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  • Francis, Princy, et al. (författare)
  • Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: hypoxia-induced transcription profile signifies metastatic potential.
  • 2007
  • Ingår i: BMC Genomics. - BMC Genomics. - 1471-2164. ; 8
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Soft tissue sarcoma (STS) diagnosis is challenging because of a multitude of histopathological subtypes, different genetic characteristics, and frequent intratumoral pleomorphism. One-third of STS metastasize and current risk-stratification is suboptimal, therefore, novel diagnostic and prognostic markers would be clinically valuable. We assessed the diagnostic and prognostic value of array-based gene expression profiles using 27 k cDNA microarrays in 177, mainly high-grade, STS of 13 histopathological subtypes. Results Unsupervised analysis resulted in two major clusters – one mainly containing STS characterized by type-specific genetic alterations and the other with a predominance of genetically complex and pleomorphic STS. Synovial sarcomas, myxoid/round-cell liposarcomas, and gastrointestinal stromal tumors clustered tightly within the former cluster and discriminatory signatures for these were characterized by developmental genes from the EGFR, FGFR, Wnt, Notch, Hedgehog, RAR and KIT signaling pathways. The more pleomorphic STS subtypes, e.g. leiomyosarcoma, malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma and dedifferentiated/pleomorphic liposarcoma, were part of the latter cluster and were characterized by relatively heterogeneous profiles, although subclusters herein were identified. A prognostic signature partly characterized by hypoxia-related genes was identified among 89 genetically complex pleomorphic primary STS and could, in a multivariate analysis including established prognostic markers, independently predict the risk of metastasis with a hazard ratio of 2.2 (P = 0.04). Conclusion Diagnostic gene expression profiles linking signaling pathways to the different STS subtypes were demonstrated and a hypoxia-induced metastatic profile was identified in the pleomorphic, high-grade STS. These findings verify diagnostic utility and application of expression data for improved selection of high-risk STS patients.
  • Aaltonen, Kristina E., et al. (författare)
  • Molecular characterization of circulating tumor cells from patients with metastatic breast cancer reflects evolutionary changes in gene expression under the pressure of systemic therapy
  • 2017
  • Ingår i: Oncotarget. - Impact Journals, LLC. - 1949-2553. ; 8:28, s. 45544-45565
  • Tidskriftsartikel (refereegranskat)abstract
    • Resistance to systemic therapy is a major problem in metastatic breast cancer (MBC) that can be explained by initial tumor heterogeneity as well as by evolutionary changes during therapy and tumor progression. Circulating tumor cells (CTCs) detected in a liquid biopsy can be sampled and characterized repeatedly during therapy in order to monitor treatment response and disease progression. Our aim was to investigate how CTC derived gene expression of treatment predictive markers (ESR1/HER2) and other cancer associated markers changed in patient blood samples during six months of first-line systemic treatment for MBC. CTCs from 36 patients were enriched using CellSearch (Janssen Diagnostics) and AdnaTest (QIAGEN) before gene expression analysis was performed with a customized gene panel (TATAA Biocenter). Our results show that antibodies against HER2 and EGFR were valuable to isolate CTCs unidentified by CellSearch and possibly lacking EpCAM expression. Evaluation of patients with clinically different breast cancer subgroups demonstrated that gene expression of treatment predictive markers changed over time. This change was especially prominent for HER2 expression. In conclusion, we found that changed gene expression during first-line systemic therapy for MBC could be a possible explanation for treatment resistance. Characterization of CTCs at several time-points during therapy could be informative for treatment selection.
  • Alkner, Sara, et al. (författare)
  • Prediction of outcome after diagnosis of metachronous contralateral breast cancer.
