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  • Abe, O, et al. (författare)
  • Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
  • 2005
  • Ingår i: The Lancet. - : Elsevier. - 1474-547X. ; 365:9472, s. 1687-1717
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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  • Aljabery, F., et al. (författare)
  • Management and outcome of muscle-invasive bladder cancer with clinical lymph node metastases. A nationwide population-based study in the bladder cancer data base Sweden (BladderBaSe)
  • 2019
  • Ingår i: Scandinavian Journal of Urology. - : TAYLOR & FRANCIS LTD. - 2168-1805 .- 2168-1813. ; 53:5, s. 332-338
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To investigate the clinical management and outcome of patients with muscle-invasive bladder cancer with clinical lymph node involvement, using longitudinal nationwide population-based data. Methods: In the Bladder Cancer Data Base Sweden (BladderBaSe), treatment and survival in patients with urinary bladder cancer clinical stage T2-T4 N + M0 diagnosed between 1997 and 2014 was investigated. Patients ' characteristics were studied in relation to TNM classification, curative or palliative treatment, cancer-specific (CSS) and overall survival (OS). Age at diagnosis was categorised as <= 60, 61-70, 71-80 and >80 years, and time periods were stratified as follows: 1997-2001, 2002-2005, 2006-2010 and 2011-2014. Results: There were 786 patients (72% males) with a median age of 71 years (interquartile range = 64-79 years). The proportion of patients with high comorbidity increased over time. Despite similar low comorbidity, curative treatment was given to 44% and to 70% of those in older (>70 years) and younger age groups, respectively. Curative treatment decreased over time, but chemotherapy and cystectomy increased to 25% during the last time period. Patients with curative treatment had better survival compared to those with palliative treatment, both regarding CSS and OS in the whole cohort and in all age groups. Conclusions: The low proportion of older patients undergoing treatment with curative intent, despite no or limited comorbidity, indicates missed chances of treatment with curative intent. The reasons for an overall decrease in curative treatment over time need to be analysed and the challenge of coping with an increasing proportion of node-positive patients with clinically significant comorbidity needs to be met.
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  • Galindo-Feria, Angeles S., et al. (författare)
  • Proinflammatory Histidyl-Transfer RNA Synthetase-Specific CD4+T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies
  • 2020
  • Ingår i: ; 72:1, s. 179-191
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Autoantibodies targeting histidyl-transfer RNA synthetase (HisRS; anti-Jo-1) are common in the idiopathic inflammatory myopathies (IIMs) and antisynthetase syndrome. This study was undertaken to investigate immunity against HisRS in the blood and lungs of patients with IIM/antisynthetase syndrome. Methods Bronchoalveolar lavage (BAL) fluid, BAL fluid cells, and peripheral blood mononuclear cells (PBMCs) from patients with IIM/antisynthetase syndrome (n = 24) were stimulated with full-length HisRS protein or a HisRS-derived peptide (HisRS(11-23)). BAL fluid and PBMCs from patients with sarcoidosis (n = 7) and healthy subjects (n = 12) were included as controls. The CD4+ T cell response was determined according to levels of CD40L up-regulation and cytokine expression using flow cytometry. Anti-Jo-1 autoantibody responses in the serum and BAL fluid were assessed by enzyme-linked immunosorbent assay. Lung biopsy samples from patients with IIM/antisynthetase syndrome (n = 14) were investigated by immunohistochemistry. Results In BAL fluid, CD4+ T cells from 3 of 4 patients with IIM/antisynthetase syndrome responded to stimulation with HisRS protein, as measured by the median fold change in CD40L expresssion in stimulated cells compared to unstimulated cells (median fold change 3.6, interquartile range [IQR] 2.7-14.7), and 2 of 3 patients with IIM/antisynthetase syndrome had the highest responses to HisRS(11-23) (median fold change 88, IQR 27-149)(.) In PBMCs, CD4+ T cells from 14 of 18 patients with IIM/antisynthetase syndrome responded to HisRS protein (median fold change 7.38, IQR 2.69-31.86; P < 0.001), whereas a HisRS(11-23) response was present in 11 of 14 patients with IIM/antisynthetase syndrome (median fold change 3.4, IQR 1.87-10.9; P < 0.001). In the control group, there was a HisRS(11-23) response in 3 of 7 patients with sarcoidosis (median fold change 2.09, IQR 1.45-3.29) and in 5 of 12 healthy controls (median fold change 2, IQR 1.89-2.42). CD4+ T cells from patients with IIM/antisynthetase syndrome displayed a pronounced Th1 phenotype in the BAL fluid when compared to the PBMCs (P < 0.001), producing high amounts of interferon-gamma and interleukin-2 following stimulation. Anti-Jo-1 autoantibodies were detected in BAL fluid and germinal center (GC)-like structures were seen in the lung biopsy samples from patients with IIM/antisynthetase syndrome. Conclusion The results of this study demonstrate a pronounced presence of HisRS-reactive CD4+ T cells in PBMCs and BAL fluid cells from patients with IIM/antisynthetase syndrome as compared to patients with sarcoidosis and healthy controls. These findings, combined with the presence of anti-Jo-1 autoantibodies in BAL fluid and GC-like structures in the lungs, suggest that immune activation against HisRS might take place within the lungs of patients with IIM/antisynthetase syndrome.
