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  • 251.
    Rosell, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bengtsson, Nils-Olof
    Umeå University Hospital, Sweden .
    Fornander, Tommy
    Karolinska University Hospital, Sweden .
    Hatschek, Thomas
    Karolinska University Hospital, Sweden .
    Lindman, Henrik
    University of Uppsala Hospital, Sweden .
    Malmstrom, Per-Olof
    Skåne University Hospital, Sweden .
    Wallgren, Arne
    Sahlgrens University Hospital, Sweden .
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Effects of adjuvant tamoxifen therapy on cardiac disease: results from a randomized trial with long-term follow-up2013Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 138, nr 2, s. 467-473Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tamoxifen is associated with a reduced risk of coronary heart disease (CHD). However, there are few reports on long-term effects. Using data from a large Swedish randomized trial of 5 and 2 years of adjuvant tamoxifen in women with early breast cancer, we here present results on morbidity and mortality from cardiac diseases during treatment and long-term after treatment. A total of 4,150 patients were breast cancer recurrence-free after 2 years. Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry were used to define events of disease. Hazard ratios were estimated using Cox regression. Patients assigned to 5 years in comparison with 2 years of postoperative tamoxifen experienced a reduced incidence of CHD [hazard ratio (HR), 0.83; 95 % CI 0.70-1.00], especially apparent during the active treatment period (HR 0.65; 95 % CI 0.43-1.00). The mortality from CHD was significantly reduced (HR 0.72; 95 % CI 0.53-0.97). During the active treatment, the morbidity of other heart diseases was also significantly reduced (HR 0.40; 95 % CI 0.25-0.64) but not after treatment stopped (HR 1.06; 95 % CI 0.87-1.30). Similar results were seen for both heart failure and atrial fibrillation/flutter. As compared to 2 years of therapy, 5 years of postoperative tamoxifen therapy prevents CHD as well as other heart diseases. The risk reduction is most apparent during the active treatment period, and later tends to diminish.

  • 252.
    Rosell, Johan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Bengtsson, N-O
    Department of Oncolog, Umea University Hospital, Sweden.
    Fornander, T
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Hatschek, T
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Lindman, H
    Department of Oncology, Uppsala University Hospital, Uppsala, Sweden.
    Malmstrom, P-O
    Department of Oncology, Lund University Hospital, Lund, Sweden.
    Wallgren, A
    Department of Oncology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
    Time dependent effects of adjuvant tamoxifen therapy on cerebrovascular disease: results from a randomised trial2011Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, nr 6, s. 899-902Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Tamoxifen has been associated with an increased risk of stroke. There is, however, little information on the effect in the post-treatment period. Using data from the Swedish Breast Cancer Group adjuvant trial of 5 vs 2 years of tamoxifen treatment, we now report both short-term and long-term effects on morbidity as well as mortality because of cerebrovascular disease. METHODS: Data from the Swedish National Hospital Discharge Registry combined with information from the Swedish Cause of Death Registry was used to define events of disease. Hazard ratios (HRs) were estimated using Cox regression. RESULTS: Comparing patients randomised to 5 years of tamoxifen with patients randomised to 2 years of tamoxifen, the incidence of cerebrovascular diseases was increased (HR 1.70, 95% CI 1.05-2.75) during the active treatment phase and reduced after the active treatment period (HR 0.78, 95% CI 0.63-0.96), and the difference in HR between the two time-periods was significant (P 0.0033). The mortality from cerebrovascular diseases was increased during the treatment period (HR 3.18, 95% CI 1.03-9.87) and decreased during the post-treatment period (HR 0.60, 95% CI 0.40-0.90) with a significant difference in HR between the two periods of follow-up (P=0.0066). Similar results were seen for subgroups of cerebrovascular diseases, such as stroke and ischaemic stroke. CONCLUSION: In an adjuvant setting, tamoxifen was associated with an increased risk of cerebrovascular disease during treatment, but a decreased risk in the post-treatment period.

  • 253.
    Rosengren, S
    et al.
    Uppsala University Hospital.
    Ahlberg, Lucia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Forsberg, K
    Umeå University Hospital.
    Lenhoff, S
    Lund University Hospital.
    Mellqvist, U
    Sahlgrenska University Hospital.
    Nahi, H
    Karolinska University Hospital.
    Carlson, K
    OUTCOME OF AUTOLOGOUS STEM CELL TRANSPLANTATION FOR AL-AMYLOIDOSIS IN SWEDEN in HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, vol 95, issue , pp 393-3932010Inngår i: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, Pensiero Scientifico / Ferrata Storti Foundation , 2010, Vol. 95, s. 393-393Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 254. Ryden, L
    et al.
    Jirstrom, K
    Bendahl, PA
    Ferno, M
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Thorstenson, Sten
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Jonsson, PE
    Landberg, G
    Tumor-specific expression of vascular endothelial growth factor receptor 2 but not vascular endothelial growth factor or human epidermal growth factor receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal breast cancer2005Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 23, nr 21, s. 4695-4704Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) are often coexpressed in breast cancer, and potentially affect cellular pathways and key proteins such as the estrogen receptor (ER) targeted by endocrine treatment. We therefore explored the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A and VEGFR2, as well as human epidermal growth factor receptor 2 (HER2), which represents a candidate gene product involved in tamoxifen resistance.

    Patients and Methods Immunohistochemical expression of tumor-specific VEGF-A, VEGFR2, and HER2 was evaluated in tumor specimens from premenopausal breast cancer patients randomly assigned to 2 years of tamoxifen or no treatment (n = 564), with 14 years of follow-up. Hormone receptor status was determined in 96% of the tumors.

    Results VEGF-A, VEGFR2, and HER2 were assessable in 460, 472, and 428 of the tumors, respectively. In patients with ER–positive and VEGFR2-low tumors, adjuvant tamoxifen significantly increased recurrence-free survival (RFS; [HR] hazard ratio for RFS, 0.53; P = .001). In contrast, tamoxifen treatment had no effect in patients with VEGFR2-high tumors (HR for RFS, 2.44; P = .2). When multivariate interaction analyses were used, this difference in treatment efficacy relative to VEGFR2 expression status was statistically significant for both ER-positive (P = .04) plus ER-positive and progesterone receptor–positive tumors. We found no significant difference in tamoxifen treatment effects in relation to VEGF-A or HER2 status.

    Conclusion Tumor-specific expression of VEGFR2 was associated with an impaired tamoxifen effect in hormone receptor–positive premenopausal breast cancer. Tamoxifen in combination with VEGFR2 inhibitors might be a novel treatment approach for VEGFR2-expressing breast cancer, and such a treatment might restore the tamoxifen response.

  • 255.
    Ryden, Lisa
    et al.
    Lund University Hospital.
    Jirstrom, Karin
    Lund University.
    Haglund, Monica
    Lund University.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Ferno, Marten
    Lund University.
    Epidermal growth factor receptor and vascular endothelial growth factor receptor 2 are specific biomarkers in triple-negative breast cancer. Results from a controlled randomized trial with long-term follow-up2010Inngår i: BREAST CANCER RESEARCH AND TREATMENT, ISSN 0167-6806, Vol. 120, nr 2, s. 491-498Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Triple-negative breast cancer (TNB) has poor prognosis and moreover patients with TNB do not benefit from established targeted drugs with endocrine therapy or trastuzumab. The aim of the study was to analyze the prevalence of candidate biomarkers in tumors from patients with TNB. Tissue microarrays were prepared from primary tumors from premenopausal breast cancer patients (500/564) randomized to adjuvant tamoxifen or no adjuvant treatment. Immunohistochemical (IHC) staining included ER, PR, HER2, epidermal receptor growth factor (EGFR), vascular endothelial growth factor A (VEGF-A), and vascular endothelial growth factor receptor 2 (VEGFR2). EGFR and HER2 gene copy number was defined by fluorescence in situ hybridization (FISH). All patients were included in the descriptive analysis, but only untreated patients in the survival analysis. TNB was diagnosed in 96 patients and correlated significantly to low age, Nottingham histological grade (NHG) III, high Ki67-index, T2 tumors, node negativity, EGFR positivity, increased EGFR gene copy number and high VEGFR2 expression. TNB was an independent prognostic factor for decreased 5-year breast cancer specific survival (BCSS) (HR 2.0 (95% CI 1.1-3.6), P = 0.01), but not for 10-year BCSS. High VEGFR2 expression was significantly correlated to decreased BCSS in TNB patients. TNB was associated with decreased BCSS and clinicopathological characteristics of an aggressive tumor type. High VEGFR2 expression, EGFR expression, and EGFR gene copy number were significantly correlated to TNB, supporting their role as putative candidate biomarkers for selection of targeted therapy in TNB.

  • 256.
    Rydén, Lisa
    et al.
    Department of Surgery, Institution of Clinical Sciences, Lund University, Sweden.
    Landberg, Göran
    Division of Pathology, Institution of Laboratory Medicine, Malmö University Hospital, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fernö, Mårten
    Department of Oncology, Institition of Clinical Sciences, Lund University, Lund, Sweden.
    Bendahl, Pär-Ola
    Department of Oncology, Institition of Clinical Sciences, Lund University, Lund, Sweden.
    HER2 status in hormone receptor positive premenopausal primary breast cancer adds prognostic, but not tamoxifen treatment predictive, information2008Inngår i: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 109, nr 2, s. 351-357Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Overexpression of human epidermal growth factor receptor 2 (HER2) or amplification of its gene is a prognostic factor in primary breast cancer and a predictor for tamoxifen treatment efficacy in oestrogen receptor (ER) positive disease. In the present study we explored a defined cohort of breast cancer patients included in a randomised trial in order to assess prognostic and tamoxifen treatment information yielded by HER2 status.

    Methods

    Premenopausal breast cancer patients with stage II tumours (n = 564) were included and allocated to 2 years of adjuvant tamoxifen treatment versus no adjuvant treatment. ER, progesterone receptor (PR) status and HER2 status was determined by immunohistochemistry using a tissue microarray. HER2 amplification was analysed by fluorescent in situ hybridisation and tumours being amplified and/or HER2 3+ were considered HER2+. HER2 status was evaluable in 83% of the patients and 12.6% were HER2+. In untreated patients, HER2 was a negative prognostic factor in ER+ patients, HR 2.95; 95% CI: 1.61–5.38, p < 0.001, but not in ER- patients, HR 0.67; 95% CI: 0.28–1.61, p = 0.4, and a significant interaction between the two markers was found, p < 0.01. HER2 status was not related to tamoxifen treatment efficacy in ER+ patients (term of interaction p = 0.95). When stratifying for PR status, similar results were achieved.

    Discussion

    HER2+ and ER+ breast cancer constituted a subgroup of tumours with poor prognosis in premenopausal breast cancer, whereas no treatment interaction was found between HER2 status and tamoxifen in ER+ tumours. The poor prognosis in HER2+ and ER+ patients may interfere with the interpretation of HER2 data in non-randomised trials of adjuvant tamoxifen.

  • 257.
    Saarinen, N M
    et al.
    University of Turku.
    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.
    Enterolactone but not genistein decreases estradiol-induced tumor growth, angiogenesis, and secreted VEGF in vivo in human breast cancer. in CANCER RESEARCH, vol 69, issue 2, pp 325S-325S2009Inngår i: CANCER RESEARCH, 2009, Vol. 69, nr 2, s. 325S-325SKonferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 258.
    Saarinen, Niina M.
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    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.
    Estrogen-induced angiogenic factors derived from stromal and cancer cells are differently regulated by enterolactone and genistein in human breast cancer in vivo2010Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 127, nr 3, s. 737-745Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Angiogenesis is a key in cancer progression and its regulators are released both by the tumor cells and the stroma. Dietary phytoestrogens, such as the lignan enterolactone (ENL) and the isoflavone genistein (GEN), may differently affect breast cancer growth. In this study, human breast cancer cells (MCF-7) were established in mice creating a tumor with species-specific cancer and stroma cells. Ovariectomized athymic mice supplemented with estradiol (E2) were fed basal AIN-93G diet (BD) or BD supplemented with 100 mg/kg ENL, 100 mg/kg GEN or their combination (ENL+GEN). We show that ENL and ENL+GEN inhibited E2-induced cancer growth and angiogenesis, whereas GEN alone did not. Microdialysis was used to sample extracellular proteins in tumors in vivo. ENL and ENL+GEN decreased both stroma- and cancer cell-derived VEGF, whereas cancer cell-derived PlGF increased. In subcutaneous Matrigel plugs in mice, ENL and ENL+GEN decreased E2-induced endothelial cell infiltration, whereas GEN alone did not. In endothelial cells, ENL inhibited E2-induced VEGFR-2 expression, whereas GEN did not. These results suggest that ENL has potent effects on breast cancer growth, even in combination with GEN, by downregulating E2-stimulated angiogenic factors derived both from the stroma and the cancer cells, whereas dietary GEN does not possess any antiestrogenic effects.