  • 2011
  • Ingår i: BMC Cancer. - BioMed Central. - 1471-2407. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Although 2-20% of breast cancer patients develop a contralateral breast cancer (CBC), prognosis after CBC is still debated. Using a unique patient cohort, we have investigated whether time interval to second breast cancer (BC2) and mode of detection are associated to prognosis. METHODS: Information on patient-, tumour-, treatment-characteristics, and outcome was abstracted from patients' individual charts for all patients diagnosed with metachronous CBC in the Southern Healthcare Region of Sweden from 1977-2007. Distant disease-free survival (DDFS) and risk of distant metastases were primary endpoints. RESULTS: The cohort included 723 patients with metachronous contralateral breast cancer as primary breast cancer event. Patients with less than three years to BC2 had a significantly impaired DDFS (p = 0.01), and in sub-group analysis, this effect was seen primarily in patients aged <50. By logistic regression analysis, patients diagnosed with BC2 within routine follow-up examinations had a significantly lower risk of developing metastases compared to those who were symptomatic at diagnosis (p < 0.0001). Chemotherapy given after breast BC1 was a negative prognostic factor for DDFS, whereas endocrine treatment and radiotherapy given after BC2 improved DDFS. CONCLUSIONS: In a large cohort of patients with CBC, we found the time interval to BC2 to be a strong prognostic factor for DDFS in young women and mode of detection to be related to risk of distant metastases. Future studies of tumour biology of BC2 in relation to prognostic factors found in the present study can hopefully provide biological explanations to these findings.
  • Alkner, Sara, et al. (författare)
  • Prior Adjuvant Tamoxifen Treatment in Breast Cancer Is Linked to Increased AIB1 and HER2 Expression in Metachronous Contralateral Breast Cancer.
  • 2016
  • Ingår i: PLoS ONE. - Public Library of Science. - 1932-6203. ; 11:3
  • Tidskriftsartikel (refereegranskat)abstract
    • The estrogen receptor coactivator Amplified in Breast Cancer 1 (AIB1) has been associated with an improved response to adjuvant tamoxifen in breast cancer, but also with endocrine treatment resistance. We hereby use metachronous contralateral breast cancer (CBC) developed despite prior adjuvant tamoxifen for the first tumor as an "in vivo"-model for tamoxifen resistance. AIB1-expression in the presumable resistant (CBC after prior tamoxifen) and naïve setting (CBC without prior tamoxifen) is compared and correlated to prognosis after CBC.
  • Arason, Adalgeir, et al. (författare)
  • Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families
  • 2010
  • Ingår i: Breast Cancer Research. - BioMed Central. - 1465-5411. ; 12:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: A significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers. Methods: GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene. Results: The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer. Conclusions: Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.
  • Baldetorp, Bo, et al. (författare)
  • Improved DNA flow cytometric, DNA ploidy, and S-phase reproducibility between 15 laboratories in analysis of breast cancer using generalized guidelines
  • 2003
  • Ingår i: Cytometry. - John Wiley and Sons Inc.. - 0196-4763. ; 56A:1, s. 1-7
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Lack of generalized guidelines for DNA flow cytometric analysis (FCM) may be the main reason for its limited use in the clinical management of breast cancer. Methods: After an initial interlaboratory reproducibility study (Round 1), we concluded that it was the evaluation of the DNA histograms rather than the technical performance of the analysis that was the main reason for discordant results between laboratories. Guidelines for the interpretation of DNA histograms were therefore drawn up. We present here data from a new reproducibility study (Round 11) using these guidelines. Results: For 10 laboratories also participating in Round 1, use of the guidelines increased the concordance in DNA ploidy status from 89% to 100% for the 46 samples used in both rounds. The concordance rate for SPF also increased; mean r(s)-value increased from 0.81 to 0.88, and mean kappa value (lower two-thirds versus upper third versus not reported) increased from 0.55 to 0.71. Five new laboratories, participating only in Round II, also agreed with the 10 original laboratories regarding DNA ploidy status. With the inclusion of all 15 laboratories, we obtained a mean r(s)-value of 0.81 and a mean kappa value of 0.72 for SPF. Conclusions: Generalized guidelines for DNA FCM increase interlaboratory agreement, which is highly important in clinical routines and in multicenter studies. Furthermore, inexperienced FCM laboratories using generalized guidelines can produce and interpret DNA FCM data equally as well as experienced laboratories. Cytometry Part A 56A:1-7, 2003. (C) 2003 Wiley-Liss, Inc.
