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G J Mufti

Publications and source records attributed to G J Mufti.

At least 91 records · Page 5Linked to original sources
PubMed1993

Methylation status within exon 3 of the c-myc gene as a prognostic marker in myeloma and leukaemia.

The third exon of the c-myc gene contains a CpG site which has been implicated as a regulatory region. When this site is methylated it has protein binding properties and binds a different set of proteins in normal and neoplastic cells. Recent work using myeloma cell lines indicates a correlation between hypomethylation at this site and enhanced expression of the myc protein. We investigated the methylation of this site in 10 cases of myeloma but found that there was no change from the high degree of methylation found in normal cells. Therefore, methylation status at this site is unlikely to serve as a prognosticator in myelomatosis. However, methylation changes at this site were observed in DNA from two cases of CMML, in which hypomethylation was observed and in three AML cases, which were completely methylated at this site.

Acute Disease↗
PubMed1993

Consistent interstitial chromosomal deletions in myeloid malignancies and their correlation with fragile sites.

Chromosomal deletions occurring in myeloid malignancies have sometimes been reported either with no breakpoints or as terminal deletions. It is of importance to deduce whether these deletions are actually terminal or interstitial because this has implications for their biologic consequences and the mechanism of their development. Chromosomal deletions have been observed in 38 patients with myeloid malignancies. Two or more deletions occurred in six cases, and in seven cases this was part of a complex abnormality. In all, 45 deletions were observed. In all cases analyzed, the deletions consistently were interstitial. Of the 38 cases, 16 were myelodysplastic syndromes (MDS) [refractory anemia (RA), three; RA with ringed sideroblasts (RARS) three; RA with excess of blasts (RAEB) eight; RAEB in transformation (RAEB-t) one; and unclassified, one], 11 cases were acute nonlymphocytic leukemia (ANLL), and 11 were other myeloproliferative disorders [polycythemia rubra vera (PRV) seven; essential thrombocytopenia (ET), three; unclassified, one]. In general, no uniformity of breakpoints could be identified other than del(9)(q13q22.2) most of which occurred with t(8;21) and del(20)(q11.2q13.3 or 13.1). The breakpoints corresponded to or were adjacent to fragile sites in 49% (proximal 64%, distal 33%). These data emphasize that chromosomal deletions in myeloid malignancies are interstitial. The uniformity of breakpoints in del 9q and del 20q supports the concept that in some instances the exact breakpoints may be important through juxtaposition of genes rather than loss of critical regions. The data also suggest that there may be different mechanisms for the development of proximal and distal breakpoints.

Adult↗
PubMed1993

Modification of standard proteinase K/phenol method for extraction of DNA from small tumour biopsies.

The standard proteinase K/phenol DNA isolation method was found to produce unsatisfactory yields of DNA from small tissue biopsies (less than 50 mg). The influences of the volume of cell lysis buffer and the amount of proteinase K on the final DNA yield and quality were studied, and an improved method was devised and compared with both the standard procedure and a phenol-free protocol. The optimal volume of cell lysis buffer was found to be 200 microliters per mg of tissue while the optimal amount of proteinase K was 60 micrograms per mg of tissue. A mean yield of 12 mu/mg tissue of pure, high molecular weight DNA was achieved from 50 frozen samples prepared by crushing. Yields from 20 microns thick cryostat sections reached 30 micrograms/mg.

1-Propanol↗
PubMed1993

Randomized comparison of oral fluconazole versus oral polyenes for the prevention of fungal infection in patients at risk of neutropenia. Multicentre Study Group.

