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Oresland T.,University of Oslo | Oresland T.,Akerhus University Hospital | Faerden A.E.,Akerhus University Hospital
Scandinavian Journal of Gastroenterology | Year: 2014

Surgery for IBD is in constant evolution; it does not appear that the introduction of biologicals has had a major effect on the chance of a patient being operated on or not. Pouch surgery had its heydays in the 80s and 90s and has since then become less frequent, but the number of patients undergoing surgery still seem about the same from one year to the other. Likewise, there is no substantial evidence that surgery for Crohn's disease is diminishing. There have been fears that patients on biological treatment have an increased risk of postoperative complications. The issue is not completely settled but it is likely that patients on biological treatment who come to surgery are those who do not benefit from biologicals. Thus, they are compromised in that they have an ongoing inflammation, are in bad nutritional state, and might have several other known risk factors for a complicated postoperative course. These factors and perhaps not the biologicals per se is what surgeons should consider. During the recent years, we have seen several new developments in IBD surgery; the ileorectal anastomosis is being used for ulcerative colitis and laparoscopic surgery usually resulting in a shorter hospital stay, less pain, and better cosmetics. We have also seen the introduction of robotic surgery, single incision minimal invasive surgery, transanal minimal invasive surgery, and other approaches to minimize surgical trauma. Time will show which of these innovations patients will benefit from. © 2015 Informa Healthcare.

Dejeux E.,French Atomic Energy Commission | Ronneberg J.A.,University of Oslo | Solvang H.,University of Oslo | Bukholm I.,University of Oslo | And 8 more authors.
Molecular Cancer | Year: 2010

Background: Breast cancer is the most frequent cancer in women and consists of a heterogeneous collection of diseases with distinct histopathological, genetic and epigenetic characteristics. In this study, we aimed to identify DNA methylation based biomarkers to distinguish patients with locally advanced breast cancer who may benefit from neoadjuvant doxorubicin treatment.Results: We investigated quantitatively the methylation patterns in the promoter regions of 14 genes (ABCB1, ATM, BRCA1, CDH3, CDKN2A, CXCR4, ESR1, FBXW7, FOXC1, GSTP1, IGF2, HMLH1, PPP2R2B, and PTEN) in 75 well-described pre-treatment samples from locally advanced breast cancer and correlated the results to the available clinical and molecular parameters. Six normal breast tissues were used as controls and 163 unselected breast cancer cases were used to validate associations with histopathological and clinical parameters.Aberrant methylation was detected in 9 out of the 14 genes including the discovery of methylation at the FOXC1 promoter. Absence of methylation at the ABCB1 promoter correlated with progressive disease during doxorubicin treatment. Most importantly, the DNA methylation status at the promoters of GSTP1, FOXC1 and ABCB1 correlated with survival, whereby the combination of methylated genes improved the subdivision with respect to the survival of the patients. In multivariate analysis GSTP1 and FOXC1 methylation status proved to be independent prognostic markers associated with survival.Conclusions: Quantitative DNA methylation profiling is a powerful tool to identify molecular changes associated with specific phenotypes. Methylation at the ABCB1 or GSTP1 promoter improved overall survival probably due to prolonged availability and activity of the drug in the cell while FOXC1 methylation might be a protective factor against tumour invasiveness. FOXC1 proved to be general prognostic factor, while ABCB1 and GSTP1 might be predictive factors for the response to and efficacy of doxorubicin treatment. Pharmacoepigenetic effects such as the reported associations in this study provide molecular explanations for differential responses to chemotherapy and it might prove valuable to take the methylation status of selected genes into account for patient management and treatment decisions. © 2010 Dejeux et al; licensee BioMed Central Ltd.