  • Baldetorp, Bo, et al. (författare)
  • Proliferative index obtained by DNA image cytometry. Does it add prognostic information in Auer IV breast cancer?
  • 1998
  • Ingår i: Analytical and Quantitative Cytology and Histology. - Science Printers. - 0884-6812. ; 20:2, s. 144-152
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To investigate whether the S + G2/M fraction (proliferative index) is a prognostic determinant in breast cancers classified as Auer IV. STUDY DESIGN: Prognostic evaluation of Auer IV DNA histograms with respect to the high versus low S + G2/M fraction, obtained by image cytometry on consecutive breast cancer imprint preparations. RESULTS: When studying recurrence-free survival (n = 136), the prognostic value of S + G2/M was found to vary with time: it was negligible before the median time to relapse (1.5 years) but thereafter statistically significant, in both univariate and multivariate analysis. The same pattern was found when overall survival was used as the end point; the effect was delayed to about the median time until death (three years). Tumors with a low S + G2/M fraction were smaller and more often estrogen receptor- and progesterone receptor-positive than those with a high S + G2/M fraction. CONCLUSION: According to ICM-DNA values corresponding to the S + G2/M region, patients with breast cancers classified as Auer IV can be divided into subgroups with different tumor characteristics and prognoses.
  • Baldetorp, Bo, et al. (författare)
  • Reproducibility in DNA flow cytometric analysis of breast cancer: comparison of 12 laboratories' results for 67 sample homogenates
  • 1995
  • Ingår i: Cytometry. - John Wiley and Sons Inc.. - 0196-4763. ; 22:2, s. 115-127
  • Tidskriftsartikel (refereegranskat)abstract
    • Flow cytometric (FCM) DNA analysis yields information on ploidy status and the S-phase fraction (SPF), variables of prognostic importance in breast cancer. The clinical value of the SPF is currently being evaluated in prospective randomized trials. The widespread use of FCM DNA analysis emphasizes the importance of reproducibility (both intra- and interlaboratory). In this study, 67 nuclear suspensions of breast cancer samples were analyzed by 12 laboratories routinely performing FCM DNA analysis in breast cancer. No general guidelines were imposed; each laboratory used its own standard protocols. For DNA ploidy status (diploid vs. non-diploid), agreement was complete for 79% (53/67) of the samples, compared with 64% (43/67) of samples when tetraploidy was considered [i.e., euploid (diploid+tetraploid) vs. aneuploid (the remaining non-diploid)]. For the SPF, pairwise comparison of the results of all 12 laboratories yielded a mean Spearman's rank correlation of 0.78 (range: 0.54-0.93). For those 39 samples being categorized in low or high SPF by all laboratories, all agreed in 14 samples (36%). Similar patterns were obtained with kappa measures, agreement being good for ploidy status (diploid vs. non-diploid; overall kappa = 0.87 and 0.74 for euploid vs. aneuploid), but moderate for the SPF [overall kappa = 0.47 (for low SPF vs. high SPF vs. "no SPF reported")]. Discrepancies were chiefly attributable to differences in the categorization of the S-phase values, rather than in FCM procedures, other critical differences being in the detection and interpretation of near-diploid and small non-diploid cell populations, the definition of tetraploidy, and the choice and execution of the method used for S-phase estimation. Based on the observations of this study, detailed guidelines for FCM analysis and interpretation of data are proposed in the Appendix. Some issues remain, however, e.g., to standardize a method for S-phase calculation and tetraploid definition.
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