PubMed Health⌕ Search

Biomedical subjects

H G Prentice

Publications and source records attributed to H G Prentice.

At least 55 records · Page 3Linked to original sources
PubMed2000

Fatal invasive cerebral Absidia corymbifera infection following bone marrow transplantation.

A 56-year-old dairy farmer received a fully HLA matched unrelated donor marrow transplant for high risk CML in chronic phase. His early post-transplant course was complicated by a series of massive intracerebral bleeds and by sepsis related to a malignant otitis externa. The microbial pathogen isolated from ear swabs was found to be Absidia corymbifera, but CT scan at the time showed no intracerebral extension. Despite neutrophil engraftment and aggressive antifungal management he succumbed. Autopsy revealed invasion of Absidia into the brain from the ear. We speculate that colonisation by Absidia resulted from occupational exposure.

Absidia↗
PubMed2000

Analysis of ETV6/AML1 abnormalities in acute lymphoblastic leukaemia: incidence, alternative spliced forms and minimal residual disease value.

The t(12;21)(p13;q22) translocation, resulting in the fusion of the ETV6 and AML1 genes, occurs in 20-25% of paediatric B-lineage acute lymphoblastic leukaemias (ALL). The identification of the fusion product has important prognostic and therapeutic implications as the translocation has been associated with a favourable clinical outcome. The aim of this study was threefold: (i) to assess the frequency and clinical association of the fusion gene in patients with and without a cytogenetically detectable chromosome 12 and/or 21 abnormality or failed cytogenetic results, (ii) to characterize alternative forms of ETV6/AML1 transcripts, and (iii) to use ETV6/AML1 as a molecular marker for the investigation of minimal residual disease (MRD). ETV6/AML1 fusion was detected in 22 (39%) of 56 cases studied by reverse transcriptase polymerase chain reaction (RT-PCR). ETV6/AML1 fusion was found in nine out of 16 (56%) cases with a cytogenetically visible chromosome 12 abnormality, but also in nine out of 29 patients (31%) without a chromosome 12 abnormality or patients with failed cytogenetics (four out of 11 patients, 36%), making this the most common cytogenetic abnormality in childhood ALL. Alternatively spliced ETV6/AML1 forms were investigated in 14 of the positive patients. Exon 5 of ETV6 was fused in frame to all AML1 exons, except exon 4. Fusion to exon 6 of AML1 resulted in one amino acid change. The presence of ETV6/AML1 was associated with a lower white blood cell count (Student's t-test; P = 0.009) and common (c)ALL phenotype (chi(2) test; P > 0.001), but no better disease-free survival. Our study shows that (i) RT-PCR is the most effective approach for the detection of t(12;21) in childhood ALL, (ii) the association of ETV6/AML1 and chromosome 12 and/or 21, seen in 56% of our cases, further confirms existing data, (iii) overall survival of patients with t(12;21) was not better than other cytogenetics groups, and (d) MRD analysis using ETV6/AML1 fusion is specific, but not sensitive enough to avoid false negative results.

Adolescent↗
PubMed2000

Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study.

Severe hepatic veno-occlusive disease (VOD) is a recognized complication of autologous and allogeneic stem cell transplantation (SCT) that is often fatal. Defibrotide (DF) is a polydeoxyribonucleotide that has been found to have anti-thrombotic, anti-ischaemic and thrombolytic properties without causing significant anticoagulation. Preliminary studies have demonstrated activity for DF in the treatment of VOD, with minimal associated toxicity. In the present study, 40 patients who fulfilled established criteria for VOD were treated with DF on compassionate grounds in 19 European centres; 28 patients met risk criteria predicting progression of VOD and fatality or had evidence of multiorgan failure (MOF), and were defined as 'poor-risk'. DF was commenced intravenously at a median of 14 d (range, -2 d to 53 d) post SCT at doses ranging from 10 to 40 mg/kg. The median duration of therapy was 18 d (range, 2--71 d). Twenty-two patients showed a complete response (CR) (bilirubin < 34.2 micromol/l and resolution of signs/symptoms of VOD and end-organ dysfunction) [CR = 55%, confidence interval (CI) 40--70%] and 17 patients (43%) are alive beyond d +100. Ten poor-risk patients showed a complete response (CR = 36%, CI 21--51%). These results demonstrate that DF is an active treatment for VOD following SCT and a randomized trial is now underway in order to further evaluate its role.

