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  • Li, Jingmei, et al. (författare)
  • Breast cancer genetic risk profile is differentially associated with interval and screen-detected breast cancers
  • 2015
  • Ingår i: Annals of Oncology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0923-7534. ; 26:3, s. 517-522
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Polygenic risk profiles computed from multiple common susceptibility alleles for breast cancer have been shown to identify women at different levels of breast cancer risk. We evaluated whether this genetic risk stratification can also be applied to discriminate between screen-detected and interval cancers, which are usually associated with clinicopathological and survival differences. Patients and methods: A 77-SNP polygenic risk score (PRS) was constructed for breast cancer overall and by estrogen-receptor (ER) status. PRS was inspected as a continuous (per standard deviation increment) variable in a case-only design. Modification of the PRS by mammographic density was evaluated by fitting an additional interaction term. Results: PRS weighted by breast cancer overall estimates was found to be differentially associated with 1,865 screen-detected and 782 interval cancers in the LIBRO-1 study (age-adjusted ORperSD [95% confidence interval]=0.91 [0.83-0.99], p=0.023). The association was found to be more significant for PRS weighted by ER-positive breast cancer estimates (ORperSD=0.90 [0.82-0.98], p=0.011). This result was corroborated by two independent studies (combined ORperSD=0.87 [0.76-1.00], p=0.058) with no evidence of heterogeneity. When enriched for “true” interval cancers among nondense breasts, the difference in the association with PRS in screen-detected and interval cancers became more pronounced (ORperSD=0.74 [0.62-0.89], p=0.001), with a significant interaction effect between PRS and mammographic density (pinteraction=0.017). Conclusion: To our knowledge, this is the first report looking into the genetic differences between screendetected and interval cancers. It is an affirmation that the two types of breast cancer may have unique underlying biology.
  • Alkner, S, et al. (författare)
  • AIB1 is a predictive factor for tamoxifen response in premenopausal women
  • 2010
  • Ingår i: ANNALS OF ONCOLOGY. - : Oxford University Press. - 0923-7534. ; 21, s. 238-244
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Clinical trials implicate the estrogen receptor ( ER) coactivator amplified in breast cancer 1 (AIB1) to be a prognostic and a treatment-predictive factor, although results are not unanimous. We have further investigated this using a controlled randomised trial of tamoxifen versus control. Materials and methods: A total of 564 premenopausal women were entered into a randomised study independent of ER status. Using a tissue microarray, AIB1 and ER were analysed by immunohistochemistry. Results: AIB1 scores were obtained from 349 women. High AIB1 correlated to factors of worse prognosis (human epidermal growth factor receptor 2, Nottingham histological grade 3, and lymph node metastases) and to ER negativity. In the control arm, high AIB1 was a negative prognostic factor for recurrence- free survival (RFS) (P = 0.02). However, ER-positive patients with high AIB1 responded significantly to tamoxifen treatment (P = 0.002), increasing RFS to the same level as for systemically untreated patients with low AIB1. Although ER-positive patients with low AIB1 had a better RFS from the beginning, this was not further improved by tamoxifen (P = 0.8). Conclusions: In the control group, high AIB1 was a negative prognostic factor. However, ER-positive patients with high AIB1 responded significantly to tamoxifen. This implicates high AIB1 to be an independent predictive factor of improved response to tamoxifen and not, as has previously been discussed, a factor predicting tamoxifen resistance.
  • Andersson, J., et al. (författare)
  • Worse survival for TP53 (p53)-mutated breast cancer patients receiving adjuvant CMF
  • 2005
  • Ingår i: Ann Oncol. - 0923-7534 .- 1569-8041. ; 16:5, s. 743-8
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: TP53 has been described as a prognostic factor in many malignancies, including breast cancer. Whether it also might be a predictive factor with reference to chemo- and endocrine therapy is more controversial. PATIENTS AND METHODS: We investigated relapse-free (RFS), breast cancer-corrected (BCCS) and overall survival (OS) related to TP53 status in node-positive breast cancer patients that had received polychemotherapy [cyclophosphamide, methotrexate, 5-fluorouracil (CMF)] and/or endocrine therapy (tamoxifen). Sequence analyses of the whole TP53 coding region was performed in 376 patients operated on for primary breast cancer with axillary lymph node metastases between 1984 and 1989 (median follow-up time 84 months). RESULTS: TP53 mutations were found in 105 patients (28%). We found 90 (82%) of the 110 mutations in the more frequently analysed exons 5-8, while the other 20 (18%) were located in exons 3-4 and 9-10, respectively. Univariate analyses showed TP53 to be a significant prognostic factor with regard to RFS, BCCS and OS in patients who received adjuvant CMF. CONCLUSIONS: TP53 mutations might induce resistance to certain modalities of breast cancer therapy. Sequence-determined TP53 mutation was of negative prognostic value in the total patient population and in the CMF treated patients.
