Lack of association of CYP3A4-V polymorphism with the risk of treatment-related leukemia.
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Biomedical subjects
Publications and source records attributed to Montserrat Batlle.
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BACKGROUND AND OBJECTIVES: The benefits of high-dose cytarabine, anthracyclines and hematopoietic stem cell transplantation in the treatment of acute myeloid leukemia (AML) are greater in younger rather than in older patients. We assessed the proportion of patients over 60 years with de novo AML who qualified for intensive therapy and determined the feasibility and results of autologous stem cell transplantation (ASCT) in first complete remission (CR). DESIGN AND METHODS: Induction therapy included idarubicin, cytarabine and etoposide. Patients who achieved CR received one cycle of mitoxantrone and cytarabine and ASCT as consolidation therapies. RESULTS: Over a 4-year period, 258 patients were registered of whom 135 (52%) were enrolled for intensive treatment. The CR rate was 61%, advanced age (p=0.033) and unfavorable cytogenetics (p=0.015) emerged as independent negative prognostic factors for CR. The 2-year overall survival (OS) was 23 % (CI 14%-30%) and was poorer in patients with unfavorable cytogenetics (p=0.035), age over 70 years (p=0.019) or leukocytosis (p=0.006). Only 27% of the potential candidates underwent ASCT. The probability of 2-year leukemia-free survival after consolidation was 39% (CI 6%-71%) for these patients and 22% (CI 6% - 39%) for candidate patients not undergoing ASCT (p=0.07). INTERPRETATION AND CONCLUSIONS: Over 25% of the patients 60 to 70 years with de novo AML benefit from standard intensive treatment. In these patients, ASCT has a tolerable toxicity and may have a positive impact on leukemia-free survival.
BACKGROUND AND OBJECTIVE: Although indications of stem cell transplantation (SCT) are increasing, a transplant may not be performed in all planned cases for several reasons. Our objective was to investigate the reasons for which SCT was not performed in patients referred to a transplant unit. PATIENTS AND METHOD: Pretransplant data of 129 patients consecutively referred to a transplant unit between December 1999 and November 2002 were collected. Frequency and causes of non transplantation were analyzed. Transplanted and non transplanted patient's characteristics were compared. RESULTS: In 119 out of 129 patients, an autologous SCT was indicated and in 10 of them an allogeneic SCT was planned. Mean (SD) age was 46 (14) years (range, 13-69) and 69 (53.5%) were males. One hundred eighteen patients had malignant hematological diseases and 11 had solid tumours. Sixty-one patients showed complete response and 68 had a partial response. At the time of the analysis, 93 SCT had been performed in 90 (69.8%) patients. Autologous SCT was performed in 81 patients (two SCT in one patient) and allogeneic SCT in 10 (two in one patient). Two (1.5%) patients were still awaiting SCT. An SCT was not performed in 37 (28.7%) patients. Causes of non transplantation included: in 12 (32.5%) cases, relapse and/or progression at the time the SCT had been planned; in 12 (32.5%), delay or change in the therapeutic decision; in 9 (24%), poor mobilization; and in 4 (11%), patient's refusal. When delay in SCT was excluded from the analysis, the frequency of no transplant was 19.4%. In 21 (57%) patients of the non-SCT group, peripheral stem cells were previously collected by apheresis. Both groups (SCT and non-SCT) were comparable regarding patients' and disease characteristics except for a more advanced age in the non-SCT group (51 [12] vs 44 [14] years, p<0.005) and status of the disease at the pretransplant visit. CONCLUSIONS: The frequency of not performing an SCT in patients referred to a SCT unit was considerable. Relapses and disease progression and poor mobilization were the main causes for it. Delay was also a relatively common cause.
The yeast G(alpha) subunit Gpa2p and its coupled receptor Gpr1p function in a signaling pathway that is required for the transition to pseudohyphal and invasive growth. A two-hybrid screen using a constitutively active allele of GPA2 identified the KRH1 gene as encoding a potential binding partner of Gpa2p. Strains containing deletions of KRH1 and its homolog KRH2 were hyper-invasive and displayed a high level of expression of FLO11, a gene involved in pseudohyphal and invasive growth. Therefore, KRH1 and KRH2 encode negative regulators of the invasive growth pathway. Cells containing krh1Delta krh2Delta mutations also displayed increased sensitivity to heat shock and decreased sporulation efficiency, indicating that Krh1p and Krh2p regulate multiple processes controlled by the cAMP/PKA pathway. The krh1Delta krh2Delta mutations suppressed the effect of a gpa2Delta mutation on FLO11 expression and eliminated the effect of a constitutively active GPA2 allele on induction of FLO11 and heat shock sensitivity, suggesting that Krh1p and Krh2p act downstream of Gpa2p. The Sch9p kinase was not required for the signal generated by deletion of KRH1 and KRH2; however, the cAMP-dependent kinase Tpk2p was required for generation of this signal. These results support a model in which activation of Gpa2p relieves the inhibition exerted by Krh1p and Krh2p on components of the cAMP/PKA signaling pathway.
