In this paper, we comparatively analyze the effects of the following different stimuli on the pro... more In this paper, we comparatively analyze the effects of the following different stimuli on the production and intracellular accumulation of the interleukin (IL)-1 beta, IL-6, IL-12, tumor necrosis factor-alpha (TNF-alpha), and IL-8 inflammatory cytokines in both normal human peripheral blood (PB) dendritic cell (DC) subsets and monocytes: lipopolysaccharide (LPS) versus Staphylococcus aureus cowan I (SAC) in the presence or absence of interferon-(IFN)-gamma-, cytokine secretion-blocking agents (brefeldin A alone versus brefeldin A plus monensin), and incubation periods (6, 12, and 24 h). For this purpose, a four-color multiple-staining direct immunofluorescence technique analyzed by flow cytometry was systematically used in all experiments (n = 19). Our results show that after stimulation, an important proportion of each of the two CD33(+) myeloid DC subsets as well as the monocytes produce significant amounts of all cytokines analyzed under each of the experimental conditions assaye...
In the last few years, cases of osteonecrosis of the jaw (ONJ) have been detected in cancer patie... more In the last few years, cases of osteonecrosis of the jaw (ONJ) have been detected in cancer patients taking bisphosphonates as part of their treatment. The publications and cases notified to date mention that the majority of the patients were on antineoplastic treatment (chemotherapy, ...
Background and Objectives. Anthracycline-based combination chemotherapy regimens are the standard... more Background and Objectives. Anthracycline-based combination chemotherapy regimens are the standard therapy for patients with diffuse large B-cell lymphoma (DLB-CL), but such regimens may be poorly tolerated in elderly patients.
14 These authors share senior authorship Corresponding authors: xaguirre@unav.es, fprosper@unav.e... more 14 These authors share senior authorship Corresponding authors: xaguirre@unav.es, fprosper@unav.es, imartins@clinic.ub.es Running Title: DNA hypermethylation of enhancers in myeloma.
Introduction: Renal function is one of the most important prognostic factors in multiple myeloma ... more Introduction: Renal function is one of the most important prognostic factors in multiple myeloma (MM). Patients with renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy schemes. The aim of this study was to analyze the outcome of MM patients with renal insuciency undergoing autologous stem cell transplantation (ASCT), including the evaluation of the quality of PB stem cell collections, kinetics of engraftment, transplant-related mortality, response to high dose chemotherapy and survival. Materials and methods: From a total of 566 valuable patients included in the MM Spanish ASCT registry, three groups of patients were de®ned: group BA, patients with abnormal renal function at diagnosis but normal at transplant (73 cases); group BB, patients with abnormal function both at diagnosis and at transplant (14 cases); and group AA (control group, 479 cases), patients who constantly had normal renal function. Results and conclusion: Patients from groups BA and BB presented with a signi®cantly higher number of adverse prognostic factors, re¯ecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insuciency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was signi®cantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent in¯uence on TRM: poor performance status (ECOG 3), hemoglobin 59.5 g/dl and serum creatinine 55 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine 52 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically signi®cant dierence favoring group AA (P50.01). PFS did not dier signi®cantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high b 2 -microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insuciency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (45 mg/dl).
Internal tandem duplications of the FLT3 gene (FLT3-ITDs) are frequent in patients with acute pro... more Internal tandem duplications of the FLT3 gene (FLT3-ITDs) are frequent in patients with acute promyelocytic leukemia (APL), however its clinical impact remains controversial.
increasing intracellular ROS levels is becoming a recognized strategy against tumor cells. Thus, ... more increasing intracellular ROS levels is becoming a recognized strategy against tumor cells. Thus, diminishing ROS levels could be also detrimental to cancer cells. We surmise that avoiding ROS generation would be a better option than quenching ROS with antioxidants. Chronic myeloid leukemia (CML) is triggered by the expression of BCR-ABL kinase, whose activity leads to increased ROS production, partly through NADPH oxidases. Here we assessed NADPH oxidases as therapeutic targets in CML.
