Biomedical subjects
Publications and source records attributed to J Maldonado.
Some new pyrazolo[3,4-b]pyrazines and related heterocycles were synthesized and evaluated for their antifungal and antiparasitic activities. The key intermediate, 6-amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyrazine-5-carbonitrile (3) was obtained in a one-pot synthesis via the reaction of 5-amino-3-methyl-4-nitroso-1-phenylpyrazole 2 with malononitrile.
New imidazole derivatives were obtained after subjecting 5-benzo[1, 3]dioxol-5-yl-1-methyl-1H-imidazole-2-carbaldehyde to a Knoevenagel reaction. Some of these compounds exhibit significant in vitro leishmanicidal activity.
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 insufficiency 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 defined: 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 significantly higher number of adverse prognostic factors, reflecting 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 insufficiency 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 significantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent influence on TRM: poor performance status (ECOG 3), hemoglobin <9.5 g/dl and serum creatinine > or =5 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 < 2 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 significant difference favoring group AA (P<0.01). PFS did not differ significantly 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 beta(2)-microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insufficiency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (>5 mg/dl).
BACKGROUND AND OBJECTIVE: Although bcr-abl polymerase chain reaction (PCR) positivity after bone marrow transplantation (BMT) for chronic myelogenous leukemia (CML) is significantly related to relapse, the predictive value of the assay is not very high and therefore most investigators consider that qualitative RT-PCR data alone are too imprecise to enable clinical decisions to be taken in individual cases. To define the clinical outcome of bcr-abl positive patients after unmanipulated BMT better, we sought the origin of hematopoiesis and traced its evolution over time. DESIGN AND METHODS: Forty-nine patients received allogeneic BMT for CML (39 in chronic phase and 10 in accelerated phase/blast crisis). Median follow-up was 61 months (range 4-92). mRNA and DNA were used to assess bcr-abl and chimerism status respectively. Quantitative VNTR-PCR on total cells and lymphoid or myeloid population allowed us to assign and measure the origin of hematopoiesis. RESULTS: Both bcr-abl positivity and the presence of mixed chimerism (MC) were significantly associated with relapse (p = 0.0009 and p < 0.0001 respectively). Relapse was observed in one of 39 patients with complete donor chimerism and in 6 of 9 patients with MC. These six cases showed increasing levels of host hemopoiesis and bcr-abl positivity in the CD15-positive population prior to relapse. The other three cases had decreasing or stable low-level MC which was restricted to the T-cells as well as bcr-abl negativity. INTERPRETATION AND CONCLUSIONS: Whereas the simple detection of bcr-abl fails to identify patients who will relapse with certainty, the assessment of MC by VNTR-PCR does identify patients headed to relapse. Confirmation of myeloid involvement and increasing levels over time further elucidates the clinical outcome of bcr-abl positive patients after BMT.
BACKGROUND: Allogeneic bone marrow transplantation (BMT) has been performed as one mode of cure-oriented therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL-Ph' positive). However, the clinical significance of the residual BCR-ABL-positive clones after BMT is still controversial. PATIENTS AND METHODS: The BCR-ABL gene (p210 and p190) was prospectively studied by nested RT-PCR in 8 ALL-Ph' positive patients undergoing BMT. RESULTS: All patients received BMT at the time of clinical remission (CR). However, minimal residual disease (MRD) was detected in 7 of them. MRD detected just before BMT seems to be eradicated by BMT protocol. Four patients remained in CR and did not show BCR-ABL transcripts. Other 4 patients, relapsed, demonstrating MRD, which preceded recurrence by a median time of 6 weeks. Three relapsed patients showed p190 transcript and only one, p210 type. CONCLUSIONS: The RT-PCR assay appears to be a useful test for predicting at high risk of relapse after BMT and may identify patients who might benefit from therapeutic interventions. The finding that the expression of p190 BCR-ABL may carry an especially high risk of relapse suggests a different clinical and biologic behaviour between p190 and p210 BCR-ABL.
