Disseminated candidiasis in patients with acute leukemia.
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Acute Disease↗
Biomedical subjects
S Brunet
Publications and source records attributed to S Brunet.
Effect of discontinuing prophylaxis with norfloxacin in patients with hematologic malignancies and severe neutropenia. A matched case-control study of the effect on infectious morbidity.
The use of fluorinated quinolones for prophylaxis of infections in neutropenic cancer patients has led to a reduction of infections with gram-negative enteric bacilli, but there is concern about the emergence of antibiotic-resistant entero-bacterial infections and a rise of gram-positive bacteremias. Due to these concerns, in mid-1995 the use of prophylactic norfloxacin was discontinued in our unit. In order to evaluate the impact of this measure on the infectious morbidity in our unit, 91 severe neutropenic episodes in 58 patients with hematologic malignancies who did not receive norfloxacin prophylaxis (NO group) were closely matched to 91 episodes in 60 patients who received norfloxacin prophylaxis (NORFLO group). There were no differences in the incidence of febrile neutropenia, fever of unknown origin or bacteremia during the first febrile episode. There was a trend for a higher rate of coagulase-negative staphylococcal bacteremia in the NORFLO group (5 vs. 11 cases in the NO and NORFLO groups, respectively, p = NS). Enterobacterial bloodstream infections were more frequent in the NO group (13 vs. 2 cases, respectively, p = 0.01), especially Escherichia coli (9 vs. 1 case, respectively, p = 0.01). Twelve of 13 enterobacterial isolates in the NO group were sensitive to the fluoroquinolones vs. 0/2 in the NORFLO group (p = 0.07). We conclude that the abrupt discontinuation of norfloxacin prophylaxis in our ward led to a rapid increase in the rate of fluoroquinolone-susceptible enterobacterial infections, with a scarce impact on infectious morbidity. This suggests that the selection of resistant flora in an inpatient ward by prophylactic antimicrobials may be reversible following the discontinuation of the prophylactic agent(s).
Adolescent↗
Cyclin synthesis controls the progression of meiotic maturation in mouse oocytes.
To study the mechanisms involved in the progression of meiotic maturation in the mouse, we used oocytes from two strains of mice, CBA/Kw and KE, which differ greatly in the rate at which they undergo meiotic maturation. CBA/Kw oocytes extrude the first polar body about 7 hours after breakdown of the germinal vesicle (GVBD), whilst the oocytes from KE mice take approximately 3-4 hours longer. In both strains, the kinetics of spindle formation are comparable. While the kinetics of MAP kinase activity are very similar in both strains (although slightly faster in CBA/Kw), the rise of cdc2 kinase activity is very rapid in CBA/Kw oocytes and slow and diphasic in KE oocytes. When protein synthesis is inhibited, the activity of the cdc2 kinase starts to rise but arrests shortly after GVBD with a slightly higher level in CBA/Kw oocytes, which may correspond to the presence of a larger pool of cyclin B1 in prophase CBA/Kw oocytes. After GVBD, the rate of cyclin B1 synthesis is higher in CBA/Kw than in KE oocytes, whilst the overall level of protein synthesis and the amount of messenger RNA coding for cyclin B1 are identical in oocytes from both strains. The injection of cyclin B1 messenger RNA in KE oocytes increased the H1 kinase activity and sped up first polar body extrusion. Finally, analysis of the rate of maturation in hybrids obtained after fusion of nuclear and cytoplasmic fragments of oocytes from both strains suggests that both the germinal vesicle and the cytoplasm contain factor(s) influencing the length of the first meiotic M phase. These results demonstrate that the rate of cyclin B1 synthesis controls the length of the first meiotic M phase and that a nuclear factor able to speed up cyclin B synthesis is present in CBA/Kw oocytes.
Animals↗
p53 mutation in a case of blastic transformation of follicular lymphoma with double bcl-2 rearrangement (MBR and VCR).