Information on the effects of imatinib mesylate (IM) on the non-clonal bone marrow (BM) cell comp... more Information on the effects of imatinib mesylate (IM) on the non-clonal bone marrow (BM) cell compartment is scanty. We have analyzed the gene expression profile of BM hematopoietic cells after IM therapy in 20 patients with chronic myeloid leukaemia (CML) in complete cytogenetic response (CCyR) and compared it with that of normal volunteer donors by oligonucleotide microarrays. In CCyR CML
Introduction: Thalidomide has recently proven to be a useful drug for treatment of refractory and... more Introduction: Thalidomide has recently proven to be a useful drug for treatment of refractory and relapsed multiple myeloma patients, up to 35% of whom achieve remission. However, little is known about the potential additive or synergistic eect upon its association with other drugs with proven ecacy in MM. Material and methods: The present pilot study was designed to evaluate the toxicity and response rate of the association of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) in 22 refractory or relapsed MM patients. The protocol scheduled the administration of thalidomide at escalating doses (200 to 800 mg/day), daily oral cyclophosphamide (CTX) (50 mg/day) and pulsed dexamethasone (40 mg/day, four days every three weeks). Results: Adverse eects were moderate (grade 42) with only two patients in whom treatment was withdrawn due to neuropathy and severe somnolence. Infections were recorded in six patients, four requiring hospitalization for intravenous antibiotic therapy. No cases of thrombocytopenia grade 52 were noted. Other side eects included grade 42 constipation (29%), somnolence (35%) or dizziness (12%). In addition, one case of meralgia paresthetica and one with a deep venous thrombosis were noted. Two cases displayed hyperglycemia and myopathy attributed to dexamethasone, which was solved upon changing to prednisone. With a median follow-up of 12 months, 17 patients were evaluable for response; 13 (77%) responded to the therapy, including nine cases (53%) with a 450% M-component reduction (two of them with a complete remission). Only two responders have already progressed, with a projected event free survival of 51% at 12 months. Seven patients have died due to disease progression (n=5), sudden death (n=1) and infection (n=1). Conclusion: This study shows that ThaCyDex is a feasible and promising therapeutic approach for patients with relapsed/refractory MM.
We have evaluated 9 new molecular mark- ers (ERG, EVI1, MLL-PTD, MN1, PRAME, RHAMM, and WT1 gene-... more We have evaluated 9 new molecular mark- ers (ERG, EVI1, MLL-PTD, MN1, PRAME, RHAMM, and WT1 gene-expression lev- els plus FLT3 and NPM1 mutations) in 121 de novo cytogenetically normal acute my- eloblastic leukemias. In the multivariate analysis, high ERG or EVI1 and low PRAMEexpressions were associated with a shorter relapse-free survival (RFS) and overall survival (OS). A 0 to
This International Myeloma Working Group consensus updates the disease definition of multiple mye... more This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working...
1. Thromb Haemost. 2010 Jan;103(1):247-9. Epub 2009 Nov 13. The role of immature platelet fractio... more 1. Thromb Haemost. 2010 Jan;103(1):247-9. Epub 2009 Nov 13. The role of immature platelet fraction in acute coronary syndrome. Gonzalez-Porras JR, Martin-Herrero F, Gonzalez-LopezTJ, Olazabal J, Diez-Campelo M, Pabon P, Alberca I, San Miguel JF. ...
Objectives. The information currently available about dendritic cells (DCs) in patients with diff... more Objectives. The information currently available about dendritic cells (DCs) in patients with different types of monoclonal gammopathy (MG) is limited and fre- quently controversial. In the present study, we analyzed the ex vivo distribution as well as the phenotypic and functional characteristics of peripheral blood (PB) DCs from different types of MG. Methods.Forthispurpose,61untreatedpatientsinto- tal with MG were analyzed—MG of undetermined
