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Biomedical subjects

G J Mufti

Publications and source records attributed to G J Mufti.

At least 55 records · Page 3Linked to original sources
PubMed1999

Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomised, double-blind, placebo-controlled study.

Liposomal amphotericin (AmBisome) 2 mg/kg three times weekly was compared with placebo as prophylaxis against fungal infection in patients undergoing chemotherapy or bone marrow transplantation (BMT) for haematological malignancies. Prophylaxis began on day 1 of chemotherapy and continued until neutrophils regenerated or infection was suspected. Of 161 evaluable patients, 74 received AmBisome and 87 received placebo. Proven fungal infections developed in no patients on AmBisome and in three on placebo (3.4%) (P = NS). Suspected fungal infections requiring intervention with systemic antifungal therapy (usually amphotericin B) occurred in 31 patients on AmBisome (42%) and in 40 on placebo (46%) (P = NS). Suspected deep-seated infections developed in 21 (28.3%) and 31 (35.6%) patients, respectively (P = NS). Time to develop a suspected or proven deep-seated infection showed a trend in favour of AmBisome (P = 0.11). Fifty patients had fungal colonisation (48 with Candida spp, two with Aspergillus spp) of at least one body site during prophylaxis; 15 patients while receiving AmBisome (20%) and 35 while on placebo (40%) (P < 0.01). Time to colonisation was significantly delayed in the group receiving AmBisome (P < 0.05). Treatment-related toxicity was modest and no additional toxicity was observed in patients receiving AmBisome. AmBisome 2 mg/kg three times weekly is safe and reduces fungal colonisation in patients receiving intensive chemotherapy or BMT. However, despite encouraging trends, prophylactic AmBisome did not lead to a significant reduction in fungal infection or in requirement for systemic antifungal therapy.

Adult↗
PubMed1999

Phenotypic and functional characteristics of monocyte-derived dendritic cells from patients with myelodysplastic syndromes.

We have compared the phenotypic and functional characteristics of dendritic cells (DC) generated in vitro from the peripheral blood mononuclear fraction of myelodysplastic syndrome (MDS) patients (four refractory anaemia, four refractory anaemia with excess of blasts) with DCs generated in a similar way from eight healthy donors. After 10 d of culture in the presence of GM-CSF and IL-4, reduced numbers and percentages of DCs were obtained in MDS subjects. MDS DCs exhibited significantly lower expression of CD1a, CD54, CD80 and MHC class II molecules. Their ability to stimulate T lymphocytes in an allogeneic mixed leucocyte reaction was reduced in comparison to normal subjects. Furthermore, MDS DCs also showed a reduced receptor-mediated endocytosis as demonstrated by FITC-dextran uptake. Simultaneous fluorescence in situ hybridization (FISH) and immunophenotypic analysis demonstrated that MDS DCs have the same cytogenetic abnormality of the malignant clone. Taken together these findings indicate that, in MDS, DCs are part of the malignant clone and exhibit a deficient antigen uptake and presentation.

Dendritic Cells↗
PubMed1998

Hemophagocytosis: a potential complication in small bowel transplantation.

BACKGROUND: Acquired hemophagocytosis is a histiocytic proliferation associated with phagocytosis of the hemopoietic elements resulting in fever, profound pancytopenia, hepatosplenomegaly, lymphadenopathy, and coagulopathy. Acquired hemophagocytic syndrome is a specific entity that can be differentiated from malignant histiocytosis and familial hemophagocytosis. It has been associated with a variety of disorders, including immunodeficiency, infection, hemopathies, cancer, and autoimmune diseases, as well as with the period following solid organ and bone marrow transplantation. METHODS: We describe a case of a fatal outcome, due to hemophagocytosis, after small bowel transplantation in a patient with systemic lupus erythematosus. RESULTS: Hemophagocytosis secondary to systemic lupus erythematosus has been reported to have a better response to steroid therapy than that associated with infection. In this case, the association of an autoimmune disease, high levels of immunosuppression, and posttransplant sepsis may have triggered the onset of hemophagocytosis. CONCLUSION: It is suggested that patients with systemic lupus erythematosus may represent a high-risk group for developing hemophagocytosis after small bowel transplantation.

Fatal Outcome↗
PubMed1998

Changes in antigen expression on differentiating HL60 cells treated with dimethylsulphoxide, all-trans retinoic acid, alpha1,25-dihydroxyvitamin D3 or 12-O-tetradecanoyl phorbol-13-acetate.

