Myasthenia gravis after allogeneic bone marrow transplantation: a case report.
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Adult↗
Biomedical subjects
M Baccarani
Publications and source records attributed to M Baccarani.
MDR-related P170-glycoprotein modulates cytotoxic activity of homoharringtonine.
Homoharringtonine (HHT) is a new drug with antileukemic activity which is currently tested for treatment of acute and chronic leukemias, either alone or in combination with other agents. Since HHT showed a low efficacy in refractory and relapsed acute leukemia and in the blastic phase of chronic myeloid leukemia (CML) which are frequently characterized by an overexpresion of the multidrug resistance (MDR)-related P170-glycoprotein, we postulated a relationship between the poor antileukemic effect of HHT in these leukemias and the expression of P170-glycoprotein. For this reason, sensitive (LOVO109 and CEM) and MDR (LOVO DX and CEM VLB) cell lines were exposed to HHT with or without some MDR modifiers, namely, Cyclosporine A (CyA), the Cyclosporine derivative SDZ PSC 833 (PSC), and the D-isomer of Verapamil (DVRP). It was found that MDR cells were about 15 times more resistant to HHT than non-MDR cells, and that resistance to HHT was significantly decreased by all the MDR modifiers that were tested. This in vitro study showed that HHT belongs to the category of MDR-related drugs, like anthracyclines, vinca alkaloids, epipodophylline derivatives, and taxol.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The role of granulocyte colony-stimulating factor (filgrastim) in maintaining dose intensity during conventional-dose chemotherapy with ABVD in Hodgkin's disease.
BACKGROUND: The aim of the study was to evaluate the role and potential benefit of granulocyte colony-stimulating factor (G-CSF, Filgrastim), administered following cytotoxic chemotherapy with the ABVD regimen in Hodgkin's disease, in maintaining cycle schedule and dose intensity and in decreasing neutropenia and number of infections. PATIENTS AND METHODS: Twenty-two patients affected by high-risk Hodgkin's disease (14 localized and 8 diffuse), aged 15 to 69 years (median, 34), were given ABVD chemotherapy for a total of 6 courses (for the purpose of this study, each single course of chemotherapy was considered as two 15-day periods). No patient was given G-CSF after the first cycle. After each cycle, G-CSF was administered only for: 1)absolute neutrophil count < 1 x 10(9)/L between cycles; 2) delay in cycle schedule due to an absolute neutrophil count < 1 x 10(9)/L on the planned day of treatment; or 3) fever or a documented infection, regardless the absolute neutrophil count. Once administered, G-CSF was maintained in the subsequent cycles. RESULTS: Seventeen of 22 patients (77%) required the administration of G-CSF (5 micrograms/kg b.w.; a median of 5 doses/cycle); most of them (13/17) before the 5th dose of chemotherapy. The main reason for introducing G-CSF into therapy was neutropenia during the interval between courses (n = 4) or on the planned day of treatment (n = 11). Comparing 112 courses where G-CSF was not administered with 124 where it was, in the latter group we observed: 1) a significantly lower (P = 0.0002) incidence of cycle delays (0 vs 13), with a median delay of 7 days (5 to 11). The main reason for cycle delay was neutropenia (n = 13); 2) a greater dose intensity delivered to the patients while on G-CSF (100% vs 95.2 +/- 8.8%; P = 0.0001); 3) an absolute neutrophil count significantly higher at day 8 (P < 0.0001) and day 15 (P < 0.0001); 4) a significantly lower (P = 0.0003) incidence of neutropenia (2 vs. 17). No difference in the incidence of infections was observed between the two groups of cycles (P = 0.5889), but the duration and severity of the same were greater during chemotherapy without G-CSF, requiring antibiotic therapy and causing cycle delay. CONCLUSIONS: In conclusion, our data suggest the use of Filgrastim in Hodgkin's disease also during conventional-dose chemotherapy with ABVD. It is not required from the first dose of therapy, but as soon as neutropenia appears between cycles or on the planned day of treatment. Then, its use allows maintenance of the chemotherapy schedule and dose intensity. It also decreases frequency, duration and severity of neutropenia and its sequelae.
Adolescent↗
Effect of unmodified triple helix-forming oligodeoxyribonucleotide targeted to human multidrug-resistance gene mdr1 in MDR cancer cells.