Melphalan and prednisone (MP) has been the standard treatment for multiple myeloma (MM) for the l... more Melphalan and prednisone (MP) has been the standard treatment for multiple myeloma (MM) for the last 30 years. Combination chemotherapy at conventional doses has not shown a significant prolongation of survival when compared to MP. There are few data comparing conventional chemotherapy at standard doses with conventional treatment at higher doses. We present the long-term outcome of 914 patients from two randomized trials comparing three different dose intensity regimens. From 1 January, 1985 to 31 December, 1989, 487 patients were randomized between MP (melphalan 9 mg/m(2) p.o. and prednisone 60 mg/m(2) days 1-4) and alternating VCMP (vincristine 1 mg i.v. on day 1, cyclophosphamide 500 mg/m(2) i.v. on day 1, melphalan 6 mg/m(2) p.o. on days 1-4, and prednisone 60 mg/m(2) on days 1-4) and VBAP (vincristine 1 mg i.v. on day 1, BCNU and doxorubicin 30 mg/m(2) i.v. each on day 1, and prednisone 60 mg/m(2) on days 1-4). From 1 January, 1990 to 31 May, 1994, 427 patients were randomized between VCMP/VBAP at the above detailed doses (VCMP/VBAP 'SD') and the same regimen increasing the doses of cyclophosphamide and doxorubicin from 500 to 1200 mg/m(2) and from 30 to 50 mg/m(2), respectively (VCMP/VBAP 'HD'). Increasing dose intensity produced a significantly higher partial response rate (31% vs 45% vs 51% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P < 0.01). However, a significantly early death rate was observed in the HD arm (7.7, 7.5 and 12.1% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = 0.05). Median duration of response (20 vs 18 vs 19 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) and median survival (25 vs 31 vs 29 months for MP, VCMP/VBAP…
Introduction: A model of a stepwise malignant transformation has been proposed for the pathogenes... more Introduction: A model of a stepwise malignant transformation has been proposed for the pathogenesis of monoclonal gammopathies. In this model, cell cycle regulators play a central role as a source of genetic events; particulary, p16/INK4a gene acts as a tumoral suppressor gene and, recently, inactivation of this gene through a methylation mechanism, has been observed in multiple myeloma patients. Under the diagnosis of monoclonal gammopathies there is a broad spectrum of disorders with very dierent outcomes, ranging from indolent courses, such as those of monoclonal gammopathy of undetermined signi®cance, WaldestroÈ n macroglobulinemia and smoldering multiple myeloma, to aggressive diseases such as symptomatic MM and primary plasma cell leukemia. To the best of our knowledge, the activity of p16 gene has not been evaluated and compared in these dierent subtypes of monoclonal gammopathies. Materials and methods: The methylation status of the p16 gene was analysed in a group of 159 patients with monoclonal gammopathies (40 monoclonal gammopathy of uncertain signi®cance, eight WaldenstroÈ m Macroglobulinemia, eight smoldering multiple myeloma, 98 symptomatic multiple myeloma and ®ve primary plasma cell leukemia) using three dierent assays (restriction enzymes and PCR or S-B and modi®cation by sodium bisulphite). Results: Forty-one of 98 MM patients (41.8%) as well as four of the ®ve (80%) primary PCL patients showed methylation of the p16 gene, while none of the patients with monoclonal gammopathy of undetermined signi®cance, WaldenstroÈ m Macroglobulinemia or smoldering multiple myeloma displayed a methylation status. Conclusion: These ®ndings suggest that the methylation of the p16 gene could be a relevant oncogenic event in the monoclonal gammopathies evolution being associated with the most aggressive forms.
Because of developments in diagnosis of haemopoietic malignant diseases during the past two decad... more Because of developments in diagnosis of haemopoietic malignant diseases during the past two decades, routine and reliable identification of very low numbers of malignant cells, known as minimal residual disease (MRD), is now possible. Several large-scale studies have shown that monitoring of MRD in haemopoietic malignant disease predicts clinical outcome. In acute lymphoblastic leukaemia, MRD detection is useful for evaluating early response to treatment and consequently for improving stratification, including treatment reduction. In acute promyelocytic leukaemia and chronic myeloid leukaemia, MRD information at specific time points enables effective early treatment intervention. MRD monitoring is also possible in other leukaemia subtypes, but in these disorders the clinical value of MRD detection is not yet known.
