| 1. |
- Egnell, Christina, et al.
(author)
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Impact of body mass index on relapse in children with acute lymphoblastic leukemia treated according to Nordic treatment protocols
- 2020
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In: European Journal of Haematology. - : WILEY. - 0902-4441 .- 1600-0609. ; 105:6, s. 797-807
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Journal article (peer-reviewed)abstract
- Objectives High body mass index (BMI) is associated with poorer survival in childhood acute lymphoblastic leukemia (ALL), but the actual impact on the risk of relapse still needs to be clarified. We evaluated the impact of BMI at diagnosis on the risk of relapse in children with ALL treated according to Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols. Method In a multicenter study, we collected data on BMI at diagnosis and outcome of 2558 children aged 2.0-17.9 years diagnosed between 1992 and 2016. Patients were divided into four groups according to International Obesity Task Force (IOTF) childhood BMI cut-offs: underweight, <17; healthy weight, 17-25; overweight, 25-30; and obese, >= 30 kg/m(2). Results In Cox multivariate regression analyses, an increased risk of relapse was observed in children aged 10-17.9 years with unhealthy BMI at diagnosis (underweight hazard ratio HR: 2.90 [95% confidence interval: 1.24-6.78],P = .01; overweight, HR: 1.95 [1.11-3.43],P = .02, and obese HR: 4.32 [95% 2.08-8.97],P < .001), compared to children with healthy weight. BMI had no impact on relapse in children under 10 years of age. Conclusion High BMI, and especially obesity at diagnosis, is an independent adverse prognostic factor for relapse in older children with ALL.
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| 2. |
- Fresard, Laure, et al.
(author)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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In: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Journal article (peer-reviewed)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 3. |
- Merker, Andrea
(author)
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Auxological tools for following growth in extreme short stature and for evaluating growth promoting interventions
- 2018
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Doctoral thesis (other academic/artistic)abstract
- Growth charts are inevitable tools for following children in clinical practice and also when evaluating growth promoting therapy. Growth is a concern especially for families to children of extreme short stature such as in skeletal dysplasias but evaluations of growth pattern with changes in height position is complicated when height develops far below normal population range. Height gain from growth hormone therapy is variable for short stature conditions without aberrant growth hormone secretion such as in Turner syndrome. This makes it difficult to communicate realistic adult height estimates to concerned families. The first part of this PhD project used semi-longitudinal data from 4,375 measuring occasions to construct growth and body proportion references for achondroplasia and to describe these in relation to normal population references. Typical for achondroplasia, tempo in head size was increased attaining final size earlier than normal. Height was at the same time compromised with major loss in height position during the first years of life, due to limited growth capacity of the legs. At adult ages, leg length was half of that in normal population and arm span almost 35 percent lower than normal contributing to severely reduced area of personal access. Pronounced body disproportions distort the BMI-value in achondroplasia, which is why specific BMI charts were constructed. Clinical achondroplasia charts were developed to support surveillance of these children and, as short stature matrix, possibly also for other children with severe short stature for which syndrome-specific charts are missing. The usability of these achondroplasia charts were tested by illustrating growth pattern of selected skeletal dysplasias. Obtained achondroplasia references for height, sitting height, leg length and arm span might contribute to a better understanding of the effect of FGFR3 signalling on growth and will also be inevitable tools for evaluation of novel treatments. In the second part, variability in response to growth hormone therapy was studied by dividing a sample of 455 girls with Turner syndrome, reported in the Swedish National Register for growth hormone treatment of children and adolescents, into good and poor response based on the distribution of total height gain from treatment. As age at treatment initiation was distributed over almost entire growth period, the sample was further grouped into those with treatment start during normally prepubertal and pubertal ages. Differences of clinical relevance were higher mid-parental height, higher GH dose at 12 months of treatment and improved body proportions in the younger good response group; and younger age and shorter height position at treatment initiation and higher GH dose in the older good response group. These findings could possibly be influenced by subgroups identified in graphic presentations. Initial height gain from treatment did not necessarily translate into better total height gain neither in younger or older poor groups. In contrast to previous claims, early initiation of growth hormone treatment per se did often not result in better total height gain.
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