    Xia, Qing-Jie
    Sun, Xiao-Feng
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Li, Yuan
    Wang, Rong
    Zheng, Xue-Lian
    Zhou, Zong-Guang
    Novel mutations and sequence variants in exons 3-9 of human T Cell Factor-4 gene in sporadic rectal cancer patients stratified by microsatellite instability2007Inngår i: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 13, nr 27, s. 3747-3751Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: To establish the role of human T Cell Factor-4 (hTCF-4) gene exons 3-9 mutation status in association with sporadic rectal cancer with microsatellite instability (MSI). Methods: Microsatellite markers were genotyped in 93 sporadic rectal cancer patients. Eleven cases were found to be high-frequency MSI (MSI-H). Sequence analysis of the coding region of the exons 3-9 of hTCF-4 gene was carried out for the 11 MSI-H cases and 10 controls (5 microsatellite stability (MSS) cases and 5 cases with normal mucosa). The sequencing and MSI identification were used. Results: Several novel mutations and variants were revealed. In exon 4, one is a 4-position continuous alteration which caused amino acid change from Q131T and S132I (391insA, 392 G > A, 393 A > G and 395delC) and another nucleotide deletion (395delC) is present in MSI-H cases (5/10 and 4/10, respectively) but completely absent in the controls. Conclusion: Novel mutations in exon 4 of hTCF-4 gene were revealed in this study, which might be of importance in the pathogenesis of sporadic rectal cancer patients with MSI-H. © 2007 WJG. All rights reserved.

  • 185.
    Miller, T W
    et al.
    Vanderbilt University.
    Perez-Torres, M
    Vanderbilt University.
    Wu, H
    Vanderbilt University.
    Shyr, Y
    Vanderbilt University.
    Guix, M
    Vanderbilt University.
    Jiang, A
    Vanderbilt University.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Arteaga, C L
    Vanderbilt University.
    Loss of PTEN engages ErbB3 and IGF-I receptor signaling to promote antiestrogen resistance in breast cancer.2009Inngår i: CANCER RESEARCH ISSN 0008-5472: Volume 69 Issue 2, 2009, Vol. 69, nr 2, s. 80S-81SKonferansepaper (Fagfellevurdert)
  • 186.
    Moparhti, Satish Babu
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Arbman, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för kirurgi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Wallin, Åsa
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi.
    Kayed, Hany
    General Surgery, University of Heidelberg, Heidelberg, Germany.
    Kleeff, Jörg
    General Surgery, University of Heidelberg, Heidelberg, Germany.
    Zentgraf, Hanswalter
    Applied Tumor Virology, University of Heidelberg, Heidelberg, Germany.
    Sun, Xiao-Feng
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Expression of MAC30 protein is related to survival and biological variables in primary and metastatic colorectal cancers2007Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 30, nr 1, s. 91-95Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    MAC30 is highly expressed in several types of tumors including colorectal cancers, however, its clinicopathological and biological significance in colorectal cancers is currently not known. The aim of our study was to investigate MAC30 expression in distant normal mucosa, adjacent normal mucosa, primary tumors and metastases of colorectal cancer, and to determine the relationship between MAC30 expression and clinicopathological and biological variables. MAC30 expression was immunohistochemically examined in distant normal mucosa (n = 54), adjacent normal mucosa (n = 123), primary tumors (n = 217) and lymph node metastases (n = 56) from colorectal cancer patients. MAC30 cytoplasmic expression was increased from distant normal mucosa to primary tumor and to metastasis (p < 0.0001-0.04). Furthermore, 40% primary and 37% metastatic tumors showed stronger cytoplasmic expression of MAC30 at the tumor invasive margins compared to inner tumor areas. Strong cytoplasmic expression of MAC30 in the metastasis was related to a poor prognosis (p = 0.04). MAC30 cytoplasmic expression was positively related to expression of proliferating cell nuclear antigen (p = 0.04), p53 (p = 0.04), nucleoporin 88 (p = 0.001), legumain (p = 0.004) and particularly interesting new cysteine-histidine rich protein (p = 0.004). However, MAC30 expression in the nucleus and stroma did not have any clinicopathological and biological significance (p > 0.05). In conclusion, MAC30 protein may play a role in development of colorectal cancer, and can be considered as a prognostic factor.