  • 259.
    Sanchez, B. C.
    et al.
    Karolinska Institute.
    Sundqvist, M.
    Kalmar Hospital.
    Fohlin, Helena
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Spyratos, F.
    Ctr Rene Huguenin, Lab Oncogenet, St Cloud, France.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Linderholm, B. K,
    Karolinska Institute.
    Prolonged tamoxifen treatment increases relapse-free survival for patients with primary breast cancer expressing high levels of VEGF2010Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 46, nr 9, s. 1580-1587Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previous retrospective studies have shown that high intratumoural levels of vascular endothelial growth factor (VEGF) correlate with an inferior outcome for patients treated with adjuvant tamoxifen. Our objectives were to validate the impact of VEGF on survival after adjuvant tamoxifen and to investigate the interaction between VEGF and treatment duration. For this purpose tumour homogenates from 402 patients with operable oestrogen receptor positive breast cancer (BC), treated with tamoxifen for 2 (n = 149) or 5 years (n = 253) as the only systemic adjuvant therapy were included. The median follow-up time for surviving patients was 9.8 years (range 0.5-14.8 years). Expression of VEGF was assessed by an enzyme-linked immunosorbent assay and investigated in relation to the standard BC parameters and survival. In the total population, higher VEGF was significantly correlated with shorter recurrence-free survival (RFS) (HR = 1.63, 95%CI = 1.11-2.39, p = 0.010), breast cancer corrected survival (BCCS) (HR = 1.82, 95%CI = 1.13-2.93, p = 0.014) and overall survival (OS) (HR = 1.51, 95%CI = 1.11-2.05, p = 0.009). High VEGF was significantly associated with reduced RFS (HR = 2.61, 95%CI = 1.45-4.70, p = 0.001) after two years of tamoxifen, whilst no difference was seen in patients treated for five years (HR = 1.09, 95%CI = 0.64-1.84, p = 0.760). A statistically significant interaction was observed between high VEGF expression and improved RFS after 5-year tamoxifen (p = 0.034). In concordance with previous studies, high VEGF was significantly correlated with shorter survival. We present data not reported previously revealing that patients expressing high levels of VEGF display a better outcome provided that tamoxifen is given for five years. Further studies on the impact of VEGF on a 5-year regimen are motivated.

  • 260.
    Sandblom, Gabriel
    et al.
    Karolinska Institute.
    Varenhorst, Eberhard
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Urologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lofman, Owe
    Norwegian University Life Science.
    Carlsson, Per
    Linköpings universitet, Institutionen för medicin och hälsa, Utvärdering och hälsoekonomi. Linköpings universitet, Hälsouniversitetet.
    Letter: PROSTATE CANCER SCREENING Authors reply2011Inngår i: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 342Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 261.
    Sandblom, Gabriel
    et al.
    Karolinska Institute.
    Varenhorst, Eberhard
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Urologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Urologiska kliniken i Östergötland.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Lofman, Owe
    Norwegian University of Life Science.
    Carlsson, Per
    Linköpings universitet, Institutionen för medicin och hälsa, Utvärdering och hälsoekonomi. Linköpings universitet, Hälsouniversitetet.
    Randomised prostate cancer screening trial: 20 year follow-up2011Inngår i: BRITISH MEDICAL JOURNAL, ISSN 0959-535X, Vol. 342, nr d1539Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective To assess whether screening for prostate cancer reduces prostate cancer specific mortality. Design Population based randomised controlled trial. Setting Department of Urology, Norrkoping, and the South-East Region Prostate Cancer Register. Participants All men aged 50-69 in the city of Norrkoping, Sweden, identified in 1987 in the National Population Register (n=9026). Intervention From the study population, 1494 men were randomly allocated to be screened by including every sixth man from a list of dates of birth. These men were invited to be screened every third year from 1987 to 1996. On the first two occasions screening was done by digital rectal examination only. From 1993, this was combined with prostate specific antigen testing, with 4 mu g/L as cut off. On the fourth occasion (1996), only men aged 69 or under at the time of the investigation were invited. Main outcome measures Data on tumour stage, grade, and treatment from the South East Region Prostate Cancer Register. Prostate cancer specific mortality up to 31 December 2008. Results In the four screenings from 1987 to 1996 attendance was 1161/1492 (78%), 957/1363 (70%), 895/1210 (74%), and 446/606 (74%), respectively. There were 85 cases (5.7%) of prostate cancer diagnosed in the screened group and 292 (3.9%) in the control group. The risk ratio for death from prostate cancer in the screening group was 1.16 (95% confidence interval 0.78 to 1.73). In a Cox proportional hazard analysis comparing prostate cancer specific survival in the control group with that in the screened group, the hazard ratio for death from prostate cancer was 1.23 (0.94 to 1.62; P=0.13). After adjustment for age at start of the study, the hazard ratio was 1.58 (1.06 to 2.36; P=0.024). Conclusions After 20 years of follow-up the rate of death from prostate cancer did not differ significantly between men in the screening group and those in the control group.

  • 262.
    Severinsson, Emelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Experimental studies on ErbB targeted therapy in malignant melanoma2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Malignant melanoma has one of the fastest increasing incidences among the different types of cancer in the Western world. This raise can partly be ascribed to the change in sun habits that has taken place during the last decades, since the major external risk factor for melanoma is exposure to ultraviolet radiation. In the case of patients with early stages of melanoma, the prognosis is usually good and the disease may be cured by surgery alone. However, with conventional anti-cancer treatments, patients diagnosed with unresectable or metastatic melanoma have a very low 5-year survival rate ranging from less than 10 percent to about 20 percent, depending on the location and extent of metastatic spread. Despite the development of novel promising targeted drugs, such as the immunomodulating antibody ipilimumab and the B-raf inhibitor vemurafenib, that have been shown to significantly extend patient survival, there is still an urgent need for new and improved treatment strategies which can further increase the survival of patients with advanced malignant melanoma.

    The aim of this thesis was to investigate the anti-tumor effect of two different tyrosine kinase inhibitors (TKIs), gefitinib and canertinib, on human malignant melanoma cell lines with wild-type BRAF and NRAS. We investigated the effect of these two drugs on cell proliferation, survival and on the ErbB1-4 receptor phosphorylation, as well as the downstream signaling molecules Akt, Erk1/2 and Stat3. We also established a melanoma cell line resistant to gefitinib treatment and studied the resistance mechanisms developed by the cells.

    The aim of this thesis was to investigate the anti-tumor effect of two different tyrosine kinase inhibitors (TKIs), gefitinib and canertinib, on human malignant melanoma cell lines with wild-type BRAF and NRAS. We investigated the effect of these two drugs on cell proliferation, survival and on the ErbB1-4 receptor phosphorylation, as well as the downstream signaling molecules Akt, Erk1/2 and Stat3. We also established a melanoma cell line resistant to gefitinib treatment and studied the resistance mechanisms developed by the cells.

    In conclusion, gefitinib and canertinib display promising anti-tumor effects on ErbB-expressing malignant melanoma and might be used in future studies in combination with conventional chemotherapy or other targeted therapies in the treatment of malignant melanoma patients not harboring BRAF or NRAS mutations.

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

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

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

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

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

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

    Tilgjengelig fra: 2012-01-12 Laget: 2012-01-12 Sist oppdatert: 2017-12-08
    3. Resistance to gefitinib in malignant melanoma cells is related to increased expression of Met and the insulin receptor and sustained Akt signaling
    Åpne denne publikasjonen i ny fane eller vindu >>Resistance to gefitinib in malignant melanoma cells is related to increased expression of Met and the insulin receptor and sustained Akt signaling
    Vise andre…
    2012 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

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

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

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

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

    Emneord
    Malignant melanoma, gefitinib, canertinib, gefitinib resistance, ErbB, Erk1/2, Akt, Stat3, Met, IR
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-85664 (URN)
    Tilgjengelig fra: 2012-11-27 Laget: 2012-11-27 Sist oppdatert: 2012-11-27bibliografisk kontrollert
  • 263.
    Shabo, Ivan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Tumor cell expression of CD163 is an independent prognostic factor in colorectal cancer patientsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    CD163 is a macrophage specific marker. Recent studies have shown that CD163 expression in breast and rectal cancer cells is associated with poor prognosis. This study was conducted to evaluate the relationship between CD163 expression, as a macrophage trait, and macrophage infiltration and their clinical-pathological significance in colorectal cancer. The hypothesis of macrophage-cancer cell fusion may explain the expression of CD163 in cancer cells.

    Immune-staining of CD163 and macrophage infiltration were evaluated in paraffinembedded specimens, earlier analyzed for Ki-67, CD31 and D2-40 and S-phase fraction, from primary tumors and normal colorectal mucosa of 77 patients with colorectal carcinoma. The outcomes were analyzed in relation to clinical-pathological data.

    CD163 is positive in cancer cells in 16-18% of the patients and it is related to advanced tumor stages (stage III-IV) and unfavorable prognosis. High macrophage infiltration may be related to lower survival but this relation was not statistically significant. The prognostic significance of CD163 expression is independent of tumor stage (p=0,015) and macrophage density in tumor stroma (p=0,007).

    The expression of macrophage phenotype in colorectal cancer cells is associated with poor prognosis independently of tumor stage and macrophage density in the tumour stroma. Macrophages may promote tumour growth and progression by an autocrine interaction with cancer cells. Macrophage – cancer cell fusion may occur in colorectal cancer and contribute to tumour progression and metastasis.

  • 264.
    Shabo, Ivan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Svanvik, Joar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    DAP12, a macrophage fusion receptor, is expressed in breast cancer cells and associated with skeletal and liver metastases and poor survivalManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    DAP12 is a transmembrane receptor present in myeloid cells and is essential for the development of functionally mature osteoclasts and microglia, and for integrin signaling in macrophages and neutrophils. The macrophage specific antigen CD163 is expressed in breast and colorectal cancer and is associated with early cancer recurrence and poor prognosis. We hypothesize that macrophage traits in cancer cells may be explained by fusion between cancer cells and tumor associated macrophages. The role of DAP12 in the fusion between cancer cells and macrophages is not known. This study was performed to investigate the expression of DAP12 in breast cancer cells and its´ relation to macrophage trait manifested by CD163 expression.

    Immunostaining of DAP12, CD163 and MAC387 were evaluated in paraffinembedded specimens from totally 133 patients with breast cancer. The outcomes were analyzed in relation to clinicopathological data.

    DAP12 expression was positive in the majority of cases (64%) with breast cancer and associated with advanced tumor grade (p= 0.015) and liver metastasis (p= 0.0465) but not lung metastasis (0.997). It tended to correlate with skeletal metastases (p=0.0673). Patients with breast cancer expressing high DAP12 had poor prognosis with higher rates of skeletal (p=0.023) and liver metastases (p=0.028) and overall shorter distant recurrence free survival (p=0.0028). DAP12 expression was neither correlated to CD163 nor MAC387 expression. To our knowledge, this is the first study where DAP12 expression is reported in breast cancer.

    In conclusion, DAP12 is expressed in breast cancer and is significantly related to skeletal and liver metastasis as well as poor prognosis. We hypothesize that DAP12 expression may promote fusion between breast cancer cells and macrophages. It may even promote homing of cancer cells in bone and liver tissue and result in increased metastasis at these sites.

  • 265.
    Shabo, Ivan
    et al.
    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.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk immunologi och transfusionsmedicin.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Svanvik, Joar
    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.
    Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time.2009Inngår i: International journal of cancer. Journal international du cancer, ISSN 1097-0215, Vol. 125, nr 8, s. 1826-1831Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Expression of the macrophage antigen CD163 in breast cancer cells is recently shown to be related to early distant recurrence and shortened survival. In this study, 163 patients with rectal cancer, included in the Swedish rectal cancer trial and followed up for a median of 71 months, were examined for the expression of CD163 in the primary tumors. The cancer cells expressed CD163 in the primary tumors in 23% (n = 32) of the patients. In pretreatment biopsies from 101 patients, 10 had CD163-positive cancers and these patients had earlier local recurrence (p < 0.044) and reduced survival time (p < 0.045) compared with those with CD163-negative tumors. When studying surgical specimens from 61 patients randomized to preoperative irradiation (5 x 5 Gy delivered in 1 week), it was found that 31% were CD163 positive whereas the corresponding figure was only 17% for 78 patients who were nonirradiated (p < 0.044), which tentatively may be consistent with X-rays inducing fusion. In CD163-positive tumors there was a reduced apoptotic activity as measured with the Termina deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling (TUNEL) technique (p = 0.018). There tended also to be an increased proliferation activity measured as an expression of Ki-67 non significant (NS). It is concluded that primary rectal cancers may express CD-163, and this phenotypic macrophage trait is related to early local recurrence, shorter survival time and reduced apoptosis. Furthermore, the expression of CD163 is more common after irradiation.

