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Biomedical subjects

J Sierra

Publications and source records attributed to J Sierra.

At least 73 records · Page 4Linked to original sources
PubMed2001

Allogeneic transplantation of CD34+-selected cells from peripheral blood in patients with myeloid malignancies in early phase: a case control comparison with unmodified peripheral blood transplantation.

An allogeneic transplantation of CD34(+)-selected cells from peripheral blood (allo-PBT/CD34(+)) from HLA-identical sibling donors was performed in 50 adult patients with acute myeloid leukemia in first complete remission (AML CR1) (n = 29), myelodysplastic syndrome (MDS) (n = 4), or chronic myeloid leukemia in first chronic phase (CML CP1) (n = 17). Clinical results were compared to a concurrent group of 50 patients transplanted with unmodified peripheral blood progenitor cells (allo-PBT), matched for age, diagnosis, and disease stage. The median follow-up period was 29 months (range 1-69). The actuarial probability of developing acute GVHD clinical grade II to IV was 16% (95%CI: 6-26) for the allo-PBT/CD34(+) group and 41% (95%CI: 29-57) for the allo-PBT group (P = 0.002). The actuarial probability of developing extensive chronic GVHD was 22% (95%CI: 8-36) for the allo-PBT/CD34(+) group and 47% (95%CI: 31-63) for the allo-PBT group (P = 0.02). Recipients of allo-PBT/CD34(+) had less toxicity associated with the transplant and better Karnofsky index at the last follow-up. For AML/MDS patients, the actuarial probability of disease-free survival (DFS) for recipients of allo-PBT/CD34(+) and allo-PBT was 65% (95%CI: 45-85) vs43% (95%CI: 28-58) (P = 0.05), respectively. These data provide a rationale for a randomised trial of allo-PBT/CD34(+) vs allo-PBT in AML/MDS patients in early stage of the disease.

Acute Disease↗
PubMed2001

Favourable effect of the combination of acute and chronic graft-versus-host disease on the outcome of allogeneic peripheral blood stem cell transplantation for advanced haematological malignancies.

To assess the influence of graft-versus-host disease (GVHD) on the outcome of patients with advanced haematological malignancies (AHM) who received a primary, unmodified allogeneic peripheral blood progenitor cells transplant (allo-PBT) from a human leucocyte antigen (HLA) identical sibling donor, we analysed 136 patients with myeloid neoplasms (n = 70) or lymphoproliferative disorders (n = 66), transplanted at 19 Spanish institutions. Median age was 35 years (range 1-61). The cumulative incidence of relapse for all patients was 34% (95% CI, 26-42%), 41% (95% CI, 33-49) for patients without GVHD and 14% (95% CI, 3-25) (P = 0.001) for patients with acute and chronic GVHD. After a median follow-up of 11 months (range 2-49), 60 (44%) patients remained alive with an actuarial probability of overall survival and disease-free survival (DFS) at 30 months of 31% (95% CI, 21-41%) and 28% (95% CI, 17-39%) respectively. In patients surviving > 100 d, the low incidence of relapse in those with acute and chronic GVHD led to a DFS of 57% (95% CI, 38-76%) compared with a DFS of 34% (95% CI, 17-51%) in the remaining patients (P = 0.03). Our results indicate a reduced incidence of relapse for patients with AHM receiving an unmodified allo-PBT and developing acute and chronic GVHD, which results in an improved DFS.

Acute Disease↗
PubMed2001

Disparity for the minor histocompatibility antigen HA-1 is associated with an increased risk of acute graft-versus-host disease (GvHD) but it does not affect chronic GvHD incidence, disease-free survival or overall survival after allogeneic human leucocyte antigen-identical sibling donor transplantation.

Disparity for the minor histocompatibility antigen HA-1 between patient and donor has been associated with an increased risk of acute graft-versus-host disease (GvHD) after allogeneic human leucocyte antigen (HLA)-identical sibling donor stem cell transplantation (SCT). However, no data concerning the impact of such disparity on chronic GvHD, relapse or overall survival are available. A retrospective multicentre study was performed on 215 HLA-A2-positive patients who received an HLA-identical sibling SCT, in order to determine the differences in acute and chronic GvHD incidence on the basis of the presence or absence of the HA-1 antigen mismatch. Disease-free survival and overall survival were also analysed. We detected 34 patient-donor pairs mismatched for HA-1 antigen (15.8%). Grades II-IV acute GvHD occurred in 51.6% of the HA-1-mismatched pairs compared with 37.1% of the non-mismatched. The multivariate logistic regression model showed statistical significance (P: 0.035, OR: 2.96, 95% CI: 1.07-8.14). No differences were observed between the two groups for grades III-IV acute GvHD, chronic GvHD, disease-free survival or overall survival. These results confirmed the association between HA-1 mismatch and risk of mild acute GvHD, but HA-1 mismatch was not associated with an increased incidence of chronic GvHD and did not affect relapse or overall survival.

