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Biomedical subjects

G J Mufti

Publications and source records attributed to G J Mufti.

At least 37 records · Page 2Linked to original sources
PubMed2003

An unusual case of pneumonia.

A previously healthy 37-year-old man was admitted with a two-month history of increasing shortness of breath and high temperature. A chest X-ray demonstrated bibasal shadowing and small bilateral pleural effusions; arterial blood gases demonstrated low pO2. Despite intravenous antibiotics no significant improvement was observed. A high-resolution chest computed tomography showed diffuse ground-glass opacification with segmental and subsegmental airways opacification, indicating fine fibrosis. Subsequently, open lung biopsy showed diffuse alveolar damage and a histopathological diagnosis of acute interstitial pneumonia (Hamman-Rich syndrome) was made. Antibiotics were stopped and high intravenous doses of steroids were given with a dramatic improvement in the patient's breathing and radiographic findings. The pathophysiological mechanisms of acute interstitial pneumonia and current therapeutic options are discussed.

Adult↗
PubMed2002

Intraperitoneal rituximab: an effective measure to control recurrent abdominal ascites due to non-Hodgkin's lymphoma.

We report a patient with an advanced stage low-grade small lymphocytic lymphoma who required regular drainage of malignant ascites for symptomatic relief despite intensive treatment. The administration of rituximab via the intraperitoneal route successfully controlled the ascites. The patient tolerated well with this unusual route of administration and has not required any further ascitic drainage for at least 8 months. In view of its simplicity, good tolerability and effectiveness to control recurrent ascites secondary to low-grade non-Hodgkin's lymphoma (NHL), this novel route of administration of rituximab is worth exploring.

Abdomen↗
PubMed2002

Fatal donor-derived Epstein-Barr virus-associated post-transplant lymphoproliferative disorder following reduced intensity volunteer-unrelated bone marrow transplant for myelodysplastic syndrome.

Post-transplant lymphoproliferative disorders (PTLD) are a well recognised complication of conventional haemopoietic stem cell transplantation (HSCT). Reduced intensity HSCT involves intensive immunosuppression to permit engraftment. Thirty reduced intensity transplants with the FBC (fludarabine 150 mg/m2, busulphan 8 mg/m2, CAMPATH-1H 100 mg) protocol have been performed at our centre, with one confirmed EBV-positive PTLD. The female recipient developed a perforated viscus day +191 following HSCT from a volunteer unrelated male donor. A large caecal mass and a retroperitoneal abscess were excised, revealing an EBV-positive diffuse large B cell lymphoma confirmed by FISH to be of donor origin. More experience is required before the risk of PTLD in this setting can be assessed.

Epstein-Barr Virus Infections↗
PubMed2002

Frequent expression of HAGE in presentation chronic myeloid leukaemias.

Cancer testis (CT) antigens provide attractive targets for cancer-specific immunotherapy. Although CT genes are expressed in some normal tissues, such as the testis and in some cases placenta, these immunologically protected sites lack MHC I expression and as such, do not present 'self' antigens to T cells. To date, CT genes have been shown to be expressed in a range of solid tumours, but rarely in haematological malignancies. We have extended previous studies to investigate the expression of a comprehensive range of CT genes (MAGE-A1, -A3, -A6, -A12, BAGE, GAGE, HAGE,LAGE-1, NY-ESO-1 and RAGE) for their expression in a cohort of acute and chronic myeloid leukaemia patient samples. CT expression was not detected in 20 normal bone marrow or peripheral blood stem cell samples. In acute myeloid leukaemia (AML) nine of the 26 (35%) samples analysed expressed one or more of the CT genes with six of the samples (23%) expressing HAGE. In chronic myeloid leukaemia (CML) 24 of 42 (57%) presentation chronic myeloid leukaemia (CML) patient samples expressed one or more CT antigen with 23 expressing HAGE. We have shown that HAGE is frequently expressed in CML, and to a lesser extent in AML patient samples. This is the first demonstration of HAGE gene expression in myeloid leukaemia patients and the frequent expression of HAGE at disease presentation opens up the possibility of early immunotherapeutic treatments.

