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Biomedical subjects

D K Webb

Publications and source records attributed to D K Webb.

At least 19 recordsLinked to original sources
PubMed2001

Relationships between age at diagnosis, clinical features, and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia.

Between May 1988 and June 2000, 698 children were treated in the Medical Research Council acute myeloid leukemia 10 and 12 trials. The presenting features and outcomes of therapy in these children were compared by age. Although there was no single cutoff in age, younger children were more likely to have intermediate risk and less likely to have favorable cytogenetics (P <.001), and they had a higher incidence of translocations involving chromosome 11q23 (P <.001). The distribution of French-American-British (FAB) types also varied with age; FAB types M5 (P <.001) and M7 (P <.001) were more common in early childhood, whereas older children were more likely to have FAB types M0 (P =.03), M1 (P =.04), M2 (P =.005), and M3 (P <.001). Involvement of the central nervous system at diagnosis was also more common in the youngest children (P =.01). Younger children had more severe diarrhea (P =.002), whereas older children had worse nausea and vomiting (P =.01) after chemotherapy. When adjusted for other important factors, complete remission rates were similar (P =.5) and although there was less resistant disease in younger children (P =.003), this was partially balanced by a slight increase in deaths during induction therapy in younger patients (P =.06). On multivariate analysis overall survival (P =.02), event-free survival (P =.02), and disease-free survival were better (P =.06) in younger children due to a lower relapse rate (P =.02) especially in the bone marrow (P =.02).

Acute Disease↗
PubMed2001

Fatal graft-versus-host disease following HLA-mismatched donor lymphocyte infusion.

We report the case of a 10-year-old boy with molecular relapse of CML following unrelated donor BMT who developed fatal grade 4 acute GVHD of the gut and liver following one antigen-mismatched donor lymphocyte infusion. Previous experience of donor lymphocyte infusion in the HLA-mismatched setting is reviewed and the role of adoptive immunotherapy in this situation is discussed.

Bone Marrow Transplantation↗
PubMed2001

Improved outcome of alternative donor bone marrow transplantation in children with severe aplastic anaemia using a conditioning regimen containing low-dose total body irradiation, cyclophosphamide and Campath.

The increasing success of human leucocyte antigen (HLA)-matched sibling donor (MSD) transplants and combination immunosuppressive treatments have dramatically improved the prognosis of severe aplastic anaemia (SAA) in children and young adults. For patients who lack a MSD there is a significant minority who fail immunosuppressive therapy or suffer from a severe constitutional aplastic anaemia in which immunosuppression would be ineffective. Alternative donor bone marrow transplantation (AD-BMT) has only had limited success in this context. We report the successful outcome of AD-BMT in eight consecutive patients aged 7 months to 15 years, six of whom had acquired aplastic anaemia who had previously failed to respond to immunosuppression, and two of whom had a severe (non-Fanconi) constitutional aplastic anaemia. All eight patients had received multiple red cell and platelet transfusions. We used a new combination of agents for pretransplant conditioning aiming to maximize immunosuppression and minimize toxicity, consisting of Campath-1G or -1H, cyclophosphamide and low-dose total body irradiation (LD TBI) or fludarabine. Toxicity was minimal and all eight children are alive, well and free of disease at a median follow-up of 32 months. We suggest that this approach could facilitate the successful treatment of children with SAA in whom immunosuppressive therapy has failed or is not appropriate.

Alemtuzumab↗
PubMed2001

Outcome for children after failed transplant for primary haemophagocytic lymphohistiocytosis.

Primary haemophagocytic lymphohistiocytosis is a rare disorder of childhood, which is usually fatal without allogeneic stem cell transplantation (SCT). For children who lack a matched family or closely matched unrelated donor, SCT using haploidentical parental stem cells has been used, but is associated with an increased risk of graft failure. The most appropriate subsequent management for those children who survive after graft rejection is currently unclear. We report the outcome for three such children. After a period of disease quiescence lasting 4 months to 8 years, disease recurrence and subsequent death occurred in each case. Accordingly, a second SCT is recommended.

Female↗
PubMed1999

Granulocyte colony-stimulating factor ameliorates toxicity of intensification chemotherapy for acute lymphoblastic leukemia.