Hepatosplenic gammadelta T-cell lymphoma (HS-gammadeltaTCL) is an uncommon type of peripheral T-cell lymphoma, which has been associated in some cases with immunosuppression, mainly after solid organ transplants. We describe a case of HSgammadeltaTCL with a leukaemic course in a patient with Crohn's disease who had received azathioprine during the previous 5.5 years. Sinusoidal infiltration by atypical lymphocytes was observed in the liver, spleen and bone marrow and the typical cytogenetic abnormalities (isochromosome 7 and trisomy 8) were found. The patient did not respond to intensive chemotherapy. This case shows the importance of ruling out HSgammadeltaTCL in patients with hepatosplenomegaly, B-symptoms and any immunosuppressive condition.
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We have retrospectively studied the influence of highly active antiretroviral therapy (HAART) on the outcome of AIDS-related lymphomas (ARL) as well as the possible influence of the virological response to HAART on complete response (CR) rate and survival in our series of ARL treated with CHOP. Two groups of patients were studied: (1) 44 patients who did not take HAART when the lymphoma was diagnosed, and (2) 26 patients treated with HAART concomitantly and after chemotherapy. There were 4 (9%) women in group 1 versus 11 (42%) in group 2 (P = 0.01), and serum lactate dehydrogenase (LDH) level was lower in group 2. The response rate to CHOP was higher in group 2 patients (15 out of 23, 65%) than in those of group 1 (16 out of 44, 36%) (P = 0.025). The factors associated with improvement of CR in the multivariate analysis were the administration of HAART (P = 0.004) and International Prognostic Index (IPI) score < or = 2 (P = 0.006). Among group 2 patients, those with a virological response to HAART and with IPI score < or = 2 had better response rate to chemotherapy (odds ratios 9.3 and 11.8, respectively). The median (95% CI) overall survival (OS) for group 1 patients was 7 (3-11) months, whereas it has not been reached for group 2 (P = 0.002). The only parameters influencing OS in the multivariate analysis were HAART (0.003), as a protective factor and IPI score > 2 (P = 0.015) with negative influence. Among patients treated with HAART, those with virological response had higher OS probability (P = 0.004), whereas those with IPI score > 2 had an unfavorable prognosis (P = 0.014). The only variable with statistical significance for disease free survival (DFS) in the univariate and multivariate analyses was HAART (P = 0.0168 and P = 0.028, respectively). We conclude that HAART is an independent prognostic factor for CR attainment, OS and DFS in patients with ARL treated with CHOP. Those patients with virological response to HAART had a better survival.
BACKGROUND: Standard therapy for suspected infections in patients with profound neutropenia is the combination of a beta-lactam antibiotic plus an aminoglycoside. Cefepime's broad-spectrum activity makes it an option for initial empirical therapy in neutropenic patients. The aim of this study is to evaluate the efficacy and safety of cefepime plus amikacin compared with piperacillin-tazobactam plus amikacin for initial empirical treatment of fever in adult haematology patients with severe neutropenia. METHODS: In this prospective multicentre trial, 969 patients with 984 febrile neutropenic episodes were randomized to receive iv amikacin (20 mg/kg every 24 h) combined with either cefepime (2 g every 8 h) or piperacillin-tazobactam (4 g/500 mg every 6 h). Clinical response was determined at 72 h and at completion of therapy. RESULTS: Eight hundred and sixty-seven episodes were assessable for efficacy (432 cefepime, 435 piperacillin-tazobactam). The frequency of success without modification of the empirical therapy was nearly identical for cefepime plus amikacin (49%) compared with piperacillin-tazobactam plus amikacin (51%). Similar rates of success were found for microbiologically documented infection: 40% versus 39%, respectively. Antibiotic modification was necessary in 49% of cefepime and 44% of piperacillin-tazobactam patients. The overall response rate, with or without modification of the assigned treatment, was 94% in both groups. Drug-related adverse events were reported in 10% of cefepime plus amikacin versus 11% of piperacillin-tazobactam plus amikacin patients. Mortality due to infection occurred in a total of 10 patients (two cefepime, eight piperacillin-tazobactam). CONCLUSION: The empirical regimen of cefepime plus amikacin is equivalent to piperacillin-tazobactam plus amikacin in febrile adult haematology patients with severe neutropenia. KEYWORDS: cefepime, piperacillin-tazobactam, amikacin, empirical antibiotic therapy, febrile neutropenia, haematological malignancy
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