The bcl-2 gene is rearranged in most cases of follicular lymphoma and the breakpoint clusters are found in two specific regions: mbr and mcr. Rearrangements of the immunoglobulin heavy chain genes (IgH) result in a deregulation of the gene and increased transcription of mRNA for the bcl-2 protein. In cases of rearrangement of the light chains (variant translocations), a third breakpoint has been described at the 5' part of the bcl-2 locus (vcr). In the present case, we report the molecular analysis of an FL transformed into a blastic phase unresponsive to chemotherapy. Molecular studies revealed a typical bcl-2 rearrangement at the major locus (mbr). Vcr rearrangements was also observed with only a single restriction enzyme. At the same time, SSCP analysis of exon 5 of the p53 locus disclosed an abnormal conformer. Direct sequencing revealed a point mutation at codon 163 (A --> G). Immunohistochemical analysis of the affected sites disclosed overexpression of p53 and bcl-2. It is concluded that p53 mutation can contribute to blastic transformation in cases of follicular lymphomas with double rearrangement at the bcl-2 locus (mbr/vcr).
Blast Crisis↗
Late intensification chemotherapy has not improved the results of intensive chemotherapy in adult acute lymphoblastic leukemia. Results of a prospective multicenter randomized trial (PETHEMA ALL-89). Spanish Society of Hematology.
BACKGROUND AND OBJECTIVE: Intensive induction and post-remission therapies have improved the prognosis in adult acute lymphoblastic leukemia (ALL). However, different from children, the impact of late intensification therapy in the overall results of treatment has not been consistently evaluated. The objective of this study was to analyze the results of a multicenter prospective protocol, PETHEMA ALL-89, in which, after intensive induction and consolidation therapy, randomization to receive delayed intensification treatment was performed. DESIGN AND METHODS: One hundred and eight adults (age > or = 15 years) diagnosed with ALL (ALL L3 excluded) in 22 Spanish hospitals from 1989 to 1994 were treated with a five-drug induction therapy, followed by four cycles of early post-remission treatment during four months, and maintenance therapy for two years. Patients in remission at the end of the first year were randomized to receive one six-week cycle of late intensification therapy. Uni- and multivariate analyses of early response to treatment, complete remission (CR), leukemia-free survival (LFS) and overall survival (OS) were performed. RESULTS: The median (range) age of the series was 28 (15-74) years and leukocyte count 26 x 10(9)/L (1-600). ALL L1/L2 was present in 38/70 patients, early pre-B in 13, common in 53, pre-B in 12 and T in 30 cases. The CR rate was 86%, and refractory disease 9%. Median LFS was 34 months, with a 5-yr probability of 41% (95% CI, 29-53), whereas median OS was 51 months and 5-year probability 47% (34-59%). There were no differences in either LFS and OS between patients who did or did not receive delayed intensification therapy. Prognostic factors for CR attainment were advanced age and slow response to therapy. These two features were, in addition to high leukocyte counts, the parameters with negative influence in both LFS and OS. INTERPRETATION AND CONCLUSIONS: The results of PETHEMA ALL-89 are similar to those referred in other chemotherapy-based protocols in adult ALL. Delayed intensification has not improved the length of remission and survival. Efforts to improve the prognosis of adult ALL patients must be mainly focused in early intensification treatment.
Adolescent↗
Achromobacter xylosoxidans bacteremia in patients with hematologic malignancies.
We report nine cases of Achromobacter xylosoxidans bacteremia diagnosed in patients with hematologic malignancies. There was not an obvious epidemiologic link between cases and the organism was not isolated from any source. Outcome was cure in all nine cases. In our experience, catheter removal is generally required for eradication of A. xylosoxidans.
Adult↗
Collection of peripheral blood progenitor cells for autografting with low-dose cyclophosphamide plus granulocyte colony-stimulating factor.
