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Biomedical subjects

O Legrand

Publications and source records attributed to O Legrand.

At least 37 records · Page 2Linked to original sources
PubMed1999

Piperacillin/tazobactam plus tobramycin versus ceftazidime plus tobramycin as empiric therapy for fever in severely neutropenic patients.

The objective of this trial was to evaluate the potential advantages of the combination of piperacillin and tazobactam in the control of fever in neutropenic patients. In this single-center study, patients who experienced a total of 247 febrile episodes were prospectively randomized to receive either our standard regimen, ceftazidime 3 g/day (1 g t.i.d.) plus tobramycin 3 mg/kg per day (1.5 mg/kg b.i.d.), or piperacillin 12 g/day plus tazobactam 1.5 g/day (4 g+0.5 g t.i.d.) plus tobramycin 3 mg/kg per day (1.5 mg/kg b.i.d.). Vancomycin was added in all cases of persistent fever in the ceftazidime arm, but only when there was microbiologically documented resistance in the piperacillin/tazobactam arm. All 247 episodes were evaluable by "intent-to-treat" analysis. The two populations were well matched in terms of age, gender, underlying disease, chemotherapy received, oral decontamination, clinical and bacterial documentation, and severity and duration of neutropenia. Initial antibacterial therapy was successful (apyrexia at 72 h, without antibiotic change) more frequently (P = 0.008) with the regimen containing piperacillin/tazobactam (54.4%) than with the one including ceftazidime (37.6%). Fewer (P = 0.02) major infectious events (infectious death or delay in treatment of underlying disease due to infection) were observed during piperacillin/ tazobactam treatment (2.6%) than with the ceftazidime regimen (11.3%), despite a lower frequency of glycopeptide addition when piperacillin/tazobactam was used (54.4% versus 77.4%) according to the rules adopted. This trial confirmed the efficacy of the piperacillin/tazobactam combination for empirical treatment of febrile neutropenic patients. This antibiotic combination permitted a dramatic decrease in empiric glycopeptide antibiotic administration in such patients.

Adult↗
PubMed1999

Role of MRP1 in multidrug resistance in acute myeloid leukemia.

The best characterized resistance mechanism in adult acute myeloid leukemia (AML) is the one mediated by the MDR1 gene which has been shown to be associated with poor outcome. However, alternative proteins such as the more recently recognized multidrug-associated protein (MRP1), may also contribute to the resistance to anthracyclines and etoposide in AML. Recently, the role of this protein was discussed and was unclear in AML. However, recent data concerning the functionality and the modulation of the activity of MRP1 may elucidate its role in comparison with other mechanisms of resistance. In this paper, we will review these recent data concerning the role of MRP1 in adult AML.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1999

Smoldering acute myelogenous leukemia in the elderly.

Out of 75 consecutive elderly AML patients who did not receive anti-leukemic treatment (52 pts) or failed to respond to differentiating agent (23 pts), 6 patients had survivals of 13.2 to 98 months with treatment restricted to supportive care. This cut-point is far longer than the median survival of the 235 elderly patients (3.5 mo.), either untreated (med. survival: 1 mo.) or treated (with treatment ranging from conventional induction to palliative chemotherapy) (4 mo.), admitted to our department within the same period of time. These cases of smoldering AML (4 women, 2 men) were all of AML2 FAB subtype (4 de novo, 2 post MDS) and presented with a significantly better performance status, lower WBC and circulating blast counts, higher platelet counts and with lower bone marrow infiltration than AML cases with more rapid progression. Cytogenetical analysis when available (3 pts) showed normal karyotypes and clonogenic assay performed in 3 of these patients showed a lack of (2 pts) or reduced in vitro leukemic cell growth (1 pt). The identification of specific characteristics of smoldering leukemia in the elderly might be an important development in the understanding of the physiopathology of acute leukemia and a tool for helping decision-making when selecting the time and intensity of cytotoxic treatment in these older patients.

Aged↗
PubMed1998

Pgp and MRP activities using calcein-AM are prognostic factors in adult acute myeloid leukemia patients.

