Boztug H.,Medical University of Vienna |
Zecca M.,Policlinico San Matteo Foundation |
Sykora K.-W.,Hannover Medical School |
Veys P.,Great Ormond Street Hospital for Children National Health Service Trust |
And 7 more authors.
Annals of Hematology | Year: 2015
Standard myeloablative conditioning regimens for children with acute lymphoblastic leukaemia are based on total body irradiation (TBI). However, TBI causes profound short-term and long-term side effects, provoking the necessity for alternative regimens. Treosulfan combines a potent immunosuppressive and antileukaemic effect with myeloablative activity and low toxicity profile. We retrospectively studied toxicity and outcome of 71 paediatric patients with acute lymphoblastic leukaemia (ALL) undergoing haematopoietic stem cell transplantation (HSCT) following treosulfan-based conditioning aiming to identify risk factors for treatment failure and dose-depending outcome differences. Early regimen-related toxicity was low. No case of veno-occlusive disease was reported. There was no association of toxicity with age or number of HSCT. Event-free survival (EFS) of infants was significantly better compared to older children. Overall survival (OS) at 3 years was 51 % and not significantly influenced by number of HSCT (first HSCT 54 %, ≥second HSCT 44 %, p = 0.71). In multivariate analysis, OS and EFS were significantly worse for patients transplanted without complete remission (p = 0.04 and 0.004). Treatment-related mortality was low at 14 %. We conclude that treosulfan-based conditioning is a safe and efficacious approach for paediatric ALL. © 2014, Springer-Verlag Berlin Heidelberg.
PubMed | University Utrecht, Barts Health National Health Service Trust, Imperial College London, University of Bristol and 10 more.
Type: | Journal: Blood | Year: 2017
The von Willebrand receptor complex, which is composed of the glycoproteins Ib and Ib, V and IX, plays an essential role in the earliest steps in hemostasis. Over the last four decades, it has become apparent that loss of function of any one of three of the genes encoding these glycoproteins namely, GP1BA, GP1BB and GP9, leads to autosomal recessive macrothrombocytopenia complicated by bleeding. A small number of variants in GP1BA have been reported to cause a milder and dominant form of macrothrombocytopenia but only two tentative reports exists of such a variant in GP1BB By analyzing data from a collection of over 1,000 genome-sequenced patients with a rare bleeding and/or platelet disorder, we have identified a significant association between rare monoallelic variants in GP1BB and macrothrombocytopenia. In order to strengthen our findings, we sought further cases in two additional collections in the UK and Japan. Across 18 families exhibiting phenotypes consistent with autosomal dominant inheritance of macrothrombocytopenia, we report on 27 affected cases carrying one of 9 rare variants in GP1BB.
Flanagan S.E.,University of Exeter |
Xie W.,University of Exeter |
Caswell R.,University of Exeter |
Damhuis A.,Royal Devon and Exeter National Health Service Foundation Trust |
And 22 more authors.
American Journal of Human Genetics | Year: 2013
Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome sequencing of the coding regions and conserved splice sites has been very successful in the identification of disease-causing mutations, and targeting of these regions has extended clinical diagnostic testing from analysis of fewer than ten genes per phenotype to more than 100. Noncoding mutations have been less extensively studied despite evidence from mRNA analysis for the existence of deep intronic mutations in >20 genes. We investigated individuals with hyperinsulinaemic hypoglycaemia and biochemical or genetic evidence to suggest noncoding mutations by using NGS to analyze the entire genomic regions of ABCC8 (117 kb) and HADH (94 kb) from overlapping ∼10 kb PCR amplicons. Two deep intronic mutations, c.1333-1013A>G in ABCC8 and c.636+471G>T HADH, were identified. Both are predicted to create a cryptic splice donor site and an out-of-frame pseudoexon. Sequence analysis of mRNA from affected individuals' fibroblasts or lymphoblastoid cells confirmed mutant transcripts with pseudoexon inclusion and premature termination codons. Testing of additional individuals showed that these are founder mutations in the Irish and Turkish populations, accounting for 14% of focal hyperinsulinism cases and 32% of subjects with HADH mutations in our cohort. The identification of deep intronic mutations has previously focused on the detection of aberrant mRNA transcripts in a subset of disorders for which RNA is readily obtained from the target tissue or ectopically expressed at sufficient levels. Our approach of using NGS to analyze the entire genomic DNA sequence is applicable to any disease. © 2013 The American Society of Human Genetics.
Flett A.S.,University College London |
Hayward M.P.,University College London |
Ashworth M.T.,Great Ormond Street Hospital for Children National Health Service Trust |
Hansen M.S.,University College London |
And 6 more authors.
