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Biomedical subjects

G J Mufti

Publications and source records attributed to G J Mufti.

At least 73 records · Page 4Linked to original sources
PubMed1996

Deletion of the acetylcholinesterase locus at 7q22 associated with myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML).

The genes for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) are located within regions subject to non-random chromosomal abnormalities in the myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Acetylcholinesterase is mapped to 7q22, within the critical deleted region presumed to contain a myeloid specific tumour suppressor gene. Butyrylcholinesterase is mapped to 3q26: abnormalities at this region are associated with sub-types of MDS and AML with thrombocytopenia, or with increased platelet counts. Both ACHE and BCHE have been implicated as playing a role in megakaryopoiesis and thrombopoiesis, and these genes have been observed to be co-amplified in acute myeloid leukaemia. Recent findings suggest a more significant role for the ACHE gene in haemopoiesis by regulating multipotent stem cell proliferation, and apoptosis in cells undergoing erythroid and myeloid differentiation. This led us to investigate gene copy-number alterations at these genes in MDS and AML. Samples were screened by slot-blot hybridization, and if changes were observed, by Southern blotting. A total of 42 samples from 31 de novo AML patients, 10 samples from eight cases of post-MDS AML and 85 samples from 67 MDS patients were analysed with probes for ACHE, BCHE, c-MYC, MDR-1 and globin control. Changes in ACHE and/or BCHE were observed in 9/31 de novo AML patients, and in 7/67 MDS patients: 1/37 cases of refractory anaemia (RA), 1/10 cases of refractory anaemia with excess blasts (RAEB) and 5/20 chronic myelomonocytic leukaemia (CMML) patients. The amplification events observed generated copy numbers no greater than 10, showed normal restriction patterns and had no clear correlation with megakaryopoiesis or thrombopoiesis. Loss of signal at the ACHE locus was observed: haploid signal intensity was seen in seven samples: one RA with thrombocytopenia, three CMML, one AML-M5a (no karyotypic abnormalities of chromosome 7), one AML-M4 (monosomy 7), and one case of AML-M7 (karyotype unknown). Homozygous deletion was observed at relapse of an additional patient with AML-M4. These data reinforce the possibility that ACHE may play a role as a myeloid tumour suppressor gene.

Acetylcholinesterase↗
PubMed1996

Acquired sideroblastic anaemia induced by a copper-chelating agent.

Acquired sideroblastic anaemia may be related to drugs and other chemicals that inhibit the activity of mitochondrial enzymes involved in haem synthesis. We report a case of secondary acquired sideroblastic anaemia following administration of triethylene tetramine dihydrochloride (trientine), a second-line copper-chelating agent used in the treatment of Wilson's disease. The anaemia improved after dose reduction of trientine. The mechanism of induction of sideroblastic anaemia in this case is unclear, but trientine does not appear to alter the function of two key mitochondrial haem enzymes, and may instead act directly on mitochondrial iron metabolism.

Adolescent↗
PubMed1996

The effect of combined expression of interleukin 2 and interleukin 4 on the tumorigenicity and treatment of B16F10 melanoma.

The recent use of interleukin 2 (IL-2) and interleukin 4 (IL-4) single cytokine modified tumour cells in rodent models has demonstrated a potential use of these cytokines to produce autologous cancer cell vaccines. Here we compare the potential therapeutic benefit of transduction with IL-2 or IL-4 alone, and combined IL-2 + IL-4 in B16F10 cells, a murine malignant melanoma of poor immunogenicity. Transduction of B16F10 cells (MHC class I and II negative) to express either IL-2 or IL-4 alone delays the formation of tumours, IL-4 being more effective than IL-2. However, combined expression of IL-2 + IL-4 reduces tumorigenicity more than either cytokine alone. The eventual formation of tumours may result from loss of gene expression, and preliminary results suggest methylation of the retroviral long terminal repeat (LTR), rather than loss of the transduced DNA sequences. Histological examination of tumours expressing either IL-2 or IL-4 alone shows a non-specific inflammatory reaction with an increased tissue infiltrate of immune effectors (monocytes/macrophages, lymphocytes, granulocytes) localised around the tumour. In comparison, when cells expressing combined IL-2 + IL-4 were injected there were more granulocytes present, and perhaps more importantly, these were mainly localised within the tumour. The benefit of combined IL-2 + IL-4 expression results from a local rather than systemic effect as the growth of tumours from cells expressing IL-2 or IL-4 alone injected at distant sites was comparable with a single inoculation of cells expressing either cytokine alone. However, when cells expressing single cytokines IL-2 or IL-4 were mixed and injected at the same site, in comparison with the clonal population of cells expressing combined IL-2 + IL-4, tumour growth was characteristic of IL-4 alone rather than IL-2 + IL-4. Treatment of established tumours with a single injection of lethally irradiated tumour cells expressing IL-2 + IL-4 was sufficient to either reject tumours, or at least delay further tumour development. Furthermore, treatment stimulated an initial non-specific immune reaction that lead to a systemic immunity. Lethally irradiated wild-type cells were also successful in treating some established tumours, although this did not induce any systemic immunity. However, although successful in treatment studies, neither wild-type nor combined IL-2 + IL-4 expressing cells were able to vaccinate animals against a subsequent challenge with live wild-type tumour. These results indicate a potential therapeutic benefit with the use of combination IL-2 + IL-4 transduction of autologous cancer cells.

