Biomedical subjects

I Hann

Publications and source records attributed to I Hann.

At least 37 records · Page 2Linked to original sources

PubMed1998

Improved survival with early intensification: combined results from the Medical Research Council childhood ALL randomised trials, UKALL X and UKALL XI. Medical Research Council Working Party on Childhood Leukaemia.

The Medical Research Council (MRC) United Kingdom trial for childhood acute lymphoblastic leukaemia (UKALL X) randomised patients aged 0-14 years inclusive with an initial white blood count of less than 100 x 10(9)/l to receive an early intensification block, a late intensification block, both, or neither. The next trial, UKALL XI, for children aged 1-14 years, randomised between different central nervous system (CNS) directed therapies. At the beginning of the trial, all patients were also randomised between late intensification alone and both early plus late blocks. The effects of both the early and the late block in UKALL X alone have been reported previously. This paper examines the effect of the addition of the early intensification block to treatment which included late intensification, combining the data from UKALL X and the first part of UKALL XI. Early intensification was associated with fewer bone marrow relapses and a reduction in the odds of death of 0.63 (95% confidence interval: 0.46-0.87). Survival was significantly improved with an increase at 5 years of 8%, from 79 to 87%. Following this demonstration that early intensification improves survival, the effect of a third intensification block is under investigation.

Adolescent↗

PubMed1998

Prothrombotic changes in children with sickle cell disease: relationships to cerebrovascular disease and transfusion.

Vascular occlusion has a central role in the pathophysiology of sickle cell disease (SCD) and, although there is little evidence that thrombosis alone is responsible, patients with sickle cell disease are known to have an ill-defined but increased thrombotic risk. The most serious complication of this in childhood is stroke which occurs in 7-10% of children and a further 14% have asymptomatic cerebrovascular disease (CVD) on imaging. We have performed a comprehensive profile of coagulation inhibitors and markers of thrombin generation in 96 children (83 nontransfused [NTx] and 13 transfused [Tx]) with steady-state SCD and 18 healthy sibling controls. The levels of protein S (free and total) and heparin cofactor II were reduced in both the NTx and Tx groups compared to controls and protein C and APC resistance ratios were reduced in the NTx group only. Antithrombin levels were not different from controls. Thrombin-antithrombin complexes and prothrombin fragment F1+2 were increased in both patient groups. In the NTx subgroups with or without CVD there were no differences for any of the parameters measured except for lower haemoglobin levels and higher white cell counts in those with asymptomatic CVD. We conclude that children with SCD have a reduction in levels of the majority of the coagulation inhibitors and increased thrombin generation in the steady-state and these are only partially reversed by transfusion. However, these abnormalities do not appear to play a primary role in the development of cerebrovascular disease.

Activated Protein C Resistance↗

PubMed1998

Inherited prothrombotic states and ischaemic stroke in childhood.

OBJECTIVE: To investigate the prevalence of currently recognised inherited prothrombotic states in a population of children with arterial stroke. METHODS: Children with arterial stroke presenting to a tertiary level paediatric neurology centre between 1990 and 1996 were investigated for inherited prothrombotic states. RESULTS: Sixty seven children with arterial stroke were investigated. Abnormalities were initially identified in 16 patients; however, only eight children (12%) had an inherited prothrombotic state. This was type 1 protein S deficiency in one patient, the factor V Leiden mutation in six, and activated protein C resistance (without the factor V Leiden mutation) in one. The prevalence of the factor V Leiden mutation was not significantly higher in children with arterial stroke (12%) than in a control population of children without thrombosis attending the same institution (5.2%; Fisher's exact test, p=0.19; difference in prevalence between patients and controls (95% confidence interval)=6.8% (-2.78% to 16.8%)). CONCLUSIONS: Currently recognised inherited prothrombotic tendencies were rarely associated with stroke in this group of children, although larger numbers of patients would be needed to confirm this. Age appropriate normal values should be used when interpreting the results of a prothrombotic screen. Prothrombotic abnormalities seen acutely are as often transient as inherited. Longitudinal assessment and family studies are required before low concentrations of an anticoagulant protein found acutely can be attributed to an inherited abnormality.

