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Biomedical subjects

G Rivera

Publications and source records attributed to G Rivera.

At least 37 records · Page 2Linked to original sources
PubMed1986

Imipenem coadministered with cilastatin compared with moxalactam: integration of serum pharmacokinetics and microbiologic activity following single-dose administration to normal volunteers.

We administered 1 g of imipenem along with equal amounts of cilastatin (a dehydropeptidase I inhibitor) or 2 g of moxalactam intravenously over a period of 30 min to six volunteers in a crossover manner 1 week apart. The antibiotic concentrations and pharmacokinetics for each drug were determined and integrated with the microbiologic activity by measuring the duration of time that the free drug concentrations remained above the MICs for 90% of 581 clinical isolates and by measuring serum bactericidal activities against organisms which commonly infect granulocytopenic cancer patients. Moxalactam produced serum levels at 1 h after infusion of 99.9 micrograms/ml; these levels were four times greater than the plasma levels of imipenem (22.8 micrograms/ml). The trough (5.5-h) moxalactam serum levels were 10 times greater than those of imipenem (18.5 and 1.7 micrograms/ml, respectively). Essentially all of the imipenem was unbound to protein, whereas 36 to 42% of the moxalactam was unbound. Moxalactam produced free antibiotic concentrations that were above the MIC for 90% of the strains tested for more than 6 h against all of the species tested except Staphylococcus aureus (5.3 h), Enterobacter hafnia (1.6 h), and Pseudomonas aeruginosa (0 h). The imipenem concentrations were above the MIC for 90% of the strains tested for 5.6 h or more against all of the bacteria tested except Proteus spp. and Pseudomonas aeruginosa (4.5 h). The geometric mean peak bactericidal titers from volunteers receiving imipenem were more than 1:8 against all bacteria and were significantly higher than the titers from volunteers receiving moxalactam against S. aureus (1:7.3) and Pseudomonas aeruginosa (1:4.5). These data, in addition to information obtained from animal models, indicate that imipenem is a promising new candidate for carefully controlled clinical trials as a single agent for therapy of serious infections, including empiric therapy for fever in granulocytopenic cancer patients.

Adolescent↗
PubMed1986

Results of treatment of advanced-stage Burkitt's lymphoma and B cell (SIg+) acute lymphoblastic leukemia with high-dose fractionated cyclophosphamide and coordinated high-dose methotrexate and cytarabine.

To address the problem of historically poor results in the treatment of children with advanced-stage Burkitt's lymphoma and B cell (SIg+) acute lymphoblastic leukemia (ALL), an intensive chemotherapy regimen was devised using the most effective single agents in high-dose short courses. Treatment commenced with a fractionated schedule of intravenous (IV) cyclophosphamide (300 mg/m2 every 12 hours for six doses) followed immediately by Adriamycin (50 mg/m2) and vincristine (1.5 mg/m2) with combined intrathecal (IT) methotrexate and cytarabine. Predictably, this treatment produced virtually complete disappearance of all tumor and profound myelosuppression. Immediately on hematologic recovery, IV high-dose methotrexate (1,000 mg/m2 over 24 hours) followed by IV cytarabine (400 mg/m2 over the next 48 hours) was administered with leucovorin rescue and repeated IT treatments. The treatment sequence described above is repeated four times, with the dose of cytarabine doubled in succeeding courses, up to 3,200 mg/m2. The entire planned therapy required approximately 24 weeks. Since 1981, we treated a total of 29 children with this approach, 19 of whom had massive unresectable intraabdominal tumor. According to initial extent of disease, 17 were classified as stage III, four as stage IV non-Hodgkin's lymphoma (NHL), and eight as B cell ALL. Eight of the 12 patients with stage IV NHL or B cell ALL had initial involvement of the CNS. Twenty-seven of 29 patients (93%) attained a complete remission. Fourteen of 17 stage III NHL patients remain disease free, for periods ranging from 3+ months to 4 1/2+ years. The actuarial estimate of the proportion of stage III patients remaining disease free at 2 years is 81%. Results in patients with initial involvement of the CNS and/or marrow are much less favorable, with only two of ten patients who attained remission apparently being cured. In addition to stage, the initial serum lactic dehydrogenase (LDH) level emerged as a prognostic indicator, higher levels (over 1,000 IU/L) being associated with the worst prognosis (P less than .05). Major toxicity consisted of severe hematopoietic suppression and febrile episodes associated with neutropenia. We conclude that this treatment is highly effective for advanced-stage Burkitt's tumors in children free of initial CNS involvement.