The present work analyzes the hematopoietic progenitor cells (HPC) in myelodysplastic syndrome (M... more The present work analyzes the hematopoietic progenitor cells (HPC) in myelodysplastic syndrome (MDS) patients using both an immunophenotypical and a functional approaches in order to know whether they are similar in patients with or without cytogenetic abnormalities. Among CD34+ HPC, the proportion of myeloid committed progenitors was higher in patients with an abnormal karyotype. Ninety MDS patients were studied. Patients
At present, a major challenge in the initial diagnosis of leukemia of large granular lymphocytes ... more At present, a major challenge in the initial diagnosis of leukemia of large granular lymphocytes (LGLs) is to establish the clonal nature of the expanded popula- tion. In the present study we have analyzed by flow cytometry immunophenotyping the TCR-V reper- toire of 98 consecutive cases of persistent expansions of CD4 or CD8bright CD3/TCR- LGLs and com- pared the results
In this paper, we comparatively analyze the effects of the following different stimuli on the pro... more In this paper, we comparatively analyze the effects of the following different stimuli on the production and intracellular accumulation of the interleukin (IL)-1 beta, IL-6, IL-12, tumor necrosis factor-alpha (TNF-alpha), and IL-8 inflammatory cytokines in both normal human peripheral blood (PB) dendritic cell (DC) subsets and monocytes: lipopolysaccharide (LPS) versus Staphylococcus aureus cowan I (SAC) in the presence or absence of interferon-(IFN)-gamma-, cytokine secretion-blocking agents (brefeldin A alone versus brefeldin A plus monensin), and incubation periods (6, 12, and 24 h). For this purpose, a four-color multiple-staining direct immunofluorescence technique analyzed by flow cytometry was systematically used in all experiments (n = 19). Our results show that after stimulation, an important proportion of each of the two CD33(+) myeloid DC subsets as well as the monocytes produce significant amounts of all cytokines analyzed under each of the experimental conditions assaye...
In the last few years, cases of osteonecrosis of the jaw (ONJ) have been detected in cancer patie... more In the last few years, cases of osteonecrosis of the jaw (ONJ) have been detected in cancer patients taking bisphosphonates as part of their treatment. The publications and cases notified to date mention that the majority of the patients were on antineoplastic treatment (chemotherapy, ...
Background and Objectives. Anthracycline-based combination chemotherapy regimens are the standard... more Background and Objectives. Anthracycline-based combination chemotherapy regimens are the standard therapy for patients with diffuse large B-cell lymphoma (DLB-CL), but such regimens may be poorly tolerated in elderly patients.
14 These authors share senior authorship Corresponding authors: xaguirre@unav.es, fprosper@unav.e... more 14 These authors share senior authorship Corresponding authors: xaguirre@unav.es, fprosper@unav.es, imartins@clinic.ub.es Running Title: DNA hypermethylation of enhancers in myeloma.
Introduction: Renal function is one of the most important prognostic factors in multiple myeloma ... more Introduction: Renal function is one of the most important prognostic factors in multiple myeloma (MM). Patients with renal failure are generally excluded from high dose therapy even though they display a poor prognosis with conventional chemotherapy schemes. The aim of this study was to analyze the outcome of MM patients with renal insuciency undergoing autologous stem cell transplantation (ASCT), including the evaluation of the quality of PB stem cell collections, kinetics of engraftment, transplant-related mortality, response to high dose chemotherapy and survival. Materials and methods: From a total of 566 valuable patients included in the MM Spanish ASCT registry, three groups of patients were de®ned: group BA, patients with abnormal renal function at diagnosis but normal at transplant (73 cases); group BB, patients with abnormal function both at diagnosis and at transplant (14 cases); and group AA (control group, 479 cases), patients who constantly had normal renal function. Results and conclusion: Patients from groups BA and BB presented with a signi®cantly higher number of adverse prognostic factors, re¯ecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insuciency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was signi®cantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent in¯uence on TRM: poor performance status (ECOG 3), hemoglobin 59.5 g/dl and serum creatinine 55 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine 52 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically signi®cant dierence favoring group AA (P50.01). PFS did not dier signi®cantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high b 2 -microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insuciency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (45 mg/dl).
Internal tandem duplications of the FLT3 gene (FLT3-ITDs) are frequent in patients with acute pro... more Internal tandem duplications of the FLT3 gene (FLT3-ITDs) are frequent in patients with acute promyelocytic leukemia (APL), however its clinical impact remains controversial.
increasing intracellular ROS levels is becoming a recognized strategy against tumor cells. Thus, ... more increasing intracellular ROS levels is becoming a recognized strategy against tumor cells. Thus, diminishing ROS levels could be also detrimental to cancer cells. We surmise that avoiding ROS generation would be a better option than quenching ROS with antioxidants. Chronic myeloid leukemia (CML) is triggered by the expression of BCR-ABL kinase, whose activity leads to increased ROS production, partly through NADPH oxidases. Here we assessed NADPH oxidases as therapeutic targets in CML.