  • 266.
    Shabo, Ivan
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Olsson, Hans
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Doré, Siv
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Linköpings universitet, Hälsouniversitetet.
    Svanvik, Joar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival2008Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 123, nr 4, s. 780-786Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cells of the monocyte/macrophage lineage are important for tumour cell migration, invasion and metastasis. Fusion between macrophages and cancer cells in animal models in vitro and in vivo causes hybrids with increased metastatic potential. Primary breast cancer cells were characterized for macrophage antigens to test if phenotypic resemblance to macrophages is related to early distant recurrence. Immunostaining for CD163, MAC387 and CD68 was performed in a breast cancer tissue micro array from 127 patients consequently followed up for a median of 13 years. Tumour-associated macrophages expressed all 3 antigens. The breast cancers expressed CD163 to 48%, MAC387 to 14% while CD68 was not expressed. TGF-β staining intensity was positively related to both CD163 and MAC387 expression. Expression of CD163 in the cancer cells was compared to their DNA ploidy, Nottingham Histological Grade, TNM-stage, node state, presence of estrogen receptors and occurrence of distant metastases and survival. Cancers of a more advanced histological grade expressed CD163 to a higher extent. Cells expressing MAC387 were more common in cancers with a high proportion of CD163 positive cells. Multivariate analysis showed that expression of the macrophage antigen CD163 in breast cancer cells has a prognostic impact on the occurrence of distant metastases and reduced patient survival time.

  • 267.
    Shen, X-G
    et al.
    Sichuan University.
    Wang, C
    Sichuan University.
    Li, Y
    Sichuan University.
    Wang, L
    Sichuan University.
    Zhou, B
    Sichuan University.
    Xu, B
    Sichuan University.
    Jiang, X
    Sichuan University.
    Zhou, Z-G
    Sichuan University.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Downregulation of caspase-9 is a frequent event in patients with stage II colorectal cancer and correlates with poor clinical outcome2010Inngår i: COLORECTAL DISEASE, ISSN 1462-8910, Vol. 12, nr 12, s. 1213-1218Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective To evaluate the clinical significance of caspase-9 mRNA expression and investigate its prognostic value in stage II colorectal cancer. Method Quantitative real-time RT-PCR was used to analyse caspase-9 mRNA expression in cancer tissue and corresponding normal mucosa from 120 patients. Results Compared with normal mucosa, the expression of caspase-9 mRNA was found to be downregulated in cancer tissue (P = 0.001). Poorly differentiated cancer showed lower mRNA expression than cancer with greater differentiation (P = 0.031). The Kaplan-Meier survival analysis demonstrated that patients with downregulated caspase-9 showed a worse overall survival (P = 0.012) and disease-free survival (P = 0.022). Coxs proportional hazards regression model confirmed that expression of caspase-9 was the strongest prognostic factor in stage II colorectal cancer. Conclusion The mRNA expression of caspase-9 can be used as an independent prognostic factor for patients with stage II colorectal cancer.

  • 268.
    Shen, Xiao-Gang
    et al.
    Sichuan University.
    Wang, Cun
    Sichuan University.
    Li, Yuan
    Sichuan University.
    Zhou, Bin
    Sichuan University.
    Xu, Bin
    Sichuan University.
    Yang, Lie
    Sichuan University.
    Zhou, Zong-Guang
    Sichuan University.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Downregulation of caspase-10 predicting poor survival after resection of stage II colorectal cancer2011Inngår i: International Journal of Colorectal Disease, ISSN 0179-1958, E-ISSN 1432-1262, Vol. 26, nr 12, s. 1519-1524Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose The aim of this study was to evaluate the prevalence and clinical significance of caspase-10 mRNA expression in stage II colorectal cancer. less thanbrgreater than less thanbrgreater thanMethods Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze caspase-10 expression in cancer tissue and corresponding normal mucosa from 120 patients with stage II colorectal cancer. Variables were analyzed by Chi-square test or Fishers exact test. Survival was evaluated with method of Kaplan-Meier. Multivariate analysis was performed with Coxs proportional hazards model. less thanbrgreater than less thanbrgreater thanResults The expression of caspase-10 mRNA was found to be downregulated in cancer tissue compared to normal mucosa (P = 0.001). Poorly differentiated cancer showed lower mRNA expression than cancer with greater differentiation (P = 0.031). Univariate survival curves, estimated using the method of Kaplan-Meier, defined a significant association between caspase-10 expression and both overall survival (P = 0.012) and disease-free survival (P = 0.021). A multivariate analysis, performed by Coxs proportional hazards regression model, confirmed that a low caspase-10 expression was the only significant factor to predict poor prognosis in patients with stage II colorectal cancer. less thanbrgreater than less thanbrgreater thanConclusion Our data indicate that caspase-10 expression, measured by quantitative real-time RT-PCR, is a possible prognostic factor in patients with stage II colorectal cancer.

  • 269.
    Shen, Yang-mei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken i Östergötland.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Overexpression of GLUT1 in colorectal cancer is independently associated with poor prognosis2011Inngår i: International Journal of Biological Markers, ISSN 0393-6155, E-ISSN 1724-6008, Vol. 26, nr 3, s. 166-172Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: To investigate the expression of glucose transporter 1 (GLUT1) in colorectal cancer (CRC) and its relationship to clinicopathological variables. Methods: The expression of GLUT1 in 163 primary tumors together with the corresponding normal mucosa, and 36 liver metastases was examined using real-time PCR. Results: The mean value of GLUT1 was higher in primary tumors (50.390 +/- 68.648) than in the corresponding normal mucosa (20.437 +/- 28.703, p less than 0.0001), while there was no significant difference in GLUT1 expression between CRC and liver metastasis (50.390 +/- 68.648 vs 52.277 +/- 52.482, p = 0.190). In CRCs, GLUT1 expression was higher in poorly differentiated than in well and moderately differentiated tumors (p = 0.022), and higher in stage III + IV than in stage I + II tumors (p = 0.035). The patients with high-expressed GLUT1 had a worse prognosis than those with low-expressed GLUT1 independently of gender, age, tumor site, stage and differentiation (p = 0.026, RR 2.737, 95% CI 1.126-6.651) in stage I-III CRCs. In liver metastasis, GLUT1 expression was higher in larger tumors than in smaller ones (p = 0.025). Conclusions: Overexpression of GLUT1 in stage I-III CRCs was independently associated with poor prognosis.

  • 270.
    Shen, Yang-mei
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Arbman, Gunnar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken i Östergötland.
    Sandström, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken i Östergötland.
    Gullstrand, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Linköpings universitet, Hälsouniversitetet.
    Wei, Yu-Quan
    Sichuan University.
    Zhang, Hong
    University of Skövde.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Peng, Feng
    Sichuan University.
    Yang, Han-Shuo
    Sichuan University.
    Wang, Chun-Ting
    Sichuan University.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Novel gene hBiot2 is an independent prognostic factor in colorectal cancer patients2012Inngår i: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 27, nr 2, s. 376-382Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The present study investigated the expression of the novel gene hBiot2 in colorectal cancer (CRC) and its relationships with clinicopathological variables in CRC patients. The expression of hBiot2 in 163 primary CRCs together with the corresponding normal mucosa, 36 liver metastases and 5 colon cancer cell lines was examined using real-time PCR. In situ hybridization (ISH) was performed to evaluate the localization of hBiot2 expression in CRC and normal mucosa. hBiot2 expression at the RNA level was localized in the nucleus of tumor cells and normal epithelial cells. The mean expression of hBiot2 in the CRCs (243.571 +/- 564.569) was higher compared to the normal mucosa (107.252 +/- 413.635, Pandlt;0.0001) and liver metastasis samples (42.002 +/- 40.809, P=0.0002). hBiot2 expression was increased from stages I + II to III (P=0.047), and no difference in the expression was found in stages III and IV (P=0.452). A high value of hBiot2 was associated with a poorer prognosis compared with a low value independently of gender, age, tumor site, stage and differentiation (P=0.007, RR 7.519, 95% Cl 1.729-32.704). Liver metastasis, smaller tumors, non-local recurrence and primary liver surgery alone were associated with a higher value of hBiot2 compared to larger tumors, local recurrence and repeated liver surgery (P=0.003, 0.044 and 0.026, respectively). An inverse relationship was found between hBiot2 expression and the metastatic potential of the colon cancer cell lines. Thus, increased expression of hBiot2 may be an early and interim event in the development of CRC. A higher expression of hBiot2 in primary CRC patients independently indicates a poorer prognosis.

  • 271.
    Simonsson, B
    et al.
    University Uppsala Hospital.
    Gedde-Dahl, M
    National Hospital Norway.
    Markevarn, M
    University Uppsala Hospital.
    Remes, P
    Turku University Hospital.
    Stentoft, R
    University Uppsala Hospital.
    Almqvist, S
    Vaasa Cent Hospital.
    Bjoreman, T
    University Uppsala Hospital.
    Flogegard, V
    Falun Cent Hospital.
    Hallman, U
    Cent Finland Cent Hospital.
    Koskenveesa, L
    University of Helsinki.
    Lindblom, A
    Malmö University Hospital.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Mustjoki, S
    University of Helsinki.
    Myhr-Eriksson, K
    Luleå Central Hospital.
    Rasanen, A
    Kymenlaakso Central Hospital.
    Sinisalo, M
    Tampere University Hospital.
    Sippola, R
    Lapland Cent Hospital.
    Sjalander, A
    Sundsvall Cent Hospital.
    Stromberg, U
    University Uppsala Hospital.
    Weiss Bjerrum, O
    Rigshospital, Copenhagen.
    Ehrencrona, H
    Uppsala University.
    Gruber, F
    Akershus University Hospital.
    Kairisto, V
    Reginal Oncology Centre, Uppsala.
    Sandin, F
    Reginal Oncology Centre, Uppsala.
    Nagler, A
    Chaim Sheba Medical Centre.
    Lanng Nielsen, J
    Aarhus University Hospital.
    Hjorth-Hansen, H
    St Olavs Hospital.
    Porkka, K
    University Helsinki.
    MAJOR MOLECULAR RESPONSE RATE AT ONE YEAR IS HIGHER IF PEGYLATED INTERFERON ALPHA-2B IS ADDED TO IMATINIB IN NON-HR CHRONIC MYELOID LEUKEMIA PATIENTS IN IMATINIB INDUCED COMPLETE HEMATOLOGICAL REMISSION in HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, vol 95, issue , pp 457-4572010Inngår i: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, Pensiero Scientifico / Ferrata Storti Foundation , 2010, Vol. 95, s. 457-457Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 272.
    Simonsson, Bengt
    et al.
    Uppsala University Hospital.
    Gedde-Dahl, Tobias
    University of Oslo, Rikshospital.
    Markevarn, Berit
    Umeå University Hospital.
    Remes, Kari
    Turku University.
    Stentoft, Jesper
    Aarhus University Hospital.
    Almqvist, Anders
    Vaasa Central Hospital.
    Bjoreman, Mats
    Örebro University Hospital.
    Flogegard, Max
    Falun Central Hospital.
    Hallman, Heikki
    Central Finland Hospital.
    Koskenvesa, Perttu
    University of Helsinki.
    Lindblom, Anders
    Malmö University Hospital.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Mustjoki, Satu
    University of Helsinki.
    Myhr-Eriksson, Kristina
    Luleå Central Hospital.
    Rasanen, Anu
    Kymenlaakso Central Hospital.
    Sinisalo, Marjatta
    Tampere University Hospital.
    Sippola, Risto
    Lapland Central Hospital.
    Sjalander, Anders
    Sunsvall Centtal Hospital.
    Stromberg, Ulla
    Uppsala University Hospital.
    Weiss Bjerrum, Ole
    Rigshospital, Copenhagen.
    Ehrencrona, Hans
    Uppsala University Hospital.
    Gruber, Franz
    Akershus University Hospital.
    Kairisto, Veli
    Turku University.
    Olsson, Karin
    Uppsala University Hospital.
    Nagler, Arnon
    Chaim Sheba Medical Centre.
    Lanng Nielsen, Johan
    Aarhus University Hospital.
    Hjorth-Hansen, Henrik
    St Olavs Hospital.
    Porkka, Kimmo
    University of Helsinki.
    A Randomized Phase II Study Comparing Imatinib and the Combination of Imatinib and Pegylated Interferon Alpha-2b in Newly Diagnosed Non-High Risk Chronic Myeloid Leukemia (CML) Patients in Complete Hematological Remission After Imatinib Induction Therapy. in BLOOD, vol 114, issue 22, pp 1269-12702009Inngår i: BLOOD, American Society of Hematology , 2009, Vol. 114, nr 22, s. 1269-1270Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 273.
    Simonsson, Bengt
    et al.
    Uppsala University.
    Gedde-Dahl, Tobias
    Oslo University Hospital.
    Markevarn, Berit
    Umea University.
    Remes, Kari
    Turku University Hospital.
    Stentoft, Jesper
    Aarhus University Hospital.
    Almqvist, Anders
    Vaasa Central Hospital.
    Bjoreman, Mats
    University Hospital, Hematol Unit, Orebro, Sweden .
    Flogegard, Max
    Falun Central Hospital.
    Koskenvesa, Perttu
    University of Helsinki.
    Lindblom, Anders
    Malmö University Hospital.
    Malm, Claes
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Mustjoki, Satu
    University of Helsinki.
    Myhr-Eriksson, Kristina
    Luleå Centralral Hospital.
    Ohm, Lotta
    Karolinska Hospital.
    Rasanen, Anu
    Kymenlaakso Central Hospital.
    Sinisalo, Marjatta
    Tampere University Hospital.
    Sjalander, Anders
    Sundsvall Central Hospital.
    Stromberg, Ulla
    Uppsala University.
    Weiss Bjerrum, Ole
    University of Copenhagen.
    Ehrencrona, Hans
    Uppsala University.
    Gruber, Franz
    University of Tromso.
    Kairisto, Veli
    Turku University.
    Olsson, Karin
    Reg Oncol Centre, Uppsala.
    Sandin, Fredrik
    Reg Oncol Centre, Uppsala.
    Nagler, Arnon
    Chaim Sheba Medical Centre.
    Lanng Nielsen, Johan
    Aarhus University Hospital.
    Hjorth-Hansen, Henrik
    St Olavs Hospital Trondheim.
    Porkka, Kimmo
    University of Helsinki.
    Combination of pegylated IFN-alpha 2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia2011Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, nr 12, s. 3228-3235Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Biologic and clinical observations suggest that combining imatinib with IFN-alpha may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-alpha 2b (Peg-IFN-alpha 2b) 50 mu g weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-alpha 2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-alpha 2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-alpha 2b treatment (andlt; 12-week MMR rate 67%, andgt; 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-alpha 2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-alpha 2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.