BACKGROUND: Intensification chemotherapy improves the prognosis for children with acute lymphoblastic leukemia (ALL), but results in considerable morbidity, primarily due to myelosuppression with resultant neutropenia. Recombinant granulocyte colony-stimulating factor (G-CSF) shortens neutropenia following intensive chemotherapy, but potential benefits in the therapy of ALL remain inadequately explored. Accordingly, a randomized, crossover study was undertaken to clarify this issue. PROCEDURE: Seventeen children with acute lymphoblastic leukemia or T-cell non-Hodgkin lymphoma and treated on standard protocols were randomized to receive G-CSF following either the first or second intensification blocks of chemotherapy. G-CSF was administered as a single daily subcutaneous injection of 5 mcg/kg from day 9 following the start of intensification therapy, and continued until the neutrophil count exceeded 0.5 x 10(9)/l for 3 days. Study endpoints were days of neutropenia (neutrophils < 1 x 10(9)/l) and severe neutropenia (neutrophils < 0.5 x 10(9)/l), days in hospital, days of fever, and days on antibiotics. RESULTS: There were significant reductions in the duration of neutropenia (95% confidence interval 3.8-8 days, P = 0.0001), severe neutropenia (95% confidence interval 1.8-7.4 days, P = 0.002), and days in hospital (95% confidence interval 0.9-6.3 days, P = 0.01) for children receiving G-CSF. Overall, the duration of neutropenia was longer following the second block (95% confidence interval 2.2-6.4 days, P = 0.0003), but this difference was abolished by G-CSF, and children, receiving G-CSF after the second intensification were more likely to restart maintenance chemotherapy on schedule (P = 0.05). CONCLUSIONS: G-CSF reduces the hematological toxicity of intensification chemotherapy and may allow improved compliance with treatment scheduling.

Adolescent↗
PubMed1999

Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party.

Between May 1988 and March 1995, 359 children with acute myeloid leukaemia (AML) were treated in the MRC AML 10 trial. Three risk groups were identified based on cytogenetics and response to treatment. One hundred and twenty-five children relapsed--103 in the bone marrow only, 12 in the bone marrow combined with other sites, and six had isolated extramedullary relapses (site was not known in four cases). Eighty-seven children received further combination chemotherapy, one all-trans retinoic acid for acute promyelocytic leukaemia, and one a matched unrelated donor allograft in relapse, and 61 achieved a second remission. One patient with no details on reinduction therapy also achieved second remission. Treatment in second remission varied--44 children received a BMT (22 autografts, 12 matched unrelated donor allografts, 10 family donor allografts), and 17 were treated with chemotherapy alone. The overall survival rate for all children (treated and untreated) was 24% at 3 years, with a disease-free survival of 44% for those achieving a second remission. Length of first remission was the most important factor affecting response rates--children with a first remission of less than 1 year fared poorly (second remission rate 36%, 3 year survival 11%), whereas those with longer first remissions had a higher response rate (second remission rate 75%, 3 year survival 49%, P < 0.0001).

Acute Disease↗
PubMed1999

Improved prognosis for acquired aplastic anaemia.

This study compared the prognosis of patients treated for aplastic anaemia at Great Ormond Street Hospital for Children from 1973-88 (group A; n = 38) with a more recent cohort from 1989-96 (group B; n = 37). The two groups were similar in terms of clinical history, age, and severity of aplasia. The main treatment differences included the use of androgen treatment in group A (21 of 38 patients) but not in group B, and the addition of cyclosporin A to immunosuppressive treatment for 14 patients in group B. Actuarial survival at eight years' follow up was significantly better for group B (84%; 95% CI, 68% to 93%) than for group A (45%; 95% CI, 30% to 60%), because of improved outcome for both immunosuppressive treatment (86% v 39%) and bone marrow transplantation (93% v 56%). There was no evidence for late clonal disorders or secondary malignancies in survivors in either group. The prognosis for aplastic anaemia has improved greatly in recent years so that over 80% of children are long term survivors.

Adolescent↗
PubMed1999

Are glomerular filtration rate estimations necessary before high dose methotrexate?

Glomerular filtration rates (GFR) were estimated in 168 children (227 estimates) before treatment for haematological malignancies with high dose, intravenous methotrexate. Clinical management was altered on the basis of GFR in only two cases, both of whom had tumour lysis syndrome. Routine estimations of GFR do not contribute to management.

Antimetabolites, Antineoplastic↗
PubMed1999

Relative osteopenia after treatment for acute lymphoblastic leukemia.