Adolescent↗
PubMed2001

Microenvironment produced by acute myeloid leukemia cells prevents T cell activation and proliferation by inhibition of NF-kappaB, c-Myc, and pRb pathways.

Tumors produce a variety of immunosuppressive factors which can prevent the proliferation and maturation of a number of normal hemopoietic cell types. We have investigated whether primary acute myeloid leukemia (AML) cells have an effect on normal T cell function and signaling. Tumor cell supernatant (TSN) from AML cells inhibited T cell activation and Th1 cytokine production and also prevented activated T cells from entering the cell cycle. These effects occurred in the absence of AML cell-T cell contact. We have demonstrated that AML TSN contained none of the immunosuppressors described to date, namely gangliosides, nitric oxide, TGF-beta, IL-10, vascular endothelial growth factor, or PGs. Furthermore, IL-2 did not overcome the block, despite normal IL-2R expression. However, the effect was overcome by preincubation with inhibitors of protein secretion and abolished by trypsinization, indicating that the active substance includes one or more proteins. To determine the mechanism of inhibition, we have studied many of the major pathways involved in T cell activation and proliferation. We show that nuclear translocation of NFATc and NF-kappaB are markedly reduced in T cells activated in the presence of primary AML cells. In contrast, calcium mobilization and activation of other signal transduction pathways, namely extracellular signal-regulated kinase1/2, p38, and STAT5 were unaffected, but activation of c-Jun N-terminal kinase 1/2 was delayed. Phosphorylation of pRb by cyclin-dependent kinase 6/4-cyclin D and of p130 did not occur and c-Myc, cyclin D3, and p107 were not induced, consistent with cell cycle inhibition early during the transition from G(0) to G(1). Our data indicate that TSN generated by AML cells induces T cell immunosuppression and provides a mechanism by which the leukemic clone could evade T cell-mediated killing.

Active Transport, Cell Nucleus↗
PubMed2001

Identification of HLA-B*0722.

A novel polymorphism was identified in a B*07 allele. B*0722 possesses a unique nucleotide substitution at nucleotide 481. This polymorphism encodes an amino acid difference from aspartic acid in B*07021 to asparagine in B*0722. The functional significance of this polymorphism on peptide binding and/or T-cell recognition is unknown.

HLA-B Antigens↗
PubMed2001

Neutrophilic eccrine hidradenitis in two neutropaenic patients.

We describe two patients, who presented with erythematous facial plaques, in keeping with neutrophilic eccrine hidradenitis, during chemotherapy for acute myeloid leukaemia. Both patients were neutropaenic and febrile. Histology showed a dermal neutrophilic infiltrate around the eccrine glands with gland destruction. The importance of recognizing this disorder is to prevent the inappropriate use of antibiotics as it is self limiting.

Acute Disease↗
PubMed2000

The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS.