Acute Disease↗
PubMed2000

Is there a graft-versus-leukaemia effect in the absence of graft-versus-host disease in patients undergoing bone marrow transplantation for acute leukaemia?

During a 13-year period, 5200 autografts, 1039 HLA-identical sibling transplants without acute or chronic graft-vs.-host disease (GVHD) and 67 twins were reported to the European Group for Blood and Marrow Transplantation EBMT. Follow-up time was a median of 32 months. Diagnoses were acute myeloid leukaemia (AML, 4521) and acute lymphoblastic leukaemia (ALL, 1785) in first complete remission. The probability of relapse at 5 years was 51 +/- 1% in the autografts, 45 +/- 8% in the twins and 34 +/- 2% among the HLA-identical siblings (auto vs. sibs, P < 0.0001). In multivariate analyses, the following factors were significantly associated with an increased risk of relapse: ALL vs. AML M3 [relapse rate (RR) 2.29, P < 0.0001], AML non-M3 vs. AML M3 (RR 1.8, P < 0.0001), autograft vs. sibling transplant (RR 1.76, P < 0.0001), interval diagnosis to transplantation < 261 d (RR 1.45, P < 0.001) and other conditioning vs. total body irradiation (RR 1.16, P = 0.001). Transplant-related mortality was the same in the three groups at approximately 10% at 2 years. Five-year leukaemia-free survival was 42 +/- 1% in the autografts, 44 +/- 8% in the twins and 58 +/- 2% among the siblings (auto vs. sibs, P < 0.0001). The factors significant for relapse were also significant in multivariate analyses for leukaemia-free survival. In addition, children had a significantly better leukaemia-free survival than adults (RR 0.82, P < 0.0001). Recipients of bone marrow from HLA-identical siblings without GVHD had a lower risk of relapse and a better leukaemia-free survival than recipients of autografts. This may be as a result of a graft-vs.-leukaemia effect in the absence of GVHD.

Acute Disease↗
PubMed2000

Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia.

PURPOSE: Preparative regimens involving total-body irradiation (TBI) produce significant late toxicities in some children who receive bone marrow transplants, including impaired growth and intellectual development. Busulfan is often used as an alternative to TBI, but there are few data regarding its relative efficacy. PATIENTS AND METHODS: We compared outcomes of HLA-identical sibling transplants for acute lymphoblastic leukemia (ALL) in children (< 20 years of age) who received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning. Patients received transplants between 1988 and 1995 and their results were reported to the International Bone Marrow Transplant Registry by 144 participating institutions. The CY/TBI and Bu/CY groups did not differ in gender, immune phenotype, leukocyte count at the time of diagnosis, chromosome abnormalities, remission status, or length of initial remission. T-cell depletion was used more frequently in the CY/TBI group; the Bu/CY group included a higher proportion of children who were less than 5 years of age. The median follow-up period was 37 months. RESULTS: The 3-year probabilities of survival were 55% (95% confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%) with Bu/CY (univariate P =.003). The 3-year probabilities of leukemia-free survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively (univariate P =.005). In a multivariate analysis, the risks of relapse were similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P =.1). Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P =.012). Death and treatment failure (relapse or death, inverse of leukemia-free survival) were more frequent in the Bu/CY group (RR, 1. 39; P =.017 for death; RR, 1.42; P =.006 for treatment failure). CONCLUSION: These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.

Adolescent↗
PubMed1999

Malignant neoplasms in long-term survivors of bone marrow transplantation. Late Effects Working Party of the European Cooperative Group for Blood and Marrow Transplantation and the European Late Effect Project Group.