  • 274.
    Sivik, Tove
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Elucidating the role of 17β hydroxysteroid dehydrogenase type 14 in normal physiology and in breast cancer2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Oestrogens play key roles in the development of the majority of breast tumours, a fact that has been exploited successfully in treating breast cancer with tamoxifen, which is a selective oestrogen receptor modulator. In post-menopausal women, oestrogens are synthesised in peripheral hormone-target tissues from adrenally derived precursors. Important in the peripheral fine-tuning of sex hormone levels are the 17β hydroxysteroid dehydrogenases (17βHSDs). These enzymes catalyse the oxidation/reduction of carbon 17β of androgens and oestrogens. Upon receptor binding, the 17β-hydroxy conformation of androgens and oestrogens (testosterone and oestradiol) triggers a greater biological response than the corresponding keto-conformation of the steroids (androstenedione and oestrone), and the 17βHSD enzymes are therefore important mediators in pre-receptor regulation of sex hormone action.

    Breast tumours differ substantially with regards to molecular and/or biochemical signatures and thus clinical courses and response to treatment. Predictive factors, which aim to foretell the response of a patient to a specific therapeutic intervention, are therefore important tools for individualisation of breast cancer therapy. This thesis focuses on 17βHSD14, which is one such proposed marker, aiming to learn more of properties of the enzyme in breast cancer as well as in normal physiology. We found that high 17βHSD14 levels were correlated with clinical outcome in two separate subsets of breast tumour materials from trials evaluating adjuvant tamoxifen therapy. Striving to understand the underlying mechanisms, immunohistochemical 17βHSD14 expression patterns were analysed in a large number of human tissues using an in-house generated and validated antibody. The 17βHSD14 protein was expressed in several classical steroidogenic tissues such as breast, ovary and testis which supports idea of 17βHSD14 being an actor in sex steroid interconversion. Furthermore, using a radio-high pressure liquid chromatography method, cultured cells transiently expressing HSD17B14 were found to oxidise both oestradiol and testosterone to their less potent metabolites oestrone and androstenedione respectively. The evaluation of a mouse model lacking Hsd17b14 revealed a phenotype with impaired mammary gland branching and hepatic vacuolisation which could further suggest a role for 17βHSD14 in oestrogen regulation.

    Although other mechanisms of the enzyme cannot be ruled out, we suggest that 17βHSD14 relevance in tamoxifen-treated breast cancer is related to oestradiol-lowering properties of the enzyme which potentiate the anti-proliferative effects of tamoxifen. Translating into the clinical setting, patients with oestrogen receptor positive tumours expressing low levels of oestradiol-oxidising enzymes such as 17βHSD14 would likely receive more clinical benefit from alternative treatments to tamoxifen such as aromatase inhibitors or in the future possibly inhibitors of reductive 17βHSD-enzymes.

    Delarbeid
    1. 17β-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer
    Åpne denne publikasjonen i ny fane eller vindu >>17β-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer
    Vise andre…
    2006 (engelsk)Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, nr 23, s. 11471-11477Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Estrogens have an important role in the progression of breast cancer. The 17β-hydroxysteroid dehydrogenase (17HSD) family has been identified to be of significance in hormone-dependent tissues. 17HSD1 and 17HSD2 are the main 17HSD enzymes involved in breast cancer investigated this far, but it is possible that other hormone-regulating enzymes have a similar role. 17HSD5 and 17HSD12 are associated with sex steroid metabolism, and 17HSD14 is a newly discovered enzyme that may be involved in the estrogen balance. The mRNA expression of 17HSD5, 17HSD12, and 17HSD14 were analyzed in 131 breast cancer specimens by semiquantitative real-time PCR. The results were compared with recurrence-free survival and breast cancer-specific survival of the patients. The breast cancer cell lines MCF7, SKBR3, and ZR75-1 were transiently transfected with 17HSD14 to investigate any possible effect on estradiol levels. We found that high 17HSD5 was related to significantly higher risk of late relapse in estrogen receptor (ER)-positive patients remaining recurrence-free later than 5 years after diagnosis (P = 0.02). No relation to 17HSD12 expression was found, indicating that 17HSD12 is of minor importance in breast cancer. Patients with ER-positive tumors with high expression levels of 17HSD14 showed a significantly better prognosis about recurrence-free survival (P = 0.008) as well as breast cancer-specific survival (P = 0.01), confirmed by multivariate analysis (P = 0.04). Transfection of 17HSD14 in the human breast cancer cells MCF7 and SKBR3 significantly decreased the levels of estradiol, presenting an effect of high expression levels of the enzyme. ©2006 American Association for Cancer Research.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-36099 (URN)10.1158/0008-5472.CAN-06-1448 (DOI)29885 (Lokal ID)29885 (Arkivnummer)29885 (OAI)
    Tilgjengelig fra: 2009-10-10 Laget: 2009-10-10 Sist oppdatert: 2018-03-26
    2. Expression Patterns of 17β-Hydroxysteroid Dehydrogenase 14 in Human Tissues
    Åpne denne publikasjonen i ny fane eller vindu >>Expression Patterns of 17β-Hydroxysteroid Dehydrogenase 14 in Human Tissues
    2012 (engelsk)Inngår i: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 44, nr 13, s. 949-956Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    17βHSD enzymes catalyze the stereospecific oxidation/reduction at carbon 17β of androgens and estrogens, and are important players in intracrine sex hormone synthesis. The biological relevance of 17βHSD14, first named retSDR3, is largely unknown. We generated and validated an antibody targeting the 17βHSD14 antigen and used this for immunohistochemical evaluation of expression patterns in 33 healthy human tissues. Furthermore, sex steroid conversional activity in HSD17B14 overexpressing HEK293 and MCF10A cells was investigated by assessing interconversion products of estrone, estradiol, androstenedione, testosterone, and dehydroepiandrosterone. Immunohistochemical staining patterns of 17βHSD14 with the enzyme being primarily expressed in glandular epithelial tissue reveal an enzyme with possible implications in the secretion or conversion of externally derived compounds. A role for 17βHSD14 in sex steroid metabolism is supported by the finding that 17HSD14 oxidizes both estradiol and testosterone into less bioactive steroid metabolites estrone and androstenedione, respectively.

    sted, utgiver, år, opplag, sider
    Georg Thieme Verlag KG, 2012
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-84681 (URN)10.1055/s-0032-1321815 (DOI)000312501800004 ()22864907 (PubMedID)
    Tilgjengelig fra: 2012-10-17 Laget: 2012-10-17 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    3. 17β-hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer
    Åpne denne publikasjonen i ny fane eller vindu >>17β-hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer
    Vise andre…
    2012 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 7, s. e40568-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Introduction: 17β-hydroxysteroid dehydrogenases (17βHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implications of 17βHSD14 in breast cancer, measuring 17βHSD14 protein expression in breast tumours.

    Methods: An antibody targeting the 17βHSD14 antigen was generated and validated using HSD17B14-transfected cells and a peptide-neutralising assay. Tissue microarrays with tumours from 912 post-menopausal women diagnosed with lymph node-negative breast cancer, and randomised to adjuvant tamoxifen or no endocrine treatment, were analysed for 17βHSD14 protein expression with immunohistochemistry.

    Results: Results were obtained from 847 tumours. Patients with oestrogen positive tumours with high 17βHSD14 expression had fewer local recurrences when treated with tamoxifen (HR 0.38; 95% C.I. 0.19–0.77, p = 0.007) compared to patients with lower tumoural 17βHSD14 expression, for whom tamoxifen did not reduce the number of local recurrences (HR 1.19; 95% C.I. 0.54–2.59; p = 0.66). No prognostic importance of 17βHSD14 was seen for systemically untreated patients.

    Conclusions: Using a highly specific validated antibody for immunohistochemical analysis of a large number of breast tumours, we have shown that tumoural expression levels of 17βHSD14 can predict the outcome of adjuvant tamoxifen treatment in terms of local recurrence-free survival in patients with lymph node-negative ER+ breast cancer. The results need be verified to confirm any clinical relevance.

    sted, utgiver, år, opplag, sider
    Plos ONE, 2012
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-80247 (URN)10.1371/journal.pone.0040568 (DOI)
    Tilgjengelig fra: 2012-08-23 Laget: 2012-08-23 Sist oppdatert: 2017-12-07
    4. Characterisation of Hsd17b14 knockout mice
    Åpne denne publikasjonen i ny fane eller vindu >>Characterisation of Hsd17b14 knockout mice
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    17β hydroxysteroid dehydrogenase (17βHSD) enzymes catalyse the stereospecific oxidation/reduction at carbon 17β of androgens and oestrogens and thereby regulate the pool of bioactive sex hormones. 17βHSD type 14 (17βHSD14) catalyses the inactivation of 17β-hydroxysteroids into their less bioactive 17-keto formation in vitro, however, as the catalytic efficiency of this reaction is relatively low, the question is whether this reaction is the biological role of the enzyme in vivo, or if the enzyme additionally or altogether acts within alternative metabolic pathways. To investigate the role of 17βHSD14 in vivo, we studied the phenotype of a mouse model in which the Hsd17b14 gene had been targeted through homologous recombination. Tissues from male and female mice sacrificed at 3-4 months of age were collected and analysed with regards to gene expression of Hsd17b14 and Hsd17b2 and histological appearance of selected organs. Wild type animals expressed Hsd17b14 in a large number of tissues, peaking in reproductive tissues. Mice globally lacking Hsd17b14 were grossly morphologically identical to their WT counterparts. The histological examination however, revealed impaired mammary gland branching and increased hepatocellular vacuolisation in Hsd1714 knockout animals compared with their WT counterparts. In conclusion, while phenotypical aberrances were absent in most tissues, which may be the result of genetic redundancy or possibly an indication that the gene in question is only modulatory, the main differences, primarily a mammary gland phenotype in female KO mice, implicate disturbed hormonal homeostasis, and thus a role for Hsd17b14 in steroidogenesis in vivo.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-84683 (URN)
    Tilgjengelig fra: 2012-10-17 Laget: 2012-10-17 Sist oppdatert: 2015-03-12bibliografisk kontrollert
  • 275.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Gunnarsson, Cecilia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Medicinsk genetik. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Fornander, Tommy
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Skoog, Lambert
    Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    17β-hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 7, s. e40568-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: 17β-hydroxysteroid dehydrogenases (17βHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implications of 17βHSD14 in breast cancer, measuring 17βHSD14 protein expression in breast tumours.

    Methods: An antibody targeting the 17βHSD14 antigen was generated and validated using HSD17B14-transfected cells and a peptide-neutralising assay. Tissue microarrays with tumours from 912 post-menopausal women diagnosed with lymph node-negative breast cancer, and randomised to adjuvant tamoxifen or no endocrine treatment, were analysed for 17βHSD14 protein expression with immunohistochemistry.

    Results: Results were obtained from 847 tumours. Patients with oestrogen positive tumours with high 17βHSD14 expression had fewer local recurrences when treated with tamoxifen (HR 0.38; 95% C.I. 0.19–0.77, p = 0.007) compared to patients with lower tumoural 17βHSD14 expression, for whom tamoxifen did not reduce the number of local recurrences (HR 1.19; 95% C.I. 0.54–2.59; p = 0.66). No prognostic importance of 17βHSD14 was seen for systemically untreated patients.

    Conclusions: Using a highly specific validated antibody for immunohistochemical analysis of a large number of breast tumours, we have shown that tumoural expression levels of 17βHSD14 can predict the outcome of adjuvant tamoxifen treatment in terms of local recurrence-free survival in patients with lymph node-negative ER+ breast cancer. The results need be verified to confirm any clinical relevance.