Acute Disease↗
PubMed2001

Allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: results of a prospective multicentre study.

Reduced-intensity conditioning (RIC) regimens for allogeneic haematopoietic stem cell transplantation (SCT) have been shown to lead to engraftment of donor stem cells without the severe extra-haematological toxicities of traditional myeloablative transplants. Between December 1998 and December 2000, 76 patients underwent a RIC peripheral blood SCT in a prospective multicentre study. The median age was 53 years, and 57 patients were beyond the early phase of their disease. The conditioning regimens consisted of fludarabine (150 mg/m2) plus melphalan (140 mg/m2) or busulphan (10 mg/kg). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A plus short-course methotrexate. The preparative regimens were well tolerated. All patients experienced severe pancytopenia, but haematological recovery was prompt in all but two cases (early deaths). The 100-d probability of developing grade II-IV acute GVHD was 32% (10% grade III-IV), and the 1-year probability of developing chronic extensive GVHD was 43%. Early complete donor chimaerism was observed in 52/68 patients, and 16 evaluable patients were in complete chimaerism 1 year post transplant. With a median follow-up of 283 d (355 in 48 survivors), the 1-year probability of transplant-related mortality was 20%, and the 1-year overall and progression-free survivals were 60% and 55% respectively. In conclusion, RIC regimens lead to low early toxicity after allografting, with stable donor haematopoietic engraftment, with an apparent low risk of acute GVHD. Chronic GVHD, however, develops in a significant proportion of patients.

Adolescent↗
PubMed2001

Safety and efficacy of low-dose amphotericin B lipid complex for empirical antifungal therapy of neutropenic fever in patients with hematologic malignancies.

Amphotericin B lipid complex (ABLC) has been investigated as an empirical antifungal treatment for neutropenic patients with persistent fever of unknown origin (FUO). We studied the safety and efficacy of low dose ABLC (1 mg/kg/day) for empirical treatment of neutropenic FUO. Sixty-one patients with hematologic malignancies developing 69 episodes of neutropenic FUO after chemotherapy or hematopoietic stem cell transplantation were included in the study. The median patient age was 47 years (18-68). The median duration of neutropenia (< 0.5 x 10(9)/l) was 17 days (7-45) and the median duration of ABLC therapy was 8 days (2-19). Thirteen patients (19%) suffered from mild to moderate infusion-related adverse events. Creatinine levels were stable in 42 cases (61%), improved in 9 (13%) and deteriorated in 18 (26%), with no other significant toxicities. Among 67 evaluable episodes, the response rate (resolution of fever during the period of neutropenia without developing a fungal infection) was 67%, while 33% were treatment failures. Low-dose ABLC is safe, well tolerated and seems to be at least as effective as c-AmB for empirical antifungal therapy of FUO. Randomized trials at this dose level comparing ABLC with c-AmB or other lipid formulations are warranted.

Adolescent↗
PubMed2001

Interleukin-3 receptor alpha chain (CD123) is widely expressed in hematologic malignancies.

BACKGROUND AND OBJECTIVES: The hematopoietic system is controlled by growth factors (cytokines) which can influence cell survival, proliferation, differentiation and functional activation. The study of cytokine receptor expression by flow cytometry could allow us to differentiate between normal and tumoral cells. DESIGN AND METHODS: We analyzed the expression of the interleukin-3 (IL-3) receptor a chain (CD123) in 22 normal samples and in a wide panel of hematologic malignancies using flow cytometry. We found that CD123 was expressed in the myeloid progenitor subpopulation but in contrast, normal lymphoid progenitors lacked CD123. We analyzed the CD123 expression pattern in 64 patients with acute leukemia, 45 with acute myeloid leukemia (AML) and 19 with acute lymphocytic leukemia (ALL) (13 B-cell lineage ALL and 6 T-cell lineage ALL). RESULTS: All the AML cases except two patients with M7 and all the B-cell lineage ALL patients were CD123 positive. In contrast, all the T-cell lineage ALL cases tested were CD123 negative. We also studied the CD123 expression pattern in 122 patients with a B-cell chronic lymphoproliferative disease (B-CLPD). CD123 was positive in three situations: 1) typical cases of hairy cell leukemia showed a specific, strong CD123 expression, 2) a subgroup of atypical chronic lymphocytic leukemia with a marked CD11c expression was also CD123 positive, and finally 3) transformed B-CLPD showed the phenomenon of transition from CD123 negativity to CD123 positivity simultaneuosly with morphologic changes. INTERPRETATION AND CONCLUSIONS: In summary, our data show high expression of IL-3 receptor a chain in hematologic malignancies. Given the high frequency of CD123 reactivity in blast cells in contrast to in normal precursors, this antigen could be applied to the study of minimal residual disease in acute leukemia. CD123 is expressed with a characteristic pattern in cases of hairy cell leukemia.