Adolescent↗

PubMed1998

Demyelination and single-carbon transfer pathway metabolites during the treatment of acute lymphoblastic leukemia: CSF studies.

PURPOSE: To investigate the hypothesis that methotrexate causes demyelination due to a deficiency in S-adenosylmethionine (SAM) during the treatment of acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twenty-four patients treated on the Medical Research Council United Kingdom ALL trial no. 11 (MRC UKALL XI) were studied. The trial randomized patients at the presymptomatic CNS treatment (PCNS) phase to receive (1) intrathecal methotrexate and cranial radiotherapy (CRTX); (2) high-dose intravenous methotrexate with folinic acid rescue and continuing intrathecal methotrexate (HDMTX); and (3) continuing intrathecal methotrexate alone (ITMTX). Serial CSF samples were collected throughout treatment and concentrations of 5-methyltetrahydrofolate (MTF), methionine (MET), SAM, and myelin basic protein (MBP) were measured. The results were grouped into treatment milestones and compared with an age-matched reference population. RESULTS: There was a highly significant effect of both treatment milestones and trial arm on the metabolite and MBP concentrations. CSF MTF reached a nadir during the induction phase of treatment, while SAM and MET reached their nadir during the consolidation phase. CSF MBP mirrored SAM concentration and there was a significant inverse relationship between the two. MTF, SAM, and MBP returned to normal values by the end of treatment, while MET was increased significantly. The effect of treatment was decremental across the ITMTX, HDMTX, and CRTX groups. CONCLUSION: Treatment of ALL causes marked abnormalities in the single-carbon transfer pathway and subclinical demyelination. Methotrexate is one cause of this. Whether these abnormalities contribute to the late cognitive deficits requires further study.

Antidotes↗

PubMed1997

A comparison of outcome from febrile neutropenic episodes in children compared with adults: results from four EORTC studies. International Antimicrobial Therapy Cooperative Group (IATCG) of the European Organization for Research and Treatment of Cancer (EORTC).

The object of this study was to determine whether there were any differences between the 'typical' child with fever and neutropenia and their adult counterpart with regard to infection type and outcome, by analysis of 3080 patients, including 759 children < 18 years of age and 2321 adults. These represented patients randomized in previous trials, between 1986 and 1994, which compared empirical antibiotic regimens for fever in neutropenic patients. There were fewer childhood acute myeloid leukaemia patients than adults but more acute lymphoblastic leukaemia cases and more with solid tumours undergoing intensive myelosuppressive therapy. The children were less likely to be undergoing first induction therapy but the relative incidence of patients receiving relapse schedules or maintenance therapies were not significantly different in the two age groups. Children less frequently had a defined site of infection than adults and where they had a defined site there were more upper respiratory tract but fewer lung infections. There was a similar low incidence of shock at presentation in the two groups but the children's median neutrophil count was lower, and their median duration of granulocytopenia before the trial was shorter. The incidence of bacteraemia was similar, but clinically documented infection was less frequent and fever of unknown origin consequently more common in children. Children developed more streptococcal bacteraemias and fewer staphylococcal bacteraemias than adults (P=0.003) but the relative incidence of various gram-negative species was similar (P=0.57). In general, the children had a better overall success rate and lower mortality than adults. Death from infection was only 1% in children versus 4% in adults (P=0.001), and time to defervescence was shorter in children. In the younger age group, univariate logistic regression models showed high temperature, prolonged neutropenia before the trial and shock as prognostic indicators for the presence of bacteraemia. Solid tumour patients were significantly less likely to have a bacteraemia. Multivariate analysis confirmed the independent prognostic value of these indicators. Using the logistic equation of the selected model, the overall discriminant ability was poor. However, it was possible to identify a small subgroup without shock or high fever and with a short prior duration of neutropenia which carries a particularly low risk of bacteraemia, who could be considered for early discharge, monotherapy and shortened courses of antibodies, in prospective trials.