Bone marrow CD34(+) cell apoptosis (annexin V), proliferation (Ki-67), and Bcl-2-related protein expression was evaluated by flow cytometry in 102 patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia secondary to MDS (MDS-AML) and in 30 normal donors (NBM). Apoptosis was significantly increased in refractory anemia (RA)/RA with ringed sideroblasts (RARS) (56.9% [20.4%-93.6%]) and refractory anemia with excess blasts (RAEB) (51.2% [25.2%-76. 6%]) compared with NBM (16.7% [3.4%-35.3%], P <.0001). In RA/RARS, apoptosis always exceeded proliferation (Ki-67-positivity, 26.1% [9.5%-47.8%]; apoptosis:proliferation ratio 2.08 [1.15-3.63]); whereas in RAEB, this ratio equalized (1.14 [0.93-2.08]) due to increased proliferation (40.4% [22%-69.5%]). Progression to RAEB in transformation (RAEB-t)/MDS-AML was associated with a significant reduction in apoptosis (22.3% [2.1%-53.2%]; P <.0001) and proliferation (16.8% [1.9%-75.8%); P =.04; ratio 1.69 [0.16-12.21]). Pro-apoptotic (Bax/Bad) versus anti-apoptotic (Bcl-2/Bcl-X) Bcl-2-related protein ratios were increased in RA/RARS compared with NBM (2.57 [1.93-9.42] versus 1.89 [0.65-4.1]; P =.06), whereas disease progression was associated with significantly reduced ratios (1.16 [0.06-3.32]; P <.0001) due primarily to increased Bcl-2 expression. Apoptosis and Bax/Bad:Bcl-2/Bcl-X ratio were inversely correlated with both International Prognostic Scoring System score and cytogenetic risk group; highest levels observed in patients with low score and/or good risk cytogenetics. There was a trend toward an association between Bcl-2-related protein expression and apoptosis (P =.07). This study indicates that MDS progression arises through multiple hits that alter levels of CD34(+) cell apoptosis and proliferation. Early disease is associated with excessive apoptosis and elevated ratio of apoptosis to proliferation. Increased proliferative rates are observed in RAEB, whereas leukemic transformation arises through inhibition of apoptosis rather than excessive cell growth. Although disease progression is accompanied by a fall in pro-apoptotic versus anti-apoptotic Bcl-2-related protein ratios, heterogeneity in patterns of protein expression indicates that factors additional to Bcl-2 family members play a role in the deregulated apoptosis in MDS. (Blood. 2000;96:3932-3938)

Acute Disease↗
PubMed2000

Colchicine: an effective treatment for refractory malignant pericardial effusion.

We report a patient with AL amyloidosis and chemo-resistant light-chain multiple myeloma who developed a progressive malignant pericardial effusion leading to cardiac tamponade. Despite pericardiocentesis and surgical intervention, the pericardial effusion failed to resolve. The administration of oral colchicine produced symptomatic relief within 5 days, with the resolution of pericardial effusion after 14 days of treatment. As the administration of colchicine is simple and the side-effect is usually minimal, further studies are warranted to establish the feasibility of using colchicine to treat malignant pericardial effusion.

Adult↗
PubMed2000

Excessive apoptosis in low risk myelodysplastic syndromes (MDS).

The paradox of peripheral cytopenias despite a normo/hypercellular marrow in MDS has been ascribed to excessive intramedullary hematopoietic cell apoptosis. Programmed cell death (PCD) in early disease might be triggered by the BM microenvironment, mediated either through inhibitory cytokines such as tumor necrosis factor alpha (TNF-alpha) or fas/fas ligand signaling or through a relative deficiency in hematopoietic growth factors. Intrinsic cellular defects giving rise to abnormalities in cell-cell or cell-stromal interaction, cell signaling or cell cycling may also underlie hematopoietic progenitor apoptosis. Alternatively, an early 'hit' in the multistep pathogenesis of MDS may result in a higher proliferative rate of the neoplastic clone. Increased apoptosis may thus represent a homeostatic process to control cell numbers. This paper shall summarize current evidence implicating a role for increased PCD in low risk MDS, outline possible etiologic factors and suggest potential therapeutic mechanisms whereby excessive hematopoietic progenitor cell apoptosis might be circumvented.

Apoptosis↗
PubMed2000

Non-caseating granulomata associated with hypocellular myelodysplastic syndrome.