Actuarial Analysis↗
PubMed1986

Cytogenetic features and serum lactic dehydrogenase level predict a poor treatment outcome for children with pre-B-cell leukemia.

Leukemic cells from 89 (24%) of 369 children with newly diagnosed acute lymphoblastic leukemia (ALL) were found to have a pre-B immunophenotype. By comparison with blasts having the common ALL phenotype, the pre-B cells were more likely to have a DNA index less than 1.16 (P = 0.02), a pseudodiploid karyotype (P less than 0.001), and a chromosomal translocation (P = 0.001). Increased serum lactic dehydrogenase levels (P = 0.001) were also characteristic of pre-B ALL; otherwise, the clinical and laboratory features of the two groups were similar. A nonrandom chromosomal translocation, t(1;19)(q23;p13.3), was identified in blast cells from 16 (23%) of the 70 patients with pre-B ALL and adequate chromosome banding studies; different translocations were found in 11 of the remaining patients. The presence of any chromosomal translocation in the pre-B group was significantly related to a higher leukocyte count, an increased level of serum lactic dehydrogenase, an increased percentage of S-phase cells, black race, and a blast cell DNA index less than 1.16. Four presenting features were found to confer an increased risk of treatment failure among pre-B patients: pseudodiploidy, chromosomal translocation, black race, and higher serum lactic dehydrogenase level. In a multivariate analysis, pseudodiploidy emerged as the strongest factor for predicting relapse in pre-B ALL. The frequent association of chromosomal abnormalities of known adverse prognostic significance and high serum lactic dehydrogenase levels with pre-B-cell ALL explains, at least in part, the poor treatment outcome reported for children with this subtype of leukemia.

Adolescent↗
PubMed1986

Chromosomal translocations play a unique role in influencing prognosis in childhood acute lymphoblastic leukemia.

Certain types of chromosomal abnormalities have been shown to exert strong independent influence on treatment outcome in acute lymphoblastic leukemia (ALL). To identify the changes most closely associated with prognosis, we analyzed the completely banded blast cell karyotypes of 161 children with this disease. One hundred twenty-five cases had one or more chromosomal abnormalities, with 45 showing translocations. The frequency of translocations was highest (58%) among patients with pseudodiploid karyotypes and lowest (0%) in the hyperdiploid group defined by 51 or more chromosomes. During the maximum 6-year follow-up period, 30 of the 45 patients with a translocation failed therapy, compared with only 27 of the 116 who lacked this feature. Life-table estimates of event-free survival indicate that only 14% of the translocation group will be in complete remission at 3 years. The percentages of failures associated with random and nonrandom translocations were virtually identical (68% v 65%). When entered in a Cox proportional hazards model with seven other types of chromosomal abnormalities, and then with 11 clinical and laboratory variables of known prognostic value in ALL, translocation emerged as the strongest single predictor of treatment outcome (P less than 0.0001). The model indicated that translocation increases the risk of treatment failure six times by comparison with the absence of this feature. These findings offer an explanation for the majority of early treatment failures in childhood ALL, including those previously attributed to ploidy classification.

Child↗
PubMed1985

Elective testicular biopsy during chemotherapy for childhood leukaemia is of no clinical value.

The clinical value of early detection of testicular leukaemia was assessed by elective wedge biopsy during the 12th or 18th month of therapy in children with acute lymphoblastic leukaemia. Biopsy samples were taken in 106 of 238 consecutively treated boys who attained complete remission; only 1 had occult disease. Samples were also taken in 2 boys with testicular leukaemia at diagnosis as soon as they achieved complete remission, and in 14 others at the end of therapy; none showed evidence of leukaemic infiltration. 13 boys, including the 1 with biopsy-confirmed occult disease, had a testicular relapse; 6 of these patients had had negative biopsy findings 12-28 months before relapse. These results indicate that elective testicular biopsy during therapy for childhood leukaemia is of no benefit clinically. They also suggest that routine use of end-of-therapy testicular biopsy should be re-evaluated, since frequency of testicular relapse is low, therapy is effective, and negative biopsy findings do not preclude eventual relapse.