  • 187.
    Moparthi, Satish Babu
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Bergman, Viveka
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Adell, Gunnar
    Karolinska University Hospital.
    Thorstensson, Sten
    Kalmar Hospital.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    pRb2/p130 protein in relation to clinicopathological and biological variables in rectal cancers with a clinical trial of preoperative radiotherapy2009Inngår i: INTERNATIONAL JOURNAL OF COLORECTAL DISEASE, ISSN 0179-1958, Vol. 24, nr 11, s. 1303-1310Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    pRb2/p130 plays a key role in cell proliferation and is a considerable progress about expression patterns of pRb2/p130 in number of malignancies. However, pRb2/p130 expression and its significance in rectal cancer remain unknown. The purpose of the present study was to investigate pRb2/p130 protein patterns and their correlations with clinicopathological and biological factors in rectal cancer patients with or without preoperative radiotherapy (RT). pRb2/p130 protein was examined by immunohistochemistry in 130 primary tumors, along with the corresponding 61 distant normal mucosa specimens, 85 adjacent normal mucosa specimens, 34 lymph node metastases, and 93 primary tumor biopsies from rectal cancer patients who participated in a Swedish clinical trial of preoperative RT. The pRb2/p130 protein was mainly localized in the cytoplasm of tumor cells. In nonradiated cases, the lack of pRb2/p130 was related to advanced tumor-node-metastases stage, poorer differentiation, weak fibrosis, less inflammatory infiltration, higher Ki-67, and positive Cox-2 expression (p andlt; 0.05). In radiated cases, the lack of pRb2/p130 was related to nonstaining of Cox-2 and survivin (p andlt; 0.05). pRb2/p130 protein in primary tumors tended to be increased after RT (27% vs 16%, p = 0.07). pRb2/p130 was mainly localized in the cytoplasm rather than in the nucleus in rectal cancer. After RT, pRb2/p130 protein seems to be increased in primary tumors, and further the relationship of the pRb2/p130 with the clinicopathological and biological variables changed compared to the nonradiated cases. However, we did not find that the pRb2/p130 was directly related to RT, tumor recurrence, and patients survival.

  • 188.
    Nilsson, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Angiogenin Regulation by Estradiol in Breast Tissue: Tamoxifen Inhibits Angiogenin Nuclear Translocation and Antiangiogenin Therapy Reduces Breast Cancer Growth In vivo2010Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, nr 14, s. 3659-3669Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Angiogenin, a 14.2-kDa polypeptide member of the RNase A superfamily, has potent angiogenic effects. Nuclear accumulation of angiogenin is essential for its angiogenic activity. Increased angiogenin expression has been associated with the transition of normal breast tissue into invasive breast carcinoma. In this article, we investigated whether estradiol (E-2) affected angiogenin in breast tissue. Experimental Design: We used microdialysis for sampling of extracellular angiogenin in vivo. In vitro cultures of whole normal breast tissue, breast cancer cells, and endothelial cells were used. Results: We show that extracellular angiogenin correlated significantly with E-2 in normal human breast tissue in vivo and that exposure of normal breast tissue biopsies to E-2 stimulated angiogenin secretion. In breast cancer patients, the in vivo angiogenin levels were significantly higher in tumors compared with the adjacent normal breast tissue. In estrogen receptor-positive breast cancer cells, E-2 increased and tamoxifen decreased angiogenin secretion. Moreover, E-2-induced angiogenin derived from cancer cells significantly increased endothelial cell proliferation. Tamoxifen reversed this increase as well as inhibited nuclear translocation of angiogenin. In vivo, in experimental breast cancer, tamoxifen decreased angiogenin levels and decreased angiogenesis. Additionally, treating tumor-bearing mice with an antiangiogenin antibody resulted in tumor stasis, suggesting a role for angiogenin in estrogen-dependent breast cancer growth. Conclusion: Our results suggest previously unknown mechanisms by which estrogen and antiestrogen regulate angiogenesis in normal human breast tissue and breast cancer. This may be important for estrogen-driven breast cancer progression and a molecular target for therapeutic interventions.