The human mdr1 gene encodes a transmembrane glycoprotein the over-expression of which is associated with development of multidrug resistance in human tumor cells. A negative modulation of human mdr1 has been attempted via a 27-mer unmodified triple helix-forming oligonucleotide, named 1D, targeted to a homopurine sequence in the coding region of the gene. By administering 10 microM of 1D we could find a significant reduction in MDR1 mRNA levels in the human drug-resistant cell line CEM-VLB100. This effect appears to be specific and due to a transient block of RNA polymerase mediated by triple helix formation.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Esophageal polyp as the sole manifestation of relapse seven years after treatment for Hodgkin's disease.
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Adolescent↗
Long-term survivors in chronic granulocytic leukaemia: a study by the International CGL Prognosis Study Group. Italian Cooperative CML Study Group.
The purpose of the present work were to identify the initial characteristics associated with long-term survival in chronic granulocytic leukaemia (CGL) and to analyse the accuracy of prognostic models in identifying long-term survivors. 813 Philadelphia (Ph) chromosome-positive, nonblastic CGL patients from six American and European institutions, the majority treated conventionally, with a minimum follow-up > 10 years, were studied. Stepwise logistic regression was performed to ascertain the association between the initial clinicohaematological variables and survival > or = 8 years, and a prognostic index was derived. The usefulness of both Sokal's and the new prognostic index to identify long-term survivors was assessed by calculating their positive and negative predictive accuracies, sensitivity and specificity. Median survival of the series was 45 months (range 1-255), with 784 patients (96.4%) having died and 109 (13.4%) surviving 8 years or longer. Younger age, smaller spleen, platelets < or = 600 x 10(9)/l, and lower blood blast percentage were associated with survival > or = 8 years; platelets < or = 600 x 10(9)/l and lower blood blast percentage were the predictive factors in patients 50 years old or younger. Two-thirds of long survivors belonged to Sokal's low-risk group, but the positive predictive accuracy and specificity for prolonged survival of Sokal's index were very low. This was also the case for the new predictive index.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Granulocyte-macrophage colony stimulating factor in acute non-lymphocytic leukaemia.
BACKGROUND: Granulocyte-macrophage colony stimulating factor (GM-CSF) is required to maintain and to regulate granulocyte and monocyte productions. It is potentially useful for accelerating and enhancing haemopoietic recovery and neutrophil function. RESULTS: In acute non-lymphocytic leukaemia (ANLL) the dependence of blast cells on GM-CSF and its role in the development and maintenance of leukaemia are still poorly defined. In vitro exposure of fresh leukaemic blast cells to a wide range of concentrations of GM-CSF leads to a stimulation of cell proliferation in the majority of cases but does not induce any detectable maturation. CONCLUSIONS: Granulocyte-macrophage colony stimulating factor may be used in the management of ANLL and the myelodysplastic syndrome (MDS) with the aim of: (i) accelerating the recovery of normal haemopoiesis; (ii) increasing cell killing by chemotherapy; and (iii) inducing cell maturation. Therefore the application of GM-CSF can potentially improve treatment outcome in ANLL and is worth testing in a clinical setting.
Clinical Trials as Topic↗
Evaluation of the clinical relevance of the anionic glutathione-s-transferase (GST pi) and multidrug resistance (mdr-1) gene coexpression in leukemias and lymphomas.
By using RNA slot-blot technique, the frequency and the degree of GST pi and mdr-1 gene coexpression were investigated in 23 AML patients, 9 ALL, 9 CLL and 11 cases of NHL in an attempt to study their clinical and prognostic relevance. GST pi and mdr-1 levels were expressed as arbitrary units (U) with respect to the negative controls (U = 0), MCF7 and HL60 sensitive cell lines, and the positive controls (U = 10), MCF7/DOXO and HL60/DNR resistant cell lines. The concomitant GST pi/mdr-1 gene overexpression showed a negative prognostic value in the set of newly diagnosed AML pts (10 cases), furthermore higher GST pi and mdr-1 mRNA levels were averagely detected in the relapsed/resistant ALL pts (4 cases), and in CLL (7 cases) and NHL (8 cases) heavily pretreated patients who were unresponsive to chemotherapy and with a disease progression. These preliminary data show that two different mechanisms of drug resistance can be coexpressed at the same time in those leukemias and lymphomas with a clinically unfavourable course.
Adult↗
Coexpression of anionic glutathione-S-transferase (GST pi) and multidrug resistance (mdr1) genes in acute myeloid and lymphoid leukemias.