Information on the effects of imatinib mesylate (IM) on the non-clonal bone marrow (BM) cell comp... more Information on the effects of imatinib mesylate (IM) on the non-clonal bone marrow (BM) cell compartment is scanty. We have analyzed the gene expression profile of BM hematopoietic cells after IM therapy in 20 patients with chronic myeloid leukaemia (CML) in complete cytogenetic response (CCyR) and compared it with that of normal volunteer donors by oligonucleotide microarrays. In CCyR CML
Introduction: Thalidomide has recently proven to be a useful drug for treatment of refractory and... more Introduction: Thalidomide has recently proven to be a useful drug for treatment of refractory and relapsed multiple myeloma patients, up to 35% of whom achieve remission. However, little is known about the potential additive or synergistic eect upon its association with other drugs with proven ecacy in MM. Material and methods: The present pilot study was designed to evaluate the toxicity and response rate of the association of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) in 22 refractory or relapsed MM patients. The protocol scheduled the administration of thalidomide at escalating doses (200 to 800 mg/day), daily oral cyclophosphamide (CTX) (50 mg/day) and pulsed dexamethasone (40 mg/day, four days every three weeks). Results: Adverse eects were moderate (grade 42) with only two patients in whom treatment was withdrawn due to neuropathy and severe somnolence. Infections were recorded in six patients, four requiring hospitalization for intravenous antibiotic therapy. No cases of thrombocytopenia grade 52 were noted. Other side eects included grade 42 constipation (29%), somnolence (35%) or dizziness (12%). In addition, one case of meralgia paresthetica and one with a deep venous thrombosis were noted. Two cases displayed hyperglycemia and myopathy attributed to dexamethasone, which was solved upon changing to prednisone. With a median follow-up of 12 months, 17 patients were evaluable for response; 13 (77%) responded to the therapy, including nine cases (53%) with a 450% M-component reduction (two of them with a complete remission). Only two responders have already progressed, with a projected event free survival of 51% at 12 months. Seven patients have died due to disease progression (n=5), sudden death (n=1) and infection (n=1). Conclusion: This study shows that ThaCyDex is a feasible and promising therapeutic approach for patients with relapsed/refractory MM.
We have evaluated 9 new molecular mark- ers (ERG, EVI1, MLL-PTD, MN1, PRAME, RHAMM, and WT1 gene-... more We have evaluated 9 new molecular mark- ers (ERG, EVI1, MLL-PTD, MN1, PRAME, RHAMM, and WT1 gene-expression lev- els plus FLT3 and NPM1 mutations) in 121 de novo cytogenetically normal acute my- eloblastic leukemias. In the multivariate analysis, high ERG or EVI1 and low PRAMEexpressions were associated with a shorter relapse-free survival (RFS) and overall survival (OS). A 0 to
This International Myeloma Working Group consensus updates the disease definition of multiple mye... more This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working...
1. Thromb Haemost. 2010 Jan;103(1):247-9. Epub 2009 Nov 13. The role of immature platelet fractio... more 1. Thromb Haemost. 2010 Jan;103(1):247-9. Epub 2009 Nov 13. The role of immature platelet fraction in acute coronary syndrome. Gonzalez-Porras JR, Martin-Herrero F, Gonzalez-LopezTJ, Olazabal J, Diez-Campelo M, Pabon P, Alberca I, San Miguel JF. ...
Objectives. The information currently available about dendritic cells (DCs) in patients with diff... more Objectives. The information currently available about dendritic cells (DCs) in patients with different types of monoclonal gammopathy (MG) is limited and fre- quently controversial. In the present study, we analyzed the ex vivo distribution as well as the phenotypic and functional characteristics of peripheral blood (PB) DCs from different types of MG. Methods.Forthispurpose,61untreatedpatientsinto- tal with MG were analyzed—MG of undetermined
Melphalan and prednisone (MP) has been the standard treatment for multiple myeloma (MM) for the l... more Melphalan and prednisone (MP) has been the standard treatment for multiple myeloma (MM) for the last 30 years. Combination chemotherapy at conventional doses has not shown a significant prolongation of survival when compared to MP. There are few data comparing conventional chemotherapy at standard doses with conventional treatment at higher doses. We present the long-term outcome of 914 patients from two randomized trials comparing three different dose intensity regimens. From 1 January, 1985 to 31 December, 1989, 487 patients were randomized between MP (melphalan 9 mg/m(2) p.o. and prednisone 60 mg/m(2) days 1-4) and alternating VCMP (vincristine 1 mg i.v. on day 1, cyclophosphamide 500 mg/m(2) i.v. on day 1, melphalan 