Biomedical subjects

Angela Thomas

Publications and source records attributed to Angela Thomas.

6 recordsLinked to original sources

PubMed2006

6-Thioguanine-related chronic hepatotoxicity and variceal haemorrhage in children treated for acute lymphoblastic leukaemia--a dual-centre experience.

BACKGROUND: 6-Thioguanine treatment in childhood acute lymphoblastic leukaemia (ALL) has been shown to cause hepatic veno-occlusive disease, but this usually resolved with drug withdrawal. Recent reports suggested that treatment of ALL with 6-thioguanine can lead to chronic hepatotoxicity and portal hypertension. We describe our experience from 2 UK centres of chronic hepatotoxicity in children receiving maintenance 6-thioguanine for ALL in the national leukaemia protocol ALL 97/99. METHODS: Retrospective review of children who were referred with liver disease secondary to 6-thioguanine treatment of ALL was performed. A paediatric pathologist blinded to the clinical features reviewed liver histology slides. RESULTS: Ten of 75 children (13%) treated with 6-thioguanine in both centres were referred at a median of 6 months (range, 2-29) after discontinuation of chemotherapy. In 8 cases, referral was due to persistent thrombocytopenia and splenomegaly. Two children presented with acute variceal bleeding. All had thrombocytopenia at referral, and ultrasonography showed coarse hepatic echo texture and splenomegaly in all. Endoscopy showed oesophageal varices in 7 and gastric varices in 1. Nine underwent liver biopsy that showed features compatible with nodular regenerative hyperplasia in 5 cases. After a median follow-up of 36 months, a further child has had a variceal haemorrhage and all but 2 children remain thrombocytopenic. CONCLUSIONS: 6-Thioguanine-induced chronic hepatotoxicity is a significant complication in children treated with this agent for ALL. Children may present several months to years after discontinuation of 6-thioguanine. All children given maintenance treatment of ALL with this agent should be screened, and affected children require long-term surveillance.

Adolescent↗

PubMed2006

Joe Burchenal and the birth of combination chemotherapy.

When Joe Burchenal started studying medicine at the University of Pennsylvania in 1934, antibiotics had not been discovered and the survival of patients diagnosed with acute leukaemia was < 4 months. By the time he retired in 1983, 58% of children with acute lymphoblastic leukaemia survived 5 years with the majority being cured of their disease. His early work in infectious diseases and antimicrobials equipped him well, both clinically and scientifically. The approach to developing antibiotics to conquer previously incurable infection was an inspiration and model for his pioneering work when searching for drugs with activity against cancer. Trials of sequential and then combination chemotherapy followed. Success in treating lymphoid malignancies in children led him to develop treatment regimens for other more resistant cancers, and as an advocate of collaborative working he introduced multimodal therapy to tackle bulky or metastatic cancers, replacing inevitable relapse with a chance of true cure.

Acute Disease↗

PubMed2005

Selective impairment of platelet activation to collagen in the absence of GATA1.

Defects in the X-linked DNA-binding megakaryocyte transcription factor GATA1 cause thrombocytopenia and abnormal platelet function. However, detailed studies of GATA1 function in platelet activation are lacking. Here, we studied platelets from GATA1-deficient mice and from a male patient (S14) with a bleeding diathesis attributed to a single amino acid substitution (R216Q) in the N-terminal GATA1 zinc finger that alters binding to DNA. In both cases there was inhibition of aggregation to collagen and decreased tyrosine phosphorylation of glycoprotein VI (GPVI)-signaling proteins. This effect was more marked in GATA1-deficient murine platelets, where it was associated with a significant reduction in surface GPVI expression. Moreover, both human and murine GATA1-mutant platelets showed reduced adhesion and aggregate formation on a collagen matrix at an intermediate rate of shear, although this could not be accounted solely by the thrombocytopenia and altered GPVI expression, indicating that GATA1 regulates additional factors important for platelet activation under shear. In contrast, there was no inhibition of responses to G protein-coupled receptor agonists in GATA1-perturbed platelets. Our results are consistent with GATA1 regulating some but not all pathways of platelet activation, leading to an impairment of aggregate formation under flow, which cannot be attributed solely to the thrombocytopenia.