  • 189.
    Nilsson, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Anti-angiogenic effects of tamoxifen in breast cancer by decreased secretion and reduced nuclear accumulation of angiogenin2009Inngår i: CANCER RESEARCH ISSN 0008-5472: Volume 69 Issue 2, 2009, Vol. 69, nr 2, s. 115S-115SKonferansepaper (Fagfellevurdert)
  • 190.
    Nilsson, Ulrika
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jill A.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Tamoxifen decreases extracellular TGF-beta 1 secreted from breast cancer cells - A post-translational regulation involving matrix metalloproteinase activity2009Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 315, nr 1, s. 1-9Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Transforming growth factor-beta 1 (TGF-beta 1) promotes cancer progression by regulating tumor cell growth and angiogenesis and high levels of TGF-beta 1 have been associated with metastatic disease and poor prognosis in breast cancer patients. We have previously reported anti-angiogenic effects of the anti-estrogen tamoxifen in breast cancer, by increased matrix metalloproteinase-9 (MMP-9) activity and generation of endostatin. Here, we show that exposure of tamoxifen to ER-positive breast cancer cells for 7 days, decreased extracellular TGF-beta 1. Intracellular TGF-beta 1 levels were unaffected by tamoxifen treatment, indicating a post-translational regulation of TGF-beta 1. Inhibition of MMP activity restored TGF-beta 1 levels, suggesting an involvement of MMP activities in the down-regulation of TGF-beta 1 by tamoxifen. Moreover, using an in vivo model of solid MCF-7 tumors in nude mice, we analyzed tumor levels of TGF-beta 1 after in vivo treatment with estradiol and tamoxifen. Exposure of tumor-bearing mice to tamoxifen significantly decreased tumor TGF-beta 1 protein levels, tumor growth and angiogenesis. In conclusion, our findings suggest a novel mechanism of action of tamoxifen in breast cancer via sex steroid dependent modulation of the proteolytic tumor microenvironment resulting in reduced extracellular TGF-beta 1 levels.

  • 191.
    Nilsson, Ulrika W.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Garvin, Stina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    MMP‐2 and MMP‐9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells2007Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, Vol. 102, nr 3, s. 253-261Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Sex steroids play a dominant role in breast carcinogenesis by still largely unknown mechanisms. Matrix metalloproteinases (MMPs) have been extensively studied in the context of matrix biology but it is not known if sex steroids affect MMPs in breast cancer. MMPs degrade extracellular matrix components enabling tumor cell invasion and metastasis, but may also regulate the bioavailability of a variety of biologically active molecules such as anti-angiogenic fragments, which may be beneficial for the host. This study shows that estradiol and tamoxifen regulate MMP-2 and MMP-9 as well as TIMP-1 and TIMP-2 in ER + PR + human breast cancer cells. The main finding was a significant effect of tamoxifen exposure, which increased intracellular and secreted protein levels whereas estradiol induced a significant decrease. The overall net effect of these alterations resulted in increased MMP-2/MMP-9 activity by tamoxifen treatment, which also significantly increased extracellular endostatin levels. We conclude that estradiol and tamoxifen have the ability to modulate MMP-2/MMP-9 activity, and endostatin levels in human breast cancer in vitro. The results suggest a possible role of MMP modulation associated with a generation of anti-angiogenic fragments in the therapeutic effect of tamoxifen in breast cancer.

  • 192. Nordengren, J
    et al.
    Fredstorp Lidebring, M
    Bendahl, P-O
    Brunner, N
    Fero, M
    Högberg, Thomas
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Stephens, RW
    Willén, RW
    Casslén, B
    High tumor tissue concentration of plasminogen activator inhibitor-2 (PAI-2) is an independent marker for shorter progression-free survival of patients with early stage endometrial cancer2002Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 97, s. 379-385Artikkel i tidsskrift (Fagfellevurdert)
  • 193.
    Nordenskjöld, Bo
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Rosell, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Rutqvist, Lars-Erik
    Department of Oncology, Södersjukhuset Hospital, Stockholm, Sweden.
    Malmström, Per-Olof
    Department of Oncology, Lund University Hospital, Lund, Sweden.
    Bergh, Jonas
    Department of Oncology, Karolinska Hospital, Stockholm, Sweden.
    Bengtsson, Nils-Olof
    Department of Oncology, Umeå University Hospital, Umeå, Sweden.
    Hatschek, Thomas
    Department of Oncology, Karolinska Hospital, Stockholm, Sweden.
    Wallgren, Arne
    Department of Oncology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Carstensen, John
    Linköpings universitet, Filosofiska fakulteten. Linköpings universitet, Institutionen för hälsa och samhälle, Tema hälsa och samhälle.
    Coronary heart disease mortality after 5 years of adjuvant tamoxifen therapy: Results from a randomized trial2005Inngår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 97, nr 21, s. 1609-1610Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    From January 1, 1983, through December 31, 1992, a total of 4610 patients entered a randomized trial that compared mortality among patients receiving 2 years of adjuvant tamoxifen therapy with that in patients receiving 5 years of adjuvant tamoxifen therapy, 4175 of whom were recurrence free after 2 years of tamoxifen therapy. Among the 2046 patients randomly assigned to the 5-year group all-cause mortality, breast cancer-specific mortality, and the incidence of contralateral breast cancer were reduced, compared with those among 2129 patients randomized in the 2-year group, but the incidence of endometrial cancer was increased. In addition, mortality from coronary heart disease was statistically significantly reduced in the 5-year group, compared with that in the 2-year group (hazard ratio = 0.67, 95% confidence interval = 0.47 to 0.94, P = .022 [two-sided Wald test]). Ten years after surgery, 2.1% of the patients in the 5-year group and 3.5% of those in the 2-year group had died from coronary heart disease. No statistically significant increases in mortality from other heart diseases, cerebrovascular diseases, or other vascular diseases were observed. © The Author 2005. Published by Oxford University Press. All rights reserved.

