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- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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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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- Wincup, C, et al.
(författare)
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ANTI-RITUXIMAB ANTIBODIES DEMONSTRATE NEUTRALISING CAPACITY, ASSOCIATE WITH LOWER CIRCULATING DRUG LEVELS AND EARLY RELAPSE IN PATIENTS UNDERGOING TREATMENT FOR SYSTEMIC LUPUS ERYTHEMATOSUS
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 1344-1345
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- A major limitation of biologic therapy is formation of anti-drug antibodies (ADA). We previously found ADA to rituximab (RTX) are more prevalent in patients undergoing treatment for systemic lupus erythematosus (SLE) than rheumatoid arthritis and vasculitis (1). In addition, we demonstrated that ADA to RTX predict subsequent infusion related reactions (2). However, little is known regarding the long-term dynamics of ADA to RTX in patients undergoing treatment for SLE.ObjectivesIn this study we evaluated the longitudinal impact of ADA positivity with particular focus on; 1) Risk factors for development of ADA. 2) Impact of ADA on treatment response. 3) Influence of ADA on RTX drug kinetics over time. 4) The capacity of ADA to neutralise RTX.MethodsPatients with SLE undergoing treatment with RTX were recruited to this study (n=35). Serum samples were collected at the following intervals post-treatment; 1-3 months (defined as ‘early’ post-treatment), 6 months, 12 months, 36 months (n=114).Clinical and laboratory data was collected pre-treatment and at each follow-up time point. Response to treatment was assessed by improvement in SLEDAI-2K score from baseline and also according to BILAG as previously described (3).ADA were detected using an electrochemiluminescent immunoassay. Serum RTX levels were measured by ELISA. ADA status was defined according to the following patterns over time; persistently negative, persistently positive (0-15 AU/ml) and persistently high positive (≥16 AU/ml, upper quartile). A complement dependent cytotoxic assay was used to determine neutralising capability of ADA in a subgroup of positive samples (n=38).ResultsADA to RTX were found to be persistently positive in 64.3% of patients over the 36-month follow-up period and there was no significant difference in baseline disease activity (BILAG / SLEDAI-2K) between those who were subsequently ADA positive vs negative. ADA positive patients had a younger age at diagnosis of SLE when compared with ADA negative (mean 22.50 ± 9.10 vs 37.29 ± 11.31 years, p=0.002, Figure 1 A). Multivariate logistic regression found a 22% decrease in risk of ADA positivity for each addition year after diagnosis (p=0.03).Figure 1.ADA positive patients had a significantly lower C3 level at baseline (mean 0.61 ± 0.23 g/L vs 0.87 ± 0.30 g/L, p=0.026), which remained lower at each subsequent time point post-treatment up to 12 months post-treatment (Figure 1B).At 1-3 months post-RTX, patients who were ADA positive had a significantly lower circulating drug level than ADA negative (p<0.001, Figure 1 C).In terms of clinical response, ADA positive patients had an initial significant improvement in disease activity (SLEDAI-2K) by 3 months (p<0.001). However, response was not maintained at 12 months (Figure 1 D). In comparison, ADA negative patients showed a significant improvement in SLEDAI-2K at 6 months and this was maintained across the 36-month follow-up period (Figure 1 E).BILAG defined relapse was more common at six months post-treatment in ADA positive patients (22%) and ADA highly positive patients (33%) than those who were ADA negative (in which there were no cases of relapse within the first six months, Figure 1 F). At 12-months post-RTX, a higher rate of BILAG defined Major Response was seen in those who were ADA negative (80%) when compared with ADA positive (44%) and high positive (36%) as shown in Figure 1 G.Finally, antibodies derived from all ADA positive samples (38/38) were found to neutralise RTX in vitro.ConclusionADA to RTX were common and persisted over the 36-month period of this study. ADA associated with earlier serum drug elimination, increased relapse rates and demonstrated neutralising capacity suggesting that ADA could be a significant limitation to sustained response to treatment in clinical practice.References[1]Faustini F et al. Arthritis research & therapy. 2021;23(1):211[2]Wincup C et al. Annals of the rheumatic diseases. 2019;78(8):1140-2[3]Md Yusof MY et al Annals of the rheumatic diseases. 2017;76(11):1829-36Disclosure of InterestsNone declared
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- de Jong, Jasper M. A., et al.
(författare)
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Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice
- 2019
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Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 1:8, s. 830-843
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Tidskriftsartikel (refereegranskat)abstract
- Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 degrees C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
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- Jakobsson, Martin, et al.
(författare)
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Arctic Ocean glacial history
- 2014
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 92, s. 40-67
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Forskningsöversikt (refereegranskat)abstract
- While there are numerous hypotheses concerning glacial interglacial environmental and climatic regime shifts in the Arctic Ocean, a holistic view on the Northern Hemisphere's late Quaternary ice-sheet extent and their impact on ocean and sea-ice dynamics remains to be established. Here we aim to provide a step in this direction by presenting an overview of Arctic Ocean glacial history, based on the present state-of-the-art knowledge gained from field work and chronological studies, and with a specific focus on ice-sheet extent and environmental conditions during the Last Glacial Maximum (LGM). The maximum Quaternary extension of ice sheets is discussed and compared to LGM. We bring together recent results from the circum-Arctic continental margins and the deep central basin; extent of ice sheets and ice streams bordering the Arctic Ocean as well as evidence for ice shelves extending into the central deep basin. Discrepancies between new results and published LGM ice-sheet reconstructions in the high Arctic are highlighted and outstanding questions are identified. Finally, we address the ability to simulate the Arctic Ocean ice sheet complexes and their dynamics, including ice streams and ice shelves, using presently available ice-sheet models. Our review shows that while we are able to firmly reject some of the earlier hypotheses formulated to describe Arctic Ocean glacial conditions, we still lack information from key areas to compile the holistic Arctic Ocean glacial history.
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