Animals↗

PubMed2003

Natural history of GATA1 mutations in Down syndrome.

Acquired mutations in megakaryocyte transcription factor GATA1 have recently been reported in Down syndrome (DS), transient myeloproliferative disorder (TMD), and acute megakaryoblastic leukemia (AMKL). To provide novel insight into GATA1 mutations in DS, genomic DNA was assayed from 12 AMKL and 4 TMD cases (including neonatal, prediagnosis samples in 4 of 16), neonatal blood spots from 21 DS children without clinically evident TMD or AMKL, and 62 non-DS cord blood samples, using techniques not previously employed with such samples. GATA1 mutations were present in all TMD and AMKL cases and at birth in 3 of 4 children without known clinical TMD, who later developed AMKL. They were present at birth in 2 of 21 DS neonates, who have not yet, but could still, develop AMKL (now 26 and 31 months). GATA1 mutations were not detected in 62 non-DS cord blood samples. In 4 AMKL patients multiple independent GATA1 mutations were observed. These data show GATA1 mutations occur in utero in most DS TMD and AMKL, that they may occur without clinical signs of disease, and that multiple separate GATA1 mutant clones can occur in an individual. The findings have implications for pathogenesis of DS TMD and AMKL and highlight parallels between DS AMKL and other childhood leukemias.

Child, Preschool↗

PubMed2003

Four factor deficiency.

Four factor deficiency is variably associated with mild to fatal bleeding. We describe a 3-month-old boy, born of consanguineous parents, who presented with a right subdural haematoma and a clotting screen showing a prothrombin time (PT) > 100 s, an activated partial thromboplastin time (aPTT) > 150 s, a fibrinogen of 0.4 g/l, and fibrinogen degradation products < 1 microg/ml. He was given 300 U of factor IX concentrate (containing factors II and X) and 1 mg of vitamin K intravenously. Forty-five minutes later, clotting tests showed a PT of 24 s, an aPTT of 31 s and a fibrinogen of 2.6 g/l. The patient was found to be deficient in all the vitamin K-dependent factors: factors II, VII, IX and X, protein C and protein S. A 14-base deletion was found in intron 1 (bases 1056-1069) of the gamma-carboxylase gene. The patient and his elder sister were homozygous for this deletion, whereas both parents were heterozygous. The deletion destroys a reverse palindromic sequence (TTGAGGCAA) of the type often associated with cis-acting elements. Our results suggest that this element may be involved in the regulation of gamma-carboxylase expression. Expression studies are being completed so that this region can be definitively ascribed as a cis-acting element involved in gene regulation.

Blood Coagulation Factors↗

PubMed2002

Does isochromosome 7q mandate bone marrow transplant in children with Shwachman-Diamond syndrome?

We report on nine children with Shwachman-Diamond syndrome (SDS), eight of whom had clonal abnormalities of chromosome 7. Seven children had an isochromosome 7 [i(7)(q10)] and one a derivative chromosome 7, all with an apparently identical (centromeric) breakpoint. Children with SDS are predisposed to myelodysplasia (MDS) and acute myeloid leukaemia (AML) often with chromosome 7 abnormalities. Allogeneic transplants have been used to treat these children, however, they are a high-risk transplant group and require careful evaluation. Three of the children were transplanted but only one survived, who to our knowledge remains the longest surviving SDS transplant patient (4.5 years +). The six non-transplanted children are well. In classic MDS, chromosome 7 abnormalities are associated with rapid progression to acute leukaemia; however, we present evidence to suggest that isochromosome 7q may represent a separate disease entity in SDS children. This is a particularly interesting finding given that the SDS gene has recently been mapped to the centromeric region of chromosome 7. Our studies indicate that i(7)(q10) is a relatively benign rearrangement and that it is not advisable to offer allogeneic transplants to SDS children with i(7)(q10) alone in the absence of other clinical signs of disease progression.

Adolescent↗