We examined the effects of nucleotide supplementation to a preterm adapted milk formula on the lymphocyte subsets and plasma IgG, IgM and IgA levels in preterm infants for the first three months of life. Two groups of preterm infants received a milk formula or the same formula supplemented with CMP, AMP, UMP, GMP and IMP to mimic the concentration of acid-soluble nucleotides found in human milk. Blood samples were obtained at birth, 10 days, 20-30 days and 3 months of age. Preterm infants fed the nucleotide formula exhibited higher plasma levels of IgM in all postnatal study periods than neonates fed the standard formula; moreover, IgA was also higher at 3 months of age in nucleotide formula fed infants. No major differences were seen between groups for IgG levels and lymphocyte subsets. Thus, dietary nucleotides appear to exert actions on immature human neonate lymphocytes enhancing the in vivo production of Ig which may have a role in the defense capacity of neonates.
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Myeloperoxidase (MPO) is found in the azurophilic granules of normal myelocytic cells. Cytochemical staining for MPO activity is used clinically to distinguish myeloid from acute lymphoid leukemias (ALL). However, using a highly sensitive RT-PCR technique, it is possible to detect MPO mRNA in otherwise clear ALL. The significance of this finding remains poorly understood. We have extended our observations to a series of 57 patients with the primary diagnosis of ALL (46 patients tested at diagnosis and 11 cases at relapse). We identified 25 cases (43.8%) of MPO mRNA(+)/enzyme(-) ALL (17 B cell and eight T cell lineage). Expression of myeloid antigens (CD13 or CD33) were detected in nine of them, and remarkably, 18 cases (72%) displayed CD34. Of these 25 MPO mRNA(+) leukemias, 10 (40%) are Bcr-Abl positive (with P210 fusion transcript in five patients while the five remaining cases carried P190 transcript). Moreover, 11 of 16 myeloid negative cases were also negative for any type of Bcr-Abl and MLL rearrangement, indicating that MPO mRNA positivity is not either invariably related to that chromosomal abnormality or necessarily associated with the presence of other myeloid differentiation features. Interestingly, six of these 11 cases are T-ALL, suggesting the presence of some overlapping phase for T and myeloid lineage commitment. Taken together, these findings could suggest a separate biological disease with immature origin and bipotential differentiation capability, which involves B and T-ALL subtypes and should lead to new investigations regarding their prognostic impact.
BACKGROUND AND OBJECTIVE: Interferon-a (IFN) is increasingly being used as the drug of choice in chronic myeloid leukemia patients. The main objectives of the study were to study the influence of the classic prognostic variables and response to IFN, and to assess the influence of this response on the course of the disease and survival. DESIGN AND METHODS: Single arm, prospective, multicenter study, without a control group. Only Ph1-positive CML patients were included. The treatment scheme was biphasic: the patients first received standard chemotherapy and thereafter IFN-a2a was used as monotherapy, with a target dose of 9 MU/d/s.c. RESULTS: Twenty-one centers in Spain enrolled 132 patients (72 men, 60 women). The median dose of IFN given was 5.8 MU/d, and the median treatment duration was 431 days (range: 18-2,597). Seventy-two percent of patients obtained a hematologic response in the first six months of IFN treatment. Genetic response was obtained in 47% of the patients, and the response was major or complete in 27% and 19%, respectively. The median time to obtain this response was 7, 9, and 18 months for minimal, partial and complete genetic response, respectively. Multivariant analysis showed that only a higher percentage of basophils at diagnosis was associated with a worse hematologic response at six months (p=0.001) (OR: 1.23) and with a worse cytogenetic response in the first year of IFN therapy (p=0.018) (OR: 1.4). Over an observation period of 8 years, 35.6% of the patients died, and 85 (64.4%) remained alive. With a median follow-up of 42 months (3.7-98), the 6-year projected probabilities of survival and transformation-free survival were 0.61+/-0.07 vs. 0.54+/-0.07, respectively. Patients with Kantarjian's stage 3 disease or in a high-risk Sokal group had lower probabilities of survival, but these systems did not adequately discriminate in our series. Obtaining a complete hematologic response in the first six months of IFN therapy was favorable in terms of overall survival (p=0.05; HR=0.33). Cox's analysis demonstrated that obtaining a cytogenetic response in the first year was independently associated with better overall survival (p=0.04; HR=0.19) and better transformation-free survival (p=0.0035; HR=0.11). INTERPRETATION AND CONCLUSIONS: Nearly half of the patients obtained some degree of Philadelphia suppression, which was major in 27%, and complete in 19%. A higher percentage of basophils at diagnosis was the only variable associated with a lower probability of cytogenetic response. Obtaining a cytogenetic response during the first year of IFN treatment was a favorable and independent variable in terms of survival and transformation-free survival. Obtaining a major cytogenetic response during this period decreased the risk of transformation twenty times. Our results suggest that the effect of IFN on survival is independent of the classic prognostic variables.