Thirteen cell lines with different levels of Pgp and MRP expression were used to assess the ability of calcein acetoxymethyl ester (calcein-AM) uptake and calcein efflux to measure Pgp and MRP functions, respectively. There was a good correlation between MRP expression and the modulatory effect of probenecid (a specific modulator of MRP) on the calcein efflux (r = .91, P = .0003) and between Pgp expression and the modulatory effect of CsA on calcein-AM uptake (r = .96, P < .0001). In light of the high correlations for both proteins, we tested calcein-AM uptake and efflux in fresh myeloid leukemic cells. In 53 acute myeloid leukemia (AML) patients, there was also a good correlation between MRP expression (measured by reverse transcription-polymerase chain reaction and by MRPm6 expression by flow cytometry) and the modulatory effect of probenecid on the calcein fluorescence (r = .92, P < .0001) and between Pgp expression as measured by UIC2 antibody binding on flow cytometry and the modulatory effect of cyclosporin A on calcein-AM uptake (r = .83, P < .0001). Pgp activity was higher in CD34+ leukemia than in CD34- leukemia (2.26 +/- 1.50 v 1.46 +/- 1.21, respectively; P = .003), and MRP activity was higher in CD34- leukemia than in CD34+ leukemia (1.77 +/- 0.40 v 1.4 +/- 0. 29, respectively; P = .004). Pgp expression and activity (P = .004 and P = .01, respectively) and MRP activity (P = .03) but not MRP expression were prognostic factors for achievement of complete remission. These results suggest that functional testing (with calcein-AM +/- modulators) for the presence of both MRP and Pgp activities is of prognostic value and that MRP contributes to drug resistance in AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Lung resistance protein (LRP) gene expression in adult acute myeloid leukemia: a critical evaluation by three techniques.

The role of LRP in clinical drug resistance in acute myeloid leukemia (AML) is controversial. We therefore compared multiple assays, including RT-PCR, immunocytochemistry (ICC) and flow cytometry (FC), in 10 cell lines and in 47 fresh and thawed AML cells in order to validate and to quantitate measures for LRP phenotype detection. We also compared different ways of expressing the results. Lastly, in cell lines, we analyzed the 50% lethal concentration (LC50), by MTT assay, of cisplatin which could estimate the functionality of LRP. The reproducibility of LRP detection measured by RT-PCR, ICC and FC was good. In the same way, within the same technique, there was good correlation between the different methods of expressing the results of LRP level. Therefore, the discrepancies noted with the three techniques used were neither a problem of reproducibility nor a problem of results expression. On the other hand, there was only a correlation between ICC and FC, and no correlation between RT-PCR and LRP protein detection techniques. Therefore, RT-PCR is probably not the optimal technique for LRP detection. We have shown in 10 cell lines a higher correlation between FC and LC50 of cisplatin than between ICC and LC50 of cisplatin and no correlation between RT-PCR and LC50 of cisplatin. For five patients, there was a dissociation between ICC and FC. Four patients were positive by FC and negative by ICC and only one patient was negative by FC and positive by ICC. Therefore, if in vitro resistance to cisplatin represents the functionality of LRP, we recommend the use of FC rather than ICC to detect LRP expression. Besides the measurement of LRP as a diagnostic tool in the evaluation of resistance to chemotherapy in patients with AML, we urgently need to establish a functional test in order to assess LRP activity.

Acute Disease↗
PubMed1998

Adult biphenotypic acute leukaemia: an entity with poor prognosis which is related to unfavourable cytogenetics and P-glycoprotein over-expression.

Biphenotypic acute leukaemia (BAL) patients represented 8% of the 287 de novo consecutive adult acute leukaemias (23 BAL, 230 acute myeloid leukaemia (AML) and 34 acute lymphoblastic leukaemia (ALL)) referred to our department during the last 4-year period. Of these 23 BAL patients, 14 patients showed myeloid morphology and nine cases lymphoid morphology according to FAB criteria. There were no differences between lymphoid and myeloid BAL according to clinical and biological presentation and treatment outcome. We confirm the poor prognosis of BAL when compared to AML or ALL seen during the same period of time, in terms of complete remission (47%, 62% and 82% respectively, BAL v AML, NS and BAL v ALL, P = 0.006) and 4-year overall survival (8.1%, 25.8% and 23.8% respectively, BAL v AML, P = 0.05 and BAL v ALL, P = 0.003). Comparing adult BAL patients with AML patients, we found an increase in poor prognostic factors: CD34+ phenotype (82% v 60% respectively, P = 0.03), unfavourable karyotype (60% v 20%, P < 0.0001) and Pgp over-expression by RT-PCR (0.705 v 0.107, P < 0.0001) and flow cytometry (0.824 v 0.391, P = 0.0001). MRP and LRP were not found to be poor prognostic factors. Comparing BAL patients with ALL patients, we found also an increase in poor prognostic factors: age (51 v 39, P = 0.003) and CD34+ phenotype (82% v 50%, P = 0.02). We conclude that BAL patients need a more aggressive treatment procedure, including high-dose AraC or the use of Pgp modulators for first-line therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Treatment of hairy cell leukaemia (HCL) with 2-chlorodeoxyadenosine (2-CdA): identification of parameters predictive of adverse effects.