Adolescent↗
PubMed1985

Comparison of morphology in ALL at presentation and relapse.

A high frequency of conversion from L1 to L2 morphology in ALL at relapse has been reported in studies made without benefit of the French-American-British (FAB) scoring system. We compared the lymphoblast morphology at presentation and first hematologic relapse for 50 consecutive children with acute lymphoblastic leukemia using the FAB scoring system to determine the frequency of morphologic conversion. Forty-eight patients presented with L1 morphology, 42 of whom (88%) relapsed with L1 blasts, four (8%) with L2 blasts, and two (4%) with blasts intermediate between L1 and L2. Two presented with L2 morphology, both relapsing with L2 blasts. These data do not support previous findings of a high frequency of conversion from L1 to L2 at relapse. They suggest, instead, that L2 morphology is not a common morphologic expression of initial treatment failure.

Adolescent↗
PubMed1985

Safety and tolerability of multiple doses of imipenem/cilastatin.

The safety and tolerability of 1 gm imipenem and cilastatin given together every 6 hours for 10 days was evaluated in a randomized, double-blind, placebo-controlled trial in normal subjects. Nausea was more common in the drug-treated group (five of six subjects) than in the control group (two of six subjects). No consistent changes in hepatic function indices were noted. Although beta 2-microglobulin excretion showed a significant trend of rising over time in the drug group, there were no differences between groups with regard to 24-hour urinary excretion of either N-acetyl-beta-glucosaminidase or beta 2-microglobulin. Urinalysis did not reveal any casts and serial creatinine clearance determinations showed no change in renal function in either the drug- or placebo-treated groups. Pure tone audiograms were performed before and after dosing in 11 of 12 subjects; no changes were noted. We conclude that the combination of imipenem and cilastatin was well tolerated and safe.

Acetylglucosaminidase↗
PubMed1985

Clinical relevance of lymphoblast biological features in children with acute lymphoblastic leukemia.

Improvements in therapy for childhood acute lymphoblastic leukemia (ALL) have led us to reevaluate the prognostic significance of lymphoblast characteristics at diagnosis. From application of univariate and multivariate statistical methods, we determined the relationship of five blast cell features to treatment outcome in 250 patients who were enrolled in two clinical trials at this center from May 1979 through April 1982. Karyotype ploidy, lymphoblast morphology, and immunophenotype were each significantly related to prognosis as measured by time to failure, while periodic acid-Schiff reactivity and glucocorticoid receptor number lacked prognostic implication for this patient population. In addition, clinical features of initial WBC count, age, and race were also significant independent variables in predicting treatment response. By multivariate analysis, both ploidy and morphology contributed prognostic information to a clinical model based on WBC count, age, and race. If the model was adjusted for impact of ploidy, however, French-American-British morphology no longer contributed additional prognostic information. Our findings suggest that many traditional biological features used to estimate prognosis in ALL can be discarded in favor of clinical features (leukocyte count, age, and race) and cytogenetics (ploidy) for planning of future clinical trials.

Adolescent↗
PubMed1985

Central nervous system morbidity following an initial isolated central nervous system relapse and its subsequent therapy in childhood acute lymphoblastic leukemia.