6 mg/m(2) p.o. on days 1-4, and prednisone 60 mg/m(2) on days 1-4) and VBAP (vincristine 1 mg i.v. on day 1, BCNU and doxorubicin 30 mg/m(2) i.v. each on day 1, and prednisone 60 mg/m(2) on days 1-4). From 1 January, 1990 to 31 May, 1994, 427 patients were randomized between VCMP/VBAP at the above detailed doses (VCMP/VBAP 'SD') and the same regimen increasing the doses of cyclophosphamide and doxorubicin from 500 to 1200 mg/m(2) and from 30 to 50 mg/m(2), respectively (VCMP/VBAP 'HD'). Increasing dose intensity produced a significantly higher partial response rate (31% vs 45% vs 51% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P < 0.01). However, a significantly early death rate was observed in the HD arm (7.7, 7.5 and 12.1% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = 0.05). Median duration of response (20 vs 18 vs 19 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) and median survival (25 vs 31 vs 29 months for MP, VCMP/VBAP…
Introduction: A model of a stepwise malignant transformation has been proposed for the pathogenes... more Introduction: A model of a stepwise malignant transformation has been proposed for the pathogenesis of monoclonal gammopathies. In this model, cell cycle regulators play a central role as a source of genetic events; particulary, p16/INK4a gene acts as a tumoral suppressor gene and, recently, inactivation of this gene through a methylation mechanism, has been observed in multiple myeloma patients. Under the diagnosis of monoclonal gammopathies there is a broad spectrum of disorders with very dierent outcomes, ranging from indolent courses, such as those of monoclonal gammopathy of undetermined signi®cance, WaldestroÈ n macroglobulinemia and smoldering multiple myeloma, to aggressive diseases such as symptomatic MM and primary plasma cell leukemia. To the best of our knowledge, the activity of p16 gene has not been evaluated and compared in these dierent subtypes of monoclonal gammopathies. Materials and methods: The methylation status of the p16 gene was analysed in a group of 159 patients with monoclonal gammopathies (40 monoclonal gammopathy of uncertain signi®cance, eight WaldenstroÈ m Macroglobulinemia, eight smoldering multiple myeloma, 98 symptomatic multiple myeloma and ®ve primary plasma cell leukemia) using three dierent assays (restriction enzymes and PCR or S-B and modi®cation by sodium bisulphite). Results: Forty-one of 98 MM patients (41.8%) as well as four of the ®ve (80%) primary PCL patients showed methylation of the p16 gene, while none of the patients with monoclonal gammopathy of undetermined signi®cance, WaldenstroÈ m Macroglobulinemia or smoldering multiple myeloma displayed a methylation status. Conclusion: These ®ndings suggest that the methylation of the p16 gene could be a relevant oncogenic event in the monoclonal gammopathies evolution being associated with the most aggressive forms.
Because of developments in diagnosis of haemopoietic malignant diseases during the past two decad... more Because of developments in diagnosis of haemopoietic malignant diseases during the past two decades, routine and reliable identification of very low numbers of malignant cells, known as minimal residual disease (MRD), is now possible. Several large-scale studies have shown that monitoring of MRD in haemopoietic malignant disease predicts clinical outcome. In acute lymphoblastic leukaemia, MRD detection is useful for evaluating early response to treatment and consequently for improving stratification, including treatment reduction. In acute promyelocytic leukaemia and chronic myeloid leukaemia, MRD information at specific time points enables effective early treatment intervention. MRD monitoring is also possible in other leukaemia subtypes, but in these disorders the clinical value of MRD detection is not yet known.
The present work analyzes the hematopoietic progenitor cells (HPC) in myelodysplastic syndrome (M... more The present work analyzes the hematopoietic progenitor cells (HPC) in myelodysplastic syndrome (MDS) patients using both an immunophenotypical and a functional approaches in order to know whether they are similar in patients with or without cytogenetic abnormalities. Among CD34+ HPC, the proportion of myeloid committed progenitors was higher in patients with an abnormal karyotype. Ninety MDS patients were studied. Patients
At present, a major challenge in the initial diagnosis of leukemia of large granular lymphocytes ... more At present, a major challenge in the initial diagnosis of leukemia of large granular lymphocytes (LGLs) is to establish the clonal nature of the expanded popula- tion. In the present study we have analyzed by flow cytometry immunophenotyping the TCR-V reper- toire of 98 consecutive cases of persistent expansions of CD4 or CD8bright CD3/TCR- LGLs and com- pared the results
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