2-chlorodeoxyadenosine (2-CdA) induces high complete remission (CR) rates in hairy cell leukaemia (HCL), but is associated with serious toxicities. Therefore we reviewed our experience with 2-CdA in 16 HCL patients, with special attention to adverse effects. One-third of patients presented severe neutropenic infections and/or required prolonged blood support. Patients with low tumour mass and moderate cytopenias were more likely to achieve CR, whereas those with high tumour burden and severe bone marrow impairment were at increased risk of severe infection and blood product requirements. All these unfavourable parameters may be corrected by short-term alpha-interferon (IFN) therapy. Therefore we suggest that patients with unfavourable presenting features might benefit from IFN therapy before 2-CdA.

Antineoplastic Agents↗
PubMed1997

Prognostic factors in elderly acute lymphoblastic leukaemia.

A retrospective study was performed on 46 unselected acute lymphoblastic leukaemia (ALL) elderly patients aged 60 years or more. Only 50% of these patients were included in the EORTC cooperative clinical trials, thus confirming the important selection bias in most of the published series on elderly ALL patients. 43% of the elderly patients achieved a complete remission (CR). The median survival was 10 months and the 5-year overall survival was only 7.6 +/- 4%. In multivariate analysis, W.H.O. performance status and peripheral blast counts at day 7 were found to significantly influence achievement of CR and survival. In patients with W.H.O. performance status > or = 2, 35% died during induction treatment versus 4% in patients with W.H.O. performance status < 2. Patients > 70 years old showed a marked drop of the CR rate (27%) compared to those aged 60-69 (67%), and a very high death rate during the induction period (38% versus 4%). This suggests that ALL protocol treatments should be proposed until 70 years in patients with good-performance status, whereas less intensive treatment should be offered to elderly patients with performance status > or = 2 and/or age > or = 70. Peripheral blast counts at day 7 may help to adjust the treatment during induction phase.

Age Factors↗
PubMed1997

Measuring multidrug resistance expression in human malignancies: elaboration of consensus recommendations.

Before the prognostic significance of P-glycoprotein (P-gp) expression can be properly evaluated in prospective clinical trials of P-gp modulators, standard techniques for the measurement of P-gp must be widely accepted. Several multicenter trials have demonstrated large discrepancies in the observed levels of P-gp expression in the same clinical samples evaluated at different centers. The greatest discrepancies occurred with samples that expressed low levels of P-gp. Although standardized procedures have dramatically increased the interlaboratory reproducibility of flow cytometry and polymerase chain reaction assays, data from immunocytochemistry remain difficult to interpret. Consensus recommendations are presented for improving data reproducibility. These recommendations emphasize the importance of using calibrated batches of antibodies and two different antibodies for immunocytochemistry, the need for an internal standard for reverse transcriptase-polymerase chain reaction (RT-PCR) assays, the need for the presentation of data as a continuous variable, and the need for setting standard parameters for flow cytometry. It is also extremely important for the success of clinical trials that multiple techniques be employed to insure accurate measurement of P-gp expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Treatment of agnogenic myeloid metaplasia with danazol: a report of four cases.

Peripheral cytopenias are common in patients with agnogenic myeloid metaplasia (AMM). They are an important cause of morbidity and mortality, and their treatment is difficult. We report on 4 patients with AMM and severe cytopenia treated with danazol (400-600 mg/ day). Three of them became independent of red blood cell (RBC) transfusion, while the other had a slight reduction in RBC requirement. In addition, correction of thrombocytopenia and disappearance of splenomegaly were observed in 1 and 2 patients, respectively. No side effects were observed. In our experience, danazol appears effective and safe in the subset of patients with AMM whose disease is mainly characterized by bone-marrow failure. These data warrant further studies to evaluate this treatment and explore its mechanism of action.

Aged↗
PubMed1996

Expression of the multidrug resistance-associated protein (MRP) mRNA and protein in normal peripheral blood and bone marrow haemopoietic cells.