BACKGROUND: Patients who receive bone marrow transplants have increased risk for new malignant conditions because of several risk factors, including conditioning with radiation and chemotherapy, immune stimulation, and malignant primary disease. The occurrence of and risk factors for malignant neoplasm in long-term survivors must be assessed. OBJECTIVE: To determine the risk and define potential risk factors for new malignant conditions in long-term survivors after marrow transplantation. DESIGN: Retrospective multicenter study. SETTING: Study of the Late Effects Working Party with 45 transplantation centers cooperating in the European Cooperative Group for Blood and Marrow Transplantation. PATIENTS: 1036 consecutive patients who underwent transplantation for leukemia, lymphoma, inborn diseases of the hematopoietic and immune systems, or severe aplastic anemia. Transplantation was done before December 1985, and patients had survived more than 5 years. MEASUREMENTS: Reports on malignant neoplasms were evaluated, and the incidence was compared to that in the general population. Patient age and sex, primary disease and status at transplantation, histocompatibility of the donor, conditioning regimen, type of prophylaxis of graft-versus-host disease, development of acute and chronic graft-versus-host disease, and treatment of chronic graft-versus-host disease were evaluated as variables. RESULTS: Median follow-up since transplantation was 10.7 years (range, 5 to 22.1 years). Malignant neoplasms were seen in 53 patients; the actuarial incidence (+/- SE) was 3.5% +/- 0.6% at 10 years and 12.8% +/- 2.6% at 15 years. The rate of new malignant disease was 3.8-fold higher than that in an age-matched control population (P < 0.001). The most frequent malignant diseases were neoplasms of the skin (14 patients), oral cavity (7 patients), uterus (including cervix) (5 patients), thyroid gland (5 patients), breast (4 patients), and glial tissue (3 patients). Median age of patients and their donors was 21 years. Malignant neoplasms were more frequent in older patients and in patients with chronic graft-versus-host disease. Older patient age and treatment of chronic graft-versus-host disease with cyclosporine were significant risk factors for new malignant neoplasms after bone marrow transplantation. CONCLUSIONS: The spectrum of neoplasms and immunosuppressive treatment with cyclosporine for chronic graft-versus-host disease as dominant risk factors indicate that immunosuppression is the major cause of malignant neoplasms in patients receiving marrow transplants.

Adolescent↗
PubMed1999

Selective removal of alloreactive cells from haematopoietic stem cell grafts: graft engineering for GVHD prophylaxis.

One of the main goals in allogeneic bone marrow transplantation is the abrogation of graft-versus-host disease with the preservation of antileukaemia and antiviral activity. We have established a novel system for the selective removal of alloreactive lymphocytes from donor grafts while retaining an effective allogeneic response to third-party stimulator cells. Initial feasibility studies were done with unrelated HLA-mismatched pairs and then extended into the matched setting. Mononuclear cells from HLA-matched donors were cocultured with irradiated recipient cells prestimulated with cytokines (gamma-IFN and TNF-alpha) in a modified mixed lymphocyte culture (MLC). Alloreactive donor lymphocytes were identified by expression of CD69, an early activation marker and selectively removed by paramagnetic bead sorting. The remaining 'non-alloreactive' lymphocytes were tested in proliferative assays against the original matched recipient and to a third-party donor. A mean depletion of proliferative capacity to 11.5 +/- 9.9% of the original matched recipient response was achieved while the residual third-party response was largely preserved at 77.8 +/- 20.9% which should translate into improved immune reconstitution and preservation of antiviral activity. The non-alloreactive lymphocytes could also possess functional antileukaemia activity. Moreover, the alloreactive cells are easily recoverable in this selective T cell depletion strategy for cryopreservation and ready for immediate access as therapeutic donor lymphocyte infusions in cases of frank relapse post transplant.

Antigens, CD↗
PubMed1999

HHV-6-related secondary graft failure following allogeneic bone marrow transplantation.