Acute Disease↗
PubMed2000

Interaction of CBF alpha/AML/PEBP2 alpha transcription factors with nucleosomes containing promoter sequences requires flexibility in the translational positioning of the histone octamer and exposure of the CBF alpha site.

Chromatin remodeling at eukaryotic gene promoter sequences accompanies transcriptional activation. Both molecular events rely on specific protein-DNA interactions that occur within these promoter sequences. Binding of CBFalpha/AML/PEBP2alpha (core binding factor alpha/acute myelogenous leukemia/polyoma enhancer binding protein 2alpha) proteins is a key event in both tissue-specific and developmentally regulated osteocalcin (OC) promoter activity. To address linkage between chromatin organization and transcription factor binding, we reconstituted segments of the rat OC gene proximal promoter into mononucleosomes and studied binding of CBFalpha proteins. We analyzed binding of bacterially produced Cbfalpha2Alpha and Cbfalpha2B, two splice variants of the human CBFalpha2 gene, and determined the effect of heterodimerization with the Cbfbeta subunit on binding activity. Our results indicate that binding of the truncated Cbfalpha2A protein to naked DNA is independent of Cbfbeta whereas Cbfalpha2A binding to nucleosomal DNA was enhanced by Cbfbeta. In contrast, the Cbfalpha2B interaction with either naked or nucleosomal DNA was strongly dependent on heterodimerization with the Cbfbeta subunit. Additionally, our results demonstrate that both Cbfalpha2A alone and Cbfalpha2B complexed with Cbfbeta can interact with nucleosomal DNA only if there is a degree of flexibility in the positioning of the histone octamer on the DNA fragment and exposure of the CBFalpha site. This situation was achieved with a DNA segment of 182 bp from the rat OC promoter that preferentially positions mononucleosomes upstream of the CBFalpha binding site and leaves this element partially exposed. Taken together, these results suggest that nucleosomal translational positioning is a major determinant of the binding of CBFalpha factors to nucleosomal DNA.

Animals↗
PubMed2000

[Mutational analysis of p53 in T-cell lymphoblastic leukemia].

BACKGROUND: p53 mutations were analysed in a consecutive series of patients with T-ALL from one hospital over a period of 9 years. PATIENTS AND METHOD: Thirty two samples from 27 patients with T-ALL were included in the study. Exons 5-9 were analysed using SSCP. RESULTS: A mutation at codon 273 was identified in a child in third relapse. The mutated clone became dominant in a sample obtained one month following a course of salvage chemotherapy. CONCLUSION: p53 mutations are not frequent in T-ALL even in patients at relapse.

Adolescent↗
PubMed2000

Effect of centre on outcome of bone-marrow transplantation for acute myeloid leukaemia. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation.

BACKGROUND: There is increasing pressure for the recognition and replication of good clinical practice. We undertook a study to assess the variability in outcome of allogeneic bone-marrow transplantation among major European centres. METHODS: We studied 13 centres, including 522 patients (aged 16-55 years), which had undertaken more than 30 bone-marrow transplantations between Jan 1, 1987, and Dec 31, 1995, for acute myeloid leukaemia in first complete remission. We undertook a (global) multivariate analysis of all factors known previously to influence outcome and a stratified analysis that initially defined, by multivariate analysis, significant variables in this study and then used a proportional-hazard model including centres. FINDINGS: The overall results at 3 years were 57% (95% CI 53-61) for leukaemia-free survival (LFS), 23% (19-27) for relapse incidence (RI), and 26% (22-30) for treatment-related mortality (TRM) with a range for centres of 36-75%, 10-37%, and 8-54%, respectively. Both methods of analysis showed the centre effect to be highly significant for LFS and TRM, but not for RI. Variables associated with a significantly poor outcome were age over 43 years (p=0.01), time from diagnosis to first complete remission longer than 65 days (p=0.02), and centre (p=0.013) for LFS, and age over 43 years (p=0.023), time from first complete remission to transplantation of longer than 93 days (p=0.03), and centre (p=0.001) for TRM. Moreover, different centres had different prognostic criteria for good-risk or bad-risk patients indicating that risk factors do not have the same impact in each individual centre. INTERPRETATION: The outcome of bone-marrow transplantation for acute myeloid leukaemia in first complete remission is influenced by the centre in which the procedure is done, even with adjustment for known prognostic risk factors. Significant prognostic factors vary among centres, which means that the relative risk is not the same in each individual centre. However, centres may treat populations with different risks of as yet unidentified prognostic factors. Experience may partly account for the difference in outcome among centres.

Adolescent↗
PubMed2000

CD66 expression in acute leukaemia.

