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Search Results: 1 - 10 of 214184 matches for " Olle St?l "
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Low ERK Phosphorylation in Cancer-Associated Fibroblasts Is Associated with Tamoxifen Resistance in Pre-Menopausal Breast Cancer
Susann Busch, Lisa Rydén, Olle Stl, Karin Jirstr?m, G?ran Landberg
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045669
Abstract: Purpose The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial. Patients and Methods Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK) and smooth muscle actin-alpha expression (SMAα) in cancer-associated fibroblasts (CAFs) and links to clinico-pathological data and treatment-predictive values were delineated. Results By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not respond to tamoxifen treatment despite having estrogen-receptor alpha (ERα-positive tumors compared to patients with high pERK levels in CAFs (P = 0.015, multivariate Cox regression interaction analysis). In both clinical materials we further show a significant association between pERK and SMAα, a characteristic marker for activated fibroblasts. SMAα expression however was not linked to treatment-predictive information but instead had prognostic qualities. Conclusion The data suggests that the presence of a subpopulation of CAFs, defined by minimal activated ERK signaling, is linked to an impaired tamoxifen response. Thus, this report illustrates the importance of the stroma for monitoring treatment effects in pre-menopausal breast cancer.
17β-Hydroxysteroid Dehydrogenase Type 14 Is a Predictive Marker for Tamoxifen Response in Oestrogen Receptor Positive Breast Cancer
Tove Sivik, Cecilia Gunnarsson, Tommy Fornander, Bo Nordenskj?ld, Lambert Skoog, Olle Stl, Agneta Jansson
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040568
Abstract: 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.
Predictive relevance of HOXB13 protein expression for tamoxifen benefit in breast cancer
Piiha-Lotta Jerevall, Agneta Jansson, Tommy Fornander, Lambert Skoog, Bo Nordenskj?ld, Olle Stl
Breast Cancer Research , 2010, DOI: 10.1186/bcr2612
Abstract: We used immunohistochemistry to analyze protein levels of HOXB13 in tumor samples from 912 postmenopausal node-negative breast cancer patients randomized to adjuvant tamoxifen therapy or no endocrine treatment.Tamoxifen-treated patients with estrogen receptor-positive tumors expressing none or low levels of HOXB13 had a clear benefit from tamoxifen in terms of longer distant recurrence-free survival (DRFS) (hazard ratio = 0.38, 95% confidence interval = 0.23 to 0.60, P = 0.000048). However, for patients with a high or intermediate HOXB13 tumor expression, tamoxifen did not prolong the DRFS compared with the untreated patients (hazard ratio = 0.88, 95% confidence interval = 0.47 to 1.65, P = 0.69). Interaction between HOXB13 expression and benefit from tamoxifen was statistically significant for DRFS (P = 0.035). No prognostic value could be ascribed to HOXB13 among systemically untreated patients.A high HOXB13 expression was associated with decreased benefit from tamoxifen, which indicates that HOXB13 protein level may be used as a predictive marker for tamoxifen treatment.There have been several recent studies aimed at discovering novel biomarkers and gene signatures usable for predicting risk of recurrence and response to endocrine therapy of breast cancer [1-4]. With the development of robust, reliable genetic markers for this purpose, it would be possible at an early stage to predict which patients would benefit from alternative hormonal therapies. Resulting gene signatures, based on genome-wide microarray analyses, are often very comprehensive and comprise a large number of genes. However, Ma and colleagues were able to show that their gene expression profiles of hormone receptor-positive invasive breast tumors could be reduced into a simple two-gene ratio predictive of tumor relapse in the setting of adjuvant tamoxifen monotherapy [5]. Subsequent studies of the HOXB13:IL17BR index have proven its significance in predicting risk of breast cancer recurrence and
Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer
Pia Wegman, Sauli Elingarami, John Carstensen, Olle Stl, Bo Nordenskj?ld, Sten Wingren
Breast Cancer Research , 2007, DOI: 10.1186/bcr1640