We report the case of an 11-year-old boy who underwent allogeneic bone marrow transplantation (BMT) for relapsed acute lymphoblastic leukaemia. Despite adequate engraftment, on day 45 he developed marrow aplasia with haemophagocytosis. HHV-6 was detected in blood and bone marrow by nested PCR. Retrospective testing showed that viraemia had started on day 24. Following therapy with foscarnet and ganciclovir, viral load declined to undetectable levels and his donor marrow recovered contemporaneously. This case suggests that HHV-6 may be a treatable cause of graft failure following BMT and provides clinical and virological evidence for the anti-HHV-6 activity of ganciclovir and foscarnet.

Antiviral Agents↗
PubMed1999

A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies. U.K. Multicentre Antifungal Prophylaxis Study Group.

Fluconazole is widely used as antifungal prophylaxis but it is ineffective against Aspergillus. Itraconazole has a broader spectrum of activity but the capsules give erratic bioavailability in neutropenic patients. We compared itraconazole oral solution (which has an improved pharmacokinetic profile) with fluconazole for antifungal prophylaxis. Adults with haematological malignancies receiving chemotherapy or bone marrow transplants were randomly allocated 5 mg/kg/d itraconazole (itra) solution (288 episodes) or 100 mg fluconazole suspension (flu) (293 episodes) from before the onset of neutropenia until neutrophil recovery or suspected fungal infection. Outcomes were assessed by independent reviewers unaware of the prophylaxis allocation. More proven systemic fungal infections occurred in flu (Aspergillus four, Candida tropicalis one, C. krusei one) than itra (C. albicans one) and more of these were fatal (four versus nil). This difference reached statistical significance when first study episodes were considered separately (six flu versus nil itra, P = 0.03). Significantly more deaths of presumed fungal origin occurred in flu than itra (seven versus nil, P = 0.024). There were significantly more cases of proven aspergillosis in flu than itra (six versus nil, P = 0.038, 5/6 cases were fatal) if those occurring outside the study period are included. Significantly more patients receiving flu required amphotericin B (58 v 39, P = 0.043) but this may have been affected by the fact that the study was not blinded. There were 11 proven mucosal candidal infections in flu and four in itra. Itraconazole solution and fluconazole provide effective prophylaxis against Candida but itraconazole affords greater protection against fatal aspergillosis.

Adolescent↗
PubMed1999

Respiratory infections in immunocompromised patients.

HIV disease has been dramatically reduced in the developed world by the introduction of highly active antiretroviral therapy, with implications that prophylactic therapy against opportunistic infections may be stopped; however, tuberculosis is an escalating problem in the HIV-infected and HIV-noninfected populations worldwide. Compliance with effective treatment regimens, especially through directly observed therapy, remains the cornerstone of tuberculosis control strategies. Although tuberculosis prophylaxis is of benefit for tuberculin skin reactors with HIV in the developed world, several reservations are voiced about this approach in resource-poor settings. Recent advances in technology, particularly in antigen-specific systems, have revolutionized the understanding of HIV immunology and helped to elucidate the mechanisms of pathogenesis in diseases such as cytomegalovirus. In bone marrow transplantation and solid-organ transplantation patients, quantitative polymerase chain reaction (PCR) to predict cytomegalovirus disease is an important advance, and patients who undergo bone marrow transplantation, CT scanning has proven useful in the diagnosis of pulmonary aspergillosis.

AIDS-Related Opportunistic Infections↗
PubMed1999

Oral and intravenous itraconazole for systemic fungal infections in neutropenic haematological patients: meeting report. London, United Kingdom, 20 June 1998.

Effective prevention, or treatment, of invasive fungal infection in the neutropenic patient has hitherto been unsatisfactory because of either an inadequate anti-fungal spectrum of the agent or important toxicity. Itraconazole is effective against a broad spectrum of the opportunistic pathogens seen in Europe and North America. Prior problems with absorption, e.g. in the marrow transplant recipient, have been overcome with the introduction of an oral solution and an i.v. preparation. The deliberations of an expert meeting held in June, 1998 include recommendations on which patient requires one of these new preparations based on clinical trials, the dose and route. Important drug interactions are also detailed.

Administration, Oral↗
PubMed1999

Generation of autologous immunity to acute myeloid leukaemia and maintenance of complete remission following interferon-alpha treatment.