BACKGROUND AND OBJECTIVE: The combination of high or intermediate-dose cyclophosphamide (CY) plus granulocyte colony-stimulating factor (G-CSF) is useful to mobilize hematopoietic progenitor cells to peripheral blood, but the patients require hospitalization. The aim of this study was to evaluate the efficiency of low-dose CY plus G-CSF (5 ug/kg/day s.c.) as an outpatient treatment in order to collect enough progenitor cells for hematopoietic rescue in autologous peripheral blood transplantation (APBSCT). DESIGN AND METHODS: We analyzed twenty-eight consecutively treated patients with lymphoma or multiple myeloma. The number of CD34+ cells in blood samples was determined from day +7. Leukapheresis (LKP) began when the absolute number of CD34+ cells in peripheral blood was > 2500/mL and the apheresis product was assayed for mononuclear cells (MNC), granulocyte-macrophage colony-forming units (CFU-GM), total nucleated cells (tNC) and CD34+ cells. RESULTS: Twenty-eight outpatients with advanced hematologic malignancies (13 non-Hodgkin lymphoma, NHL; 10 Hodgkin's disease, HD; and 5 multiple myeloma, MM), median age 44 years (range 23-65) received a single dose of CY (1.5 g/m2 i.v. day 0) followed by G-CSF (5 ug/kg/day s.c.) from day +1 to the end of LKP. Considering patients who had successful mobilization (64%), a median of 7.1 x 10(6)/kg CD34+ cells (range 3.5-11.9), 5.7 x 10(5)/kg CFU-GM (range 1.5-9.2), 4.4 x 10(8)/kg MNC (range 1.9-7.9) were collected. Treatment was well tolerated and none of these patients was hospitalized due to neutropenic fever. Only one patient received two packed red blood cells following chemotherapy. Autologous peripheral blood stem cell transplantation (APBSCT) has been performed in 18 patients (64%). The mean number of days to achieve > 0.5 x 10(9) PMN/L and > 20 x 10(9) PLT/L was 12 (10-17) and 12.6 (8-24), respectively. INTERPRETATION AND CONCLUSIONS: Considering a pre-established threshold of 2.5 x 10(6)/kg CD34+ cells to proceed to APBSCT, the mobilization therapy was successful in 64% of the patients but was unsuccessful in 10 patients (5 NHL, 4 HD and 1 MM). Hematopoietic recovery was complete and stable in all patients. Low-dose CY plus G-CSF is efficient to collect enough PBSC for hematopoietic rescue after myeloablative therapy in patients with lymphoprolipherative disorders or multiple myeloma.
Adult↗
Allogeneic transplantation of purified CD34+ cells from peripheral blood: Spanish experience of 62 cases. Spanish Group of allo-PBT.
This report summarizes the Spanish experience of 62 cases of allogeneic transplantation of purified CD34+ cells from peripheral blood. HLA-identical sibling donors received G-CSF. After leukapheresis, peripheral blood progenitor cells were purified using one of two methods: Ceprate (n = 38), or Isolex 300 (n = 24). Sixty-two patients median age 42 years (range 17-60) diagnosed with hematological malignancies were conditioned with either cyclophosphamide and total body irradiation (n = 43) or busulphan and cyclophosphamide (n = 19). GVHD prophylaxis consisted of cyclosporin A (CsA) and prednisone (n = 48), CsA alone (n = 11), and CsA and methotrexate (n = 3). The median yield and purity of CD34+ cells after the procedure was 65% and 66% with Ceprate, and 48% and 86% with Isolex, respectively. The median number of CD34+ cells infused into the patients was 3.5 x 10(6)/kg (range 1-9.6). The median number of CD3+ cells administered was 0.4 x 10(6)/kg (range 0.01-2) using Ceprate and 0.14 x 10(6)/kg (range 0.03-2.5) using Isolex. Neutrophil recovery >500 and >1000/microl was achieved at a median of 13 days (range 8-22) and 14 days (range 9-31), respectively. Platelets recovered to >20,000 and >50,000/microl at a median of 13 days (range 0-128) and 18 days (range 0-180), respectively. The actuarial probability of acute GVHD II-IV was 10% (95% CI, 1-19%), and of extensive chronic GVHD 12% (95% CI, 11-13%).
