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ABSTRACT: INTRODUCTION: During routine analysis of chimerism in bone marrow transplant patients pre-transplant genotype of the recipient or the donor might lack. We aimed to develop a new method to analyze DNA results suitable when reference genotypes are not available. METHODS: The method was based on the balance between heterozygotes. It was implemented in a standard computer spreadsheet, and considered the hypothetical donor-recipient genotype combinations. Hypotheses with peak height ratios and allele sharing tendency above a critical threshold were accepted. The results were compared with those obtained with prior knowledge of reference genotypes. RESULTS: The algorithm predicted correctly the proportion of donor/recipient chimerism, even in the absence of reference genotypes. In fact, the predicted values were closely correlated (r(2)>0.98) and free of systematic bias (slope 0.98-1.04), in comparison with the reference values obtained with prior knowledge of the donor and recipient genetic profiles. CONCLUSIONS: This study constitutes a proof-of-concept of the application of the heterozygote balance for the quantitative study of chimerism. The algorithm computes post-transplant chimerism in an easy and time-efficient way, even when the donor and recipient reference genotypes are unavailable. Therefore, it can be a useful tool for laboratories involved in chimerism analysis.
Clinica chimica acta; international journal of clinical chemistry 09/2012; 414C:85-90. · 2.54 Impact Factor
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Arancha Bermúdez,
German Pérez-Vázquez,
Andres Insunza,
Julio Baro,
Mercedes Colorado,
Eulogio Conde,
Zuriñe Díez-Gallarreta,
Maria Luisa Gutiérrez,
Monica López-Duarte,
Ignacio Olalla,
Pedro Sanroma,
Lucrecia Yañez,
Arturo Iriondo,
Carlos Richard
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ABSTRACT: We investigated a FLAGIDA-lite protocol (fludarabine 40 mg/m(2)/d orally days 1-5, cytarabine 20 mg/m(2)/d subcutaneously days 1-5, G-CSF 300 μg/d subcutaneously days 1-5, and idarrubicin 15 mg/m(2)/d orally days 1-3) in 38 consecutive patients older than 70 years of age with acute myeloid leukemia (32 patients) or refractory anemia with excess blasts-2 (six patients) and no prior therapy. Seventy-nine percent had intermediate/unfavorable karyotype and 79% had a high comorbidity. Overall response was 55% [complete response (CR) 47%] and 37% were refractory. CR rate was 52% in patients between 71 and 79 years of age and 38% in patients 80 years or older. The 4-week induction mortality was 16% (8% in patients between 70 and 79 years of age and 32% in patients 80 years or older). Overall survival (OS) at 3 years was 22% (31.3% in patients between 70 and 79 years and 15.4% in patients 80 years or older). Relapse-free survival (RFS) at 3 years was 15%. A total of 65 cycles (47 as induction and 18 as consolidation) were administered, 46 of them (70%) in an outpatient setting. In summary, this FLAGIDA-lite protocol is an effective and well-tolerated option for patients between the ages of 70 and 79 years with acute myeloid leukemia or refractory anemia with excess blasts-2 and is usually feasible as outpatient treatment, but is not beneficial for most patients 80 years or older.
American Journal of Hematology 01/2012; 87(1):42-4. · 4.67 Impact Factor
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Arancha Bermúdez,
German Pérez-Vázquez,
Andres Insunza,
Julio Baro,
Mercedes Colorado,
Eulogio Conde,
Zuriñe Díez-Gallarreta,
Maria Luisa Gutiérrez,
Monica López-Duarte,
Ignacio Olalla,
Pedro Sanroma,
Lucrecia Yañez,
Arturo Iriondo,
Carlos Richard
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ABSTRACT: We investigated a FLAGIDA-lite protocol (fludarabine 40 mg/m2/d orally days 1–5, cytarabine 20 mg/m2/d subcutaneously days 1–5, G-CSF 300 μg/d subcutaneously days 1–5, and idarrubicin 15 mg/m2/d orally days 1–3) in 38 consecutive patients older than 70 years of age with acute myeloid leukemia (32 patients) or refractory anemia with excess blasts-2 (six patients) and no prior therapy. Seventy-nine percent had intermediate/unfavorable karyotype and 79% had a high comorbidity. Overall response was 55% [complete response (CR) 47%] and 37% were refractory. CR rate was 52% in patients between 71 and 79 years of age and 38% in patients 80 years or older. The 4-week induction mortality was 16% (8% in patients between 70 and 79 years of age and 32% in patients 80 years or older). Overall survival (OS) at 3 years was 22% (31.3% in patients between 70 and 79 years and 15.4% in patients 80 years or older). Relapse-free survival (RFS) at 3 years was 15%. A total of 65 cycles (47 as induction and 18 as consolidation) were administered, 46 of them (70%) in an outpatient setting. In summary, this FLAGIDA-lite protocol is an effective and well-tolerated option for patients between the ages of 70 and 79 years with acute myeloid leukemia or refractory anemia with excess blasts-2 and is usually feasible as outpatient treatment, but is not beneficial for most patients 80 years or older. Am. J. Hematol., 2012. © 2011 Wiley Periodicals, Inc.