  • 276.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Hakkarainen, Janne
    Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
    Hilborn, Erik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Rodriguez-Martinez, Heriberto
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Utvecklingsbiologi. Linköpings universitet, Hälsouniversitetet.
    Zhang, Fuping
    Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
    Poutanen, Matti
    Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Characterisation of Hsd17b14 knockout miceManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    17β hydroxysteroid dehydrogenase (17βHSD) enzymes catalyse the stereospecific oxidation/reduction at carbon 17β of androgens and oestrogens and thereby regulate the pool of bioactive sex hormones. 17βHSD type 14 (17βHSD14) catalyses the inactivation of 17β-hydroxysteroids into their less bioactive 17-keto formation in vitro, however, as the catalytic efficiency of this reaction is relatively low, the question is whether this reaction is the biological role of the enzyme in vivo, or if the enzyme additionally or altogether acts within alternative metabolic pathways. To investigate the role of 17βHSD14 in vivo, we studied the phenotype of a mouse model in which the Hsd17b14 gene had been targeted through homologous recombination. Tissues from male and female mice sacrificed at 3-4 months of age were collected and analysed with regards to gene expression of Hsd17b14 and Hsd17b2 and histological appearance of selected organs. Wild type animals expressed Hsd17b14 in a large number of tissues, peaking in reproductive tissues. Mice globally lacking Hsd17b14 were grossly morphologically identical to their WT counterparts. The histological examination however, revealed impaired mammary gland branching and increased hepatocellular vacuolisation in Hsd1714 knockout animals compared with their WT counterparts. In conclusion, while phenotypical aberrances were absent in most tissues, which may be the result of genetic redundancy or possibly an indication that the gene in question is only modulatory, the main differences, primarily a mammary gland phenotype in female KO mice, implicate disturbed hormonal homeostasis, and thus a role for Hsd17b14 in steroidogenesis in vivo.

  • 277.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Progesterone and levonorgestrel regulate expression of 17 beta HSD-enzymes in progesterone receptor positive breast cancer cell line T47D2012Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 422, nr 1, s. 109-113Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The use of combined hormone replacement therapy (HAT) with oestrogens and progestins in postmenopausal women has been associated with an increased risk for developing breast cancer. The reasons are not fully understood, but influence of HRT on endogenous conversion of female sex hormones may be involved. The expression of 17 beta hydroxysteroid dehydrogenases (17 beta HSD), which are enzymes catalysing the conversion between more or less potent oestrogens, may partly be regulated by progestins. The breast cancer cell lines T47D, MCF7 and ZR75-1 were treated with progesterone, medroxyprogesterone acetate (MPA) or levonorgestrel for 48 and 72 h at 10(-7) and 10(-9) M to investigate influence on 17 beta HSD1, 17 beta HSD2 and 17 beta HSD5 mRNA expression measured by real time PCR. The expression of 17 beta HSD1 increased in progesterone and levonorgestrel treated T47D cells (48 h 10(-7) M P = 0.002; P andlt; 0.001) and 17 beta HSD5 increased after progesterone treatment (48 h 10(-7) M P = 0.003), whereas the expression of 17 beta HSD2 decreased after the (48 h 10(-7) M P = 0.003; P andlt; 0.001). Similar, but less prominent effects were seen in MCF7 and ZR75-1. The progestin effects on 17 beta HSD-expression were lost when T47D cells were co-treated with progestins and the progesterone receptor (PgR) inhibitor mifprestone. We show that both reductive (17 beta HSD1 and 17 beta HSD5) and oxidative (17 beta HSD2) members of the 17 beta HSD-family are under control of progesterone and progestins in breast cancer cell lines. This is most clear in T47D cells which have high PgR expression. 17 beta HSD-enzymes are important players in the regulation of sex steroids locally in breast tumours and tumoural expression of various 17 beta HSD-enzymes have prognostic and treatment predictive relevance. We propose a mechanism for increased breast cancer risk after HRT in which hormone replacement affects the expression of 17 beta HSD-enzymes, favouring the expression of reductive enzymes, which in turn could increase levels of bioactive and mitogenic estrogens in local tissue, e.g. breast tissue.

  • 278.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Fornander, T
    Karolinska Institute.
    Skoog, L
    Karolinska Institute.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Significance of 17bHSD Type 14 as a Predictive Factor for Adjuvant Tamoxifen Treatment Response in Breast Cancer in CANCER RESEARCH, vol 69, issue 24, pp 596S-597S2009Inngår i: CANCER RESEARCH, 2009, Vol. 69, nr 24, s. 596S-597SKonferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 279.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Greén, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    A validated and rapid high-performance liquidchromatography method for the quantification ofconversion of radio-labelled sex steroids2010Inngår i: Hormone Molecular Biology and Clinical Investigation, ISSN 1868-1891, Vol. 3, nr 1, s. 375-381Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The 17b -hydroxysteroid dehydrogenase enzymes modify the availability of potent sex steroids and have thus attracted interest in the study of several steroid-dependent pathologies including breast, endometrial and prostate cancers. An increased awareness of the importance of steroidogenic enzymes has brought forth a demand for efficient assays to study the effects of individual enzymes on steroid levels. Methods used for assessing steroid conversion are often laborious and frequently involve hazardous sample preparation steps. We developed and validated an optimised simple method for sample preparation of sex steroids using protein precipitation by the addition of zinc sulphate/sodium hydroxide. The interconversion of radio-labelled oestrogens and androgens was quantified using high-performance liquid chromatography separation of oestrone, oestradiol, androstenedione and testosterone followed by online radiometric flow scintillation analysis. The method, which can be applied for assessing, e.g., the efficacy of inhibitors of steroidogenic enzymes, was successfully used for evaluating oestrogenic interconversion in breast cancer cell lines MCF7 and T-47D.

  • 280.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Expression Patterns of 17β-Hydroxysteroid Dehydrogenase 14 in Human Tissues2012Inngår i: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 44, nr 13, s. 949-956Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    17βHSD enzymes catalyze the stereospecific oxidation/reduction at carbon 17β of androgens and estrogens, and are important players in intracrine sex hormone synthesis. The biological relevance of 17βHSD14, first named retSDR3, is largely unknown. We generated and validated an antibody targeting the 17βHSD14 antigen and used this for immunohistochemical evaluation of expression patterns in 33 healthy human tissues. Furthermore, sex steroid conversional activity in HSD17B14 overexpressing HEK293 and MCF10A cells was investigated by assessing interconversion products of estrone, estradiol, androstenedione, testosterone, and dehydroepiandrosterone. Immunohistochemical staining patterns of 17βHSD14 with the enzyme being primarily expressed in glandular epithelial tissue reveal an enzyme with possible implications in the secretion or conversion of externally derived compounds. A role for 17βHSD14 in sex steroid metabolism is supported by the finding that 17HSD14 oxidizes both estradiol and testosterone into less bioactive steroid metabolites estrone and androstenedione, respectively.

  • 281.
    Sjödahl, Rune
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Kirurgiska kliniken US.
    Rosell, Johan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Starkhammar, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Causes of death after surgery for colon cancer-impact of other diseases, urgent admittance, and gender2013Inngår i: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 48, nr 10, s. 1160-1165Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective. In patients with colon cancer, high age and comorbidity is common. In this population-based retrospective study we have investigated causes of death and the influence of urgent operation, and gender on survival. Material and methods. Medical records of 413 patients with verified colon cancer were reviewed. The diagnosis was made during 2000-2006 and operation was performed in 385 patients (93%). Results. The overall 5-year survival after surgery was 48.3%. At the end of the follow-up, 128 patients (54.9%) had verified colon cancer when they died but 105 patients (45.1%) had no signs of colon cancer. Their 5-year survival was 5.5% and 41.9%, respectively (p andlt; 0.0001). Median survival time was significantly shorter after urgent compared with elective admittance, 20.7 months versus 77.9 months, and the 5-year survival 32.4% versus 57.9% (p = 0.0001). The tumor stage at operation was more favorable in patients dying with no signs of colon cancer than in those dying with cancer regarding stage I-II (66.7% versus 16.4%), and stage IV (1.0% versus 53.1%), but not regarding stage III (30.5% versus 29.7%). The overall survival in women who were operated was longer than in men (p = 0.045) as well as survival after elective admittance (p = 0.013). Conclusion. After a median follow-up of 56.1 months almost half of the patients who were dead had died from other causes than colon cancer. Ten percent of those patients had an incorrectly reported diagnosis of colon cancer as cause of death. Urgent admittance was associated with reduced survival time. The median survival time was longer in women than in men.

  • 282.
    Sorbe, B.
    et al.
    Department of Gynecological Oncology, University Hospital, Örebro, Sweden, Department of Gynecological Oncology, University Hospital, SE-701 85 Örebro, Sweden.
    Andersson, H.
    Department of Gynecological Oncology, University Hospital, Gothenburg, Sweden.
    Boman, K.
    Department of Gynecological Oncology, University Hospital, Umeå, Sweden.
    Rosenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Kalling, M.
    Department of Gynecologic Oncology, University Hospital, Lund, Sweden.
    Treatment of primary advanced and recurrent endometrial carcinoma with a combination of carboplatin and paclitaxel - Long-term follow-up2008Inngår i: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 18, nr 4, s. 803-808Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is no generally accepted standard chemotherapy in treatment of advanced and recurrent endometrial carcinoma. Cisplatin and doxorubicin with or without cyclophosphamide are widely used. Response rates have improved with combination chemotherapy compared with single-agent therapy. A platinum analog seems to be an important part of the chemotherapy regimen. Since few patients are cured from their disease and since the duration of response is short, further improvement of this therapy is warranted. During the past years, the taxanes (paclitaxel) are being added to prior evaluated regimens and not only improved response rates are reported but also increased toxicity is observed. In a prospective, phase II, multicenter study, carboplatin (area under the curve = 5) and paclitaxel (175 mg/m2) were evaluated in treatment of primary advanced and recurrent endometrial carcinoma. In total, 66 patients were recruited during the years 2000-2004. Eighteen primary advanced tumors and 48 recurrences were treated. All histologic types and tumor grades were allowed. The median follow-up was 57 months (range 37-69 months). The overall response rate was 67% (95% CI 55-78). The complete response rate was 29% and the partial response rate 38%. Primary advanced and recurrent tumors as well as endometrioid and nonendometrioid tumors showed similar response rates. The median response duration was 14 months. The 1- and 3-year survival rates were 82% and 33%, respectively. The main toxicities were hematologic and neurologic (sensory neuropathy). The response rates were encouraging, superior to prior platinum-containing regimens, but response duration and the long-term survival rate were still short. The neurologic toxicity was frequent and was a substantial problem in this series of patients. Further research is highly needed to improve the treatment of advanced and recurrent endometrial cancer. © 2007, Copyright the Authors.

  • 283.
    Starkhammar, Hans
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Aspects on priority settings in cancer treatment and care2005Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 44, nr 7, s. 667-672Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The widening gap between available resources and increasing possibilities to diagnose and treat different medical conditions has resulted in new attention to priority setting. The issue is complicated and harbours several obstacles because of different valuations concerning the needs of patient groups, the true results ( patient benefit) of medical actions, and also important ethical considerations. Earlier attempts have been unsuccessful in introducing a prioritisation milieu into the medical profession, probably due to vague requests for an open and sharp prioritisation process. With a sharpened competition of allocating resources for different medical actions, the medical profession of the cancer sector needs to have a tool for explaining consequences for the different cancer patient groups and what is achieved by the cancer treatments and the care. A model for ranking lists consisting of pairs of patient conditions and medical actions is presented, and the principle for using these lists for priority setting in medical society is discussed.

  • 284.
    Stendahl, M.
    et al.
    Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02 Malmö, Sweden, Department of Medicine, Ryhov Regional Hospital, Jönköping, Sweden.
    Ryden, L.
    Rydén, L., Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02 Malmö, Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Jonsson, P.E.
    Jönsson, P.E., Department of Surgery, Helsingborg Hospital, Helsingborg, Sweden.
    Landberg, G.
    Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02 Malmö, Sweden.
    Jirstrom, K.
    Jirström, K., Department of Laboratory Medicine, Lund University, Malmö University Hospital, S-205 02 Malmö, Sweden.
    High progesterone receptor expression correlates to the effect of adjuvant tamoxifen in premenopausal breast cancer patients2006Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 12, nr 15, s. 4614-4618Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Tamoxifen has long been the drug of choice in adjuvant endocrine therapy of steroid hormone receptor-positive breast cancer, and it still remains important due to its well-documented beneficial effect. Hormone receptor status is often reported as "positive" or "negative" using 10% positive nuclei as a cutoff. In this study, we aimed to assess whether a further subclassification of hormone receptor status could enhance the treatment predictive value. Experimental Design: The immunohistochemical expression of estrogen receptor (ER) and progesterone receptor (PR) was quantified in tissue microarrays with tumors from 500 premenopausal breast cancer patients previously included in a randomized trial of adjuvant tamoxifen compared with an untreated control group. Results: Our findings show a gradually increasing tamoxifen effect in tumors with >10% ER-positive nuclei. However, when analyzing tamoxifen response according to various PR fractions, we found that it was primarily patients with tumors showing >75% PR-positive nuclei that responded to tamoxifen treatment, with an improved recurrence-free [relative risk, 0.42 (0.25-0.70), P = 0.001] as well as overall [relative risk, 0.49 (0.28-0.84), P = 0.010] survival. Conclusions: Adjuvant tamoxifen improved recurrence-free and overall survival for premenopausal patients with tumors showing >75% PR-positive nuclei. No effect could be shown in tumors with fewer PR-positive nuclei. The PR was a stronger predictor of treatment response than the ER. Based on these findings, we suggest the implementation of a fractioned rather than dichotomized immunohistochemical evaluation of hormone receptors in clinical practice, possibly with greater emphasis on the PR than the ER. © 2006 American Association for Cancer Research.