Circulation | Year: 2010
Background-: Diffuse myocardial fibrosis is a final end point in most cardiac diseases. It is missed by the cardiovascular magnetic resonance (CMR) late gadolinium enhancement technique. Currently, quantifying diffuse myocardial fibrosis requires invasive biopsy, with inherent risk and sampling error. We have developed a robust and noninvasive technique, equilibrium contrast CMR (EQ-CMR) to quantify diffuse fibrosis and have validated it against the current gold standard of surgical myocardial biopsy. Methods and results-: The 3 principles of EQ-CMR are a bolus of extracellular gadolinium contrast followed by continuous infusion to achieve equilibrium; a blood sample to measure blood volume of distribution (1-hematocrit); and CMR to measure pre-and postequilibrium T1 (with heart rate correction). The myocardial volume of distribution is calculated, reflecting diffuse myocardial fibrosis. Clinical validation occurred in patients undergoing aortic valve replacement for aortic stenosis or myectomy in hypertrophic cardiomyopathy (n=18 and n=8, respectively). Surgical biopsies were analyzed for picrosirius red fibrosis quantification on histology. The mean histological fibrosis was 20.5±11% in aortic stenosis and 17.1±7.4% in hypertrophic cardiomyopathy. EQ-CMR correlated strongly with biopsy histological fibrosis: aortic stenosis, r=0.86, Kendall Tau coefficient (T)=0.71, P<0.001; hypertrophic cardiomyopathy, r=0.62, T=0.52, P=0.08; combined r=0.80, T=0.67, P<0.001. Conclusions-: We have developed and validated a new technique, EQ-CMR, to measure diffuse myocardial fibrosis as an add-on to a standard CMR scan, which allows for the noninvasive quantification of the diffuse fibrosis burden in myocardial diseases. © 2010 American Heart Association, Inc.
Noone D.G.,Great Ormond Street Hospital for Children National Health Service Trust |
Marks S.D.,Great Ormond Street Hospital for Children National Health Service Trust |
Marks S.D.,University College London
Journal of Pediatrics | Year: 2013
Objective: To assess the prevalence and associations of hyperuricemia in a cohort of pediatric patients with chronic kidney disease (CKD). Study design: This was an observational cross-sectional study of clinical and laboratory data in pediatric patients being followed in a nephrology clinic. All patients with CKD were included. ORs and risk estimates of having stage III-V CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) with hyperuricemia were calculated. The relationships among eGFR, body mass index (BMI), and hyperuricemia were estimated using both correlation and regression models. Results: A total of 116 children (61% male), aged 0.4-17 years, were included in the analysis. The prevalence of hyperuricemia in those with an eGFR <60 mL/min/1.73 m2 was 70%. Children with hyperuricemia were more likely to have an eGFR <60 mL/min/1.73 m2 than those with a normal urate level (OR, 4.6) and were more likely to be hypertensive (OR, 2.1). Hyperuricemia was significantly associated with increased BMI, albuminuria, renal dysfunction with reduced eGFR, and hypertension. Significant linear relationships between eGFR and urate (P = .0001) and between BMI and urate (P = .0001) were detected. Conclusions: Hyperuricemia is common in pediatric patients with CKD and is associated with renal dysfunction, hypertension, obesity, and albuminuria. Future prospective studies should be undertaken to further assess the role of hyperuricemia in pediatric patients with CKD. Copyright © 2013 Mosby Inc.
Ghorashian S.,University College London |
Pule M.,University College London |
Amrolia P.,University College London |
Amrolia P.,Great Ormond Street Hospital for Children National Health Service Trust
British Journal of Haematology | Year: 2015
T cells can be redirected to recognize tumour antigens by genetic modification to express a chimeric antigen receptor (CAR). These consist of antibody-derived antigen-binding regions linked to T cell signalling elements. CD19 is an ideal target because it is expressed on most B cell malignancies as well as normal B cells but not on other cell types, restricting any 'on target, off tumour' toxicity to B cell depletion. Recent clinical studies involving CD19 CAR-directed T cells have shown unprecedented responses in a range of B cell malignancies, even in patients with chemorefractory relapse. Durable responses have been achieved, although the persistence of modified T cells may be limited. This therapy is not without toxicity, however. Cytokine release syndrome and neurotoxicity appear to be frequent but are treatable and reversible. CAR T cell therapy holds the promise of a tailored cellular therapy, which can form memory and be adapted to the tumour microenvironment. This review will provide a perspective on the currently available data, as well as on future developments in the field. © 2015 John Wiley & Sons Ltd.
Guasti L.,Queen Mary, University of London |
Silvennoinen S.,Kuopio University Hospital |
Bulstrode N.W.,Great Ormond Street Hospital for Children National Health Service Trust |
Ferretti P.,University College London |
And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014
Objective: The objective of the studywasto assess the role of FGF21 in growth regulation inhumans using postnatal growth failure of very preterm infants as a model.Design: FGF21 levels were measured serially in very preterm infants, and their linear growth evaluated from birth to term-equivalent age. Primary chondrocytes obtained from pediatric donors were used to test whether FGF21 can directly interfere with GH signaling.Context: The hormone fibroblast growth factor 21 (FGF21) is a key metabolic regulator in the adaptation to fasting. In food-restricted mice, inhibition of skeletal growth is mediated by the antagonistic effect of FGF21 on GH action in the liver and growth plate.Results: Anegative association (β-.415, P <.005, linear regression model) of FGF21 levels with the change in SD score for length was found. In primary chondrocytes, FGF21 upregulated basal and GH-induced SOCS2 expression and inhibited GH-induced signal transducer and activator of transcription 5 (STAT5) phosphorylation as well as GH-induced COLII and ALP expression. Finally, FGF21 inhibited GH-induced IGF-1 expression and cell proliferation, indicating GH resistance. However, FGF21 did not affect IGF-1-induced cell proliferation.Conclusions: Elevated FGF21 serum levels during the first weeks of life are independently associated with postnatal growth failure in preterm infants. Furthermore, our data provide mechanistic insights into GH resistance secondary to prematurity and may offer an explanation for the growth failure commonly seen in chronic conditions of childhood. Copyright © 2014 by the Endocrine Society.