We studied the expression of multidrug resistance-associated protein (MRP) in normal haemopoietic cells from peripheral blood and bone marrow. The MRP mRNA levels were estimated by RT/PCR and in situ hybridization (ISH) assay, and the protein levels by flow cytometry. 21 samples of peripheral blood and 21 samples of bone marrow (11 normal bone marrow donors, 10 patients in complete remission after chemotherapy for large cell lymphoma or acute myeloid leukaemia) were analysed. In peripheral blood the mean MRP mRNA level in CD3+ cells was statistically higher than in the other cells (3-fold by the methods used). The levels of MRP in CD3+ varied from one individual to another (4.5-34.8 units by RT/PCR and 5-23 grains/cell by ISH); however, this was proportional to the variation in all the cell lineages of same individual (r = 0.84). In bone marrow the mean MRP levels of the various cell lineages (including CD34+) were similar to the basal level in HL60 cells. Individual expression levels were again variable; however, there was no difference between untreated normal bone marrow and post chemotherapy normal bone marrow. MRP protein expression was determined by flow cytometry with the monoclonal antibody MRPm6. The CD4+ lymphocytes exhibited a higher MRP protein expression than the other cell lineages, including CD8+ cells. There was a good correlation between the three methods used (RT/PCR and ISH, P = 0.0001, r = 0.87; RT/PCR and flow cytometry, P = 0.0001, r = 0.85; ISH and flow cytometry, P = 0.002, r = 0.67).

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Glutathione-S-transferases pi, alpha, mu and mdr1 mRNA expression in normal lymphocytes and chronic lymphocytic leukemia.

Chronic B cell lymphoproliferative disorders are frequently sensitive to alkylating agents. To assess the glutathione-S-transferases (GSTs) gene expression in B tumoral lymphocytes, possibly responsible for this sensitivity, we developed a sensitive RT-PCR assay for the three isoenzymes GST pi, GST mu and GST alpha mRNA. Normal B and T lymphocytes from 11 blood donors were separated by magnetic beads and tested with this assay. The GST pi was the most abundant transferase, and was detected in all B and T cell samples. GST mu was undetectable ('null' phenotype) in 6/11 normal donors, either in B or T cells. GST alpha was very stable from donor to donor, and was highly correlated between B and T cells of the same individual (P < 0.0001). There is no correlation between the three isoenzymes, and between each isoenzyme and mdr1 gene expression. Twenty-three B lymphoproliferative disorders (20 B-CLL, 3 CD5- chronic lymphoproliferative syndromes) were tested with the same technique. An average decrease of 57% of the GST pi expression was noted in the mononuclear cells of these patients (P < 0.02), with no differences between the untreated and treated cases. The GST alpha and mdr1 mRNA levels did not differ from normal B lymphocytes, but the proportion of patients with no detectable expression of GST mu is lower than in the control (13%). Interestingly, the low content of GST pi in B-CLL could explain the frequent sensitivity of this disease to alkylating agents.

Adult↗
PubMed1994

Early cytoreduction: a major prognostic factor in adult acute lymphoblastic leukemia.

Prognostic factors in acute lymphoblastic leukemia (ALL) are used for treatment stratification of ALL. Definition of simple parameters such as the presence or absence of peripheral leukemic cells after one week of treatment could help for stratification. A retrospective study was conducted on 79 previously untreated adult patients with ALL followed in the Hematology department of Hotel Dieu from 1981 to 1991. 84% of patients achieved complete remission (CR), 7% were refractory to induction treatment, and 7 patients (9%) died during the first month after diagnosis. After multivariate analysis the only independent statistically significant factors for achieving CR were the absence of peripheral blast cells at day 7 (PBC D7) (p = 0.009) and age (< 50 years) (p = 0.03). For CR duration the same independent statistically significant factors were found (PBC D7 = 0 versus > 0, p = 0.008; and age < or > or = 30 years, p = 0.045). The PBC D7 value was more significant when circulating blast cells were present at diagnosis. In patients with more than 50,000 PBC at diagnosis, the 10- years event free disease was 62% +/- 20% when PBC were absent at day 7 versus 0% when PBC were present (p < 0.002). All 20 patients with prolonged DFS had PBC D7 = 0 achieving CR by 28 days. The persistence of PBC at Day 7 could be used as a factor to identify a subgroup of poor prognosis adults with ALL.

Adolescent↗
PubMed1992

Multidrug resistance (MDR) gene expression in acute non lymphoblastic leukemia: sequential analysis.

Sequential evaluation of P-glycoprotein expression was performed in 29 patients with acute nonlymphoblastic leukemia using immunocytochemistry with the C219 antibody. At diagnosis, 32% of the patients exhibited more than 5% of the P-gp(+) leukemic cells. Under chemotherapy, 62% of the patients eventually expressed a subset of P-gp positive leukemic cells. After conventional doses of cytosine-arabinoside (Ara-C) and daunorubicin or mitoxantrone, positive P-gp cells were noted in 65% of the cases. This percentage was significantly higher (p = 0.002) than the proportion of positive cases (15%) observed after regimens containing either intermediate doses of Ara-C or cyclosporine A, a P-gp modulator.

ATP Binding Cassette Transporter, Subfamily B, Mem↗