  • 285.
    Stendahl, Maria
    et al.
    Lund University.
    Nilsson, Sofie
    University of Manchester.
    Wigerup, Caroline
    Lund University.
    Jirstrom, Karin
    Lund University.
    Jonsson, Per Ebbe
    Helsingborgs Lasarett.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Landberg, Goran
    University of Manchester.
    p27(Kip1) is a predictive factor for tamoxifen treatment response but not a prognostic marker in premenopausal breast cancer patients2010Inngår i: INTERNATIONAL JOURNAL OF CANCER, ISSN 0020-7136, Vol. 127, nr 12, s. 2851-2858Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The cell-cycle regulating protein p27(Kip1) (p27) has dual roles by acting as both a cdk inhibitor and as an assembly factor for different cdk complexes. Loss of p27 has been linked to malignant features in tumours; however, the exact role of p27 deregulation in breast cancer regarding prognostic and treatment predictive information has not been fully clarified. We have evaluated p27 expression in 328 primary, Stage II breast cancers from premenopausal patients who had been randomised to either tamoxifen treatment or no adjuvant treatment after surgery. p27 was associated with the oestrogen receptor and cyclin D1, and p27 downregulation was associated with high proliferation. There was no association between recurrence-free survival (RFS) and p27 (HR = 0.800, 95% CI 0.523-1.222, p = 0.300), indicating that p27 is not a prognostic marker. The predictive value of p27 was analysed by comparing RFS in tamoxifen-treated and untreated patients in subgroups of low and high p27 expression (HR = 0.747, 95% CI 0.335-1.664, p = 0.474 and HR = 0.401, 95% CI 0.240-0.670, p andlt; 0.001, respectively). Only patients with p27-high tumours benefited from tamoxifen (multivariate interaction analysis p = 0.034). Our study suggests that p27 downregulation is associated with tamoxifen resistance in premenopausal breast cancer but is not linked to impaired prognosis.

  • 286.
    Strand, Carina
    et al.
    Lund University, Skåne University Hospital, Lund, Sweden.
    Bak, Martin
    Odense University Hospital, Denmark.
    Borgquist, Signe
    Lund University, Skåne University Hospital, Lund, Sweden.
    Chebil, Gunilla
    Unilabs, Mammography, Helsingborg, Sweden.
    Falck, Anna-Karin
    Helsingborg Hospital, Sweden.
    Fjällskog, Marie-Louise
    Uppsala University, Sweden.
    Grabau, Dorthe
    Lund University, Skåne University Hospital, Lund, Sweden.
    Hedenfalk, Ingrid
    Lund University, Skåne University Hospital, Lund, Sweden.
    Jirström, Karin
    Lund University, Sweden.
    Klintman, Marie
    Lund University, Skåne University Hospital, Lund, Sweden.
    Malmström, Per
    Lund University, Skåne University Hospital, Lund, Sweden.
    Olsson, Hans
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Ryden, Lisa
    Lund University, Skåne University Hospital, Lund, Sweden.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bendahl, Pär-Ola
    Lund University, Skåne University Hospital, Lund, Sweden.
    Fernö, Mårten
    Lund University, Skåne University Hospital, Lund, Sweden.
    The combination of Ki67, histological grade and estrogen receptor status identifies a low-risk group among 1,854 chemo-naïve women with N0/N1 primary breast cancer2013Inngår i: SpringerPlus, E-ISSN 2193-1801, Vol. 2, nr 111Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    The aim was to confirm a previously defined prognostic index, combining a proliferation marker, histological grade, and estrogen receptor (ER) in different subsets of primary N0/N1 chemo-naïve breast cancer patients.

    METHODSDESIGN:

    In the present study, including 1,854 patients, Ki67 was used in the index (KiGE), since it is the generally accepted proliferation marker in clinical routine. The low KiGE-group was defined as histological grade 1 patients and grade 2 patients which were ER-positive and had low Ki67 expression. All other patients made up the high KiGE-group. The KiGE-index separated patients into two groups with different prognosis. In multivariate analysis, KiGE was significantly associated with disease-free survival, when adjusted for age at diagnosis, tumor size and adjuvant endocrine treatment (hazard ratio: 3.5, 95% confidence interval: 2.6-4.7, P<0.0001).

    DISCUSSION:

    We have confirmed a prognostic index based on a proliferation marker (Ki67), histological grade, and ER for identification of a low-risk group of patients with N0/N1 primary breast cancer. For this low-risk group constituting 57% of the patients, with a five-year distant disease-free survival of 92%, adjuvant chemotherapy will have limited effect and may be avoided.

  • 287.
    Stratmann, Johannes
    et al.
    Skovde University.
    Wang, Chaojie
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi.
    Gnosa, Sebastian
    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.
    Hinselwood, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Sun, Xiao-Feng
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Zhang, Hong
    Skovde University.
    Dicer and miRNA in relation to clinicopathological variables in colorectal cancer patients2011Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 11, nr 345Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Dicer is aberrantly expressed in several types of cancers. Applying real-time PCR, we detected the expression of Dicer mRNA in normal mucosa (n = 162), primary colorectal cancer (CRC) (n = 162) and liver metastasis (n = 37), and analysed the relationship between Dicer expression and clinicopathological features. We also correlated the expression of Dicer mRNA to the miRNA expression of miR-141, miR-200a, miR-200b, mir-200c and miR-429 in liver metastases. less thanbrgreater than less thanbrgreater thanMethods: RT-PCR and qPCR were used to analyse the Dicer expression in normal mucosa, primary tumour and liver metastasis by using the High Capacity cDNA Reverse Transcription Kit and TaqMan (TM)(R) Gene Expression assays for Dicer and GAPDH. RT-PCR and qPCR were used to detect miRNA expression in liver metastases by utilizing TaqMan (R) MicroRNA Reverse Transcription Kit and TaqMan (R) miRNA Assays. Statistical analyses were performed with STATISTICA. less thanbrgreater than less thanbrgreater thanResults: Dicer expression in rectal cancer (3.146 +/- 0.953) was higher than in colon cancer (2.703 +/- 1.204, P = 0.018). Furthermore the Dicer expression was increased in primary tumours (3.146 +/- 0.952) in comparison to that in normal mucosa from rectal cancer patients (2.816 +/- 1.009, P = 0.034) but this is not evident in colon cancer patients. Dicer expression in liver metastases was decreased in comparison to that of either normal mucosa or primary tumour in both colon and rectal cancers (P andlt; 0.05). Patients with a high Dicer expression in normal mucosa had a worse prognosis compared to those with a low Dicer expression, independently of gender, age, tumour site, stage and differentiation (P andlt; 0.001, RR 3.682, 95% CI 1.749 - 7.750). In liver metastases, Dicer was positively related to miR-141 (R = 0.419, P = 0.015). less thanbrgreater than less thanbrgreater thanConclusion: Dicer is up-regulated in the early development of rectal cancers. An increased expression of Dicer mRNA in normal mucosa from CRC patients is significantly related to poor survival independently of gender, age, tumour site, stage and differentiation.

  • 288.
    Stål, Olle
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Jerevall, Piiha-Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Institutionen för klinisk och experimentell medicin.
    Ma, Xiai-Jun
    bioTheranostics, San Diego, CA, USA.
    Li, Hongying
    bioTheranostics, San Diego, CA, USA.
    Salunga, Ranelle
    Massachusetts General Hospital, USA.
    Erlander, Mark
    Karolinska Institute, Stockholm, Sweden.
    Sgroi, Dennis
    Harvard Medical School, Boston, MA, USA.
    Holmlund, Birgitta
    Karolinska Institute, Stockholm, Sweden.
    Skoog, Lambert
    Karolinska Institute, Stockholm, Sweden.
    Fornander, Tommy
    Karolinska Institute, Stockholm, Sweden.
    Validation of Prognostic Utility of HOXB13:IL17BR and Molecular Grade Index in Early Stage Breast Cancer: in CANCER RESEARCH, vol 69, issue 24, pp 504S-504S2009Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Background. HOXB13:IL17BR (H:I) is a two gene expression index, which has been shown to be an independent prognostic factor in estrogen receptor (ER)-positive lymph node-negative (N0) breast cancer. A molecular grade index (MGI) measures the expression of five proliferation-related genes. An algorithm based on dichotomized H:I and MGI stratifying patients into three risk groups has been shown to be superior to either alone in predicting risk of distant metastasis in ER+/N0 patients. Further validation in larger cohorts is needed to establish its clinical performance. A continuous predictor combining H:I and MGI is desirable for making individualized risk assessment in the clinical setting.

    Methods. During 1976 through 1990 the Stockholm Breast Cancer Group conducted a randomized clinical trial comparing adjuvant tamoxifen with control in 1780 postmenopausal women considered to be at low risk of recurrence (N0 and tumor size < 3 cm). We measured H:I and MGI using a real time PCR assay in 769 patients from this trial based on sample availability. Correlation of gene expression indices with distant metastasis and death due to breast cancer was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. Modeling was also used to develop a continuous risk index as a function of both H:I and MGI.

    Results. Using pre-specified cutoff points and combination algorithm, H:I, MGI and their combination each was significantly associated with both distant metastasis-free survival and breast cancer-specific survival (Table 1). Furthermore, we used the ER+ tamoxifen-treated subset (n=314) to develop a continuous risk model (Breast Cancer Index or BCI) combining both H:I and MGI. The prognostic utility of BCI was then successfully validated in the untreated subset in this trial and three additional previously published cohorts. BCI consistently identified ∼50% patients with a very low 10-year recurrence risk (< 5%). Discussion. This large retrospective analysis of a randomized clinical trial cohort validated the prognostic utility of H:I, MGI, and their combination. With the continuous risk model, this RT-PCR-based assay allows prediction of risk of recurrence at the individual level, which may help tailor personalized treatment strategy.

  • 289.
    Stål, Olle
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Perez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Åkerberg, Lind
    Olsson, Birgit
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Division of Cytology, Karolinska Hospital, Stockholm, Sweden .
    Rutqvist, Lars
    Department of Oncology, Huddinge University Hospital, Stockholm, Sweden .
    Akt kinases in breast cancer and the results of adjuvant therapy2003Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 5, nr 2, s. R37-R44Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    The serine/threonine kinase Akt, or protein kinase B, has recently been a focus of interest because of its activity to inhibit apoptosis. It mediates cell survival by acting as a transducer of signals from growth factor receptors that activate phosphatidylinositol 3-kinase.

    Methods

    We analysed the expression of the isoforms Akt1 and Akt2 as well as phosphorylated Akt (pAkt) by immunohistochemistry in frozen tumour samples from 280 postmenopausal patients who participated in a randomised trial comparing cyclophosphamide–methotrexate–5-fluorouracil chemotherapy and postoperative radiotherapy. The patients were simultaneously randomised to tamoxifen or to no endocrine treatment.

    Results

    Marked staining was found in 24% of the tumours for Akt1, but in only 4% for Akt2. A low frequency of Akt2-positive cells (1–10%) was observed in another 26% of the tumours. pAkt was significantly associated with both Akt1 and Akt2 expression. Overexpression of erbB2 correlated significantly with pAkt (P = 0.0028). The benefit from tamoxifen was analysed in oestrogen receptor (ER)-positive patients. Patients with a negative status of Akt (no overexpression of Akt1, Akt2 or pAkt) showed significant benefit from tamoxifen. The relative rate of distant recurrence, with versus without tamoxifen, was 0.44 (95% confidence interval [CI], 0.25–0.79) for ER+/Akt1- patients, while it was 0.72 (95% CI, 0.34–1.53) for ER+/Akt1+ patients. The difference in rate ratio did not reach statistical significance. The rate of locoregional recurrence was significantly decreased with radiotherapy versus chemotherapy for Akt-negative patients (rate ratio, 0.23; 95% CI, 0.08–0.67; P = 0.0074), while no benefit was evident for the Akt-positive subgroup (rate ratio, 0.77; 95% CI, 0.31–1.9; P = 0.58). The interaction between Akt and the efficacy of radiotherapy was significant in multivariate analysis (P = 0.042).

    Conclusion

    Activation of the Akt pathway is correlated with erbB2 overexpression in breast cancer. The results suggest that Akt may predict the local control benefit from radiotherapy.