Adolescent↗
Iron-salicylate complex induces peroxidation, alters hepatic lipid profile and affects plasma lipoprotein composition.
Iron overload, with its associated toxic effects, has serious health consequences and results in damage to the liver, heart and other organs. Salicylate may be used as the lipophilic carrier, transporting more iron into hepatocytes. In this study, we examined the effect of the combined administration of these compounds on plasma lipid profile and lipoprotein composition, as well as on hepatic lipid concentration. Male Spraque-Dawley rats were injected i.p. with Fe (15 mg/kg weight). This injection was repeated 24 h later with a gavage of sodium salicylate (700 mg/kg). Control rats received 0.9% NaCl only. The peroxidation indices TBARS (P < 0.001) and conjugated dienes (P < 0.05) significantly increased in the blood (50 and 122%, respectively) and liver (333 and 101%, respectively) of Fe salicylate-treated rats. Concomitantly, blood and liver arachidonic acid content was diminished by iron treatment. In parallel, the plasma lipid profile was markedly affected in Fe-salicylate treated-rats. Lower plasma concentrations of total cholesterol (25%, P < 0.0001) cholesteryl ester, (34%, P < 0.001) and high-density lipoprotein-cholesterol (50%, P < 0.001) were observed. Lipoprotein composition analysis revealed enrichment of free cholesterol and depletion of cholesterol ester in very low-density, intermediate-density, low-density and high-density (HDL2, HDL3) lipoproteins. Furthermore, SDS-polyacrylamide gel electrophoresis revealed several alterations in the apolipoprotein distribution of these lipoproteins. The activity of lecithin:cholesterol acyltransferase was unchanged and could not account for the reduction of cholesterol esterification. As for the plasma, the liver exhibited a significant (P < 0.001) decrease in total cholesterol (2.42 +/- 0.07 versus 1.89 +/- 0.06 mg/g liver), essentially due to a reduction in cholesteryl ester (0.93 +/- 0.07 versus 0.51 +/- 0.03 mg/g, P < 0.001). Again, the activity of ACAT (dpm/mg microsomal protein) was not lower (12,700 +/- 1250) than that of controls (9650 +/- 1080). Thus, the iron-salicylate was able to induce peroxidation and to profoundly affect the intravascular and intrahepatic lipid, and plasma lipoprotein metabolism. Additional work is needed to elucidate the mechanisms involved in the underlying lipid and lipoprotein abnormalities.
Animals↗
Oxidative tyrosylation of high density lipoprotein impairs biliary sterol secretion in rats.
The oxidation of low density lipoprotein plays a central role in the pathogenesis of atherosclerosis. Oxidative modification could also occur in high density lipoprotein (HDL), which may alter reverse cholesterol transport. It has recently been proposed that myeloperoxidase-generated tyrosyl radical may modify HDL. In the present study we have examined whether the oxidative tyrosylation of HDL by peroxidase may alter biliary cholesterol secretion and bile acid transformation. HDL was modified by exposure to L-tyrosine, H2O2 and peroxidase labelled with [14C]cholesterol and injected i.v. into rats with bile diversion. A reduced excretion of radioactivity (14-20%) was recovered in the bile of animals administered with tyrosylated HDL at the different periods of collection. Both labelled cholesterol (14.3%, P < 0.05) and bile acids (18.9%, P < 0.05) were decreased in these rats, similarly to results obtained from malondialdehyde-modified HDL. Consequently, this kind of oxidative modification resulted in a loss of the hepatobiliary systems capacity to normally process HDL.
Animals↗
Autologous stem cell transplantation for poor prognosis Hodgkin's disease in first complete remission: a retrospective study from the Spanish GEL-TAMO cooperative group.