  • 194. Nyström, Lennarth
    et al.
    Andersson, Ingvar
    Bjurstam, Nils
    Frisell, Jan
    Nordenskjöld, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Rutqvist, Lars Erik
    Long-term effects of mammography screening: Updated overview of the Swedish randomised trials2002Inngår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 359, nr 9310, s. 909-919Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There has been much debate about the value of screening mammography. Here we update the overview of the Swedish randomised controlled trials on mammography screening up to and including 1996. The Kopparberg part of the Two-County trial was not available for the overview, but the continuation of the Malm÷ trial (MMST II) has been added. The article also contains basic data from the trials that have not been presented before. Methods: The trials (n=247 010, invited group 129 750, control group 117 260) have been followed up by record linkage to the Swedish Cancer and Cause of Death Registers. The relative risks (RR) for breast cancer death and mortality were calculated for the invited and the control groups. The trial-specific as well as the age-specific effects were analysed. RRs were calculated by the density method, with total person-time experience of the cohort by time interval of follow-up as a basis for estimating mortality rates. We calculated weighted RRs and 95% CI with the Mantel-Haenszel procedure. Findings: The median trial time - the time from randomisation until the first round was completed for the control group or if the control group was not invited, until end of follow-up - was 6.5 years (range 3.0-18.1). The median follow-up time, the time from randomisation, to the end of follow-up, was 15.8 years (5.8-20.2). There were 511 breast cancer deaths in 1 864 770 women-years in the invited groups and 584 breast cancer deaths in 1 688 440 women-years in the control groups, a significant 21% reduction in breast cancer mortality (RR=0.79, 95% CI 0.70-0.89). The reduction was greatest in the age group 60-69 years at entry (33%). Looking at 5-year age groups, there were statistically significant effects in the age groups 55-59, 60-64, and 65-69 years (RR=0.76, 0.68, and 0.69, respectively). There was a small effect in women 50-54 years at randomisation (RR=0.95). The benefit in terms of cumulative breast cancer mortality started to emerge at about 4 years after randomisation and continued to increase to about 10 years. Thereafter the benefit in absolute terms was maintained throughout the period of observation. The age-adjusted relative risk for the total mortality was 0.98 (0.96-1.00). Interpretation: The advantageous effect of breast screening on breast cancer mortality persists after long-term follow-up. The recent criticism against the Swedish randomised controlled trials is misleading and scientifically unfounded.

  • 195. Pachkoria, Ketevan
    et al.
    Zhang, Hong
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Avdelningen för dermatologi och venereologi.
    Adell, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Jarlsfelt, Ingvar
    Sun, Xiao-Feng
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för biomedicin och kirurgi, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Significance of Cox-2 expression in rectal cancers with or without preoperative radiotherapy2005Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 63, nr 3, s. 739-744Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Radiotherapy has reduced local recurrence of rectal cancers, but the result is not satisfactory. Further biologic factors are needed to identify patients for more effective radiotherapy. Our aims were to investigate the relationship of cyclooxygenase-2 (Cox-2) expression to radiotherapy, and clinicopathologic/biologic variables in rectal cancers with or without radiotherapy. Methods and Materials: Cox-2 expression was immunohistochemically examined in distal normal mucosa (n = 28), in adjacent normal mucosa (n = 107), in primary cancer (n = 138), lymph node metastasis (n = 30), and biopsy (n = 85). The patients participated in a rectal cancer trial of preoperative radiotherapy. Results: Cox-2 expression was increased in primary tumor compared with normal mucosa (p < 0.0001), but there was no significant change between primary tumor and metastasis. Cox-2 positivity was or tended to be related to more p53 and Ki-67 expression, and less apoptosis (p ≤ 0.05). In Cox-2-negative cases of either biopsy (p = 0.01) or surgical samples (p = 0.02), radiotherapy was related to less frequency of local recurrence, but this was not the case in Cox-2-positive cases. Conclusion: Cox-2 expression seemed to be an early event involved in rectal cancer development. Radiotherapy might reduce a rate of local recurrence in the patients with Cox-2 weakly stained tumors, but not in those with Cox-2 strongly stained tumors. © 2005 Elsevier Inc.