Acute Disease↗

PubMed1997

Continuous infusion therapy with very high purity von Willebrand factor concentrate in patients with severe von Willebrand disease.

Five patients with severe (type III) von Willebrand disease received, by continuous infusion, a solvent-detergent treated von Willebrand factor high purity concentrate to control haemostasis. The clinical indications for treatment included prophylaxis prior to orthopaedic, abdominal and tympanic membrane surgery, and treatment of epistaxis and trauma-related bleeding. Plasma vWf antigen and activity were normalized sooner than factor VIII:C levels after initial bolus followed by infusion of the concentrate. Haemostasis was established in all five patients. The degree of shortening of the bleeding time correlated with concentrate infusion rate and, therefore, with administered dose of high molecular weight multimers. Concentrate clearance decreased over time with continued infusion. The product was shown to be stable and sterile at 24 h after reconstitution with no evidence of neoantigen expression. This report illustrates the effectiveness of high purity vWf concentrate administered by continuous infusion and shows that high-molecular-weight multimers are required to shorten the bleeding time to within the normal range.

Adolescent↗

PubMed1996

Intravenous immunoglobulin, splenectomy, and antibiotic prophylaxis in Wiskott-Aldrich syndrome.

AIM: To assess the results of supportive treatment with intravenous immunoglobulin (IVIG) and antibiotic prophylaxis in combination with splenectomy in patients with Wiskott-Aldrich syndrome. STUDY DESIGN: Retrospective review of case records of 21 patients from March 1984 to February 1996. RESULTS: Thrombocytopenia was cured in 14 of 15 patients who had splenectomy, but it recurred intermittently in three. Mean platelet volume (MPV) was normal transiently in some patients, but all MPV values were subnormal 8-23 months after splenectomy. Antibiotic and IVIG prophylaxis may have contributed to the lack of a detectable increase in the number of severe acute bacterial infections in the 451 months after splenectomy. Four patients died in 2205 months of observation before and after splenectomy (median 82, range 16-248): two of cerebral B cell lymphoma, one of progressive multifocal leucoencephalopathy, and one with severe chronic chest disease of pneumonia. CONCLUSION: Adequate supportive treatment with IVIG and antibiotic prophylaxis together with splenectomy enables good survival and quality of life in the short and medium term in patients with Wiskott-Aldrich syndrome. Persistence of infection, bleeding, and vasculitic and allergic symptoms in a significant minority and the risk of development of lymphoma, however, suggest that bone marrow transplantation may be indicated if an HLA identical donor is available.

Anti-Bacterial Agents↗

PubMed1995

Primary extra-thoracic T-cell non-Hodgkin's lymphoma of childhood. The United Kingdom Children's Cancer Study Group.

Between 60-80% of non-Hodgkin's lymphoma (NHL) of T-cell lineage in children, present with primary mediastinal disease. On current therapy, this and nodal low-stage disease are associated with a relatively favourable outcome. In order to evaluate whether the primary site of disease is a prognostic factor, we examined the clinical characteristics and outcome of 36 children with primary extrathoracic T-cell NHL diagnosed during a 7-year period by the United Kingdom Children's Cancer Study Group. Eight, eight, 11 and nine children had stage I, II, III and IV disease, respectively. The primary site of disease was nodal in 22, skin and subcutaneous tissue in five, abdominal in three, bone in three and at other sites in three. Eighteen (50%) had lymphoblastic, ten (28%) large cell anaplastic (LCA) and seven (19%) pleomorphic large or medium cell (PLC) tumours. In one child the histology was inconclusive. All children with lymphoblastic, three with LCA, three with PLC disease and one with unknown histology were treated on intensive, sustained and continuous leukaemia protocols. Ten, seven with LCA and three with PLC, were treated on regimens of short duration pulsed therapy and one child with PLC with radiotherapy only. The three-year event-free survival (EFS) was 78% for the group as a whole. Those with stage IV lymphoblastic disease had a significantly worse prognosis (p < 0.0005). Primary site of disease, gender, therapeutic regimen and histology were not predictive for survival. In primary extrathoracic T-cell NHL with lymphoblastic histology, leukaemia-like therapy is recommended. For non-lymphoblastic disease, in particular the Ki-1 positive tumours, evidence suggests that short duration pulsed therapy may be optimal.