Haakensen V.D.,University of Oslo | Biong M.,University of Oslo | Lingjaerde O.C.,University of Oslo | Holmen M.M.,University of Oslo | And 13 more authors.
Breast Cancer Research | Year: 2010

Introduction: Mammographic density (MD), as assessed from film screen mammograms, is determined by the relative content of adipose, connective and epithelial tissue in the female breast. In epidemiological studies, a high percentage of MD confers a four to six fold risk elevation of developing breast cancer, even after adjustment for other known breast cancer risk factors. However, the biologic correlates of density are little known.Methods: Gene expression analysis using whole genome arrays was performed on breast biopsies from 143 women; 79 women with no malignancy (healthy women) and 64 newly diagnosed breast cancer patients, both included from mammographic centres. Percent MD was determined using a previously validated, computerized method on scanned mammograms. Significance analysis of microarrays (SAM) was performed to identify genes influencing MD and a linear regression model was used to assess the independent contribution from different variables to MD.Results: SAM-analysis identified 24 genes differentially expressed between samples from breasts with high and low MD. These genes included three uridine 5'-diphospho-glucuronosyltransferase (UGT) genes and the oestrogen receptor gene (ESR1). These genes were down-regulated in samples with high MD compared to those with low MD. The UGT gene products, which are known to inactivate oestrogen metabolites, were also down-regulated in tumour samples compared to samples from healthy individuals. Several single nucleotide polymorphisms (SNPs) in the UGT genes associated with the expression of UGT and other genes in their vicinity were identified.Conclusions: Three UGT enzymes were lower expressed both in breast tissue biopsies from healthy women with high MD and in biopsies from newly diagnosed breast cancers. The association was strongest amongst young women and women using hormonal therapy. UGT2B10 predicts MD independently of age, hormone therapy and parity. Our results indicate that down-regulation of UGT genes in women exposed to female sex hormones is associated with high MD and might increase the risk of breast cancer. © 2010 Haakensen et al.; licensee BioMed Central Ltd.

Koppen H.,Leiden University | Koppen H.,Haga Hospital | Vis J.C.,Interuniversity Cardiology Institute of the Netherlands | Knudsen S.,Glostrup University Hospital | And 3 more authors.
Cephalalgia | Year: 2012

Aim: To assess the lifetime prevalence of migraine in patients with Marfan syndrome (MFS) and to investigate a history of aortic root replacement (AR) as a possible risk factor.Methods: In a multicentre study 123 MFS patients (n = 52 with AR, n = 71 without AR), 82 age- and sex-matched controls and 51 patients with AR but without MFS, were interviewed using a semi-structured headache questionnaire. A multinomial logistic regression model was used to investigate risk factors for migraine with and without aura, adjusting for age and gender.Results: Lifetime migraine prevalence was increased in female MFS patients (51%) compared to healthy female controls (29%), p = 0.017. In males lifetime migraine prevalence among MFS patients was only numerically increased. Lifetime prevalence of migraine with aura was increased among MFS patients compared to healthy controls both in males (19% vs. 3%, p = 0.048) and females (30% vs. 14%, p = 0.049). A history of AR, independently from MFS, gender and age, increased the lifetime prevalence of migraine with aura (OR 3.1 [1.2-8.0]). In all but one patient migraine started before the AR.Conclusions: The lifetime prevalence of migraine with aura, but not migraine without aura, is increased in patients with MFS. This association is driven by a history of AR. The replacement procedure itself is unlikely to be causally associated with migraine as in nearly all subjects, migraine started before the procedure. However this study adds to the evidence that underlying vessel wall pathology may be involved in migraine with aura. © International Headache Society 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Aasebo W.,University of Oslo | Aasebo W.,Akerhus University Hospital | Strom E.H.,University of Oslo | Hovig T.,University of Oslo | And 4 more authors.
NDT Plus | Year: 2010