An open, randomized study was performed at 18 European centres to compare the efficacy, safety and tolerance of oral fluconazole with oral polyenes for the prophylaxis of fungal colonization and infection in adults at high risk of developing neutropenia. Five hundred and thirty-six hospitalized patients with malignant disease, about to receive chemotherapy, radiotherapy, or bone marrow transplantation, and who were already neutropenic or were expected to develop neutropenia were included in the study. Before therapy or transplantation, patients commenced either oral fluconazole therapy (50 mg/day as a single dose) or oral polyenes therapy (amphotericin B 2 g/day and/or nystatin 4 x 10(6) units/day in four or more divided doses), for a mean of 29.3 days and 31.3 days, respectively. After baseline clinical and mycological testing, patients were re-evaluated at least weekly during prophylaxis, at the end of prophylaxis and two to six weeks later to identify proven or suspected fungal infection and to determine rates of colonization with fungi. Fungal infection was diagnosed in 41 of 511 evaluable patients, 10 (3.9%) of 256 in the fluconazole group and 31 (12.2%) of 255 in the polyene group (P = 0.001). This total included four patients (1.6%) in the fluconazole group who developed oropharyngeal candidiasis compared with 22 (8.6%) in the polyene group (P < 0.001). Systemic infections comprised 6 (2.3%) in the fluconazole group and 9 (3.5%) in the polyene group (P = not significant), and included three Candida krusei infections in each group. Parenteral amphotericin B therapy was given empirically for persistent fevers in an additional 62 (24.2%) patients receiving fluconazole and 59 (23.1%) receiving polyenes (P = not significant). Colonization with fungi was generally similar in each treatment group, although an increased proportion of patients receiving fluconazole developed colonization of the faeces (P < 0.01). Adverse reactions, possibly related to treatment, were recorded in 15 (5.6%) of 269 patients in the fluconazole group and 14 (5.2%) of 267 in the polyene group; these necessitated discontinuation of therapy in seven patients in each group. Once-a-day fluconazole was therefore more effective than oral polyenes for the prevention of oropharyngeal fungal infection and as effective for the prevention of infections at other sites in patients with neutropenia.

Administration, Oral↗
PubMed1993

A pilot study of low-dose recombinant human granulocyte-macrophage colony-stimulating factor in chronic neutropenia.

Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) is under investigation for the treatment of a wide range of haematological disorders. At commonly used doses of > 120 micrograms/m2/d, extramedullary toxicity is common. We report the effects of low-dose (LD) rhGM-CSF in patients with chronic neutropenia related to HIV infection, myelodysplastic syndrome and idiopathic neutropenia. Nine patients with a mean pre-treatment neutrophil count of 0.6 x 10(9)/l (range 0.2-1.4 x 10(9)/l) received daily rhGM-CSF at doses of between 5 and 15 micrograms/m2. Eight patients responded with a mean post-treatment ANC of 3.2 x 10(9)/l (range 1.9-4.6 x 10(9)/l). There was no significant therapy-related morbidity. We conclude that in chronic neutropenia, LD rhGM-CSF is an acceptable treatment which has important cost/benefit implications.

Adult↗
PubMed1993

Familial MDS with 5q- abnormality.

Abnormalities of chromosome 5 and 7 are frequently found in primary MDS. Cases with familial monosomy 7 are well recognized, but there are no reports of familial MDS with deletion of 5q. We describe two sisters, aged 38 and 36 years, both of whom had MDS and interstitial deletion of 5q. The occurrence of this chromosomal abnormality reinforces the concept of tumour suppressor gene hypothesis in some cases with familial MDS.

Adult↗
PubMed1993

Myelodysplastic syndromes: from morphology to molecular biology. Part I. Classification, natural history and cell biology of myelodysplasia.

The myelodysplastic syndromes are a heterogeneous group of clonal hematopoietic disorders predominantly affecting the elderly. Patients frequently develop acute leukemia, but the majority suffer from the consequences of bone marrow failure. The underlying acquired genetic abnormality is the inadequate production of dysplastic and poorly functional cells resulting from defective differentiation and premature cell death of the abnormal hematopoietic clone. Although the pathogenesis is unknown, recent evidence suggests that a sequence of DNA lesions leads to alteration of the cellular function, emergence and consequent evolution of the premalignant clone.

Humans↗
PubMed1993

Myelodysplastic syndromes: from morphology to molecular biology. Part II. The molecular genetics of myelodysplasia.