Animals↗
PubMed1996

Myelosuppressive chemotherapy to mobilize normal stem cells in chronic myeloid leukemia.

Ten patients with Ph+ chronic myeloid leukemia (CML) were treated with idarubicin, cytarabine and etoposide followed by G-CSF to harvest Ph-negative progenitor cells. Six were in first chronic phase (CP1), and four beyond CP1. Between two and six aphereses (median 3, total 36) were performed starting 9-26 days (median 14.5) after chemotherapy when the leukocyte count was 0.6-4.7 x 10(9)/l (median 1.2). 1.3-3.6 x 10(8) mononuclear cells/kg (median 2.8), 0-128.4 x 10(4) CFU-GM/kg (median 1.2; seven patients) and 0.3-25.1 x 10(6) CD34+ cells/kg (median 9.8; seven patients) were collected. Seven of 27 harvests showing metaphases were 100% Ph-negative, 11 partially Ph-negative, and nine were 100% Ph+. All three patients with 100% Ph-negative collections were in CP1 and within 4-26 months of diagnosis. Four of six CP1 patients showed significant cytogenetic response compared with none of four beyond CP1 (P = 0.036). The absolute neutrophil count remained < 0.5 x 10(9)/l for 9-44 days (median 15.5) following chemotherapy. Four patients (three Ph-negative) were autografted after 16 mg/kg busulfan (n = 2) or 200 mg/m2 melphalan (n = 2). One of the three patients receiving Ph-negative cells died of graft failure, and two are alive with 15% and 50% Ph-negative cells at 15 and 11 months on interferon-alpha. We conclude that it is possible to harvest Ph-negative cells after myelosuppressive chemotherapy in some CML patients treated early in the course of CP1. However, in view of lack of consistent response, investigation of alternative approaches is necessary.

Adolescent↗
PubMed1995

Possible co-existence of RAS activation and monosomy 7 in the leukaemic transformation of myelodysplastic syndromes.

The frequency of RAS activation was studied in 48 patients with acute myeloid leukaemia (AML) or with myelodysplastic syndromes (MDS), in order to address the question of whether patients possessing monosomy 7 or other alterations of chromosome 7 have a higher incidence of RAS activation than those lacking chromosome 7 abnormalities. Samples were screened for oncogenic point mutation by DNA amplification followed by oligonucleotide hybridization analysis at codons 12, 13 and 61 of N-RAS and codons 12 and 13 of K-RAS. Two additional samples were considered to have activated RAS due to additional karyotypic abnormalities t(5;12) or loss of both copies of chromosome 17 and hence, the neurofibromatosis (NF1) loci. The group of chronic myelomonocytic leukaemia (CMML) patients had activated RAS in 4/11 cases and inclusion of two CMMLt patients (with monosomy 7) brings this incidence to 5/13. No change in frequency of RAS activation was seen between groups containing de novo AML samples with or without chromosome 7 abnormalities (1/5 and 2/12, respectively). However, assessment of MDS samples in the process of, or subsequent to, leukaemic progression showed a difference between the two groups. The frequency of RAS activation in samples with monosomy 7 was 4/9 samples while none of the seven samples without chromosome 7 changes showed RAS activation. The co-existence of RAS activation and monosomy 7 in MDS indicates that these lesions can co-operate in the multistep process of leukemogenesis.

Base Sequence↗
PubMed1995

Genotype study of non-Hodgkin's lymphoma.

DNA from 47 patients with non-Hodgkin's lymphoma (NHL) was studied for immunoglobulin and T-cell receptor (TCR) gene rearrangements with Southern blot hybridization. In 83% of the cases the genotypic changes were consistent with immunophenotypic and morphologic examination. Two cases showed mixed genotype and 9 cases of B-cell NHL (67% of centroblastic, 36% of follicular and 33% of large cell anaplastic) showed a population of cells with TCR gamma rearrangements in addition to immunoglobulin rearranged bands. We compared the TCR gamma variable region usage in these rearrangements in B-cell NHL with T-cell NHL and reactive hyperplasia. In T-cell NHL TCR gamma variable regions located at the 3' part of the variable locus were used more often, whilst in B-cell NHL regions of the 5' portion of the locus were preferentially used. Our results confirm the genotypic heterogeneity of histologically defined subtypes of NHL.