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  • Gerstner, Christina, et al. (författare)
  • Multi-HLA class II tetramer analyses of citrulline-reactive T cells and early treatment response in rheumatoid arthritis
  • 2020
  • Ingår i: ; 21:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background HLA class II tetramers can be used for ex vivo enumeration and phenotypic characterisation of antigen-specific CD4+ T cells. They are increasingly applied in settings like allergy, vaccination and autoimmune diseases. Rheumatoid arthritis (RA) is a chronic autoimmune disorder for which many autoantigens have been described. Results Using multi-parameter flow cytometry, we developed a multi-HLA class II tetramer approach to simultaneously study several antigen specificities in RA patient samples. We focused on previously described citrullinated HLA-DRB1*04:01-restricted T cell epitopes from alpha-enolase, fibrinogen-beta, vimentin as well as cartilage intermediate layer protein (CILP). First, we examined inter-assay variability and the sensitivity of the assay in peripheral blood from healthy donors (n = 7). Next, we confirmed the robustness and sensitivity in a cohort of RA patients with repeat blood draws (n = 14). We then applied our method in two different settings. We assessed lymphoid tissue from seropositive arthralgia (n = 5) and early RA patients (n = 5) and could demonstrate autoreactive T cells in individuals at risk of developing RA. Lastly, we studied peripheral blood from early RA patients (n = 10) and found that the group of patients achieving minimum disease activity (DAS28 < 2.6) at 6 months follow-up displayed a decrease in the frequency of citrulline-specific T cells. Conclusions Our study demonstrates the development of a sensitive tetramer panel allowing simultaneous characterisation of antigen-specific T cells in ex vivo patient samples including RA 'at risk' subjects. This multi-tetramer approach can be useful for longitudinal immune-monitoring in any disease with known HLA-restriction element and several candidate antigens.
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  • Godman, Brian, et al. (författare)
  • Dabigatran - a continuing exemplar case history demonstrating the need for comprehensive models to optimize the utilization of new drugs
  • 2014
  • Ingår i: Frontiers in Pharmacology. - 1663-9812 .- 1663-9812. ; 5
  • Forskningsöversikt (refereegranskat)abstract
    • Background: There are potential conflicts between authorities and companies to fund new premium priced drugs especially where there are effectiveness, safety and/or budget concerns. Dabigatran, a new oral anticoagulant for the prevention of stroke in patients with non-valvular atrial fibrillation (AF), exemplifies this issue. Whilst new effective treatments are needed, there are issues in the elderly with dabigatran due to variable drug concentrations, no known antidote and dependence on renal elimination. Published studies showed dabigatran to be cost-effective but there are budget concerns given the prevalence of AF. These concerns resulted in extensive activities pre- to post-launch to manage its introduction. Objective: To (i) review authority activities across countries, (ii) use the findings to develop new models to better manage the entry of new drugs, and (iii) review the implications based on post-launch activities. Methodology: (i) Descriptive review and appraisal of activities regarding dabigatran, (ii) development of guidance for key stakeholder groups through an iterative process, (iii) refining guidance following post launch studies. Results: Plethora of activities to manage dabigatran including extensive pre-launch activities, risk sharing arrangements, prescribing restrictions and monitoring of prescribing post launch. Reimbursement has been denied in some countries due to concerns with its budget impact and/or excessive bleeding. Development of a new model and future guidance is proposed to better manage the entry of new drugs, centering on three pillars of pre-, pen-, and post-launch activities. Post-launch activities include increasing use of patient registries to monitor the safety and effectiveness of new drugs in clinical practice. Conclusion: Models for introducing new drugs are essential to optimize their prescribing especially where concerns. Without such models, new drugs may be withdrawn prematurely and/or struggle for funding.