We describe changes in antigen expression on HL60 cells with differentiation into granulocytes induced by all-trans retinoic acid (ATRA) or dimethylsulphoxide (DMSO), into monocytes by alpha1,25-dihydroxyvitamin D3 (D3), or into macrophages by 12-O-tetradecanoyl phorbol-13-acetate (TPA). Undifferentiated cells expressed CD13, CD14 (at a low level), CD15, CDw17, CD32, CD33, CD49e, CD63, CD64, CDw65, CD71 and CD87 antigens and bound the unclustered mAb D171 and Mo5. Differentiated and undifferentiated cells were negative for CD16, CD34, CD61, CD66abcde, CD68, CD88, CDw90 and CD93. Four panels of markers were identified whose expression changes significantly following differentiation. CD15, CD49e, CD63, CDw65, CD71 and mAb D171 and IGR-2,1A6 for DMSO; CD13, CD15, CDw17, CD49e, CD63, CDw65, CD71, CD87, CDw92 and mAb D171 and IGR-2,1A6 for ATRA; CD14, CD31, CD35, CD71, CD87, CDw92 and mAb D171 and BRIC18 for D3; CDw12, CD13, CD15, CD31, CD35, CD49e, CD71, CD87, CDw92 and mAb D171 for TPA. These will be useful for analyzing the pathways that regulate differentiation, whether the observed changes are consequences of differentiation or more direct effects of the inducers. HL60 cells provide a model for investigating the regulation of these antigens.

Antigens, CD↗
PubMed1998

The myelodysplastic syndromes: towards a functional classification.

The French-American-British classification of myelodysplastic syndromes (MDS) has contributed greatly to better communication and conduct of clinical trials. However, the advent of novel cytogenetic, immunological and molecular techniques in recent years warrant some alterations to this purely morphological classification. This review aims at highlighting the advances which reflect more closely the unique biological and clinical features of various subtypes of MDS. We propose a comprehensive classification of MDS, to include the newly defined categories, as well as those not included in previous classifications, such as the therapy-induced and hereditary MDS. We hope that this classification will help in focusing attention on the biological features of MDS, the understanding of which will be crucial to combat this disease.

Adult↗
PubMed1998

Blast counts in blood progenitor cell (BPC) correlate with CD34+ cells and CFU-GM and are useful predictor of haemopoietic recovery after autologous BPC transplantation collections.

Assessment of the quality of blood progenitor cell (BPC) collections is based mainly on CD34+ cell enumeration by flow cytometry, or scoring of granulocyte-macrophage colony-forming cells (CFU-GM). A minimum cell dose for haemopoietic recovery can be defined by both assays; however, the CFU-GM assay can not be used for 'real-time' decisions, whereas CD34+ cell scoring requires facilities and expertise which are not universally available. We have investigated the possibility of using morphologically defined blast cells within BPC harvests as a surrogate marker of harvest haemopoietic stem/progenitor cell content, as well as their correlation with CD34+ cells and CFU-GM within the harvests. We have found that blast counts correlate strongly with both CD34+ cell counts and CFU-GM within BPC harvests, as well as with time to granulocyte and platelet recovery after autologous BPC transplantation (ABPCT). Furthermore, we have defined a threshold value of 1.3 x 10(6)/kg blasts, above which there is a high probability of rapid haemopoietic recovery after ABPCT. We conclude that blast count is a simple, rapid and reliable method of assessing BPC harvest quality.

Antigens, CD34↗
PubMed1998

Variable expression of CD3-zeta and associated protein tyrosine kinases in lymphocytes from patients with myeloid malignancies.

In myeloid malignancies, T-cell and NK function has been shown to deteriorate with transformation from pre-leukaemia to advanced disease. Immune dysfunction in solid tumours has been attributed to abnormal signal transduction, possibly through altered expression of intracellular components of the TCR/CD3 complex (e.g. CD3-zeta), receptors on NK cells and their associated protein tyrosine kinases (PTKs; p56lck, p59fyn and ZAP-70). Using a flow cytometric method to detect dual-expression of surface proteins and intracellular components of the TCR/CD3 complex, we have studied 46 patients with myeloid malignancies. CD3-zeta expression was abnormal in 64% of patients, and was more prominent in those with advanced disease. Three patients with reduced CD3-zeta were analysed both pre- and post-treatment, and recovery of CD3-zeta expression was associated with successful remission induction (expression of PTKs was variable and reduced levels were seen all disease stages). The results of this study suggest that loss of signalling proteins is not a result of direct contact of leukaemic cells with lymphocytes per se or the extent of the leukaemia burden, but to a specific property of some myeloid malignancies, which is more frequently acquired with greater malignant transformation.

Adult↗
PubMed1998

'Low-risk' myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro- versus anti-apoptotic bcl-2-related proteins.