American Journal of Hematology 10/2011; 87(1):42 - 44. · 4.67 Impact Factor
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ABSTRACT: Untreated chronic myeloid leukemia (CML) progresses from chronic phase to blastic crisis (BC). Increased genomic instability, deregulated proliferation, and loss of differentiation appear associated to BC, but the molecular alterations underlying the progression of CML are poorly characterized. MYC oncogene is frequently deregulated in human cancer, often associated with tumor progression. Genomic instability and induction of aberrant DNA replication are described as effects of MYC. In this report, we studied MYC activities in CML cell lines with conditional MYC expression with and without exposure to imatinib, the front-line drug in CML therapy. In cells with conditional MYC expression, MYC did not rescue the proliferation arrest mediated by imatinib but provoked aberrant DNA synthesis and accumulation of cells with 4C content. We studied MYC mRNA expression in 66 CML patients at different phases of the disease, and we found that MYC expression was higher in CML patients at diagnosis than control bone marrows or in patients responding to imatinib. Further, high MYC levels at diagnosis correlated with a poor response to imatinib. MYC expression did not directly correlate with BCR-ABL levels in patients treated with imatinib. Overall our study suggests that, as in other tumor models, MYC-induced aberrant DNA synthesis in CML cells is consistent with MYC overexpression in untreated CML patients and nonresponding patients and supports a role for MYC in CML progression, possibly through promotion of genomic instability.
Molecular Cancer Research 04/2011; 9(5):564-76. · 4.29 Impact Factor
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Christelle Ferrá,
Jaime Sanz,
Rafael de la Cámara,
Guillermo Sanz, Arancha Bermúdez,
David Valcárcel,
Montserrat Rovira,
David Serrano,
Dolores Caballero,
Ildefonso Espigado, [......],
Carlos Solano,
Rafael Duarte,
Cristina Barrenetxea,
Ana García-Noblejas,
José L Díez-Martin,
Arturo Iriondo,
Enric Carreras,
Jordi Sierra,
Miguel-Angel Sanz,
Josep-Maria Ribera
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ABSTRACT: Adults with high-risk acute lymphoblastic leukemia (HR-ALL) have a poor outcome with standard chemotherapy and usually undergo unrelated stem cell transplantation (SCT) if a matched sibling donor is not available. We analyzed the outcome of adult patients with unrelated SCT for HR-ALL and studied the possible effect of the hematopoietic stem cell source of the transplant. A total of 149 adult patients (median age, 29 years, range, 15-59 years) with HR-ALL underwent unrelated SCT in 13 Spanish institutions between 2000 and 2007. Patients in first complete remission (CR1) at transplantation had at least one adverse prognostic factor (advanced age, adverse cytogenetics, hyperleukocytosis, or slow response to induction therapy). ALL was in CR1 in 81 patients (54%), in second CR (CR2) in 37 patients (25%), in third CR (CR3) in 11 patients (7%), and with overt disease in 20 patients (13%). The hematopoietic source was unrelated cord blood (UCB) in 62 patients and an unrelated donor (UD) in 87 patients. The patients undergoing UCB-SCT and UD-SCT were comparable in terms of the main clinical and biological features of ALL, except for a higher frequency of patients with more overt disease in the UCB-SCT group. There was no statistically significant difference in overall survival (OS) or disease-free survival (DFS) at 5 years between the 2 groups. Treatment-related mortality (TRM) was significantly lower in the UCB-SCT group (P = .021). The probability of relapse at 1 year was 17% (95% confidence interval [CI], 7%-27%) for the UD-SCT group and 27% (95% CI, 14%-40%) for the UCB-SCT group (P = .088), respectively. Only disease status at transplantation (CR1, 41% [95% CI, 18%-64%] vs CR2, 51% [95% CI, 17%-85%] vs advanced disease, 66% [95% CI, 46%-86%]; P = .001) and the absence of chronic graft-versus-host disease (74% [95% CI, 46%-100%] vs 33% [95% CI, 17%-49%]; P = .034) were significant factors for relapse. All unrelated transplantation modalities were associated with high treatment-related mortality for adult HR-ALL patients without a sibling donor. UCB-SCT and UD-SCT were found to be equivalent options. Disease status at transplantation and chronic GVHD were the main factors influencing relapse in both transplantation modalities.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2010; 16(7):957-66. · 3.15 Impact Factor
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British Journal of Haematology 12/2009; 149(2):166. · 4.94 Impact Factor