Adolescent↗

PubMed1993

Detection of missense mutations by single-strand conformational polymorphism (SSCP) analysis in five dysfunctional variants of coagulation factor VII.

Five unrelated subjects with dysfunctional coagulation factor VII (FVII) were studied in order to identify missense mutations affecting function. Exons 2 to 8 and the intron-exon junctions of their FVII genes were amplified from peripheral white blood cell DNA by PCR and screened by SSCP analysis. DNA fragments showing aberrant mobility were sequenced. The following mutations were identified: in case 1 (FVII:C < 1%, FVII:Ag 18%) a heterozygous A to G transition at nucleotide 8915 in exon 6 results in the amino acid substitution Lys-137 to Glu near the C-terminus of the FVIIa light chain; in case 2 (FVII:C 7%, FVII:Ag 47%) a heterozygous A to G transition at nucleotide 7834 in exon 5 results in the substitution of Gln-100 by Arg in the second EGF-like domain; in case 3 (FVII:C 20%, FVII:Ag 76%) a homozygous G to A transition at nucleotide position 6055 in exon 4 was detected resulting in substitution of Arg-79 by Gln in the first EGF-like domain; in case 5 (FVII:C 10%, FVII:Ag 52%) a heterozygous C to T transition at nucleotide position 6054 in exon 4 also results in the substitution of Arg79, but in this case it is replaced by Trp; case 4 (FVII:C < 1%, FVII:Ag 100%) was homozygous for a previously reported mutation (G to A) at nucleotide position 10715 in exon 8, substituting Gln for Arg at position 304 in the protease domain. Cases 1, 2 and 5 evidently have additional undetected mutations.

Amino Acid Sequence↗

PubMed1993

Assessment of graft status following allogeneic bone marrow transplantation for haematological disorders in children using locus-specific minisatellite probes.

We have examined peripheral blood or bone marrow DNA following allogeneic bone marrow transplantation (BMT) in children suffering from a variety of haematological disorders. Using either locus-specific minisatellite probes separately or in combination with a Y specific probe for sex-mismatched transplants, complete haematological chimaerism, autologous reconstitution, or mixed chimaeric states have been defined immediately post-BMT. We have also been able to identify emerging autologous cells or relapse prior to morphological diagnosis. Forty-two children, mean age 6.4 years (range 9 months to 15 years), received an allogeneic BMT for: acute lymphoblastic leukaemia (ALL), n = 17; acute myeloid leukaemia (AML), n = 5; biphenotypic leukaemia, n = 1; myelodysplastic syndrome (MDS), n = 5; chronic granulocytic leukaemia (CGL), n = 1; severe aplastic anaemia (SAA), n = 7; familial erythrophagocytic lymphohistiocytosis (FEL), n = 2; beta thalassaemia major (beta thal), n = 1; and juvenile chronic myeloid leukaemia (JCML), n = 3. Immediately post-transplant, 78% had achieved complete haematological chimaerism, 12% had failed to engraft (DNA analysis confirmed autologous reconstitution) and 10% had mixed chimaerism. SAA was the underlying disease in two of the chimaeric cases, the third case having had a matched unrelated donor (MUD) BMT for MDS. In 3/4 cases which subsequently relapsed, DNA analysis showed re-emergence of autologous cells (indicative of relapse), prior to their morphological identification. We conclude that DNA analysis using minisatellite probes to assess graft status provides a useful contribution to patient management following allogeneic BMT.

Bone Marrow Transplantation↗

PubMed1992

Treatment of advanced stage T cell lymphoblastic lymphoma: results of the United Kingdom Children's Cancer Study Group (UKCCSG) protocol 8503.