  • 290.
    Sun, Xiao-Feng
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    p73 overexpression is a prognostic factor in patients with colorectal adenocarcinoma2002Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 8, nr 1, s. 165-170Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To examine the expression of p73 in the different stages of colorectal cancer development and the association of p73 expression with patient survival. Experimental Design: Expression of p73 protein was evaluated by immunohistochemistry in 221 primary colorectal cancer patients, including 58 patients with matched normal mucosa and metastases in the regional lymph nodes. Results: Frequency and intensity of p73 expression were markedly increased from the normal samples (19%) to primary tumors (67%) and to metastases (95%). Overexpression of p73 predicted poor outcome in the whole group of patients (P = 0.014) and the subgroups with left-sided (P = 0.002) or ras-positive tumors (P = 0.019). The prognostic significance remained in the whole group (P = 0.008) and the subgroup with left-sided tumors (P = 0.019) after adjustment for the patient's sex, age, tumor stage, growth pattern, and differentiation. The p73 expression was positively correlated with ras expression (P = 0.006). The 5-year survival rates were 37, 53, 72, and 74% for the patients with p73+/ras+, p73+/ras-, p73-/ras+, and p73-/ras- tumors, respectively (P = 0.007). Conclusion: Our data indicate that overexpression of p73 independently predicted poor prognosis in the patients with colorectal cancer.

  • 291.
    Sun, Xiao-Feng
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Zhang, Hong
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
    Carstensen, John
    Linköpings universitet, Institutionen för medicin och hälsa, Hälsa och samhälle. Linköpings universitet, Filosofiska fakulteten.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Heat shock protein 72/73 in relation to cytoplasmic p53 expression and prognosis in colorectal adenocarcinomas1997Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 74, nr 6, s. 600-604Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Heat shock proteins (hsp) are molecular chaperones that are increased by various environmental and patho-physiological stimuli. Hsp can bind to mutant/wild-type p53 in tumors and, consequently, could not only regulate p53 accumulation or localization but also modulate its biological effects on cells. However, there is little information available on the significance of hsp expression in colorectal cancer. The aim of our study was to investigate the relationship of hsp to p53 expression, clinico-pathological factors and prognosis in a series of 256 patients with colorectal adenocarcinomas, using immuno-histochemistry. Seventy-five cases exhibited hsp expression in the cytoplasm, with 11 presenting both cytoplasmic and nuclear staining. Hsp expression was related positively to cytoplasmic p53 expression but not to nuclear p53 expression. In the subgroup of rectal tumors, hsp over-expression appeared to predict unfavorable survival, though its prognostic value diminished using multivariate analysis. There were no significant relationships of hsp with patient sex or age, tumor site, Duke's stage, growth pattern or differentiation.

  • 292.
    Sundquist, M
    et al.
    County Hospital Kalmar.
    Holmberg, E
    ROC, Gothenburg.
    Holmberg, S
    Sahlgrenska University Hospital.
    Kovacs, A
    Sahlgrenska University Hospital.
    Mathe, G
    Sahlgrenska University Hospital.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Tejler, Göran
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Assessments of Proliferation in Breast Cancer in EUROPEAN JOURNAL OF CANCER, vol 47, issue , pp S333-S3332011Inngår i: EUROPEAN JOURNAL OF CANCER, Elsevier , 2011, Vol. 47, s. S333-S333Konferansepaper (Fagfellevurdert)
    Abstract [en]

    n/a

  • 293.
    Suzuki, Chikako
    et al.
    Karolinska University Hospital, Sweden .
    Blomqvist, Lennart
    Karolinska University Hospital, Sweden .
    Hatschek, Thomas
    Karolinska Institute, Sweden .
    Carlsson, Lena
    Sundsvall Gen Hospital, Sweden .
    Einbeigi, Zakaria
    Sahlgrens University Hospital, Sweden .
    Linderholm, Barbro
    Sahlgrens University Hospital, Sweden .
    Lindh, Birgitta
    University of Umeå Hospital, Sweden .
    Loman, Niklas
    Skåne University Hospital, Sweden .
    Malmberg, Martin
    Helsingborg Gen Hospital, Sweden .
    Rotstein, Samuel
    Karolinska University Hospital, Sweden .
    Soderberg, Martin
    Skåne University Hospital, Sweden .
    Sundqvist, Marie
    Kalmar Gen Hospital, Sweden .
    Walz, Thomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Astrom, Gunnar
    Uppsala University, Sweden .
    Fujii, Hirofumi
    National Cancer Centre Hospital East, Japan .
    Jacobsson, Hans
    Karolinska University Hospital, Sweden .
    Glimelius, Bengt
    Karolinska Institute, Sweden .
    Impact of the first tumor response at eight weeks on overall survival in metastatic breast cancer patients treated with first-line combination chemotherapy2013Inngår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 30, nr 1Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this was to determine whether the change of size observed at the first response evaluation after initiation of first-line combination chemotherapy correlates with overall survival (OS) in patients with metastatic breast cancer (MBC). The change in size of tumors derived from measurements according to Response Evaluation Criteria In Solid Tumors (RECIST) at the first evaluation on computed tomography (CT) was obtained from a multicenter, randomized phase III trial ("TEX trial," n = 287) comparing treatment with a combination of epirubicin and paclitaxel alone or with capecitabine (TEX). Cox regression and Kaplan-Meier analyses were performed to evaluate the correlations between the first change in tumor size, response according to RECIST and OS. Data from CT evaluations of 233 patients were available. Appearance of new lesions or progression of non-target lesions (new/non-target) indicated short OS by univariable regression analysis (HR 3.76, 95 % CI 1.90-7.42, p andlt; 0.001). A decrease by andgt;30 % at this early time point was prognostic favorable (HR 0.69, 95 % CI 0.49-0.98, p = 0.04) and not significantly less than the best overall response according to RECIST. After adjustment for previous adjuvant treatment and the treatment given within the frame of the randomized trial, OS was still significantly shorter in patients with new/non-target lesions after a median 8 weeks of treatment (HR 4.41, 95 % CI 2.74-7.11, p andlt; 0.001). Disease progression at the first evaluation correlates with OS in patients with MBC treated with first-line combination chemotherapy. The main reason for early disease progression was the appearance of new lesions or progression of non-target lesions. These patients had poor OS even though more lines of treatment were available. Thus, these factors should be focused on in the response evaluations besides tumor size changes.

  • 294.
    Söderholm, Johan D
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Juliusson, Gunnar
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Sjödahl, Rune
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Kirurgi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Kirurgiska kliniken i Östergötland med verksamhet i Linköping, Norrköping och Motala.
    Long-term endoscopic remission in a case of Crohn's disease after autologous bone marrow transplantation.2000Inngår i: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 118, nr 4, s. 4212-Konferansepaper (Annet vitenskapelig)
  • 295.
    Söderlund, Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Queseth, Siv
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Fornander, Tommy
    Karolinska University Hospital.
    Marie Stenmark, Askmalm
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Low expression of Ku70/80, but high expression of DNA-PKcs, predict good response to radiotherapy in early breast cancer2010Inngår i: INTERNATIONAL JOURNAL OF ONCOLOGY, ISSN 1019-6439, Vol. 37, nr 6, s. 1547-1554Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The purpose was to study the prognostic and predictive roles of DNA protein kinase catalytic subunit (DNA-PKcs), Ku70/80 and p53 for the effect of radiotherapy in breast cancer patients Protein expressions of Ku70/80, DNA-PKcs and p53 were examined using immunohistochemistry in tumours from 224 breast cancer patients, who were randomised to receive post-operative radiotherapy or adjuvant chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil) One hundred and twenty-nine (60%) of the tumours had low expression of Ku70180, 122 (57%) had low expression of DNA-PKcs and 65 (30%) had altered p53 expression None of the proteins were indicative to the prognosis of local recurrence-free survival Even though the expression of Ku70/80 and DNA-PKcs correlated well, they were not associated with treatment outcome in the same way Low expression of Ku70/80 predicted good effect of radiotherapy (RR=0 31, 95% CI 0 13-0 76, p=0 01) In contrast, the greatest benefit of radiotherapy over chemotherapy was seen in patients with high DNA-PKcs expression (RR=0 25, 95% CI 0 07-0 84, p=0 02) Altered p53 expression predicted poor response to radiotherapy We believe that the results reflect the different roles of DNA-PKcs and Ku70/80 in repair and cell death regulation after DNA damage These differences could be of importance when developing drugs that target DNA repair

  • 296.
    Söderlund, Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Fornander, Tommy
    Departmen of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer2007Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 84, nr 3, s. 242-251Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and Purpose: The breast cancer susceptibility genes BRCA1 and BRCA2 interact with Rad51, one of the central components in the homologous recombination repair pathway. This study evaluates the prognostic and predictive role of BRCA1, BRCA2 and Rad51, individually and as a complex, in breast cancer.

    Material and Methods: Expression of BRCA1, BRCA2 and Rad51 was investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive postoperative radiotherapy or adjuvant chemotherapy (CMF).

    Results: 53% (112/212) of the tumours had reduced expression of the BRCA1/BRCA2/Rad51 complex. Low expression correlated to high histologic grade (p=0.05). Patients with low expression of the complex developed significantly more local recurrences as compared to patients with high expression (RR=3.20, 95% C.I. 1.48-6.88, p=0.003). Expression of the BRCA1/BRCA2/Rad51 complex was an independent prognostic factor in multivariate analysis (p=0.03). Patients with low expression of the complex responded well to radiotherapy (RR=0.31, 95% C.I. 0.14-0.70, p=0.005), whereas patients with high expression had few local recurrences and no additional benefit from radiotherapy (RR=1.08, 95% C.I. 0.40-2.90, p=0.88).

    Conclusions: Low expression of the BRCA1/BRCA2/Rad51 complex is a marker of poor prognosis, but predicts good effect of radiotherapy in patients with early breast cancer.

  • 297.
    Söderlund, Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Svensson, Susanne
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Bendrik, Christina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Robertson, Jennifer
    McMaster University, Hamilton, Ontario, Canada.
    Gauldie, Jack
    McMaster University, Hamilton, Ontario, Canada.
    Olsson, Anna-Karin
    Uppsala University, Sweden .
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer2013Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, nr 8, s. 4420-4430Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Matrix metalloproteinases (MMPs) have been suggested as therapeutic targets in cancer treatment, but broad-spectrum MMP inhibitors have failed in clinical trials. Recent data suggest that several MMPs including MMP-9 exert both pro-and antitumorigenic properties. This is also the case of the natural inhibitors of MMPs, tissue inhibitor of metalloproteinases (TIMPs). The inhibitor of MMP-9 is TIMP-1, and high levels of this enzyme have been associated with decreased survival in breast cancer. Inflammation is one hallmark of cancer progression, and MMPs/TIMPs may be involved in the local immune regulation. We investigated the role of MMP-9/TIMP-1 in regulating innate antitumor immunity in breast cancer. Breast cancers were established in nude mice and treated with intratumoral injections of adenoviruses carrying the human TIMP-1 or MMP-9 gene (AdMMP-9). In vivo microdialysis for sampling of cancer cell-derived (human) and stroma-derived (murine) proteins, immunostainings, as well as cell cultures were performed. We report a dose-dependent decrease of tumor growth and angiogenesis after AdMMP-9 treatment. In addition to increased generation of endostatin, AdMMP-9 promoted an antitumor immune response by inducing massive neutrophil infiltration. Neutrophil depletion prior to gene transfer abolished the therapeutic effects of AdMMP-9. Additionally, AdMMP-9 activated tumor-infiltrating macrophages into a tumor-inhibiting phenotype both in vivo and in vitro. AdMMP-9 also inhibited tumor growth in immune-competent mice bearing breast cancers. Adenoviruses carrying the human TIMP-1 gene had no effect on tumor growth or the immune response. Our novel data identify MMP-9 as a potent player in modulating the innate immune response into antitumor activities. The Journal of Immunology, 2013, 190: 4420-4430.

  • 298.
    Söderlund Leifler, Karin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    DNA repair pathways and the effect of radiotherapy in breast cancer2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    A large proportion of breast cancer patients are treated with radiotherapy. Ionising radiation induces different DNA damages, of which double-strand breaks are the most severe. They are mainly repaired by homologous recombination or non-homologous end-joining. Different protein complexes have central roles in these repair processes. In addition to the ability to repair DNA damage, cellular radiosensitivity is also affected by mitogenic signals that stimulate survival and inhibit apoptosis. The phosphatidylinositol 3-kinase (PI3-K)/AKT pathway controls cell proliferation, invasiveness and cell survival. AKT is regulated by upstream growth factor receptors, one of them being HER2 (also called ErbB2). HER2 is overexpressed in 15-30% of all breast cancers and associated with poor prognosis.

    In this thesis, we have studied factors that affect tumour cell resistance to ionising radiation. In Paper I, the role of HER2/PI3-K/AKT signalling in radiation resistance was investigated in two breast cancer cell lines. The results support the hypothesis that the HER2/PI3-K/AKT pathway is involved in resistance to radiation-induced apoptosis in breast cancer cells in which this signalling pathway is overstimulated.