Adult↗
PubMed1995

VAPEC-B chemotherapy in the treatment of aggressive non-Hodgkin's lymphoma: a retrospective analysis of 45 patients.

We performed a retrospective analysis on 45 patients who, between January 1989 and October 1993, received VAPEC-B chemotherapy for high and intermediate grade non-Hodgkin's lymphoma. The aim was to assess response and tolerance to treatment. The weekly regimen consisted of: doxorubicin 35 mg/m2 i.v. weeks 1,3,5,7,9,11; cyclophosphamide 350 mg/m2 i.v. weeks 1, 5, 9; etoposide 100 mg/m2 p.o. daily for 5 days, weeks 3, 7, 11; vincristine 1.4 mg/m2 i.v. (2 mg max.) weeks 2, 4, 6, 8, 10; bleomycin 10 mg/m2 i.v. weeks 2, 6, 10; methotrexate 12.5 mg i.t. weeks 1, 5, 9; prednisolone 50 mg p.o. daily for 6 weeks, reduced to 25 mg daily for 6 weeks. The patients treated were aged 22-71 years, 34 (75%) had high grade (Working Formulation) non-Hodgkin's lymphoma (NHL); 11 (24%) had intermediate grade NHL; 25 had Stage III/IV disease; and 14 (31%) had marrow involvement. The majority of patients (76%) received VAPEC-B as first line chemotherapy; the remainder received it for relapsing disease. Follow-up time from completion of VAPEC-B chemotherapy ranged from 6 months to 50 months (median 25). VAPEC-B, as first line therapy, induced a complete response (CR) and partial response (PR) in 79% and 18% respectively, whilst 3% had no response to treatment. VAPEC-B used for relapsing disease produced CR and PR in 64% and 27% respectively, whilst 9% failed to respond. Six patients in PR and five patients in CR have subsequently undergone an autologous bone marrow transplant or a peripheral blood stem cell transplant. In the group who received VAPEC-B first line but did not proceed to transplant (27 patients), five relapsed (three with CNS disease who had not had CNS prophylaxis). Tolerance to treatment was measured by WHO toxicity scores. The haemoglobin (Hb) toxicity median score for all patients was grade 1 (Hb 9.5-10.9 g/dl), and the white cell count (WCC), toxicity score was grade 2 (WCC 2.0-2.9 x 10(9)/l). No platelet toxicity was observed. Ten per cent of patients suffered grade 3 severity infections requiring antibiotics and there was one treatment related death. The majority of patients received VAPEC-B on time, however, 24% patients had a 2-week delay. VAPEC-B chemotherapy is an effective regimen for malignant lymphoma, either as a first line or as a salvage treatment. Although chemotherapy was given weekly, the tolerance to treatment was acceptable, thus making this short regimen a good alternative to CHOP chemotherapy.

Adult↗
PubMed1995

High-dose methylprednisolone, low-dose cytosine arabinoside, and mitoxantrone in children with myelodysplastic syndromes.

High-dose methylprednisolone (HDMP) has been shown to induce differentiation of myeloid leukemic cells with a remarkable antileukemic effect in children with various subtypes of acute myeloblastic leukemia (AML), therefore we used HDMP in the treatment of four children with myelodysplastic syndrome (MDS). Two patients had refractory anemia with an excess of blasts in transformation (RAEB-t) with extramedullary infiltration (EMI), one had chronic myelomonocytic leukemia with pleural effusion, and one had RAEB. HDMP was administered orally at a single dose of 20-30 mg/kg/day combined with low-dose cytosine arabinoside (LD Ara-C) (10 mg/m2, 12-hourly s.c.) for 2 weeks. The treatment continued with mitoxantrone (10 mg/m2, i.v.) and Ara-C (5 mg/kg, i.v.) once a week for four doses followed by maintenance chemotherapy. All patients achieved hematologic remission 2-4 weeks after initiation of treatment. Extramedullary infiltration disappeared in all cases within 2 weeks to 3 months after initiation of therapy. With the exception of two patients who relapsed 6 and 24 months after remission, treatment could be stopped in others who remained in remission for 36 months without evidence of EMI; 6 months later one of them developed myelodysplastic relapse (RAEB). No side effects related to HDMP treatment were noted, but hyperleukocytosis developed in two patients who initially had high WBC counts. We suggest that the addition of HDMP with or without LD Ara-C to cytotoxic chemotherapy offers a promising alternative in cases not considered suitable for bone marrow transplantation.