Antibodies against CD66 identify antigens from the carcinoembryonic antigen (CEA) family of proteins, which belong to the immunoglobulin gene superfamily. Despite being usually restricted to cells of myeloid or monocytic origin, CD66 expression has also been reported in blasts from children with B-cell lineage acute lymphocytic leukaemia (ALL). An analysis of the CD66 expression was undertaken in a series of acute leukaemia patients. Antigenic expression was analysed using triple combinations of monoclonal antibodies (mAbs) in forty-five patients. The CD66 Kat4 fluorescein isothiocyanate clone was purchased from Dako (Glostrup, Denmark). CD66 was expressed in 2 of 29 patients with AML (acute myeloblastic leukemia) (6.8%) and in 8 of 12 patients with B-cell lineage ALL (66.7%; P<0.001); in blast crisis (BC) of chronic myelocytic leukaemia (CML), CD66 was expressed in two patients with lymphoid BC but not in the two with myeloid BC. The co-expression of CD66 with other myeloid antigens was observed in all CD66+ ALL/ Ly-BC cases tested: CD 13 in six patients, CD33 in seven and CD117 in two patients. The CD66 expression is more frequent in ALL than in AML. Furthermore, we analysed minimal residual disease (MRD) in eight patients in complete remission. CD66 expression was associated with an abnormal B-cell differentiation pattern and with increases in CD34/CD19+ cells in all but one case. These findings suggest that an aberrant expression of CD66 could be used to investigate MRD in ALL. The association between CD66 reactivity and bcr-abl in adult ALL remains to be investigated.

Acute Disease↗
PubMed2000

Bacteraemia caused by non-glucose-fermenting gram-negative bacilli and Aeromonas species in patients with haematological malignancies and solid tumours.

The clinical characteristics and outcome of bacteraemia caused by non-glucose-fermenting gram-negative bacilli and Aeromonas spp. were examined in 115 adults with haematological malignancies or solid tumours. The most aggressive pathogens were Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Aeromonas spp., Acinetobacter spp. and Burkholderia cepacia, all of which caused either septic syndrome or pneumonia in more than 40% of cases. Pseudomonas aeruginosa was involved less often in catheter-related bacteraemia than other species. Polymicrobial bacteraemia (n=28) was more often catheter-related than monomicrobial bacteraemia and more often required catheter removal for definitive cure. The most important predictors of catheter-related bacteraemia and its outcome were polymicrobial infection, the presence of pneumonia or septic syndrome and the species involved.

Adolescent↗
PubMed2000

Typical CBFbeta/MYH11 fusion due to insertion of the 3'-MYH11 gene into 16q22 in acute monocytic leukemia with normal chromosomes 16 and trisomies 8 and 22.

In a case of acute monocytic leukemia, M5a according to the FAB classification, with a 48,XY,+8,+22 karyotype, amplification of the CBFbeta/MYH11 fusion transcript type A was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Fluorescence in situ hybridization (FISH) using an appropriate panel of DNA probes showed that insertion of the 3'-MYH11 within the CBFbeta gene on chromosome 16q22 was the mechanism producing the same molecular rearrangement as in typical inv(16)(p13q22)/t(16;16)(p13;q22).

Adult↗
PubMed2000

Mobilization kinetics of peripheral blood progenitor cells after IAPVP-16 salvage chemotherapy plus G-CSF in lymphoproliferative disorders.

We have explored the efficacy of salvage chemotherapy combination, IAPVP-16 (ifosfamide 5 g/m2 on day 1; VP-16 100 mg/m2 on days 1-3; ara-C 1.2 g/m2/12 h on days 1 and 2; methylprednisolone 80 mg/m2 on days 1-5) plus G-CSF for PBPC mobilization. This protocol was used in 45 patients with relapsed or refractory lymphoproliferative diseases who underwent 85 leukaphereses. In 41 patients > 2 x 106/kg CD34+ cells were obtained after a median of two procedures. The median number of CD34+ cells harvested was 3.2 x 106/kg per apheresis and 8.4 x 106/kg per patient. Seven of 10 patients who had failed previous mobilization attempts achieved more than 2 x 106 CD34+ cells/kg in a maximum of three aphereses. A history of previous mobilization failure and a low platelet count (<150 x 109/l) negatively influenced the CD34+ cell yield in univariate and multivariate analyses. A good correlation was found between the circulating CD34+ cells/microl and the CD34+ cells and CFU-GM in the leukaphereses products (r = 0.93 and r = 0.73, P < 0.001), and > or =17 CD34+ cells/microl predicted the achievement of > 2 x 106/kg CD34+ cells in a single leukapheresis in more than 90% of cases. IAPVP-16 plus G-CSF may be specially indicated in tandem transplantations or CD34+ selection and in patients who have failed previous mobilization attempts.

Adult↗