By using RNA slot-blot technique the frequency and degree of GST pi and mdr1 gene coexpression was investigated in 23 patients with acute myeloid leukemia (AML), and nine patients with acute lymphoid leukemia (ALL). With respect to the negative controls, MCF7 and HL-60 cell lines, increased GST pi and mdr1 mRNA levels, expressed as arbitrary units (U), were respectively detected both in AML and in ALL patients. A positive and significant correlation between GST pi and mdr1 gene expression was found in the group of AML patients, while in the smaller group of ALL patients only a trend could be shown. These data show that two different mechanisms of drug resistance can be coexpressed at the same time in patients with acute myeloid and lymphoid leukemia. From this evidence many important clinical and therapeutic questions arise.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Expression of multidrug resistance gene (MDR1) in normal hematopoietic cells.
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Drug Resistance↗
Infections in patients with acute non-lymphocytic leukemia nursed with central or peripheral venous access.
AIMS AND BACKGROUND: Infections are a major problem in patients undergoing induction chemotherapy for acute leukemia. Granulocytopenia is the single most important risk factor, but the pattern of infecting organisms can change according to nursing facilities or bacterial and fungal prophylaxis. METHODS: We reviewed the patterns and types of infections in 30 patients with acute non-lymphocytic leukemia. Eighty-nine periods of neutropenia following chemotherapy were evaluated: in 60 courses patients had central and in 29 had peripheral venous access. RESULTS: Almost all patients (97%) became febrile after the 1st course of therapy, but one-third remained apyretic after the fourth course (P = 0.002). In this series, the incidence of gram-positive, gram-negative and mycotic isolations were respectively 76%, 18% and 6%. The need for antimicrobic treatment varied in relation to the course of chemotherapy. CONCLUSIONS: We conclude that in acute non-lymphocytic leukemia the first neutropenic period following the onset of disease is the most critical regarding infectious problems. Both quinolonic prophylaxis and central venous access could be responsible for the microbiologic findings.
Adolescent↗
D-verapamil downmodulates P170-associated resistance to doxorubicin, daunorubicin and idarubicin.
Verapamil (VRP) is an effective modulator of P170-associated multidrug resistance (MDR), but its clinical application is limited by cardiovascular side-effects. The D-isomer of VRP (D-VRP) is 10 times less active than the racemic mixture on the cardiovascular system, but retains a MDR modulating activity. Daunorubicin (DNR) and doxorubicin (DX) are two anthracyclines whose cytotoxicity is strongly related with the expression of P170, while their respective lipophylic derivatives idarubicin (IDA) and iododoxorubicin (IDX) are less P170-dependent. We studied the effect of D-VRP on intracellular retention and on the cytotoxicity of these four anthracyclines in two MDR cell systems (LOVO and CEM) by flow cytometry and by a microcultured tetrazolium colorimetric assay (MTT). We found that in MDR cells D-VRP increased intracellular anthracycline concentration and increased the cytotoxicity of DNR, IDA and DX but not of IDX. The effect of D-VRP was dose-related, but it was already consistent at D-VRP concentrations that can be readily maintained in vivo (2-3 microM). These data suggest that at a clinically tolerable concentration D-VRP can downmodulate the resistance to DNR and DX and can restore full sensitivity to IDA.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The type of BCR/ABL junction does not predict the survival of patients with Ph1-positive chronic myeloid leukaemia.
The prognostic value of the location of the breakpoint on chromosome 22 in patients with Ph1+ chronic myeloid leukaemia (CML) is still controversial. We analysed both DNA rearrangement and transcript type in a new continuous series of CML patients. By Southern blotting analysis, we found that, out of 72 patients, 43 had a 5' rearrangement and 29 a 3' one, of the 43 5'-rearranged patients, 35 carried an a2b2 transcript and eight an a2b3 one, while, of the 29 patients rearranged in the 3' part of the M-BCR area, 26 had an a2b3 transcript, one had an a2b2 transcript and two carried both types of transcript. Thus, mRNA studies allow to detect an a2b3 transcript in 17.7% of 5' rearranged patients. However, no correlation was observed between type of transcript and survival, as after DNA studies.
Adolescent↗
Proliferative advantage rather than classical drug resistance as the cause of treatment failure in chronic myelogenous leukemia.