Most studies of the clonal origin of the underlying lesion(s) and all investigations using X-inactivation, have concluded that the myelodysplastic syndromes arise from a multipotent stem cell. Non-random chromosomal abnormalities, particularly deletions of 5q and 7q, are common, most notably in therapy related MDS. Progression to AML is also frequently accompanied by increased genomic instability as evidenced by the emergence of multiple karyotypic abnormalities. While some evidence hints at the presence of tumour suppressor genes on chromosomes 5, 7, 20 and 12, no such genes have yet been identified. The search for point mutations in known oncogenes has concentrated on two oncogenes RAS and c-FMS. Point mutation frequency generating active forms of RAS oncogenes is approximately 40% in MDS overall, up to 80% in studies of CMML. 60% of all MDS RAS mutation involves a G to A transition, producing a substitution of aspartate for glycine at a frequency of 50% (of total ras mutants). RAS mutation is associated with progression to AML, although the presence of a RAS point mutation alone is neither necessary nor sufficient for leukaemic transformation. Mutation of c-FMS is also more common in CMML in comparison to other MDS subtypes and, as yet, point mutation potentiating the response of the receptor to CSF-1 (codon 969) has been found more frequently than point mutation resulting in permanently activated receptor (codon 301). However, recent work has identified additional mutations which produce transforming proteins, and mutation rates at these sites may be relevant in MDS.

Humans↗
PubMed1992

Primary myelodysplastic syndromes: diagnostic and prognostic significance of immunohistochemical assessment of bone marrow biopsies.

Material from 63 cases with primary myelodysplastic syndromes (P-MDS) (French-American-British [FAB] types: refractory anemia [RA] = 21; RA with ring sideroblasts [RARS] = 8; RA with excess of blasts (RAEB) = 10; RAEB in transformation (RAEBt) = 6; chronic myelomonocytic leukemia [CMML] = 10 and unclassifiable = 8, ie, bone marrow aspiration was inadequate and stringent FAB criteria were not applicable) was analyzed for bone marrow histologic and immunohistochemical patterns. Standard Giemsa, hematoxylin and eosin (H&E) and reticulin stains were used for morphologic assessment. To identify the cell lineage precisely, chloroacetate esterase staining and an indirect immunoperoxidase technique using mouse monoclonal antibodies CD15, CD68, HLA-DR, and rabbit polyclonal CD3 and UEA-1 (lectin) was developed on formalin-fixed paraffin embedded bone marrow biopsies (BMB). The immunohistochemical assessment permitted accurate identification of dysplastic features such as mononuclear and binuclear megakaryocytes, Pelger-Huet neutrophils, and binuclear erythroblasts. Additional bone marrow histologic and immunohistochemical features observed were heterogeneity of immunohistochemical staining in various cell lineages, megakaryocytic emperipolesis, alteration of bone marrow microarchitecture, intravascular clusters of hematopoietic cells, and the types of benign lymphoid aggregates. The nature of abnormally localized immature precursors (ALIP) was discerned. Three types of clusters of immature cells were found that were difficult to distinguish on Giemsa and H&E morphology, these were erythroid aggregates (n = 18); megakaryocytic aggregates (n = 4), and immature granulocytic and monocytic aggregates (n = 32). The bone marrow histologic and immunohistologic patterns permitted the identification of four groups of clinical relevance: Group 1, cases with predominant erythroid hyperplasia and without ALIP (n = 15); group 2, cases with prominent myeloid hyperplasia and presence of ALIP (n = 32); group 3, cases with hypoplastic MDS (n = 10); and group 4, cases with hyperfibrotic MDS (n = 6). Statistical analysis showed a significant difference in survival and leukemic transformation between groups 1, 2, 3, and 4, with cases in group 2 showing the worst prognosis with early death due to increased propensity to leukemic transformation and cytopenia-related complications (P less than .0001). We conclude that immunohistochemistry is feasible on routinely processed BMB and the information obtained is of diagnostic and prognostic importance in P-MDS. The phenotype of ALIP varies with the morphologic and histologic subtypes of MDS and the term should be reserved for cases in whom the clusters in the intertrabecular region are of myeloid (granulocytic and monocytic) lineage on immunohistochemistry.

Aged↗
PubMed1992

Chromosomal deletions in the myelodysplastic syndrome.