  • 196. Pestalozzi, B. C.
    et al.
    Francis, P.
    Quinaux, E.
    Dolci, S.
    Azambuja, E.
    Gelber, R. D.
    Viale, G.
    Balil, A.
    Andersson, M.
    Nordenskjöld, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Gnant, M.
    Gutierrez, J.
    Láng, I.
    Crown, J. P. A.
    Piccart-Gebhart, M.
    Is risk of central nervous system (CNS) relapse related to adjuvant taxane treatment in node-positive breast cancer? Results of the CNS substudy in the intergroup phase III BIG 02-98 trial2008Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 19, nr 11, s. 1837-1841Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Breast cancer central nervous system (CNS) metastases are an increasingly important problem because of high CNS relapse rates in patients treated with trastuzumab and/or taxanes. Patients and methods: We evaluated data from 2887 node-positive breast cancer patients randomised in the BIG 02-98 trial comparing anthracycline-based adjuvant chemotherapy (control arms) to anthracycline-docetaxel-based sequential or concurrent chemotherapy (experimental arms). After a median follow-up of 5 years, 403 patients had died and detailed information on CNS relapse was collected for these patients. Results: CNS relapse occurred in 4.0% of control patients and3.7% of docetaxel-treated patients. CNS relapse occurred in 27% of deceased patients in both treatment groups. CNS relapse was usually accompanied by neurologic symptoms (90%), and 25% of patients with CNS relapse died without evidence of extra-CNS relapse. Only 20% of patients survived 1 year from the diagnosis of CNS relapse. Prognosis of CNS relapse was worse for patients with meningeal carcinomatosis when compared with brain metastases. Unexpected findings included a higher rate of positive cerebrospinal fluid cytology (8% versus 3%) and more frequent use of magnetic resonance imaging for diagnosis (47% versus 30%) in the docetaxel-treated patients. Conclusion: There is no evidence that adjuvant docetaxel treatment is associated with an increased frequency of CNS relapse. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

  • 197.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Drug therapy of cancer2011Inngår i: EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, ISSN 0031-6970, Vol. 67, nr 5, s. 437-447Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Cancer chemotherapy was introduced at the same time as antibacterial chemotherapy but has not been nearly such a success. However, there is a growing optimism in oncology today due to the introduction of several more or less target-specific drugs as complements to the conventional cytotoxic drugs introduced half a century ago. The success in the treatment of chronic myelogenous leukemia by imatinib, inhibiting the bcrabl-activated tyrosine kinase and thereby interrupting the signal transduction pathways that lead to leukemic transformation with impressive survival benefit, has paved the way for this new optimism. Another success story is the introduction of trastuzumab in breast cancers overexpressing the HER-2 receptor. In contrast, there has been little progress in other malignancies such as metastatic malignant melanoma, although very recently, clinical trials with new targeted drugs have shown increased survival. All major pharmaceutical companies now have ambitious development programs in the cancer area. However, the high costs of the novel drugs cause economic distress in the health care system in many countries leading to an intense debate on the cost-effectiveness of these drugs in relation to other health care activities.