Ninety-five unselected patients with stage III and IV T cell lymphoblastic lymphoma were treated according to the United Kingdom Children's Cancer Study Group protocol 8503. This was a continuous, intensive leukaemia type regimen including cranial irradiation (18 Gy in 10 fractions) and continuing chemotherapy for 2 years identical to the concurrent Medical Research Council ALL protocol. Four-year event-free survival was 65% (95% CI 50-80%) with no significant difference between stage III and stage IV cases. 4.2% of patients died of infection or non-tumour related events. Following relapse salvage was unlikely without high dose chemotherapy and bone marrow rescue. These results show an improvement over previous U.K. studies but we need to continue to search for subsets of patients with resistant disease for whom even more intensive therapy possibly combined with bone marrow rescue is required.

Adolescent↗

PubMed1991

Outcome in stage III non-Hodgkin's lymphoma in children (UKCCSG study NHL 86)--how much treatment is needed? United Kingdom Children's Cancer Study Group.

Forty-four children aged 3-13 years with Murphy stage III B cell non-Hodgkin's lymphoma were treated between May 1986 and December 1989. All have been followed up for at least 12 months. The primary site was the abdomen in 37 children, 24 of whom had involvement of other organs or nodal disease outside the abdomen. Twenty-eight received a standard dose regimen (regimen 1) and 16 had a more intensive regimen (regimen 2--MACHO). Fourteen patients (87%) who received MACHO had extensive multi-organ disease compared to 15 (53%) on regimen 1. Most of the latter had only pleural effusions. Thirty-four children are alive relapse free and considering the early relapse pattern in this disease are probably cured (actuarial event free survival = 76%). There has been one relapse (6%) after MACHO, but three toxic deaths. Six patients (21%) on the less intensive regimen have relapsed. Morbidity was high in terms of infection and need for haematological support and hospitalisation in the one third of children electively given the more intensive regimen. It is concluded that the vast majority of children with stage III disease who have disease limited to lymph nodes are curable with a moderately intensive regimen. Those with multiorgan involvement probably require more intensive treatment. It is therefore of importance to clarify prognostic factors in these patients to determine who can be cured with a less intensive regimen and who requires further dose intensification.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

Immunohistological diagnosis of "plasmacytoid T cell lymphoma" in paraffin wax sections.

An immunohistological study of paraffin wax embedded tissue from three cases of plasmacytoid monocyte neoplasms, using a panel of antibodies which react with fixation resistant leucocyte markers, is reported. This neoplasm was found to have a distinctive antigenic profile, being negative for CD3 and elastase, but positive for CD43 and CD68. This immunological phenotype, coupled with its characteristic morphological features, should facilitate the recognition of this rare neoplasm in routinely processed tissue. Furthermore, the term "plasmacytoid monocyte sarcoma" is proposed to designate it because it is inappropriate to refer to it as a lymphoma. As all cases have been associated with a myeloproliferative disorder (usually an acute or chronic myeloid leukaemia), these tumours probably represent the accumulation in lymphoid tissue of neoplastic cells which have differentiated along the plasmacytoid monocyte pathway.

Aged↗

PubMed1989

Hepatocarcinoma in a child: a clinical and experimental study.

An inoperable hepatocarcinoma in a 2-year-old female was treated with chemotherapy. Regression of the tumour allowed complete surgical excision. The tumour was successfully xenografted into athymic rats. Growth of tumour was monitored by external measurement and plasma alphafetoprotein (AFP) assays. AFP levels meanwhile in the patient fell from 2 x 10(6) international units/ml preoperatively to 10 units/ml post-operatively. The value of AFP as a tumour marker in hepatic tumours and the availability of xenograft material for experimentation enabled the measurement of plasma AFP levels as well as assessing the tumour mass.

Animals↗

PubMed1988

A randomized trial of empirical antibiotic therapy with one of four beta-lactam antibiotics in combination with netilmicin in febrile neutropenic patients.