Enzyme replacement therapy (ERT) has been introduced for Fabry disease and has been reported to clear some renal cell types of accumulated glycolipids and to reduce the accumulation in other cell types. We describe two patients without Fabry disease who were transplanted with kidney allografts from a male donor with Fabry disease. Biopsies were taken at transplantation and after 3 years in the first case and after 12 years in the second case. Even though these Fabry kidney allografts for many years had been exposed to normal levels of circulating α-galactosidase A (α-gal-A), the amount of accumulated lysosomal deposits in the podocytes remained unchanged. Additionally, small deposits were also found in tubular cells and glomerular endothelial cells as long as 12 years after transplantation. © 2009 The Author. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Halvorsen A.R.,University of Oslo | Helland A.,University of Oslo | Fleischer T.,University of Oslo | Haug K.M.,University of Oslo | And 11 more authors.
International Journal of Cancer | Year: 2014

Radiotherapy (RT) is a central treatment modality for breast cancer patients. The purpose of our study was to investigate the DNA methylation changes in tumors following RT, and to identify epigenetic markers predicting treatment outcome. Paired biopsies from patients with inoperable breast cancer were collected both before irradiation (n = 20) and after receiving 10-24 Gray (Gy) (n = 19). DNA methylation analysis was performed by using Illumina Infinium 27K arrays. Fourteen genes were selected for technical validation by pyrosequencing. Eighty-two differentially methylated genes were identified in irradiated (n = 11) versus nonirradiated (n = 19) samples (false discovery rate, FDR = 1.1%). Methylation levels in pathways belonging to the immune system were most altered after RT. Based on methylation levels before irradiation, a panel of five genes (H2AFY, CTSA, LTC4S, IL5RA and RB1) were significantly associated with clinical response (p = 0.041). Furthermore, the degree of methylation changes for 2,516 probes correlated with the given radiation dose. Within the 2,516 probes, an enrichment for pathways involved in cellular immune response, proliferation and apoptosis was identified (FDR < 5%). Here, we observed clear differences in methylation levels induced by radiation, some associated with response to treatment. Our study adds knowledge on the molecular mechanisms behind radiation response. What's new? Radiotherapy is a central treatment modality for breast cancer patients. This study set to investigate DNA methylation changes in tumors following radiotherapy and identify epigenetic markers predicting treatment outcome. Genome-wide methylation effects were studied by comparing breast cancer biopsies before and after irradiation. 82 differentially methylated genes enriched for immune regulation pathways were identified. Based on methylation levels before irradiation, a combination of 5 genes was significantly associated with response to radiotherapy. A dose dependency was seen for 2516 probes, mainly involved in immune response and apoptosis. This study sheds light on the genes and pathways involved in radiation response. © 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

Haugen E.B.,Akershus University Hospital | Benth J.S.,Akerhus University Hospital | Benth J.S.,University of Oslo | Nakstad B.,University of Oslo
Acta Paediatrica, International Journal of Paediatrics | Year: 2011

Aim: Torticollis in infancy is routinely treated by child physiotherapists. The addition of manual therapy to the treatment is a new approach in Norway. As the effect of manual therapy for this condition is poorly documented, we designed a pilot study to evaluate measurement methods and examine the short-time effect of manual therapy in addition to child physiotherapy. Methods: Randomized controlled trial, double blinded. Thirty-two patients aged 3-6 months were randomized to intervention group (manual therapy and child physiotherapy) and control group (child physiotherapy alone). Primary outcome: Change of symptoms because of torticollis evaluated by video recordings. Secondary outcomes: 12 parameters including spontaneous movements, active and passive range of motion and head righting reaction. Results: We found a nonsignificant tendency to greater improvement in lateral flexion (p = 0.092) and head righting reaction (p = 0.116) in the intervention group. Conclusion: In this pilot study, we found that in patients with moderate symptoms related to torticollis, the short-time effect of manual therapy in addition to physiotherapy is not significantly better than physiotherapy alone. © 2011 The Author(s)/Acta Pædiatrica © 2011 Foundation Acta Pædiatrica.