This presentation discusses the role that proliferative advantage plays in making both the chronic and blastic phases of CML resistant to therapy. A case is made for the addition of "regrowth" inhibitors between courses of chemotherapy as a means of increasing the efficacy of therapy by suppressing or reducing the proliferative advantage that the target cells enjoy over those cells which one would like to repopulate the hematopoietic system.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
A comparative analysis of the sensitivity of multidrug resistant (MDR) and non-MDR cells to different anthracycline derivatives.
Because of the fact that tumor cell sensitivity to cytotoxic agents may play a major role in cancer treatment, and several anthracyclines are widely used for first-line treatment of leukemia, lymphoma and other tumors, and since the overexpression of the mdr-1 gene-coded 170 Kd glycoprotein (P170) decreases cell sensitivity to anthracyclines, we investigated the relationship between P170 overexpression and the cytotoxicity of two classic anthracyclines (Daunorubicin or DNR and Doxorubicin or DX) and two lipophilic anthracycline derivatives (Idarubicin or IDA and Iododoxorubicin or IDX). For these purposes, we used multidrug resistant (MDR) and non-MDR tumor and leukemia cell lines and the MTT-microcultured tetrazolium colorimetric assay. We showed that mdr-1 gene overexpression was strongly associated with the development of a high level of resistance to DNR and DX, but not to the derivatives IDA and IDX. These data suggest that more lipophilic anthracycline derivatives may also be active in MDR cell systems.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
CD34+ cell selection: focus on immunomagnetic beads and chymopapain.
The aim of the present study was to develop immunoadsorption techniques for purifying CD34+ cells from the peripheral blood (PB) and the bone marrow (BM). First, we compared two methods for isolating CD34+ cells from patients with acute non-lymphocytic leukemia. Twenty-two samples (17 PB, 5 BM) were obtained from 19 patients, were density cut and, after incubation with My10 antibody, were separated by panning or by immunomagnetic beads. Beads allowed a significantly better separation, either in terms of purification of CD34+ cells (85.5% +/- 11.1% vs 55.7 +/- 23.8%, p = 0.003) or in terms of depletion of CD34+ cells from the negative fractions (3.9 +/- 7.6 vs 30.9 +/- 25.1%, p = 0.008). In a second study, 2 BMs from healthy subjects and 1 BM and 2 PBs from chronic myeloid leukemia patients were separated using immunomagnetic beads. The results confirmed the previous study the overall frequency of CD34+ cells in the isolated positive fractions was 85.0 +/- 10.6% (with a recovery of 64.0 +/- 5.7%), while it was only 2.7 +/- 6.6% in the negative fractions. In particular the purity in the two normal BMs was respectively 86 and 97%. According to these results, the great majority of clonogenic cells was separated in the CD34+ fractions. Chymopapain, that was used to detach the beads from the cells, was shown to be non-toxic to the clonogenic cells. Positive selection of CD34+ cells with immunomagnetic beads and chymopapain is a useful method for isolating almost pure progenitors from the PB and the BM for experimental use and is under investigation for clinical applications.
Antigens, CD↗
[Gaucher's disease: study of a family from Friuli].
Gaucher's disease is the most frequent of lysosomal storage diseases. In a family study two affected sisters of a type I patient were identified. Two of them underwent splenectomy, so reaching hematological normalization.
Female↗
[Update on Gaucher's disease].
Gaucher's disease is a lipidosis caused by deficiency of the enzyme glucocerebrosidase (glucosylceramidase) with secondary accumulation of glucocerebrosides in macrophage lysosomes. Three clinical forms of the disease have been described with autosomal recessive genetic basis. They are caused by many different mutations in glucocerebrosidase gene which have been recently identified. The infantile (type III) and juvenile (type II) forms involve the central nervous system and are very rare. Type I is a non neuronopathic form and is the most common lysosomal storage disease, reaching an incidence of 1 in 2500 births among Ashkenazi jews. Clinical manifestations include splenomegaly and hypersplenism, while bone and lung involvement are less common. Most patients have a mild course and a normal life expectancy, but some others suffer for heavy bone pain that greatly inhabilitate them. A distinctive storage cell is present in bone marrow, but diagnostic confirmation is based upon leucocytes or fibroblasts enzyme assay. Total or partial splenectomy is the treatment of choice for correcting hematological abnormalities. Allogeneic bone marrow transplantation was successfully employed in some cases, while studies on retroviral-mediated gene transfer are undergoing. Promising clinical results were obtained in last two years by chronic infusion of purified macrophage-targeted glucocerebrosidase enzyme. New experience is required in selecting patients for this expensive regimen and establishing duration of therapy.
Gaucher Disease↗