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BACKGROUND: To compare standard chemotherapy CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) with the regimen CHOP/VIA (VP-16, iphosphamide and cytarabine) in terms of response to therapy, response duration, survival and toxicity in patients with aggressive lymphoma. PATIENTS AND METHODS: 132 patients (84 males and 48 females; median age, 55 years) were included from 12 Spanish Institutions, diagnosed of non-Hodgkin's lymphoma of intermediate or high grade, in stages II-IV and previously untreated. Patients were randomized to receive CHOP or CHOP/VIA. RESULTS: After excluding 14 not assessable cases, 62 patients (52.5%) received CHOP, and 56 (47.5%) CHOP/VIA. No significant differences were found on main prognostic factors between such groups. Response was assessable in 114 cases (CHOP: 61; CHOP/VIA: 53) 39 patients (64%) receiving CHOP achieved complete response (CR), and 2 (3%) partial response (PR), whereas in the CHOP/VIA group CR and PR rates were 63% (34/53), and 7% (4/53), respectively. 14 patients (36%) treated with CHOP and 12 (35%) treated with CHOP/VIA eventually relapsed, with an actuarial risk of relapse at 36 months of 43% and 40%, respectively. Median survival was 37 months. No differences were found between both therapeutic groups, with an overall survival at 36 months from diagnosis of 53.5% (CI 95%: 40-67) for CHOP and 48% (CI 95%: 34-62) for CHOP/VIA. Finally, toxicity was not different for both arms. CONCLUSION: In the present study in patients with aggressive NHL chemotherapy regimens CHOP and CHOP/VIA showed similar results in terms of response, response duration, survival and toxicity.
Because some gangliosides bind bacteria, we tested the influence of supplementating an adapted milk formula with gangliosides, at a total concentration of 1.43 mg/100 kcal, on the fecal microflora of preterm infants. At all sampling times, feces from infants fed with ganglioside-supplemented formula had significantly lower relative content of Escherichia coli than feces from infants fed with control milk formula: the difference was especially significant at age 7 days postnatal < .001). At age 30 days postnatal, fecal bifidobacterial counts were higher in infants fed with ganglioside-supplemented formula (P < .05). We conclude that gangliosides at concentrations present in human milk significantly modify the fecal flora.
The purpose of the present study was to evaluate the effects of feeding human milk or milk formula on the fatty acid composition of plasma and red blood cell (RBC) lipids in at term small for gestational age infants (SGA) for the first 3 months of life. One group of infants received a formula with a linoleic:alpha-linolenic acid ratio of 10:1 (MF group). Another group served as control and received their own mother's milk (HM group). Blood samples were taken at birth and at 1 week, 4 weeks, and 3 months of life. Plasma and RBC fatty acid composition were analyzed by gas liquid chromatography and results of total plasma lipids were expressed as concentrations by adding an internal standard. Concentrations of saturated and monounsaturated fatty acids increased in total plasma lipids with age in all infants. In contrast, those fatty acids decreased when results were expressed as percentages of total fatty acids. Long-chain polyunsaturated fatty acids (LCP) decreased regardless of how results were expressed, but the absolute concentrations of these fatty acids in plasma available for tissue accretion were greater than suggested by the percentage results. Plasma and RBC docosahexaenoic acid (22:6n-3) decreased in the MF group in comparison to the HM group. Arachidonic acid (20:4n-6) was lower in plasma of MF-fed infant but not in RBC phospholipids. We conclude that term SGA infants fed an adapted milk formula with a linoleic:alpha-linolenic acid ratio of 10:1 but devoid of LCP may lead to a low n-3 LCP status.