  • Andren, O., et al. (författare)
  • Cabazitaxel followed by androgen deprivation therapy (ADT) significantly improves time to progression in patients with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) : A randomized, open label, phase III, multicenter trial
  • 2017
  • Ingår i: Annals of Oncology. - : Elsevier. - 0923-7534 .- 1569-8041. ; 28:S5, s. v281-v281
  • Tidskriftsartikel (övrigt vetenskapligt)abstract
    • Background: Patients with newly diagnosed mHSPC have a poor prognosis with a 3-year overall survival (OS) rate of 50%. Recently, combination of docetaxel (75mg/m2 every 6 weeks for 6 cycles) with ADT has become a new standard for such patients, based on results of 2 large phase 3 trials showing a significant OS benefit. In these trials, docetaxel was initiated within 3 months after ADT start. Timing of ADT and chemotherapy (CT) is controversial. In breast cancer, endocrine therapy is always started after CT, the rational being that ADT will turn clones of tumor cells in to a stage of dormancy where CT is less effective.Methods: This phase 3 trial randomized newly diagnosed mHSPC patients to receive cabazitaxel (CABA), 25 mg/m2 every 3 weeks for 10 cycles, followed by ADT (immediately after last CABA cycle) versus ADT alone. Primary end-point was OS. Secondary end-point was progression free survival. The study planned to include 400 patients but was closed prematurely due to low inclusion rate. A total 31 patients with newly diagnosed mHSPC were included and here we present the results.Results: Median follow up was 31 month. Of the CABA treated patients, 66.8% got six cycles or more and 46.7% completed all 10 courses. Median OS was 32,5 months with CABA followed by ADT and 29,5 months with ADT alone (HR 1.43, 95% CI 0.38-5.38). Median progression free survival was significantly longer in CABA treated patients (29 vs 12 months, HR 3.96 (95% CI 1.49-10.49). Main grade ≥ 3 toxicities were neutropenia (66%).Conclusions: In conclusion, results from this prematurely terminated trial suggest that CABA followed by ADT is effective in newly diagnosed mHSPC and shows a manageable toxicity. These results have to be validated in larger randomized trials.
  • Barkholt, L., et al. (författare)
  • Allogeneic haematopoietic stem cell transplantation for metastatic renal carcinoma in Europe
  • 2006
  • Ingår i: Annals of Oncology. - : Oxford University Press. - 1569-8041. ; 17:7, s. 1134-1140
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: An allogeneic antitumour effect has been reported for various cancers. We evaluated the experience of allogeneic haematopoietic stem cell transplantation (HSCT) for renal cell carcinoma (RCC) in 124 patients from 21 European centres. Patients and methods: Reduced intensity conditioning and peripheral blood stem cells from an HLA-identical sibling (n = 106), a mismatched related (n = 5), or an unrelated (n = 13) donor were used. Immunosuppression was cyclosporine alone, or combined with methotrexate or mycophenolate mofetil. Donor lymphocyte infusions (DLI) were given to 42 patients. The median follow-up was 15 (range 3-41) months. Results: All but three patients engrafted. The cumulative incidence of moderate to severe, grades II-IV acute GVHD was 40% and for chronic GVHD it was 33%. Transplant-related mortality was 16% at one year. Complete (n = 4) or partial (n = 24) responses, median 150 (range 42-600) days post-transplant, were associated with time from diagnosis to HSCT, mismatched donor and acute GVHD II-IV. Factors associated with survival included chronic GVHD (hazards ratio, HR 4.12, P < 0.001), DLI (HR 3.39, P < 0.001), < 3 metastatic sites (HR 2.61, P = 0.002) and a Karnofsky score > 70 (HR 2.33, P = 0.03). Patients (n = 17) with chronic GVHD and given DLI had a 2-year survival of 70%. Conclusion: Patients with metastatic RCC, less than three metastatic locations and a Karnofsky score > 70% can be considered for HSCT. Posttransplant DLI and limited chronic GVHD improved the patient survival.
  • Berglund, U. W., et al. (författare)
  • Validation and development of MTH1 inhibitors for treatment of cancer
  • 2016
  • Ingår i: Annals of Oncology. - 0923-7534 .- 1569-8041. ; 27:12, s. 2275-2283
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. Material and methods: Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. Results: Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. Conclusion: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.
  • Bergqvist, Jenny, et al. (författare)
  • Quantitative real-time PCR analysis and microarray-based RNA expression of HER2 in relation to outcome
  • 2007
  • Ingår i: Annals of Oncology. - 0923-7534 .- 1569-8041. ; 18:5, s. 845-850
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Our aim was to use quantitative real-time PCR (Q-PCR) and RNA expression profiles (RNA-EPs) to investigate HER2 status in relation to outcome. PATIENTS AND METHODS: Cut-off levels for Q-PCR and RNA-EP were established in relation to immunohistochemistry (IHC) validated by FISH in a test set of frozen tissue samples from 40 primary breast cancers. The HER2 status was subsequently studied in another validation set of 306 tumors, where Q-PCR and RNA-EP results were compared with previously carried out IHC that we had validated by chromogenic in situ hybridization (CISH). RESULTS: Q-PCR and RNA-EP offered similar sensitivity (90% versus 77%), specificity (93% versus 95%), and negative (99% versus 98%) and positive (63% versus 61%) predictive values for HER2 determinations. Analyses of relapse-free survival (RFS) and overall survival on the basis of 5 and 10 years of follow-up indicated equivalent hazard ratios for all three techniques. In contrast to IHC/CISH, both Q-PCR and RNA-EP analyses of HER2 also gave statistically significant results regarding RFS and breast cancer-corrected survival after 10 years of follow-up. CONCLUSION: The use of RNA-EP and Q-PCR to analyze HER2 in frozen and formalin-fixed breast cancer samples may be an alternate approach to IHC in combination with FISH/CISH.
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