| 1. |
- Wahl, Simone, et al.
(författare)
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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
- 2017
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 541:7635, s. 81-
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type (2) diabetes, cardiovascular disease and related metabolic and inflammatory disturbances(1,2). Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation(3-6), a key regulator of gene expression and molecular phenotype(7). Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 x 10(-7), range P = 9.2 x 10(-8) to 6.0 x 10(-46); n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 x 10(-6), range P = 5.5 x 10(-6) to 6.1 x 10(-35), n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 x 10(-54)). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
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| 2. |
- Baccarani, Michele, et al.
(författare)
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European LeukemiaNet recommendations for the management of chronic myeloid leukemia : 2013
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 122:6, s. 872-884
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Forskningsöversikt (refereegranskat)abstract
- Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels <= 10% at 3 months, <1% at 6 months, and <= 0.1% from 12 months onward define optimal response, whereas >10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome-positive [Ph1]>95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved. (Blood. 2013; 122(6):872-884)
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| 3. |
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| 4. |
- Ortí, Guillermo, et al.
(författare)
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Graft-versus-Host Disease Prophylaxis with PostTransplantation Cyclophosphamide in Chronic Myeloid Leukemia Patients Undergoing Allogeneic Hematopoietic Cell Transplantation from an Unrelated or Mismatched Related Donor : A Comparative Study from the Chronic Malignancies Working Party of the EBMT (CMWP-EBMT)
- 2024
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Ingår i: Transplantation and Cellular Therapy. - : Elsevier. - 2666-6375 .- 2666-6367. ; 30:1, s. 93.e1-93.e12
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Tidskriftsartikel (refereegranskat)abstract
- Outcomes following allogeneic hematopoietic cell transplantation (allo-HCT) for chronic myeloid leukemia (CML) with post-transplantation cyclophosphamide (PTCy) using an unrelated donor (UD) or a mismatched related donor (MMRD) remain unknown. We report a retrospective comparison of PTCy-based allo-HCT from a UD, non-PTCy allo-HCT from a UD, and PTCy allo-HCT from an MMRD. Inclusion criteria were adult patients with CML undergoing first allo-HCT between 2012 and 2019 from a UD with either PTCy or non-PTCy graft-versus-host disease (GVHD) prophylaxis or from an MMRD using PTCy. The primary endpoint was GVHD-free/relapse-free survival (GRFS). A total of 1341 patients were included (82% in the non-PTCy UD cohort). With a median follow-up of 34.9 months, the 3-year GRFS was 43% in the non-PTCy cohort, 37% in the PTCy-UD cohort, and 39% PTCy-MMRD cohort (P = .15). Multivariable analyses revealed no significant differences among the 3 cohorts in terms of overall survival (OS), progression-free survival, RI, and nonrelapse mortality. Factors independently associated with worse OS in the overall cohort were Karnofsky Performance Status <90 (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.41 to 2.45; P < .001), older age (HR, 1.24, 95% CI, 1.11 to 1.38; P < .001), and disease stage (compared to chronic phase [CP] 1): blast phase (HR, 2.25; 95% CI, 1.60 to 3.16; P < .001), accelerated phase (HR, 1.63; 95% CI, 1.05 to 2.54; P = .03), and CP >2 (HR, 1.58; 95% CI, 1.15 to 2.17; P = .005). These results suggest that allo-HCT in patients with CML using either a UD or an MMRD with PTCy-based GVHD prophylaxis are feasible transplantation, platforms and that the disease stage at allo-HCT remains a major prognostic factor, highlighting the importance of closely monitoring CML patients and proposing transplantation when indicated when still in CP1.
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| 5. |
- Padula, William V., et al.
(författare)
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Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase After Generic Entry of Imatinib in the United States
- 2016
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 108:7
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Tidskriftsartikel (refereegranskat)abstract
- Background: We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib's price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness ("imatinib-first") would be cost-effective compared with the current standard of care: "physicians' choice" of initiating treatment with any one of the three TKIs. Methods: We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician's choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models' clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven's MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study's conduct. Results: Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician's choice ($365 744, 3.97 QALYs). The imatinibfirst incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses. Conclusion: When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP.
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| 6. |
- Pearce, Kim F., et al.
(författare)
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Regulation of advanced therapy medicinal products in Europe and the role of academia
- 2014
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Ingår i: Cytotherapy. - : Elsevier BV. - 1477-2566 .- 1465-3249. ; 16:3, s. 289-297
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Forskningsöversikt (refereegranskat)abstract
- Background aims. Advanced therapy medicinal products (ATMP) are gene therapy, somatic cell therapy or tissue-engineered products regulated under (EC) No. 1394/2007 to ensure their free movement within the European Union while guaranteeing the highest level of health protection for patients. Academic good manufacturing practice (GMP) centers are major contributors in the development of ATMPs and this study assessed the impact of regulations on them. Methods. European academic and non-industrial facilities (n = 747) were contacted, and a representative sample of 50 replied to a detailed questionnaire. Experienced centres were further selected in every Member State (MS) for semi-structured interviews. Indicators of ATMP production and development success were statistically assessed, and opinions about directive implementation were documented. Results. Facilities experienced in manufacturing cell therapy transplant products are the most successful in developing ATMPs. New centres lacking this background struggle to enter the field, and there remains a shortage of facilities in academia participating in translational research. This is compounded by heterogeneous implementation of the regulations across MS. Conclusions. GMP facilities successfully developing ATMPs are present in all MS. However, the implementation of regulations is heterogeneous between MS, with substantial differences in the definition of ATMPs and in the approved manufacturing environment. The cost of GMP compliance is underestimated by research funding bodies. This is detrimental to development of new ATMPs and commercialization of any that are successful in early clinical trials. Academic GMP practitioners should strengthen their political visibility and contribute to the development of functional and effective European Union legislation in this field.
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