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Arancha Bermúdez,
Enric Carreras,
Rafael De la Cámara,
Elena Eraso,
Jesús Fortún,
Juan Carlos García-Ruiz,
Josep Guarro,
Isidro Jarque,
Enrique Marcos de Lucas,
Emilio Mayayo,
F Javier Pastor,
Javier Pemán,
José Pontón,
Guillermo Quindós,
Miguel Salavert,
Miguel Angel Sanz,
Rafael Zaragoza
Revista Iberoamericana de Micología 01/2009; Suppl:3-199. · 1.16 Impact Factor
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ABSTRACT: Scedosporium prolificans is an emerging fungus that causes rapid progressive and disseminated infections in immunodepressed patients. We present a case of a 34-year-old woman with chronic myelogenous leukemia who received a bone marrow transplantation and suffered a sudden respiratory failure in +67 day. Chest radiographies showed growing bilateral patchy condensations. Computed Tomography depicted bilateral nodular condensation of alveolar space. S. prolificans was detected from sputum, but the patient died 72 h later. Imaging findings of lung scedosporiosis are nonspecific, but CT may provide a prompter diagnosis and allow to add newer antifungal treatments. This report presents the first imaging report of lung scedosporiosis.
Emergency Radiology 02/2008; 15(1):47-9.
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Enrique Marco de Lucas,
Pablo Sádaba,
Pedro Lastra García-Barón,
María Luisa Ruiz Delgado,
Jorge Cuevas,
Ricardo Salesa, Arancha Bermúdez,
Andrés González Mandly,
Agustín Gutiérrez,
Fidel Fernández,
Fernando Marco de Lucas,
Consuelo Díez
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ABSTRACT: Scedosporium prolificans is an emerging opportunistic fungal agent encountered in severely neutropenic patients. The purpose of this paper is to describe the main cranial CT findings from a retrospective review of six patients (four men and two women, 18-66 years old) afflicted with disseminated infection by S. prolificans with neurological symptoms. They were severely neutropenic and presented with severe respiratory failure and conscience deterioration, with a subsequent 100% mortality. The final diagnosis was established by autopsy (performed in five patients) and blood culture findings. Cranial CT showed multiple low-density lesions in four patients without contrast enhancement located in the basal ganglia and corticomedullary junction. Autopsy findings of these lesions demonstrated necrosis and hyphae proliferation inside brain infarcts. Also, two of the patients had a subarachnoid hemorrhage, but angiography could not be performed. CT and autopsy findings were fairly similar to those encountered in cerebral aspergillosis; however, possibly because of its rapid and fatal evolution, no edema or ring enhancing lesions were encountered. Thus, Scedosporium can be included as a rare but possible cause of invasive fungal disseminated central nervous system infections in severely neutropenic patients.
European Radiology 03/2006; 16(2):496-502. · 3.22 Impact Factor
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Enrique Marco de Lucas,
Pablo Sádaba,
Pedro Lastra García-Barón,
María Luisa Ruiz Delgado,
Jorge Cuevas,
Ricardo Salesa, Arancha Bermúdez,
Andrés González Mandly,
Agustín Gutiérrez,
Fidel Fernández,
Fernando Marco de Lucas,
Consuelo Díez
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ABSTRACT: Scedosporium prolificans is an emerging opportunistic fungal agent encountered in severely neutropenic patients. The purpose of this paper is to describe the main cranial CT findings from a retrospective review of six patients (four men and two women, 18–66 years old) afflicted with disseminated infection by S. prolificans with neurological symptoms. They were severely neutropenic and presented with severe respiratory failure and conscience deterioration, with a subsequent 100% mortality. The final diagnosis was established by autopsy (performed in five patients) and blood culture findings. Cranial CT showed multiple low-density lesions in four patients without contrast enhancement located in the basal ganglia and corticomedullary junction. Autopsy findings of these lesions demonstrated necrosis and hyphae proliferation inside brain infarcts. Also, two of the patients had a subarachnoid hemorrhage, but angiography could not be performed. CT and autopsy findings were fairly similar to those encountered in cerebral aspergillosis; however, possibly because of its rapid and fatal evolution, no edema or ring enhancing lesions were encountered. Thus, Scedosporium can be included as a rare but possible cause of invasive fungal disseminated central nervous system infections in severely neutropenic patients.
