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Biomedical subjects

A Mijovic

Publications and source records attributed to A Mijovic.

At least 19 recordsLinked to original sources
PubMed2006

Preoperative autologous blood donation for bone marrow harvests: are we wasting donors' time and blood?

Predeposit autologous blood donation (PAD) is frequently offered to bone marrow donors, but its cost-effectiveness is dubious. We assessed the impact of PAD and bone marrow donation on transfusion requirements; and the use of donated blood units in a retrospective study of 61 bone marrow donors. The mean haemoglobin (Hb) concentration fell from 12.9 to 11.8 g dL(-1) in women who predonated one unit and from 13.2 to 10.9 g dL(-1) in those who predonated two units. In men who donated two units of blood, the Hb concentration decreased to 12.9 g dL(-1). Bone marrow harvest led to a further decline in Hb concentration by 2.3 g dL(-1) in women and by 2.4 g dL(-1) in men. The postharvest Hb fell to or= 9.0 g dL(-1); overtransfusion was even more apparent in men: 71% units were given with a Hb >or= 10.0 g dL(-1). PAD in bone marrow donors is associated with high wastage and increases the likelihood of requiring a transfusion. We recommend that PAD should not be routinely offered to bone marrow donors.

Blood Transfusion, Autologous↗
PubMed2005

Transfusion-transmitted malaria: current donor selection guidelines are not sufficient.

A case of transfusion-transmitted malaria was identified in a 50-year-old male patient with sickle cell disease. The donor was Ghanaian, but had migrated to the UK some years previously and had not left the UK for 8 years. The donor met all of the extant donor selection guidelines [1] and a donation was consequently collected. However, on subsequent investigation of the case, the donor was found to be parasitaemic and have high titre malarial antibodies. As a result of this case, changes to the United Kingdom donor selection guidelines have been proposed. These changes will prevent any such further transmissions.

Animals↗
PubMed2004

Differentially expressed genes in adult familial myelodysplastic syndromes.

The precise genetic events leading to myelodysplastic syndromes (MDSs) and leukemic transformation remain poorly defined. Even less is known about adult familial MDS. We report an adult MDS family in whom enriched tissue-specific transcripts were derived by subtractive hybridization of cDNA from the mononuclear and CD34+ cells of affected and unaffected family members. These expression libraries were then hybridized to Genome Discovery arrays containing 18 404 genes and expressed sequence tags, and several clusters of differentially expressed genes were identified. A group of 21 genes was underexpressed (>5-fold) in affected vs unaffected family members, and among these were transcription factors and genes involved in myeloid differentiation, such as ZNF140 and myeloid nuclear differentiation antigen (MNDA). Another group of 36 genes was overexpressed (>5-fold), and these encoded proteins belonging to signaling pathways, such as Ras- and Fos-related genes. The top two genes downregulated in this MDS family, ZNF140 and MNDA, were similarly altered in another MDS family, and in some cases of sporadic MDS. Our data suggest that we have identified genes differentially expressed in adult familial MDS, and that alteration of some of these genes may also be important for the evolution of different stages or severity of sporadic MDS.

Adolescent↗
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↗
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↗
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↗
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

'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↗
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

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↗
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↗
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↗