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  • Jerlström, Tomas, et al. (författare)
  • No increased risk of short-term complications after radical cystectomy for muscle-invasive bladder cancer among patients treated with preoperative chemotherapy : a nation-wide register-based study
  • Ingår i: World Journal of Urology. - : Springer. - 0724-4983 .- 1433-8726. ; 38:2, s. 381-388
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Preoperative chemotherapy is underused in conjunction with radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) due to concerns for complications and delay of surgery. Prospective data on short-term complications from population-based settings with frequent use of preoperative chemotherapy and standardised reporting of complications is lacking. Methods: We identified 1,340 patients who underwent RC between 2011 and 2015 in Sweden due to MIBC according to the Swedish Cystectomy Register. These individuals were followed through linkages to several national registers. Propensity score adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for complications and death within 90 days of surgery, comparing patients receiving preoperative chemotherapy or not. Results: Minimum two cycles of preoperative chemotherapy were given to 519 (39%) of the patients, who on average tended to be younger, have higher education, better physical status, and more advanced bladder cancer than patients not receiving chemotherapy. After adjusting for these and other parameters, there was no association between treatment with preoperative chemotherapy and short-term complications (OR 1.06 95% CI 0.82–1.39) or mortality (OR 0.75 95% CI 0.36–1.55). We observed a risk reduction for gastrointestinal complications among patients who received preoperative chemotherapy compared with those who did not (OR 0.49 95% CI 0.30–0.81). Conclusion: This nation-wide population-based observational study does not suggest that preoperative chemotherapy, in a setting with high utilisation of such treatment, is associated with an increased risk of short-term complications in MIBC patients treated with radical cystectomy.
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  • Joshua, Vijay, et al. (författare)
  • Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells
  • 2016
  • Ingår i: ; 18:1, s. 284-
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Antibodies against citrullinated proteins (ACPA) are common in patients with rheumatoid arthritis (RA). ACPA can appear before disease onset and target many self-antigens. Citrullinated fibrin/fibrinogen represents a classical ACPA target antigen, and mass spectrometry of RA synovial fluid reveals elevated citrullinated (cit) fibrinogen (Fib) peptides compared to non-RA controls. We investigated the extent to which these less-studied peptides represent autoantibody targets and sought to visualize the corresponding cit-Fib-reactive B cells in RA patients. Methods: An in-house ELISA was established against four cit-Fib alpha-subunit peptides (cit-Fib alpha-35; cit-Fib alpha-216,218; cit-Fib alpha-263,271 and cit-Fib alpha-425,426) and serum from patients with established RA (n = 347) and disease controls with psoriatic arthritis (PsA) or ankylosing spondylitis (AS) (n = 236) were analyzed. RA patients were genotyped for HLA-DR alleles, PTPN22 R620W and screened for anti-CCP2 and cit-Fib protein antibodies. The cit-Fib peptides were also used to assemble antigen tetramers to identify cit-Fib-reactive B cells in peripheral blood by flow cytometry. Results: The frequencies of autoantibodies against different cit-Fib epitopes in RA patients compared to PsA/AS patients were: cit-Fib alpha-35 (RA 20%, vs PsA/AS 1%); cit-Fib alpha-216,218 (13% vs 0.5%); cit-Fib alpha-263,271 (21% vs 0.5%) and cit-Fib alpha-425,426 (17% vs 1%). The presence of autoantibodies against these peptides was associated with presence of anti-CCP2 and anti-cit-Fib protein antibodies. No association was found between HLA-DR shared epitope and antibodies to the different cit-Fib peptides. However, association was observed between the PTPN22 risk allele and positivity to cit-Fib alpha-35 and cit-Fib alpha-263,271. B cells carrying surface Ig reactive to these cit-Fib peptides were found in RA peripheral blood and these tend to be more common in PTPN22 risk allele carriers. Conclusions: Our data show that several cit-Fib peptides are targeted by autoantibodies in RA, but not in PsA/AS, implicating that these are not due to arthritis but more specific for RA etiology. The RA-associated anti-cit protein response is broad with many parallel immune responses. The association between cit-Fib autoantibodies and the PTPN22 R620W risk allele supports the hypothesis of altered B cell regulation, such as autoreactive B cells evading tolerance checkpoints.
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