Although more than 50% of Hodgkin's disease patients are cured with conventional chemotherapy, many will relapse and eventually die from their disease. Many efforts have been made to identify poor prognostic factors that could be useful in selecting high-risk patients in 1st CR who may benefit from high-dose chemo/radiotherapy. However, the role of early transplantation in 1st CR remains unclear. We have retrospectively analyzed the results obtained with this procedure in 22 hospitals belonging to the Spanish GEL/TAMO cooperative group. Twenty-seven patients, of whom 19 were males, underwent autologous transplantation for Hodgkin's disease in 1st CR between January 1987 and January 1996. Remission had been achieved after one (n = 22) or two (n = 5) lines of treatment. Twenty-four patients had advanced stage disease, 12 patients bulky mediastinal disease, nine bone marrow involvement and 18 had extranodal disease. Peripheral blood was used as the source of hematopoietic stem cells in 15 patients, BM in nine, and both in three. All but three patients received chemotherapy-based conditioning regimens (16 CBV, four BEAM and four BEAC), while three were conditioned with CY and TBI. There were no transplant-related deaths. Median (range) times to recover >0.5 x 10(9)/l neutrophils and >50 x 10(9)/l platelets were 14 (8-56) days and 16 (8-240) days, respectively. With a median follow-up of 30 (8-66) months, 21 patients are alive and in continuous CR. Four patients who relapsed after transplant at 8, 17.5, 22 and 26 months achieved a second CR with conventional chemotherapy; one patient relapsed 92 months post-transplant and died 5 months afterwards. Another patient died 30.5 months post-transplant from a secondary malignancy. In conclusion, high-dose therapy in poor prognosis Hodgkin's disease in 1st CR was well tolerated with no transplant-related mortalities. Although the follow-up of this series is relatively short, our results seem promising. Nevertheless, late relapses can occur, and the role of this procedure vs conventional treatment in very high-risk patients should be assessed in prospective randomized studies.
Adolescent↗
Peripheral blood stem cell mobilization in refractory autoimmune Evans syndrome: a cautionary case report.
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Adult↗
Efficient peripheral blood stem cell mobilization with low-dose G-CSF (50 microg/m2) after salvage chemotherapy for lymphoma.
We compared the use of low-dose G-CSF (50 microg/m2/day), following salvage chemotherapy, for mobilization of PBSC with the results obtained in a comparable historical control group who received a standard dose of G-CSF (5 microg/kg/day, approximately 200 microg/m2/day). Thirty adult patients with relapsed or refractory lymphoma were treated with ifosfamide, VP-16, intermediate-dose Ara-C, methylprednisolone (IAPVP-16) and G-CSF 5 microg/kg/day (group A, n = 15) or 50 microg/m2/day (group B, n = 15) from day 6 until the end of leukaphereses. The duration of neutropenia and thrombocytopenia were equal in both groups. A median of two (1-3) leukaphereses were performed in both groups to harvest >3.5 x 10(6)/kg CD34+ cells. The numbers of circulating CD34+ cells on the first day of leukocyte recovery were similar in both groups in those patients mobilized after a first cycle of IAPVP-16. The numbers of circulating CD34+ cells were similar in patients mobilized after a first and after a second IAPVP-16 in group A. In the low-dose group (group B), however, the numbers of circulating CD34+ cells were significantly lower in those mobilized after a second than after a first course. Additionally, the product of the first leukapheresis contained significantly fewer CD34+ cells in those mobilized after a second course only in group B, with no differences in group A. Nevertheless, the final products harvested did not differ in the content of MNC, CFU-GM and CD34+ cells, suggesting that these differences are not clinically important. These results indicate that the use of low-dose G-CSF (50 microg/m2/day) is as effective as 5 microg/kg/day in accelerating neutrophil recovery and mobilizing CD34+ cells after a first cycle of IAPVP-16 salvage chemotherapy, resulting in a substantial decrease in costs, while more heavily pretreated patients may require higher doses of G-CSF for an equivalent mobilization.
Adolescent↗
Low-dose donor CD8+ cells in the CD4-depleted graft prevent allogeneic marrow graft rejection and severe graft-versus-host disease for chronic myeloid leukemia patients in first chronic phase.