Interferon-alpha (IFN-alpha) is established as part of the treatment for chronic myeloid leukaemia, although its precise mode of action remains largely unknown. Its use in acute myeloid leukaemia (AML) has been limited. We have previously documented autologous cytolytic activity against AML blasts in patients after autologous bone marrow transplantation. Here we present a patient with poor-risk AML who relapsed from first complete remission (CR) and was unwilling to undergo high-dose chemotherapy with stem cell rescue. In second chemotherapy-induced CR, the patient had no evidence of antileukaemia cytolytic activity in an in vitro assay, and she commenced IFN-alpha (Roferon). She subsequently developed high levels of leukaemia-specific cytotoxicity, and has remained in second CR for two years. These findings support the use of IFN-alpha in patients with poor-risk AML, and suggest that one mechanism of action may be immunological.

Adult↗
PubMed1998

Improving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection.

Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T-cell depletion increases the risk of graft rejection. This study examined the use of CD52 monoclonal antibodies to eliminate T cells from both donor marrow and recipient to prevent both GVHD and rejection. Seventy patients receiving HLA-identical sibling transplants for acute myelogenous leukemia (AML) in first remission were studied. An IgM (CAMPATH-1M) was used for in vitro depletion of the graft and an IgG (CAMPATH-1G) for in vivo depletion of the recipient before graft infusion. No posttransplant immunosuppression was given. Results were compared with two control groups: (1) 50 patients who received bone marrow depleted with CAMPATH-1M, but no CAMPATH-1G in vivo; and (2) 459 patients reported to the International Bone Marrow Transplant Registry (IBMTR) who received nondepleted grafts and conventional GVHD prophylaxis with cyclosporin A (CyA) and methotrexate (MTX). The incidence of acute GVHD was 4% in the treatment group compared with 35% in the CyA/MTX group (P <.001). Chronic GVHD was also exceptionally low in the treatment group (3% v 36%; P <.001). The problem of graft rejection, which had been frequent in the historic CAMPATH-1M group (31%), was largely overcome in the treatment group (6%). Thus, transplant-related mortality of the treatment group (15% at 5 years) was lower than for the CyA/MTX group (26%; P =.04). There was little difference in the risk of leukemia relapse between the treatment group (30% at 5 years) and the CyA/MTX group (29%). Survival of the treatment group at 6 months was better than the CyA/MTX group (92% v 78%), although at 5 years the difference was not significant (62% v 58%) and neither was the difference in leukemia-free survival (60% v 52%). We conclude that T-cell depletion is a useful strategy to prevent GVHD, provided that measures are taken to ensure engraftment. Using CAMPATH-1G to deplete residual host lymphocytes is a simple and practical method to do this. At least in AML, the beneficial reduction in GVHD can be achieved without an increased risk of relapse.

Alemtuzumab↗
PubMed1998

Molecular typing shows a high level of HLA class I incompatibility in serologically well matched donor/patient pairs: implications for unrelated bone marrow donor selection.

In comparison with HLA-matched sibling bone marrow transplants, unrelated donor transplants are associated with increased graft-versus-host disease and graft failure. This is likely in part due to HLA incompatibilities not identified by current matching strategies. High resolution DNA-based typing methods for HLA class II loci have improved donor selection and treatment outcome in unrelated donor bone marrow transplantation. By using DNA-based typing methods for HLA-A and -B on a cohort of 100 potential bone marrow donor/patient pairs, we find that serological typing for HLA class I is limited in its ability to identify incompatibilities in unrelated pairs. Furthermore, the incompatibilities identified are associated with the presence at high frequency of alloreactive cytotoxic T-lymphocyte precursors. DNA typing also indicates that HLA-C mismatches are common in HLA-A and -B serologically matched pairs. Such mismatches appear to be significantly less immunogenic with respect to cytotoxic T-lymphocyte recognition, but are expected to influence natural killer cell activity. Thus, improved resolution of HLA class I shows many previously undisclosed mismatches that appear to be immunologically functional. Use of high resolution typing methods in routine matching is expected to improve unrelated donor selection and transplant outcome.

Base Pair Mismatch↗