  • 198.
    Pfeifer, Daniella
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Polymorphism of the p73 gene in relation to colorectal cancer risk and survival2005Inngår i: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 26, nr 1, s. 103-107Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The results regarding a GC/AT polymorphism in the p73 gene in relation to cancer risk are inconsistent, and the significance of loss of heterozygosity (LOH) of the gene is unclear. In the present study, we investigated whether this polymorphism was related to the risk of colorectal cancer, and whether there were relationships between the polymorphism and LOH, protein expression or clinicopathological variables. 179 patients with colorectal cancer and 260 healthy controls were genotyped for the polymorphism by PCR-restriction fragment length polymorphism (RFLP). Fifty informative cases were examined for LOH in tumours. Immunohistochemistry was performed on distant (n = 42) and adjacent normal mucosa (n = 33), primary tumour (n = 6 9) and lymph node metastasis (n = 12). The frequencies of the genotypes were 63% for wild-type (GC/GC), 30% for heterozygotes (GC/AT) and 7% for variants (AT/AT) in patients, and 62, 36 and 2% in controls, respectively. The frequencies of the genotypes in the patients and controls were significantly different (P = 0.02). The patients carrying the AT allele had a better prognosis than those with the GC/GC genotype (OR = 0.42, 95% CI = 1.15-5.02, P = 0.02). No LOH was observed at the p73 locus. Expression of p73 protein was increased from normal mucosa to primary tumours (P = 0.02), but was not significantly changed between primary tumours and metastases (P = 1.0). In conclusion, the AT/AT homozygotes may have a greater risk of developing colorectal cancer, while the patients who carried the AT allele had a better prognosis.

  • 199.
    Pfeifer, Daniella
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gao, Jingfang
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Adell, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Expression of the p73 protein in rectal cancers with or without preoperative radiotherapy2006Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 65, nr 4, s. 1143-1148Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To investigate p73 expression in normal mucosa, primary tumor, and metastasis in relation to radiotherapy (RT) response and clinicopathologic/biologic variables in rectal cancers.

    Methods and Materials: p73 was immunohistochemically examined on biopsies (unirradiated, n = 102), distant (from the large bowel, n = 82), and adjacent (adjacent to primary tumor, n = 89) normal mucosa samples, primary tumors (n = 131), and lymph node metastasis (n = 32) from rectal cancer patients participating in a clinical trial of preoperative RT. Seventy-four patients received surgery alone and 57 received additional RT.

    Results: Cytoplasmic p73 was increased in the primary tumor compared with the distant or adjacent mucosa (p ≤ 0.0001). Nuclear (p = 0.02) and cytoplasmic (p = 0.003) p73 was higher in irradiated distant mucosa samples than in unirradiated ones, and nuclear p73 tended to be increased in irradiated primary tumors compared with unirradiated ones (p = 0.06). p73 was positively related to cyclooxygenase-2 expression in irradiated tumors (p = 0.03). p73-negative tumors tended to have a lower local recurrence after RT compared with unirradiated cases (p = 0.06).

    Conclusions: Normal epithelial cells seem more sensitive to RT than tumor cells regarding p73 expression. Patients with p73-negative rectal tumors may have a lower risk of local recurrence after RT.

  • 200.
    Pfeifer, Daniella
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Wallin, Åsa
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Holmlund, Birgitta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Protein expression following gamma-irradiation relevant to growth arrest and apoptosis in colon cancer cells with mutant p532009Inngår i: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 135, nr 11, s. 1583-1592Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We previously found that p53, p73, survivin and PRL were implicated in the outcome of radiotherapy in rectal cancer patients. In the present study, we tried to understand mechanisms of colon cancer cell line response to radiation based on protein expression related to proliferation and apoptosis. KM12C, KM12SM and KM12L4a, cell lines with one origin, were radiated with 0, 10 or 15 Gy γ-radiation. Radiosensitivity was determined with cell cycle and apoptosis analysis, and protein expression of TAp73, ΔNp73, mutated p53, survivin and PRL-3 was determined by Western blot. KM12C showed transient G2-arrest, low apoptosis and up-regulation of resistance factors such as PRL-3. In KM12C expression of ΔNp73 increased after 10Gy, but not after 15Gy. KM12SM had permanent G2-arrest, low apoptosis and showed up-regulation of the anti-apoptotic survivin and down-regulation of the pro-apoptotic TAp73 and the radioresistance factor PRL-3 was down-regulated. KM12L4a, the most radiosensitive cell line, showed up-regulation of TAp73 and down-regulation/no up-regulation of resistance factors such as ΔNp73, survivin and PRL-3 after radiation. In conclusion, the KM12C cell line was more radioresistant than KM12L4a regarding apoptosis and certain apoptotic proteins. The radiosensitivity of KM12L4a might partly depend on the lack of up-regulation of proteins negative for the outcome of radiotherapy.

     

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