Based on previous experiences in animals and humans, low doses of CD8+ lymphocytes infused together with the marrow graft seem to enhance engraftment after allogeneic T cell-depleted marrow transplantation. From April 1994 to February 1997, 12 patients with chronic myelogenous leukemia in first chronic phase receiving a bone marrow transplant (BMT) from an HLA-identical sibling were included in a pilot study of T cell subset depletion. Total depletion of CD4+ cells of the marrow graft and partial depletion of CD8+ cells was performed by immunomagnetic separation. In order to improve the engraftment rate, we infused a low fixed number of CD8+ lymphocytes (0.25 x 10(6)/kg). All the patients were at high risk of developing acute graft-versus-host disease (GVHD), with a recipient age of >30 years, and/or donor sensitized by previous pregnancies or transfusions. All of them received cyclosporin A and methotrexate post-BMT. No graft failure was observed. The grade III-IV GVHD rate was 16.6%, and the actuarial survival at 3 years is 81.8%. Immunological recovery showed persistent CD8+ HLA-DR+ lymphocytosis 8 months after transplant. Relapses were not observed. This experience shows the importance of CD8+ cells to ensure correct engraftment, decreasing the GVHD rate.
Adult↗
Successful treatment of pure red cell aplasia after major ABO-incompatible T cell-depleted bone marrow transplantation with erythropoietin.
A 40-year-old woman with acute myeloid leukemia in first remission developed pure red cell aplasia after a T cell-depleted ABO-incompatible bone marrow transplant from her HLA-identical sister. She remained transfusion-dependent for 11 months despite conversion of the ABO blood group to donor type, and titers of anti-donor isohemagglutinin being undetectable. Treatment with erythropoietin resulted in rapid improvement of the anemia with no further need for transfusions up to 21 months post-transplant. This case suggests that erythropoietin may provide effective therapy for pure red cell aplasia after ABO-incompatible bone marrow transplantation without the additional risks of further immunosuppression.
ABO Blood-Group System↗
Pentoxifylline, ciprofloxacin and prednisone failed to prevent transplant-related toxicities in bone marrow transplant recipients and were associated with an increased incidence of infectious complications.
TNF-alpha (Tumor necrosis factor-alpha) is involved in many immunological and inflammatory processes, and might be expected to play an important role in the development of BMT-related complications. Triple therapy (pentoxifylline, ciprofloxacin and prednisone) with known anti-TNF activity was tested in 37 patients undergoing a hematopoietic progenitor transplant (HPT). A control group of 16 patients with similar characteristics was selected among consecutive patients receiving a HTP in a neighboring center who did not receive anti-TNF prophylaxis. Major transplant-related complications were registered (VOD, acute GVHD, infectious episodes, renal failure and mucositis) and survival status. TNF plasma concentrations were determined by ELISA, and pentoxifylline plasma concentrations were determined by HPLC. Among patients treated with pentoxifylline (PTX), ciprofloxacin and steroids, no difference in the mean survival time was observed compared with the control group. The incidence of procedure-related death up to day +35 was 11% in the study group and 6% in the control group. In spite of a tendency to a lower incidence of mucositis there was a higher incidence of infections (positive blood cultures) in the study group (49%) than in the control group (16.7%) (P = 0.16). This difference achieved statistical significance in patients receiving an allogeneic HPT (P = 0.05). It is likely that the use of steroids in the early period after transplant increases infectious episodes and makes control of GVHD difficult. The combined administration of steroids with pentoxifylline and ciprofloxacin has not proved beneficial in preventing mucositis, renal failure, VOD or GVHD, or in improving patient survival.
Adolescent↗
[Allogenic transplant of non-manipulated hematopoietic progenitor peripheral blood cells. Spanish experience of 79 cases. Allo-Peripheral Blood Transplantation Group].
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Adolescent↗
[Allogeneic transplant of CD34+ peripheral blood cells from HLA-identical donors: Spanish experience of 40 cases. Allo-Peripheral Blood Transplantation Group].
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Adolescent↗