We performed flow cytometric analysis of CD34+ cell apoptosis in 59 patients with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) secondary to MDS (MDS-AML) using annexin V-FITC, which binds to exposed phosphatidylserine on apoptotic cells. Apoptosis was significantly increased in FAB subtypes RA, RARS and RAEB (<10% blasts) (56.5% (15.1-86.5%)) compared to normal controls (18.5% (3.4-33.4%), P<0.0001) and RAEB-t/MDS-AML (16% (2.1-43.2%), P<0.0001). There was no correlation between % apoptosis, Full blood count or cytogenetics in any disease category. Two-colour cytometric analysis of permeabilized CD34+ cells stained with antibodies to Bcl-2, Bcl-X (anti-apoptotic), Bax and Bad (pro-apoptotic), demonstrated significantly higher ratios of pro- v anti-apoptotic proteins in early MDS (2.47 (1.19-9.42) compared to advanced disease (1.14 (0.06-3.32), P=0.0001). Moreover, using repeated measures of variants (ANOVA), we found that variations between individual Bcl-2-related proteins differed significantly according to disease subtype (P<0.0005). Our results confirm that CD34+ cell apoptosis was significantly increased in MDS subtypes RA and RARS and fell with disease progression. Early MDS was also associated with a significantly higher CD34+ cell pro- v anti-apoptotic Bcl-2-family-protein ratio than advanced disease. Furthermore, patterns of expression of individual Bcl-2 related proteins differed significantly between different disease categories. However, no correlation between pro- v anti-apoptotic Bcl-2-family-protein ratios and the degree of apoptosis was observed.

Acute Disease↗
PubMed1998

Adult T-cell leukemia/lymphoma in London: clinical experience of 21 cases.

Adult T-cell leukemia/lymphoma (ATLL) is uncommon in the United Kingdom and has so far been restricted to people of Afro-Caribbean extraction. Between 1981 and 1995, 21 cases presented to 2 inner London teaching hospitals where 17% of the population are of Afro-Caribbean origin. Clinical presentations were similar to those of the disease in HTLV-I-endemic areas. Major responses (CR + PR) were obtained in 10/16 assessable patients (63%) treated with combination chemotherapy. However, median survival was only 5.5 months. Disease progression and opportunistic infection were the major causes of treatment failure and death. Three patients (14%) relapsed in the central nervous system (CNS). Our cases confirm the profound immunosuppression in ATLL. The poor prognosis of acute and lymphoma types of ATLL highlight the need for new approaches to treatment such as zidovudine and alpha-interferon, incorporating prophylaxis against CNS disease and opportunistic infections.

Adult↗
PubMed1997

Irradiated NC adenocarcinoma cells transduced with both B7.1 and interleukin-2 induce CD4+-mediated rejection of established tumors.

Previous studies have shown that expression of the immune co-stimulator B7.1 reduces the tumorigenicity of some, but not all, malignant cell lines. However, B7.1-expressing tumor cells are not very effective in inducing the rejection of established tumors. This may in part be due to induction of anergy in the potentially reactive T cells. Previous studies have shown that IL-2 can reverse the anergic state both in vitro and in vivo. Therefore, we have examined the effect of retrovirus-mediated delivery and expression of murine B7.1 and interleukin-2 on tumor formation and rejection of established MHC class I+/II- NC adenocarcinomas. Neither the expression of B7.1 nor IL-2 alone had a significant effect on NC tumorigenicity. In contrast, combined expression of B7.1 and IL-2 substantially decreased the tumorigenicity of these cells in the immunecompetent syngeneic hosts. T-cell depletion studies show this to be dependent primarily on the activation of CD4+ cells. Furthermore, distant subcutaneous injection of irradiated NC/IL-2/B7.1 can induce, much more effectively than NC/B7.1 or NC/IL-2, the rejection of small NC tumors, and prevent the recurrence of large surgically resected tumors. Together, these results suggest that tumor cells genetically modified to express B7.1 and IL-2 can induce the immune-mediated rejection of established class II- tumors by a mechanism involving CD4+ cells.

Adenocarcinoma↗
PubMed1997

The clinical diversity and role of chemotherapy in lymphoproliferative disorder in liver transplant recipients.

BACKGROUND/AIMS: Post-transplant lymphoproliferative disorder is a well-documented complication with an incidence ranging from 2 to 10%, depending on the organ transplanted. Yet despite our increased understanding of the pathophysiology of this disease and the various treatments available, the mortality remains high at 60-80%. We present the clinical and histological features of ten adult liver transplant recipients with post-transplant lymphoproliferative disorder presenting over a 15-year period and review the therapeutic options. METHODS: CD20/CD45RO immunostaining was used for T/B-cell markers; polymerase chain reaction and in-situ hybridisation for Epstein-Barr virus genome detection; kappa/lambda immunostaining and gene rearrangement analysis for clonality. RESULTS: There were six females and four males (age range 24-56) with onset of post-transplant lymphoproliferative disorder-symptoms ranging from 3 to 72 months post transplant. Sites of post-transplant lymphoproliferative disorder included liver (n=4), lymph nodes (n=5), bone marrow (n=2), lungs (n=2), kidneys (n=2), brain, ovaries,: and pancreas (n=1). All lesions were classified as high-grade lymphoma, of B-cell lineage (9 tested); Epstein-Barr virus genome was detected in 7/10 cases. Three tumours were monoclonal; four were polyclonal and three undetermined. Treatment included immunosuppression reduction, antiviral therapy with acyclovir and/or chemotherapy (CHOP or VAPEC-B). Survival times for those patients not treated with chemotherapy were from 9 days to 30 months, whereas those receiving chemotherapy had remission times of 4 to 48 months. CONCLUSIONS: Longer-term remissions can be achieved in patients treated with systemic chemotherapy, although not without morbidity. Clonality assessment is important but treatment decisions should be based primarily on clinical features of progression, as polyclonal tumours can behave as aggressively as monoclonal tumours.