Over a two year period 174 evaluable episodes of fever in neutropenic patients were treated in a randomized study comparing four beta-lactam antibiotics, each given in combination with netilmicin. Exclusions included episodes due to viral or fungal infection, and trial violations. Most patients were receiving treatment for leukaemia, including 18% undergoing bone marrow transplantation. The overall response rate (EORTC criteria) was 66%, ranging from 56% for cefoperazone to 76% for mezlocillin. Microbial documentation was obtained in 31% of episodes; Gram-positive isolates were most frequent but Pseudomonas aeruginosa was found in 18 patients. In patients with microbiologically documented infection 70% improved, overall--from 40% with cefoperazone to 80% with piperacillin (P less than 0.05). Nephrotoxicity was seen in 6.7% and was associated with severe documented sepsis. Hypokalaemia was seen in 29% and was most marked in patients receiving ticarcillin. Rashes occurred in 6.6% overall, with no difference between the groups. Ototoxicity, shown by serial audiograms, was seen in 4.7% of patients. No evidence of vestibular dysfunction was seen in 62 patients studied. Of thirteen deaths due to the primary infection, seven were caused by Ps. aeruginosa and five by fungi.

Agranulocytosis↗

PubMed1988

Autologous bone marrow transplantation in acute lymphoblastic leukemia--preclinical immunologic studies.

Immunologic aspects of autologous bone marrow transplantation (ABMT), immunodiagnosis, patient monitoring, and the purging of bone marrow have been studied in individual patients. It was demonstrated that the most sensitive method for detecting lymphoid cells which show the phenotypes of ALLs of B or T lineage was double immunofluorescence staining for nuclear terminal transferase (TdT) and B or T lineage antigens. With the help of these sensitive tests in the presence of rabbit complement (C'), MAbs CD10 (RFAL3 of IgM class), CD19 (SB4 of IgM class), and their cocktail were capable of eliminating greater than 3 log blast cells of B lineage ALL in 84%, 75.5%, and 90% of cases, respectively. The same reagents lysed 26.8%, 0%, and 45% of blasts in the presence of human C'. CD7 (RFT2, IgG2) eliminated greater than 3 log T-ALL blast cells in 73% of cases. The proliferative fractions of leukemic blasts were also TdT+ and sensitive to lysis with MAb and C'. On the basis of these observations MABs were selected for purging in 36 patients undergoing ABMT in first remission (10 patients considered to be at a high risk of relapse), second and third remissions (23 and 2 patients), and without entering into remission (1 patient). The efficacy of eliminating the MAb-reactive cells from the bone marrow inoculum was also documented in five patients. By the use of sensitive immunologic assay (TdT/cytoplasmic CD3 double staining) in patients with T-ALL, no residual leukemia (less than 10(-4] could be detected at the time of transplantation. Following an observation period of 5-34 months, 24 of the 36 patients are alive and well with no procedure-related mortality.

Antibodies, Monoclonal↗

PubMed1987

Scottish validation study of Cancer Registration data childhood leukaemia 1968-1981--I.

This study attempted to validate central registration data on all childhood leukaemia cases in Scotland between 1968 and 1981 in line with the Black Enquiry concerning West Cumbria. Missing files precluded a complete verification, but minor errors of registration were found in 44% of cases. A small number of important mistakes of omission (eight cases), wrong diagnosis (six cases) and postal code errors (nine cases) were found which might affect epidemiological studies of these relatively rare diseases. Precise and verified prospective data collection at the time of diagnosis is essential if the spatial distribution of childhood cancers is being studied.

Adolescent↗

PubMed1986

A prospective study of the histological changes in the skin in patients receiving bone marrow transplants.

Fourteen patients who received a bone marrow transplant (BMT) as treatment for leukaemia were included in a prospective study of the histological changes in the skin. The aim of this study was to improve the early diagnosis of graft-versus-host disease (GVHD). It was found that the clinically 'normal' pre-transplant skin was in some cases histologically abnormal on H & E examination in patients who were on regular maintenance cytotoxic chemotherapy. These changes were similar to some of the features of GVHD. Immunocytochemistry, although not specific, was found to be helpful in the diagnosis of some cases of GVHD. Suggestive features included a reduction in the numbers of Langerhans cells, an increase in the number of suppressor (OKT8+) cells in the dermal infiltrate and the presence of Ia positivity of the keratinocytes in the epidermis.

Adult↗