Osteoporosis in adult life is associated with a significant morbidity and may be predisposed to by osteopenia and failure to reach peak bone mass in childhood. Children treated for acute lymphoblastic leukemia (ALL) may be at risk of osteopenia as a result of previous therapy or as a consequence of the disease process itself. Dual energy x-ray absorptiometry measurements of bone mineral content (BMC) for the whole body and at the lumbar spine and hip were taken in 35 (14 male) long-term survivors of ALL and compared with results in 20 (10 male) survivors of other malignancies and 31 (17 male) healthy sibling controls. The measured BMC was expressed as a percentage of a predicted value derived from the control group and based on the variables that had influence upon it. BMC (%) was reduced at the spine in the ALL group compared with controls [92.4 (8.0)% versus 100.4 (9.7)%, respectively; p < 0.005] and at the hip compared with both other malignancies and controls [89.0 (11.5)% versus 96.1 (11.7)% and 100.4 (9.2)%, respectively; p < 0.0005]. Increasing length of time off therapy was associated with a significant increase in %BMC at both the spine and the hip. For the spine, this association was significantly different between the ALL group and other malignancies, suggesting that any gain in %BMC after therapy was slower in children treated for ALL. Both exercise capacity and levels of physical activity were correlated with %BMC at the hip (r = 0.44, p < 0.001 and r = 0.29, p < 0.01, respectively). Previous exposure to methotrexate, ifosfamide, and bleomycin was associated with a reduction in %BMC at the spine. Exposure to 6-mercaptopurine and cisplatin was associated with a reduction at the hip. In conclusion, children treated for ALL are osteopenic. The mechanism is probably multifactorial but is partially related to previous chemotherapy, limited exercise capacity, and relative physical inactivity.

Adult↗
PubMed1998

Measured and predicted bone mineral content in healthy boys and girls aged 6-18 years: adjustment for body size and puberty.

Dual-energy X-ray absorptiometry (DEXA) is a rapid and precise technique for the assessment of bone mineralization in children. Interpretation of the results in growing children is complex as results are influenced by age, body size (height and weight) and puberty. Conventionally, bone mineral data derived from DEXA have been presented as an areal density [BMD; bone mineral content (BMC, g)/projected bone area (BA, cm2)], yet this fails to account for changes in BMC that result from changes in age, body size or pubertal development. Measurement of BMC and BA of the whole body, lumbar spine and left hip were made in 58 healthy boys and girls using DEXA. The relationship between BMC and BA was curvilinear, with the best fit being that of a power model (BMD = BMC/BAlambda, where lambda is the exponent to which BA is raised in order to remove its influence on BMC). The value of lambda changed when measures of body size and puberty were taken into account (e.g. for lumbar spine from 1.66 to 1.49). Predictive formulae for BMC were produced using regression analysis and based on the variables of age, body size and pubertal development. This provides a method for interpreting the measured BMC which is independent of such variables and a constant reference range for children aged 6-18 y.

Absorptiometry, Photon↗
PubMed1998

Daily energy expenditure and physical activity in survivors of childhood malignancy.

Changes in body composition, in particular the onset of obesity, may result from reductions in total daily energy expenditure (TDEE) as a consequence of relative physical inactivity. Children previously treated for acute lymphoblastic leukemia (ALL) become obese, yet the mechanism remains undefined. TDEE and physical activity levels [PAL = TDEE/basal metabolic rate (BMR)] were measured in 34 long-term survivors of ALL and compared with results from 21 survivors of other malignancies and 32 healthy sibling control subjects using the flex-heart rate technique. Body composition was measured by dual energy x-ray absorptiometry. The median TDEE was reduced in the ALL group (150 kJ x kg d(-1)) compared with other malignancies and controls (207 and 185 kJ x kg d(-1), respectively, p < 0.01). This reduction was accounted for mainly by a relative decrease in the PAL of the ALL group (1.24) compared with both other malignancies and controls (1.58 and 1.47, respectively, p < 0.01). TDEE and PAL were correlated with percentage body fat (r = -0.39, p < 0.001 and r = -0.24, p < 0.05, respectively). Obesity in survivors of ALL may, in part, be explained by a reduction in TDEE as a consequence of reduced PAL. The cause of such reduction is uncertain.

Adolescent↗
PubMed1997

Relationship between cardiopulmonary response to exercise and adiposity in survivors of childhood malignancy.