Abstract: In all, 677 tamoxifen-treated postmenopausal patients with breast cancer, of whom 238 were randomised to either 2 or 5 years of tamoxifen, were genotyped by using PCR with restriction fragment length polymorphism or PCR with denaturing high-performance liquid chromatography.The prognostic evaluation performed in the total population revealed a significantly better disease-free survival in patients homozygous for CYP2D6*4. For CYP3A5, SULT1A1 and UGT2B15 no prognostic significance was observed. In the randomised group we found that for CYP3A5, homozygous carriers of the *3 allele tended to have an increased risk of recurrence when treated for 2 years with tamoxifen, although this was not statistically significant (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 0.68 to 11.99, P = 0.15). In the group randomised to 5 years' tamoxifen the survival pattern shifted towards a significantly improved recurrence-free survival (RFS) among CYP3A5*3-homozygous patients (HR = 0.20, 95% CI = 0.07 to 0.55, P = 0.002). No reliable differences could be seen between treatment duration and the genotypes of CYP2D6, SULT1A1 or UGT2B15. The significantly improved RFS with prolonged tamoxifen treatment in CYP3A5*3 homozygotes was also seen in a multivariate Cox model (HR = 0.13, CI = 0.02 to 0.86, P = 0.03), whereas no differences could be seen for CYP2D6, SULT1A1 and UGT2B15.The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely to be explained by a single polymorphism; instead it is a combination of several mechanisms. However, the present data suggest that genetic variation in CYP3A5 may predict response to tamoxifen therapy.Tamoxifen is widely used as an endocrine treatment for patients with oestrogen-receptor (ER)-positive breast cancer. Five years of adjuvant tamoxifen therapy reduces the risk of recurrence and prolongs the survival of women with ER-positive tumours [1]. Nevertheless, in a proportion of patients, tumours are res
Cyclosporin A Enhances Callus Formation in Rabbit Tibia Fractures  [PDF]
Anders L. Ekelund, Olle Nilsson
International Journal of Clinical Medicine (IJCM) , 2013, DOI: 10.4236/ijcm.2013.47A1005
Abstract: Purpose: Drugs that modify the production of cytokines may affect fracture healing.The immunosuppressive drug cyclosporin A is widely used to modify the immune response in transplantations and in treatment of rheumatoid disorders. We wanted to analyze the effect of cyclosporin A on fracture healing and on the development of trauma induced osteopenia.Methods: Experimental tibia fractures were stabilised with intramedullary pins in 26 rabbits. The animals were given 5mg/kg/day of cyclosporin A or placebo for 5 weeks. Bone mineral content, callus volume and biomechanical testing were performed on both tibias and femurs.Results: At 5 weeks cyclosporin A treatment resulted in increased bone mineral content and increased callus volume of the fractured bone. The femora on the operated side had significantly lower bone mineral content compared to the non-operated side. This trauma induced osteopenia was unaffected by cyclosporin A treatment. Failure torque and stiffness of the tibia and femora were similar in both groups.Interpretation: Cyclosporin A stimulates bone formation in fracture repair. The mechanism is unclear, but a direct or cytokine mediated effect on bone forming cells, or enhanced bone induction resulting in increased bone formation, is possible.


Akt kinases in breast cancer and the results of adjuvant therapy
Olle Stl, Gizeh Pérez-Tenorio, Linda ?kerberg, Birgit Olsson, Bo Nordenskj?ld, Lambert Skoog, Lars Rutqvist
Breast Cancer Research , 2002, DOI: 10.1186/bcr569
Abstract: 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.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).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.The regulation of cell proliferation and cell survival in breast cancer is a complex interplay between steroid hormones, growth factors and their receptors. The understanding of the signalling pathways involved in these p
Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients
Pia Wegman, Linda Vainikka, Olle Stl, Bo Nordenskj?ld, Lambert Skoog, Lars-Erik Rutqvist, Sten Wingren
Breast Cancer Research , 2005, DOI: 10.1186/bcr993
Abstract: The patients were genotyped using PCR followed by cleavage with restriction enzymes.Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041).The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.The majority of breast tumours express oestrogen receptors (ERs). Several studies have shown that 5 years of tamoxifen therapy in breast cancer patients with receptor-positive tumours reduces the risk of recurrence and mortality [1]. However, about 30% of patients acquire tamoxifen resistance and relapse in the disease [1]. Several possible mechanisms for this have been suggested [2-4].Tamoxifen and its metabolites compete with endogenous oestrogen for the ligand-binding domain of the ER. The complex formation between tamoxifen, or its active metabolites, and the ER inhibits recruitment of co-activator complexes necessary for transcription of oestrogen-responsive genes [5]. The biotransformation of tamoxifen is mediated by cytochrome P450 enzymes mainly through demethylation and hydroxylation to form several primary metabolites, principally 4-OH-tamoxifen, α-OH-tamoxifen, N-desmethyl-tamoxifen, and 4-OH-N-desmethyl-tamoxifen. 4-OH-tamoxifen is considered to be a more potent anti-oestrogen than the mother substance and is capable of b
Exploring cancer register data to find risk factors for recurrence of breast cancer – application of Canonical Correlation Analysis
Amir R Razavi, Hans Gill, Olle Stl, Marie Sundquist, Sten Thorstenson, Hans ?hlfeldt, Nosrat Shahsavar, the South-East Swedish Breast Cancer Study Group