    We also investigated if the protein expression of several DNA repair-associated proteins influence the prognosis and treatment response in early breast cancer. Moderate/strong expression of the MRE11/RAD50/NBS1 (MRN) complex predicted good response to radiotherapy, whereas patients with negative/weak MRN had no benefit from radiotherapy as compared to chemotherapy (Paper II). These results suggest that an intact MRNcomplex is important for the tumour-eradicating effect of radiotherapy. In Paper III, low expression of the BRCA1/BRCA2/RAD51 complex was associated with an aggressive phenotype, an increased risk of local recurrence and good response to radiotherapy.

    In Paper IV, we studied if a single nucleotide polymorphism, RAD51 135G/C, was related to RAD51 protein expression, prognosis and therapy resistance. We found that genotype was not correlated to neither protein expression nor prognosis. Patients who were G/G homozygotes had a significant benefit from radiotherapy. The results also suggested that the RAD51 135G/C polymorphism predicts the effect of chemotherapy in early breast cancer.

    In conclusion, DNA repair proteins are potential prognostic and predictive markers. The results indicate that proteins in different repair pathways may contribute differently to the effect of radiotherapy. Also, the HER2/PI3-K/AKT signalling pathway protects cells from radiation-induced apoptosis. In the future, it might be possible to target some of these proteins with inhibitory drugs to sensitise tumours to radiotherapy.

    Delarbeid
    1. Activation of the phosphatidylinositol 3-kinase/Akt pathway prevents radiation-induced apoptosis in breast cancer cells
    Åpne denne publikasjonen i ny fane eller vindu >>Activation of the phosphatidylinositol 3-kinase/Akt pathway prevents radiation-induced apoptosis in breast cancer cells
    2005 (engelsk)Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 26, nr 1, s. 25-32Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Radiotherapy is widely used in the treatment of breast cancer and reduces the risk of loco-regional recurrence. Overexpression of the erbB2 receptor occurs in 20-30% of all breast cancers, and seems to be involved in chemotherapeutic resistance of breast cancer cells and radioresistance of lung cancer cells. The hypothesis of this study was that erbB2 confers resistance to radiation-induced apoptosis in breast cancer cells through the phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway. Two human breast cancer cell lines were used, BT-474 and MCF-7. BT-474 cells overexpress erbB2 and have mutated p53, while MCF-7 have normal expression of erbB2 and functional p53. The cells were treated with the PI3-K inhibitor wortmannin or the erbB receptor ligand heregulin-ß1, which is expressed by both malignant and stromal cells in vivo. After pharmacological treatment, the cells were irradiated with 10 Gy gamma-radiation. Consistent with the p53 status in the cell lines, gamma-radiation caused G1 arrest in MCF-7 cells, but not in BT-474 cells. 10 Gy gamma-radiation increased apoptosis by on an average 76% (95% CI, 44-109%) in MCF-7. Treatment of MCF-7 with heregulin-ß1 decreased apoptosis by 66% (95% CI, 48-84%) compared to the untreated controls. In BT-474 cells, wortmannin in combination with radiation resulted in 119% (95% CI, 76-161%) more apoptosis compared to wortmannin alone, whereas radiation alone resulted in 45% (95% CI, 15-75%) increased apoptosis. This radiosensitising effect was not seen in MCF-7. Furthermore, transfection of MCF-7 cells with constitutively active Akt made the cells more resistant against apoptosis. Taken together, our results support the hypothesis that the erbB2/PI3-K/Akt signalling pathway is involved in resistance to radiation-induced apoptosis in breast cancer cells in which this signalling pathway is overstimulated.

    Emneord
    HER2/neu, erbB2, protein kinase B, Akt, ionising radiation, apoptosis, breast cancer
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-17951 (URN)
    Tilgjengelig fra: 2009-04-27 Laget: 2009-04-27 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer
    Åpne denne publikasjonen i ny fane eller vindu >>Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer
    Vise andre…
    2007 (engelsk)Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 68, nr 1, s. 50-58Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose: Post-operative radiotherapy is offered to a majority of breast cancer patients, since it significantly reduces the risk of local recurrence. However, some patients still develop recurrences. Owing to their vital roles in the repair of radiation-induced double-strand breaks, the Mre11/Rad50/Nbs1 (MRN) complex and the ATM protein might be implicated in tumour cell resistance to radiotherapy. The aim of this study was to investigate the expression and predictive role of these DNA repair proteins for the outcome of radiotherapy in breast cancer patients.

    Patients and Methods: The protein expression of ATM and the proteins in the MRN complex were investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive post-operative radiotherapy or adjuvant chemotherapy (CMF).

    Results: Compared to normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1 and ATM was reduced in a majority of the tumours. Weak expression of the MRN complex was correlated to high histological grade and ER negativity (p=0.01 and p=0.0001). Radiotherapy significantly reduced the risk of local recurrence as compared to chemotherapy (p=0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (RR=0.27, 95% C.I. 0.098-0.72, p=0.009), whereas patients with negative/weak MRN had no benefit of radiotherapy compared to CMF. These results suggest that an intact MRN complex is important for the tumour cell eradicating effect of radiotherapy.

    Emneord
    Radiotherapy, breast cancer, mre11, rad50, nbs1
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-17952 (URN)10.1016/j.ijrobp.2006.12.005 (DOI)
    Tilgjengelig fra: 2009-04-27 Laget: 2009-04-27 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    3. The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer
    Åpne denne publikasjonen i ny fane eller vindu >>The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer
    2007 (engelsk)Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 84, nr 3, s. 242-251Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background and Purpose: The breast cancer susceptibility genes BRCA1 and BRCA2 interact with Rad51, one of the central components in the homologous recombination repair pathway. This study evaluates the prognostic and predictive role of BRCA1, BRCA2 and Rad51, individually and as a complex, in breast cancer.

    Material and Methods: Expression of BRCA1, BRCA2 and Rad51 was investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive postoperative radiotherapy or adjuvant chemotherapy (CMF).

    Results: 53% (112/212) of the tumours had reduced expression of the BRCA1/BRCA2/Rad51 complex. Low expression correlated to high histologic grade (p=0.05). Patients with low expression of the complex developed significantly more local recurrences as compared to patients with high expression (RR=3.20, 95% C.I. 1.48-6.88, p=0.003). Expression of the BRCA1/BRCA2/Rad51 complex was an independent prognostic factor in multivariate analysis (p=0.03). Patients with low expression of the complex responded well to radiotherapy (RR=0.31, 95% C.I. 0.14-0.70, p=0.005), whereas patients with high expression had few local recurrences and no additional benefit from radiotherapy (RR=1.08, 95% C.I. 0.40-2.90, p=0.88).

    Conclusions: Low expression of the BRCA1/BRCA2/Rad51 complex is a marker of poor prognosis, but predicts good effect of radiotherapy in patients with early breast cancer.

    Emneord
    Radiotherapy; Breast cancer; BRCA1; BRCA2; Rad51
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-17953 (URN)10.1016/j.radonc.2007.06.012 (DOI)
    Tilgjengelig fra: 2009-04-27 Laget: 2009-04-27 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    4. The RAD51 135G/C polymorphism is related to the effect of adjuvant therapy in early breast cancer
    Åpne denne publikasjonen i ny fane eller vindu >>The RAD51 135G/C polymorphism is related to the effect of adjuvant therapy in early breast cancer
    2015 (engelsk)Inngår i: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 141, nr 5, s. 797-804Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose: A single-nucleotide polymorphism, RAD51 135G/C, in the untranslated region of the RAD51 gene has been found to elevate breast cancer risk among BRCA2 carriers. The purpose of this study was to investigate if this polymorphism is related to RAD51 protein expression, prognosis of early breast cancer and if it contributes to resistance to radiotherapy or cyclophosphamide/5-fluorouracil/methotrexate (CMF) chemotherapy.

    Methods: We genotyped 306 patients with early breast cancer, who were randomised to receive post-operative radiotherapy or CMF chemotherapy, for the RAD51 135G/C polymorphism. Expression of RAD51 protein was evaluated with immunohistochemistry.

    Results: The frequency of C-allele was 15.4% (including three C/C homozygotes). There was no correlation between genotype and protein expression pattern in tumours. Patients who were homozygous for the wildtype G/G genotype had a significant benefit of radiotherapy (RR=0.32, 95% C.I. 0.16-0.64, p=0.001). CMF chemotherapy significantly reduced the risk of distant recurrence during the first 20 years in patients who had the C-allele (RR=0.29, 95% C.I. 0.10-0.88, p=0.03), whereas patients who were G/G homozygotes had no benefit from chemotherapy over radiotherapy (RR=1.09, 95% C.I. 0.77-1.6, p=0.61). There was a significant interaction between chemotherapy and genotype (p=0.02). Genotype was not related to the rate of distant recurrence among patients treated with radiotherapy.

    Conclusion: Breast cancer patients who were homozygous for the wildtype G allele had a significant benefit of radiotherapy. The results suggest that the RAD51 135G/C polymorphism predicts the effect of CMF chemotherapy in early breast cancer.

    sted, utgiver, år, opplag, sider
    Springer Publishing Company, 2015
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-17954 (URN)10.1007/s00432-014-1859-0 (DOI)000352859700003 ()
    Tilgjengelig fra: 2009-04-27 Laget: 2009-04-27 Sist oppdatert: 2017-12-13bibliografisk kontrollert
  • 299.
    Söderlund Leifler, Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    ¨, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Skoog, Lambert
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Rutqvist, Lars Erik
    Department of Medicine/Huddinge, Karolinska Institute, Stockholm,Sweden.
    Nordenskjöld, Bo
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Stenmark Askmalm, Marie
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer2007Inngår i: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 68, nr 1, s. 50-58Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Post-operative radiotherapy is offered to a majority of breast cancer patients, since it significantly reduces the risk of local recurrence. However, some patients still develop recurrences. Owing to their vital roles in the repair of radiation-induced double-strand breaks, the Mre11/Rad50/Nbs1 (MRN) complex and the ATM protein might be implicated in tumour cell resistance to radiotherapy. The aim of this study was to investigate the expression and predictive role of these DNA repair proteins for the outcome of radiotherapy in breast cancer patients.

    Patients and Methods: The protein expression of ATM and the proteins in the MRN complex were investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive post-operative radiotherapy or adjuvant chemotherapy (CMF).

    Results: Compared to normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1 and ATM was reduced in a majority of the tumours. Weak expression of the MRN complex was correlated to high histological grade and ER negativity (p=0.01 and p=0.0001). Radiotherapy significantly reduced the risk of local recurrence as compared to chemotherapy (p=0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (RR=0.27, 95% C.I. 0.098-0.72, p=0.009), whereas patients with negative/weak MRN had no benefit of radiotherapy compared to CMF. These results suggest that an intact MRN complex is important for the tumour cell eradicating effect of radiotherapy.

  • 300.
    Söderlund Leifler, Karin
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Pérez-Tenorio, Gizeh
    Linköpings universitet, Institutionen för biomedicin och kirurgi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Activation of the phosphatidylinositol 3-kinase/Akt pathway prevents radiation-induced apoptosis in breast cancer cells2005Inngår i: International Journal of Oncology, ISSN 1019-6439, Vol. 26, nr 1, s. 25-32Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radiotherapy is widely used in the treatment of breast cancer and reduces the risk of loco-regional recurrence. Overexpression of the erbB2 receptor occurs in 20-30% of all breast cancers, and seems to be involved in chemotherapeutic resistance of breast cancer cells and radioresistance of lung cancer cells. The hypothesis of this study was that erbB2 confers resistance to radiation-induced apoptosis in breast cancer cells through the phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway. Two human breast cancer cell lines were used, BT-474 and MCF-7. BT-474 cells overexpress erbB2 and have mutated p53, while MCF-7 have normal expression of erbB2 and functional p53. The cells were treated with the PI3-K inhibitor wortmannin or the erbB receptor ligand heregulin-ß1, which is expressed by both malignant and stromal cells in vivo. After pharmacological treatment, the cells were irradiated with 10 Gy gamma-radiation. Consistent with the p53 status in the cell lines, gamma-radiation caused G1 arrest in MCF-7 cells, but not in BT-474 cells. 10 Gy gamma-radiation increased apoptosis by on an average 76% (95% CI, 44-109%) in MCF-7. Treatment of MCF-7 with heregulin-ß1 decreased apoptosis by 66% (95% CI, 48-84%) compared to the untreated controls. In BT-474 cells, wortmannin in combination with radiation resulted in 119% (95% CI, 76-161%) more apoptosis compared to wortmannin alone, whereas radiation alone resulted in 45% (95% CI, 15-75%) increased apoptosis. This radiosensitising effect was not seen in MCF-7. Furthermore, transfection of MCF-7 cells with constitutively active Akt made the cells more resistant against apoptosis. Taken together, our results support the hypothesis that the erbB2/PI3-K/Akt signalling pathway is involved in resistance to radiation-induced apoptosis in breast cancer cells in which this signalling pathway is overstimulated.

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