Many long term sequelae result from previous treatment for malignancy in childhood. However, little information exists on cardiopulmonary response and energy expenditure during exercise and their possible associations with excess body fat. Measurements of body composition and exercise capacity both at low intensity and maximal aerobic capacity were made on 56 long term survivors of childhood malignancy (35 survivors of acute lymphoblastic leukaemia (ALL) and 21 survivors of other malignancies) and 32 siblings acting as controls. Female survivors of ALL had significantly greater mean (SD) body fat than survivors of other malignancies and siblings (32.5 (6.4)% v 24.3 (4.4)% and 26.3 (8.5)% respectively, p < 0.005). Energy expenditure at low intensity exercise was reduced in survivors of ALL, and negatively correlated with body fat after controlling for weight (partial r range -0.21 to -0.47, p < 0.05). Stroke volume, measured indirectly, was reduced and heart rate raised in ALL survivors at sub-maximal exercise levels. Peak oxygen consumption was significantly reduced in girls and boys treated for ALL compared with siblings (30.5 v 41.3 ml/kg/min for girls, p < 0.05 and 39.9 v 47.6 ml/kg/min for boys, p < 0.05 respectively). Reduced exercise capacity may account in part for the excess adiposity observed in long term survivors of ALL.

Adolescent↗
PubMed1996

DNA repair fine structure in Werner's syndrome cell lines.

Werner's syndrome (WS) is a human segmental progerioid disorder with an autosomal recessive pattern of inheritance. Patients with WS exhibit a number of symptoms resembling a premature aging phenotype. We have examined the fine structure of the DNA repair of UV-induced cyclobutane pyrimidine dimers in Epstein-Barr virus (EBV)-transformed WS lymphoblastoid cell lines and in a primary WS fibroblast cell line. The repair was measured at the level of the gene and also in the general genome. Gene-specific and strand-specific DNA repair was measured in the actively transcribed genes dihydrofolate reductase (DHFR), c-myc, and p53, and in the transcriptionally inactive regions, delta globin and the X-linked 754 domain. Both gene-specific repair and strand-specific repair were deficient in the transformed WS lymphoblastoid cell lines compared to normal controls. In normal cells, repair in the transcribed strand was 25 (4 h), 43 (8 h), and 72% (24 h); in the WS cells on average, repair in the transcribed strand was 18 (4 h), 27 (8 h), and 44% (24 h). However, in the primary WS fibroblast cell line, we found a pattern of preferential gene repair which was similar to that in normal human cells. In contrast to cells from patients with the gene-specific repair deficient disease Cockayne's syndrome, which show greatly delayed RNA synthesis recovery after UV irradiation, the WS cells had normal recovery of RNA synthesis. The DNA repair results differ for the different cell types, and our findings thus do not establish a general DNA repair phenotype for WS cells. The fibroblasts had proficient repair, but in the WS lymphoblasts we find a deficiency in DNA repair which could contribute to the reported hypermutability in these cells. The lymphoblasts are, however, transformed cells, and it raises the concern that biological findings in transformed cells may not reflect the situation in primary cells.

Blotting, Southern↗
PubMed1996

Histiocyte disorders.

Histiocyte disorders are characterised by tissue infiltration with cells of monocyte/macrophage lineage, with two disorders, Langerhans' cell histiocytosis (LCH) and haemophagocytic lymphohistiocytosis (HLH) accounting for the overwhelming majority of cases in childhood and, apart from monocyte variants of acute myeloid leukaemia, histiocytic malignancy is very rare. Although both LCH and HLH are considered reactive disorders, the prognosis of these conditions differs greatly, LCH is usually self limiting, with a mortality of 10%, but HLH is usually fatal, with a mortality of over 80% in the absence of bone marrow transplantation. Increased levels of cytokines have been demonstrated in these disorders, and may be responsible for many of the clinical features: it is unclear whether histiocytes themselves, or other immune cells, particularly T lymphocytes, are the abnormal cell population. Due to the rarity of histiocyte disorders, collaborative studies are essential to improve understanding and advance treatment.

Child, Preschool↗
PubMed1995

Evidence of clonality in a child with haemophagocytic lymphohistiocytosis.

DNA from the bone marrow of a child with haemophagocytic lymphohistiocytosis was examined by polymerase chain reaction for evidence of rearrangement of the T-cell receptor delta chain gene. Evidence of clonal rearrangement was detected, supporting a role for abnormalities of T-cell function in the pathogenesis of this disorder.

Clone Cells↗