Karyotypic abnormalities in primary myelodysplastic syndrome (P-MDS) are less frequent than in secondary myelodysplasia. A review of the literature involving over 3000 reported cases, shows the incidence of karyotypically abnormal clones at presentation in nearly 48% of cases. Approximately 50% of the abnormalities comprise of deletions of chromosomes 5, 7, 11, 12, 13 and 20. Localisation of a number of haemopoietic growth factors and their receptors to the deleted segments of the chromosomes, has invoked considerable interest in the molecular pathology of the interstitial deletions and their consequent role in the multistep pathogenesis of MDS. Present evidence suggests chromosome abnormalities are a later event in the multistep painogenesis, and it is suggested their occurrence may be restricted to a restricted myeloid progenitor cell, although the initial event(s) occur at the common lymphoid-myeloid progenitor. Much has been gleaned from the dominant modes of leukaemogenesis, such as the occurrence of missense mutations at specific positions of RAS and FMS mutations. It is suggested that a similar enquiry into the mechanisms of chromosomal deletions in P-MDS is required in order to delineate the role of these abnormalities in the clonal evolution of this group of diseases.

Chromosome Aberrations↗
PubMed1992

Primary myelodysplastic syndrome in children: the clinical experience in 33 cases.

We describe the clinicomorphological features in 33 cases of primary myelodysplastic syndrome classified according to the FAB classification which presented to a single centre over a 12 year period. Presenting features were typically related to pancytopenia although hepatosplenomegaly and granulocytic sarcomas were far more prevalent than in the adult population. Morphological assessment of the peripheral blood and the bone marrow showed seven patients had refractory anaemia (RA), 13 patients had RA with excess of blasts (RAEB), nine patients had RAEB in transformation (RAEB-t) and four patients had chronic myelomonocytic leukaemia (CMML). The overall mean survival was short (9.9 months) in all the subgroups and the leukaemic transformation rate was high. None of the patients scored 0-1 according to the Bournemouth Scoring System; four patients scored 2 whereas 29 patients scored 3 to 4. We conclude that unlike adults, the myelodysplastic syndromes in children run an aggressive clinical course, irrespective of the FAB subtype, and the pathogenesis of these diseases in paediatric practice warrants scientific scrutiny. Intensive chemotherapy such as the one used in de novo-AML lead to complete remission in some children and these early results suggest that this should be the treatment of choice in paediatric MDS.

Adolescent↗
PubMed1992

Detection of HIV in haemopoietic progenitors.

Peripheral blood cytopenias present a major problem in the management of patients with HIV infection. Their pathophysiology is likely to be multifactorial, although there is controversy as to whether haemopoietic progenitors are a target for HIV. In order to investigate the haemopoietic defect in HIV infection, we looked at bone marrow culture characteristics of marrow from eight HIV+ patients compared to normal controls. We performed long-term liquid culture (LTC) and colony forming assays for granulocyte-macrophage (CFU-GM) and granulocyte, erythroid, megakaryocyte, macrophage (CFU-GEMM). In LTC we found normal stromal appearance and haemopoietic focus formation. There was no difference in colony assays of CFU-GM and CFU-GEMM between HIV+ and normal controls. Colonies taken from CFU-GM and CFU-GEMM were analysed for HIV DNA sequences, and we were able to detect HIV DNA in colonies from all HIV+ patients. Our results indicate that despite infection of haemopoietic progenitor cells by HIV, bone marrow function is preserved. This suggests that HIV-related cytopenias may be due to alternative mechanisms not present in our in vitro system.

Adult↗
PubMed1992

A guide to risk assessment in the primary myelodysplastic syndrome.

The heterogeneity of primary myelodysplastic syndromes, the concentrated efforts of discerning their multistep pathogenesis, and the availability of recombinant hemopoietic growth factors have made these diseases a focus for clinical and scientific research. In order to compare therapeutic modalities in these clinically diverse diseases it is essential to select relatively homogeneous groups of patients based on easily available prognostic features. A guide to risk assessment is outlined in this article with a view to answering the question, "Whom should we treat and when?"

Bone Marrow↗