Adult↗
PubMed1997

Idiopathic hyperammonaemia syndrome following allogeneic peripheral blood progenitor cell transplantation (allo-PBPCT).

An idiopathic hyperammonaemia syndrome has been reported in, and following chemotherapy for, various haematological malignancies as well as following bone marrow transplantation. It should be considered in the differential diagnosis of any neurological deterioration, and we describe a further case associated with an allogeneic peripheral blood progenitor cell transplant (allo-PBPCT).

Adult↗
PubMed1997

Enhanced immune costimulatory activity of primary acute myeloid leukaemia blasts after retrovirus-mediated gene transfer of B7.1.

Gene modification of malignant cells to express immune stimulators (cytokines and immune costimulators) has provided the basis for a novel form of immunotherapy. Using a MPSV-based retroviral vector with hygromycin resistance gene as a selectable marker, we have studied retrovirus-mediated gene transfer of an immune costimulator, B7.1, into primary human acute myeloid leukaemia (AML) cells and the subsequent induction of immune costimulatory function. AML blasts from 10 patients were transduced by co-culture for 48 h with or without haemopoietic growth factors (HGFs). In the absence of HGFs, transduction efficiency (TE), as judged by % B7.1 expressing cells, was low, varying from 0.3 to 8.2% (median 1.5%). Addition of HGFs increased the median TE 1.8-fold with stem cell factor alone and 2.6-fold with SCF, interleukin-3 and GM-CSF. Effects on cell cycling alone could not explain this difference, suggesting other factors such as virus binding and promoter activity, are also involved. CFU-AL assays indicated a higher transduction efficiency of clonogenic cells, which was not improved by growth factors. Limited duration of cell growth prevented significant expansion of transduced populations by culture in the presence of hygromycin. Although not increasing transduction efficiency, CD34 enrichment enhanced drug selection, by targeting cells with the greatest self-renewal capacity. Immunoselection of B7.1 expressing cells produced transduced populations with 30-60% expressing B7.1. In an allogeneic mixed leukaemic cell/T lymphocyte reaction (MLLR) transduced AML cells enriched by immunoselection were able to stimulate allogeneic T cells (CD4 and CD8 positive), which could be inhibited by a solubilised B7 receptor, CTLA4.Ig. Our results demonstrate that using a replication incompetent retroviral vector, it is possible to introduce the immune costimulator B7.1 into primary AML-blasts and by immunoselection, enrich the transduced cells, which may be used for subsequent administration as an autologous cellular vaccine.

B7-1 Antigen↗
PubMed1997

Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia.

Nineteen patients with high-risk myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) received fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF), and idarubicin chemotherapy (de novo MDS/MDS-AML, nine; relapsed/refractory MDS/AML, seven; therapy-related MDS, three). Median age was 44 years and median disease duration 10 months. 16/19 (84%) patients had abnormal cytogenetics with seven (37%) harbouring abnormalities of chromosome 7. 18/19 (94.7%) patients responded to FLAG-idarubicin with 12 (63%) achieving complete remission (CR) (< 5% blasts and normal cytogenetics). 7/9 (78%) patients with de novo MDS/MDS-AML achieved CR compared to 5/10 (50%) with alternative diagnoses. Response was associated with age < 50 years, disease duration < 3 months, and cytogenetics other than abnormalities of chromosome 7. Haemopoietic regeneration was rapid in most patients and there were no toxic deaths. Nine patients received a second course of chemotherapy, three have proceeded to allogeneic bone marrow transplant and three to autologous blood stem cell/bone marrow transplantation. Follow-up is short (median 10 months). 12/19 (63%) patients remain alive and 5/12 (42%) have relapsed at a median 5 months following CR achievement. FLAG-idarubicin was well tolerated. High rates of morphological and cytogenetic remission, especially in de novo MDS, offer a window of opportunity for assessment of autologous BMT in this group of diseases where no treatment except alloBMT has led to prolongation of survival.

Acute Disease↗