Haakensen V.D.,University of Oslo | Lingjaerde O.,University of Oslo | Luders T.,University of Oslo | Riis M.,University of Oslo | And 18 more authors.
BMC Medical Genomics | Year: 2011

Background: Increased understanding of the variability in normal breast biology will enable us to identify mechanisms of breast cancer initiation and the origin of different subtypes, and to better predict breast cancer risk. Methods. Gene expression patterns in breast biopsies from 79 healthy women referred to breast diagnostic centers in Norway were explored by unsupervised hierarchical clustering and supervised analyses, such as gene set enrichment analysis and gene ontology analysis and comparison with previously published genelists and independent datasets. Results: Unsupervised hierarchical clustering identified two separate clusters of normal breast tissue based on gene-expression profiling, regardless of clustering algorithm and gene filtering used. Comparison of the expression profile of the two clusters with several published gene lists describing breast cells revealed that the samples in cluster 1 share characteristics with stromal cells and stem cells, and to a certain degree with mesenchymal cells and myoepithelial cells. The samples in cluster 1 also share many features with the newly identified claudin-low breast cancer intrinsic subtype, which also shows characteristics of stromal and stem cells. More women belonging to cluster 1 have a family history of breast cancer and there is a slight overrepresentation of nulliparous women in cluster 1. Similar findings were seen in a separate dataset consisting of histologically normal tissue from both breasts harboring breast cancer and from mammoplasty reductions. Conclusion: This is the first study to explore the variability of gene expression patterns in whole biopsies from normal breasts and identified distinct subtypes of normal breast tissue. Further studies are needed to determine the specific cell contribution to the variation in the biology of normal breasts, how the clusters identified relate to breast cancer risk and their possible link to the origin of the different molecular subtypes of breast cancer. © 2011Haakensen et al; licensee BioMed Central Ltd.

Haakensen V.D.,University of Oslo | Bjoro T.,University of Oslo | Luders T.,Akershus University Hospital | Riis M.,Akershus University Hospital | And 11 more authors.
BMC Cancer | Year: 2011

Background: High serum levels of estradiol are associated with increased risk of postmenopausal breast cancer. Little is known about the gene expression in normal breast tissue in relation to levels of circulating serum estradiol.Methods: We compared whole genome expression data of breast tissue samples with serum hormone levels using data from 79 healthy women and 64 breast cancer patients. Significance analysis of microarrays (SAM) was used to identify differentially expressed genes and multivariate linear regression was used to identify independent associations.Results: Six genes (SCGB3A1, RSPO1, TLN2, SLITRK4, DCLK1, PTGS1) were found differentially expressed according to serum estradiol levels (FDR = 0). Three of these independently predicted estradiol levels in a multivariate model, as SCGB3A1 (HIN1) and TLN2 were up-regulated and PTGS1 (COX1) was down-regulated in breast samples from women with high serum estradiol. Serum estradiol, but none of the differentially expressed genes were significantly associated with mammographic density, another strong breast cancer risk factor. In breast carcinomas, expression of GREB1 and AREG was associated with serum estradiol in all cancers and in the subgroup of estrogen receptor positive cases.Conclusions: We have identified genes associated with serum estradiol levels in normal breast tissue and in breast carcinomas. SCGB3A1 is a suggested tumor suppressor gene that inhibits cell growth and invasion and is methylated and down-regulated in many epithelial cancers. Our findings indicate this gene as an important inhibitor of breast cell proliferation in healthy women with high estradiol levels. In the breast, this gene is expressed in luminal cells only and is methylated in non-BRCA-related breast cancers. The possibility of a carcinogenic contribution of silencing of this gene for luminal, but not basal-like cancers should be further explored. PTGS1 induces prostaglandin E2 (PGE2) production which in turn stimulates aromatase expression and hence increases the local production of estradiol. This is the first report studying such associations in normal breast tissue in humans. © 2011 Haakensen et al; licensee BioMed Central Ltd.

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