Non-caseating granuloma (NCG) remains a histopathological hallmark for sarcoidosis. Although the exact mechanism for NCG formation is unknown, the pathogenesis may involve a disordered antigen presentation in the monocyte/macrophage system, functional abnormalities in activated T-lymphocytes and uncontrolled cytokine production. Similar immunological dysfunction has been described in myelodysplastic syndrome (MDS). However, the association of NCG and MDS is rarely documented. We report a case of hypocellular MDS associated with generalized NCG. Despite treatment for both sarcoidosis and tuberculosis, the patient failed to respond. A clonal myeloid disorder which was initially suppressed by T-cell immunosurveillance evolved after treatment with anti-thymocyte globulin. Although the coexistence of sarcoidosis remains a possibility, the lack of supportive clinical evidence of sarcoidosis, the abnormal appearances of the bone marrow, together with the failure to improve on high-dose steroid favour the clonal myeloid disorder as the sole pathology.

Adult↗
PubMed1999

Effect of costimulation and the microenvironment on antigen presentation by leukemic cells.

Costimulatory signals supplied by genetically modified tumor cells can enable T-cell recognition of tumor-associated antigens that were previously silent when presented by unmodified tumor cells. Although the mechanism of the CD80/CD28 costimulation has been studied extensively in the normal T-cell/antigen-presenting cell (APC) interactions, it is unclear how expression of CD80 by tumor cells mediates its effect. We demonstrate here that optimal CD80 expression on a leukemic cell enhances T-cell recognition of alloantigen primarily by lowering the level of T-cell receptor (TCR) stimulation required for activation. CD80 expression by leukemic cells leads to increased survival of activated T cells by inducing upregulation of the antiapoptotic protein BCL-2, but not BCL-X(L). The cytokine microenvironment in which T cells are activated is crucial in determining their differentiation and consequently the nature of the immune response generated. Many tumor cells produce immunosuppressive cytokines that may not favor the induction of cell-mediated immunity. In this study, the presence of CD80 on leukemic cells increased T-cell activation in vitro, but this did not result in the production of Th1 cytokines. We show that this is due to a leukemia-derived soluble factor that inhibits the production of Th1 cytokines. Optimal expression of a costimulatory molecule, therefore, enhances the ability of leukemic cells to present antigen by amplifying TCR signals, but the microenvironment generated by leukemic cells may suppress the immune response required for their eradication. Thus, strategies aimed at inducing antileukemic immunity by providing leukemic cells with costimulatory functions must ensure the presence of an appropriate microenvironment.

Antigen Presentation↗
PubMed1999

The "G-CSF test": the response to a single dose of granulocyte colony-stimulating factor predicts mobilization of hemopoietic progenitors in patients with hematologic malignancies.

A significant proportion of patients with hematologic malignancies fail to mobilize sufficient hemopoietic progenitor cells (HPC), thereby restricting wider application of autologous transplantation. It would be of considerable use to develop a test that could be used prospectively to assess an individual patient's capacity to mobilize HPC. Twenty-two patients with lymphoma, myeloma, and chronic lymphocytic leukemia were given a single dose of 12 microg/kg SC of granulocyte colony-stimulating factor (G-CSF). Blood colony-forming unit granulocyte-macrophage (CFU-GM) and CD34+ cells were scored prior to the test dose, and 72, 96, and 120 hours later. The patients were then mobilized with a standard cyclophosphamide and G-CSF regimen and had blood stem cells harvested. Patients were categorized as good, poor, or intermediate mobilizers on the basis of the CFU-GM/CD34+ cell harvest content and the number of aphereses required to reach established threshold counts. The outcome of cyclophosphamide/G-CSF mobilization was correlated with the response to the test dose of G-CSF. Good mobilizers had significantly higher peak CFU-GM values and CFU-GM increment in response to the test dose of G-CSF compared to intermediate and poor mobilizers. A peak CFU-GM count of > or = 250/mL identified the good mobilizers; conversely, all poor mobilizers had a peak CFU-GM count of <102/mL. An increment in CD34+ cells counts of > or = 2.5/microL was only observed in good mobilizers. The "G-CSF" test is a reliable test that can be used successfully for the assessment of mobilizable HPC in patients with hematologic malignancies. It can also be used to stratify patients enrolled in trials of mobilizing agents.

Adult↗