European Radiology 01/2006; 16(2):496-502. · 3.22 Impact Factor
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ABSTRACT: Combinations of beta-lactams plus aminoglycosides have become standard therapy for suspected infections in patients with profound neutropenia. However, it is not clear whether such combinations are advantageous over therapy with a broad-spectrum antibiotic.
To assess the clinical effectiveness and the cost-effectiveness ratio of empirical therapy of febrile neutropenia with imipenem/cilastatin (I/C) versus piperacillin/tazobactam plus amikacin (P/T+A).
Prospective, multicenter observational study with 2 matched parallel cohorts treated with I/C (500 mg/6 h iv) or P/T+A (P/T: 4 g/6 h iv; A: 20 mg/kg/day iv).
Therapeutic success was defined as the resolution of fever following > or = 7 days of unchanged antibiotic treatment. An economic comparison was conducted focusing on the daily treatment costs, and the management of its toxicity.
There were 343 eligible patients (180 I/C, 163 P/T+A), of whom 290 were evaluable for the primary clinical effectiveness analysis. Follow-up information beyond 7 days of study inclusion was only available for 52% of all evaluable patients. Treatment success was observed in 42% of I/C patients compared with 31% of P/T+A patients (95% CI: -0.01, 21.4). The incidence of drug-related adverse experiences was 13% for I/C and 6% for P/T+A, with no differences in moderate or severe adverse experiences nor in those causing discontinuation of antibiotic therapy. Treatment costs were 189.55 euros (95% CI: 127.46-251.46) lower per episode of febrile neutropenia for patients treated with I/C.
The clinical effectiveness of I/C was similar to that of P/T+A. In both treatment groups toxicity was low and did not limit antibiotic therapy. Resource consumption was lower with I/C.
Current Medical Research and Opinion 06/2005; 21(5):645-55. · 2.38 Impact Factor
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ABSTRACT: Background: Combinations of beta-lactams plus aminoglycosides have become standard therapy for suspected infections in patients with profound neutropenia. However, it is not clear whether such combinations are advantageous over therapy with a broad-spectrum antibiotic. Objective: To assess the clinical effectiveness and the cost-effectiveness ratio of empirical therapy of febrile neutropenia with imipenem/cilastatin (I/C) versus piperacillin/tazobactam plus amikacin (P/T+A). Research design and methods: Prospective, multicenter observational study with 2 matched parallel cohorts treated with I/C (500 mg/6 h iv) or P/T+A (P/T: 4 g/6 h iv; A: 20 mg/kg/day iv). Main outcome measures: Therapeutic success was defined as the resolution of fever following ≥ 7 days of unchanged antibiotic treatment. An economic comparison was conducted focusing on the daily treatment costs, and the management of its toxicity. Results: There were 343 eligible patients (180 I/C, 163 P/T+A), of whom 290 were evaluable for the primary clinical effectiveness analysis. Follow-up information beyond 7 days of study inclusion was only available for 52% of all evaluable patients. Treatment success was observed in 42% of I/C patients compared with 31% of P/T+A patients (95% CI: –0.01, 21.4). The incidence of drug-related adverse experiences was 13% for I/C and 6% for P/T+A, with no differences in moderate or severe adverse experiences nor in those causing discontinuation of antibiotic therapy. Treatment costs were 189.55 euros (95% CI: 127.46–251.46) lower per episode of febrile neutropenia for patients treated with I/C. Conclusions: The clinical effectiveness of I/C was similar to that of P/T+A. In both treatment groups toxicity was low and did not limit antibiotic therapy. Resource consumption was lower with I/C.
03/2005; 21(5):645-655.
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ABSTRACT: The increase in oral anticoagulant (OA) treatment has led to development of new strategies for its control. We tested the efficacy of the GAO software (Dade Behring) in providing adequate acenocoumarol dosages for patients whose international normalised ratios (INRs) were no more than 0.5 points out of range. From December 1998 to August 1999, all outpatients in this setting were randomly assigned to receive computer-generated or traditionally fixed OA doses. Patients in their first 4 weeks of treatment were excluded. Overall, 8352 dosages were calculated by the computer and 7586 by the medical staff. The main endpoint of the study was the time spent in target INR range. The computer matched the traditional dosing, achieving a small but statistically significant greater efficacy in maintaining patients within the INR target range. The percentage of INR determinations over 5.5 was very low in both groups. Our results validate the computerised acenocoumarol dosing in our centre, achieving at least similar levels of effectiveness and safety compared with traditional dosage by medical staff.
Pathophysiology of Haemostasis and Thrombosis 33(2):59-63. · 2.23 Impact Factor