Aurora P.,University College London |
Aurora P.,Great Ormond Street Hospital for Children National Health Service Trust |
Stanojevic S.,University College London |
Wade A.,University College London |
And 8 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2011
Rationale: The markedly improved life expectancy of children with cystic fibrosis (CF) has created a new challenge, as traditional markers of lung disease are frequently normal in young children. This prevents identification of individuals who may benefit from more aggressive therapy and also obliges large study numbers and prolonged duration for intervention studies. There is an urgent need for alternative surrogates that detect early lung disease and track through early childhood. Objectives: This study aimed to determine whether multiple-breath washout (MBW) results at preschool age can predict subsequent abnormal lung function. Methods: Preschool children (3-5 yr) with CF and healthy control subjects underwent spirometry and MBW with testing repeated during early school age (6-10 yr). Primary outcomes were FEV1 from spirometry and lung clearance index (LCI) from MBW. Measurements and Main Results: Forty-eight children with CF and 45 healthy children completed testing. Thirty-five (73%) children with CF had abnormal LCI at preschool age, whereas only five had abnormal FEV1. The positive predictive value of preschool LCI for predicting any abnormal school-age result was 94%, with a negative predictive value of 62%. Only one child with abnormal FEV1 at school age had had a normal preschool LCI. In contrast, for preschool FEV1 the positive predictive value was 100%, but negative predictive value was only 25%. Conclusions: This study demonstrates that an abnormal preschool LCI predicts subsequent lung function abnormalities, whereas a normal preschool LCI usually remains normal. MBW has potential as a clinical and research outcome in young children with CF.
Kiely E.M.,Great Ormond Street Hospital for Children National Health Service Trust |
Pierro A.,Great Ormond Street Hospital for Children National Health Service Trust |
Pierro A.,University College London |
Pierce C.,Great Ormond Street Hospital for Children National Health Service Trust |
And 3 more authors.
Pediatrics | Year: 2012
Midgut volvulus due to malrotation may result in loss of the small bowel. Until now, after derotation of the volvulus, pediatric surgeons do not deal with the mesenteric thrombosis, which causes continuing ischemia of the intestine. On occasion, a "second look" laparotomy is performed in the hope that some improvement in blood supply to the intestine has occurred. We describe a new combined treatment to restore intestinal perfusion based on digital massage of the superior mesenteric vessels after derotation and systemic infusion of tissuetype plasminogen activator. This new therapy has been successful in 2 neonates with severe intestinal ischemia due to volvulus. Copyright © 2012 by the American Academy of Pediatrics.
Williams J.E.,University College London |
Wells J.C.K.,University College London |
Benden C.,Great Ormond Street Hospital for Children National Health Service Trust |
Jaffe A.,University of New South Wales |
And 4 more authors.
American Journal of Clinical Nutrition | Year: 2010
Background: Malnutrition is an indicator of a poor prognosis in patients with cystic fibrosis (CF). Previous body-composition (BC) studies in children with CF used 2-component models (2CMs) to assess fat mass (FM) and fat-free mass (FFM), but to our knowledge no study has used the gold-standard 4-component model (4CM), which allows for a more accurate evaluation of the nature of both elements. Objective: We measured BC by using the 4CM in 6-12-y-old children with CF to 1) compare findings with those of healthy, matched control children and reference data; 2) relate BC to lung spirometry [forced expired volume in 1 s (FEV1)]; and 3) compare findings with those from more commonly used 2CM techniques. Design: One hundred clinically stable children with CF (57% girls) aged 6-12 y were measured by using the 4CM. Children with CF underwent spirometry (FEV1). Results: Girls with CF had significantly less FM than did healthy girls, even after adjustment for height and pubertal status; boys with CF had higher body mass index SD scores than did healthy boys. FM in girls was positively associated with the FEV1 percentage predicted. The 2CM FM was significantly different from the 4CM FM, with differences dependent on sex and condition, although most techniques identified a relation between FM and FEV1 in girls. Conclusions: Although shorter than healthy children, boys with CF were heavier and had a BC within the normal range; however, girls with CF had lower FM than did healthy girls, and this was associated with poorer lung function. Given the worse prognosis in girls, this finding merits more attention. The reliability of 2CM techniques varied with sex and health status. © 2010 American Society for Nutrition.