Adolescent↗
PubMed1994

The rate of disease progression predicts the quality of remissions following intensive chemotherapy for myelodysplastic syndromes.

The use of intensive chemotherapy in the treatment of myelodysplastic syndromes (MDS) has met with some disappointment, although subgroups of patients have been identified in which the response approaches that of de novo acute myeloid leukaemia (AML). We hypothesized that it is not the FAB classification per se, but the biological behaviour of the blasts as shown by their rate of accumulation that influences the response. We have, therefore, included AML with trilineage dysplasia (AML/TLD) as it represents one extreme of the evolution of MDS to AML. We have analysed the results of intensive chemotherapy in 22 patients (median age 60 years; range 26-77 years) with MDS (14) and AML/TLD (8). Response to treatment was analysed by age, interval from diagnosis to treatment, the number of cytopenias, bone marrow blasts and karyotype. Patients were also divided according to the rate of disease progression, shown by the time from diagnosis to treatment (group A = < 3 months; group B = > 3 months). The overall response rate was 87%; 13 (60%) complete responses (CR) and 6 (27%) partial responses. The rate of disease progression was identified as the most significant predictive factor of achieving CR (p = 0.003) (group A 10/12; group B 3/10). Patients presenting with more than 20% blasts also had a better response (p = 0.031). The combined response rates, however, did not differ significantly between the two groups (group A 92%; group B 80%) as 50% of group B achieved a PR. The failure to normalize blood counts was not related to the number of cytopenias before starting treatment. In all cases, PR was associated with persistence of dysplastic morphology and cytogenetic abnormalities. CR was associated with complete morphological and cytogenetic response except in two patients in group B. Dysplastic morphology re-emerged in patients who achieved CR and of these, all but one acquired a new cytogenetic abnormality. Patients in group B who achieved CR all needed two courses compared with a mean of 1.1 for the other group. The median survival from treatment for both groups was 10 months, however, no patient in group B survived more than 20 months. In comparison 33% in group A were alive at 5 years. The rate of accumulation of blasts predicts the response to chemotherapy and the quality of remissions achieved. Patients with rapidly increasing blasts can achieve complete morphological and cytogenetic remissions, although they eventually have a dysplastic relapse. In contrast, intensive chemotherapy for patients with a slow accumulation of blasts may reduce the blast population but with much less benefit on haemopoiesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

CD4+ lymphocytopenia due to common variable immunodeficiency mimicking AIDS.

There are an increasing number of published reports of patients with acquired immunodeficiency without evidence of HIV infection, who have been labelled as having "idiopathic CD4+ lymphocytopenia". The case is reported here of a young man who presented with Pneumocystis carinii pneumonia (PCP), CD4+ lymphopenia, and hypogammaglobulinaemia attributable to common variable immunodeficiency (CVID). The presentation of this condition, with many of the clinical and laboratory features of AIDS, highlights CVID as a diagnosis to be considered in the differential diagnosis of CD4+ lymphocytopenia.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Quantification of HIV by PCR in monocytes and lymphocytes in patients receiving antiviral treatment and low dose recombinant human granulocyte macrophage colony stimulating factor.

Neutropenia induced by antiviral treatment, in particular AZT, can be improved with recombinant human granulocyte macrophage colony stimulating factor (RHGMCSF) in HIV positive patients. However, there has been concern that this may increase the HIV load in the mononuclear cells of such patients. Five patients receiving AZT plus low dose RHGMCSF are reported. There was no consistent change in the levels of HIV DNA in the monocytes and lymphocytes. Additionally, all patients had stable disease with no opportunistic infection during the study period. It is concluded, therefore, that low dose RHGMCSF does not significantly change the viral DNA load in patients receiving AZT.

Adult↗
PubMed1994

Autologous blood stem cell transplantation in hematological malignancies.

Autologous blood stem cell transplants (ABSCT) are increasingly used for the treatment of haematological malignancies. The use of hemopoietic growth factors, in conjunction with stem cell mobilization by chemotherapeutic agents, has permitted successful harvests requiring only a few leukaphereses; cells mobilized in this manner contain a relatively large number of committed precursors of all lineages, as well as early progenitor cells capable of maintaining long-term haemopoiesis. Haematological recovery after ABSCT is rapid, thereby significantly shortening the period of post-chemotherapy neutropenia and thrombocytopenia. Furthermore, blood-derived grafts may contain fewer malignant cells than the bone marrow cells. The preliminary results have been so encouraging that it is envisaged that in myeloma, Hodgkin's disease and non-Hodgkin lymphomas, ABSCT may eventually replace autologous marrow transplantation.

Blood Component Transfusion↗