BMC Medical Informatics and Decision Making , 2005, DOI: 10.1186/1472-6947-5-29
Abstract: One essential outcome after breast cancer treatment is recurrence of the disease. It is important to understand the relationship between different predictors and recurrence, including the time interval until recurrence. This study describes the application of CCA to find important predictors for two different outcomes for breast cancer patients, loco-regional recurrence and occurrence of distant metastasis and to decrease the number of variables in the sets of predictors and outcomes without decreasing the predictive strength of the model.Data for 637 malignant breast cancer patients admitted in the south-east region of Sweden were analyzed. By using CCA and looking at the structure coefficients (loadings), relationships between tumor specifications and the two outcomes during different time intervals were analyzed and a correlation model was built.The analysis successfully detected known predictors for breast cancer recurrence during the first two years and distant metastasis 2–4 years after diagnosis. Nottingham Histologic Grading (NHG) was the most important predictor, while age of the patient at the time of diagnosis was not an important predictor.In cancer registers with high dimensionality, CCA can be used for identifying the importance of risk factors for breast cancer recurrence. This technique can result in a model ready for further processing by data mining methods through reducing the number of variables to important ones.Breast cancer is the most common type of cancer diagnosed in women in Western countries. Sweden has had a high incidence of breast cancer for several decades, although mortality rates have been lower than in most other Western countries [1].Breast cancer prognosis is influenced by many factors such as morphological and pathological tumor specifications and biological tumor markers. Studying these predictors and finding those of most importance can give clinicians better insight regarding the prognosis.As a rule, data on cancer patients h
The Role of MicroRNA-200 in Progression of Human Colorectal and Breast Cancer
Linda Bojmar, Elin Karlsson, Sander Elleg?rd, Hans Olsson, Bergthor Bj?rnsson, Olof Hallb??k, Marie Larsson, Olle Stl, Per Sandstr?m
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084815
Abstract: The role of the epithelial-mesenchymal transition (EMT) in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200–ZEB–E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMT-markers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200 – ZEB – E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.
Gene expression profiling in primary breast cancer distinguishes patients developing local recurrence after breast-conservation surgery, with or without postoperative radiotherapy
Emma Niméus-Malmstr?m, Morten Krogh, Per Malmstr?m, Carina Strand, Irma Fredriksson, Per Karlsson, Bo Nordenskj?ld, Olle Stl, G?rel ?stberg, Carsten Peterson, M?rten Fern?
Breast Cancer Research , 2008, DOI: 10.1186/bcr1997
Abstract: We performed gene expression analysis (oligonucleotide arrays, 26,824 reporters) on 143 patients with lymph node-negative disease and tumor-free margins. A support vector machine was employed to build classifiers using leave-one-out cross-validation.Within the estrogen receptor-positive (ER+) subgroup, the gene expression profile clearly distinguished patients with local recurrence after radiotherapy (n = 20) from those without local recurrence (n = 80 with or without radiotherapy). The receiver operating characteristic (ROC) area was 0.91, and 5,237 of 26,824 reporters had a P value of less than 0.001 (false discovery rate = 0.005). This gene expression profile provides substantially added value to conventional clinical markers (for example, age, histological grade, and tumor size) in predicting local recurrence despite radiotherapy. Within the ER- subgroup, a weaker, but still significant, signal was found (ROC area = 0.74). The ROC area for distinguishing patients who develop local recurrence from those who remain local recurrence-free in the absence of radiotherapy was 0.66 (combined ER+/ER-).A highly distinct gene expression profile for patients developing local recurrence after breast-conservation surgery despite radiotherapy has been identified. If verified in further studies, this profile might be a most important tool in the decision making for surgery and adjuvant therapy.The addition of postoperative radiotherapy to breast-conservation surgery in patients with lymph node-negative breast cancer has been shown to reduce the 10-year risk of local recurrence from 29.2% to 10% [1]. However, more than half of the patients will never develop local recurrence whether given radiotherapy or not and a small proportion of the patients will develop local recurrence despite being given radiotherapy. Besides tumor-involved margins, generally accepted risk factors for the development of local recurrence are young age and multicentricity [2-5]. A number of other risk fact
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