Special formulas should only be used by medical prescription and for those lactating infants with diagnosed nutritional problems. Lactose-free formulas or those based on soy are the logical choice when the exclusion of lactose from the diet is considered necessary. At present, there is no concensus on the appropriateness of soy formulas for the treatment and prevention of nutritional allergies and current opinion seems to favour hydrolyzed protein formulas. High-degree protein hydrolysate formulas are used to treat lactating infants with an allergy to cow milk proteins or with serious nutritional problems. These formulas are not without risk, as they may contain residual epitopes capable of provoking a severe allergic reaction. Before using these formulas, allergenicity tests should be performed, particularly for highly sensitive infants. The unpleasant taste and high cost of these formulas, in addition to possible nutritional problems, limit their use in the prevention of atopic disease, although their efficacy is well established. Partially protein hydrolysate formulas are only used for preventive purposes and are not suitable for lactating infants with a proven allergy to cow milk. Although these formulas can reduce the incidence or delay the appearance of certain atopic symptoms, they have not been shown to prevent IgE-mediated allergic reactions to cow's milk and so their effectiveness is open to question.
Gangliosides are glycosphingolipids that are widely distributed in vertebrate tissues and body fluids and which are specially abundant in neural tissues. Milk from different species has a particular ganglioside content and profile. Human milk has a higher content of gangliosides than bovine milk. GD3 and GM3 are the predominant individual gangliosides in bovine milk. In human colostrum GD3 is also the main ganglioside whereas in human mature milk GM3 predominates over the other gangliosides. Human milk also contains GM1 and a number of highly polar gangliosides, which may play an important role in infant physiology. GM1 has been shown to inhibit Escherichia coli and Vibrio cholerae enterotoxins. We have found that a ganglioside-supplemented infant formula modifies the intestinal ecology of preterm newborns, increasing the Bifidobacteria content and lowering that of Escherichia coli. Although the exact mechanism by which dietary gangliosides reduce the fecal content of Escherichia coli is unknown, in vitro experiments suggest that they may act as false intestinal receptors for some strains of this bacteria. Since GD3 and other gangliosides have been involved in mechanisms of lymphocyte activation and differentiation, dietary gangliosides might have a function in intestinal immunity development.
We have studied the effect of two preterm commercial infant formulas with different calcium and phosphorus contents on the mineral balance and bone mineralization of 30 preterm infants at 1 month of age. Bone mineralization was measured by dual energy X-ray densitometry. The formula supplying a higher content of calcium and phosphorus promoted higher mineral retention (P<0.01) as well as higher bone mineral content (1.556 vs. 1.073 g, P<0.01) and bone mineral density (0.458 vs. 0.424 g/cm2, P<0.05), approaching values of the control group, which comprised a cohort of 15 preterm newborns whose gestational age was 4 weeks older than the subjects selected to be fed with the formulas. The intake of calcium correlated with retention (r=0.69); the phosphorus intake also correlated with phosphorus retention (r=0.95). Intakes of calcium and phosphorus correlated with the bone mineral content (r=0.65) and with bone mineral density (r=0.49). We conclude that formulas for preterm infants should not have a calcium content lower than 120 mg/100 kcal and should have a calcium/phosphorus ratio of about 2 to promote adequate bone mineralization.
The human milk composition may be influenced by several factors, such as gestational age or genetic characteristics and dietary habits of different populations. To analyze the total lipid and fatty acid contents of human milk, we have conducted two studies, one on mothers who had delivered preterm and term newborns and another on mothers from two different sociocultural backgrounds (Spain and Panama). The total lipid content (g/100 g wet weight) was significantly higher in term (2.76 +/- 0.66; mean +/- SD) than in preterm mature milk (1.06 +/- 0.4). The relative amount of 18:1n-9 was significantly higher in preterm than in term milk for transitional and mature milk, whereas that for the colostrum followed the opposite trend. Concerning the comparison between milk from mothers born in different countries, the relative contents of each of the fatty acids 16:0, 16:1n-7, 18:2n-6, 18:3n-3, and 22:5n-3 were higher in Panamanian than in Spanish milk, whereas the mean percentages of saturated fatty acids < 14:0, of 16:1n-9, and of 18:1n-9 were higher in Spanish than in Panamanian milk. Statistically significant differences were found during the three periods of lactation considered for almost all the fatty acids mentioned above, especially for 18:1n-9 and 18:3n-3. Although the potential biological significance of the changes in oleic acid content between preterm and term milk remains unclear, differences in fatty acid content between Spanish and Panamanian milk reflect the different composition of the diet among women from these countries.
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.