The frequency and types of major CNS toxicity and morbidity were analyzed in 107 children with acute lymphoblastic leukemia (ALL) following an isolated primary CNS relapse. Seventy-nine (73%) have had multiple subsequent marrow or CNS relapses requiring intensive and prolonged therapy to the CNS. Median survival time is two years. Of these 79 patients, two thirds have had one or more types of major CNS toxicity, including epileptiform seizures (35), moderate to severe structural abnormalities (24 of 27 evaluated), major motor disabilities (9), blindness (2), CNS infection (6), cranial nerve palsies (2), and intracranial lymphoma (2). The remaining 28 patients (26%) have had no or one additional CNS relapse and have received therapy for a median of eight years. One half of this surviving group of patients have had major CNS toxicity, including seizures (9), major motor disability (2), and intracranial calcifications (12/19). When neuropsychologic evaluations were compared between the 28 survivors and 50 of their contemporaries who had been in initial continuous complete remission, the CNS survivors had significantly lower Full Scale IQ scores (83 +/- 16 v 99 +/- 14, P = less than .001) with similarly lower measures of academic performance. The relative contributions of meningeal leukemia itself and intrathecal or radiation therapy to these effects cannot be determined. Since major CNS sequelae occurred in the majority of patients who had a primary isolated CNS relapse, and the frequency of CNS relapse is dependent on the efficacy of the method of CNS prophylaxis, the best method of avoiding major CNS sequelae is the most effective form of CNS prophylaxis.

Acute Disease↗
PubMed1985

Etoposide (VP-16) with prednisone and vincristine for the treatment of refractory acute lymphoblastic leukemia.

Fifty children with acute lymphoblastic leukemia (ALL) in first to fifth relapse were treated with a three-drug reinduction regimen consisting of prednisone (40 mg/m2/d for seven days), vincristine (1.5 mg/m2 on day 1) and etoposide (VP-16, 250 mg/m2 on days 1 through 3). The intent was to assess the efficacy of VP-16 in an otherwise conventional reinduction plan, especially in patients who had previously received teniposide (VM-26), the close congener of VP-16. Among the 46 patients who received at least two courses of the therapy, 16 (0.34) achieved complete remission. Seven others showed improvement in their bone marrow status. Each child had been heavily pretreated with prednisone and vincristine, and 14 had received VM-26. That seven patients judged to be clinically resistant to VM-26 had complete responses to prednisone-vincristine-VP-16 indicates that prior treatment with one podophyllotoxin derivative does not preclude responses to the other. We are uncertain about the pharmacologic basis of these results but suggest that the increased dosage and more frequent administration of VP-16, relative to that of VM-26, was sufficient to overcome apparent resistance to the latter compound. Remission durations ranged from one to eight months (median, four months), emphasizing the need to devise more effective continuation therapy, including investigational agents such as the epipodophyllotoxins.

Acute Disease↗
PubMed1985

Prognostic importance of blast cell DNA content in childhood acute lymphoblastic leukemia.

Using flow cytometric techniques, we determined the pretreatment distribution of DNA content in propidium iodide-stained leukemic blasts from 205 children with "standard-risk" acute lymphoblastic leukemia (ALL). Risk assignment was based on an initial WBC count less than 100 X 10(9)/L, no thymic mass, no meningeal leukemia, and lymphoblasts lacking sheep erythrocyte receptors or surface immunoglobulin. A single aneuploid leukemic line was detected in 74 cases (36.1%): 70 hyperdiploid and four hypodiploid. For hyperdiploid cases, the DNA index (DI, or ratio of the DNA content of leukemic v normal G0/G1 cells) ranged from 1.06 to 2.0 (median, 1.20). A secondary leukemic line with hyperdiploid cellular DNA content was identified in 21 cases with diploid primary lines. Children whose primary leukemic line showed a DI greater than or equal to 1.16 (n = 57) had significantly better responses to treatment than did those with either a diploid DI (n = 130; P = .002) or values in the range of 1.01 to 1.15 (n = 14; P = .001). The relative risk of failure for hyperdiploid cases with DI greater than or equal to 1.16, corresponding to greater than or equal to 53 chromosomes, was one-third that of the other two groups. Treatment responses of patients with both diploid and hyperdiploid lines were identical to those associated with single diploid lines, but significantly worse than those associated with single hyperdiploid lines with DI greater than or equal to 1.16 (P = .016). The most favorable prognostic variables selected by a Cox proportional hazards model were: DI greater than or equal to 1.16 (P = .001), white race (P = .022), WBC less than or equal to 25 X 10(9)/L (P = .032), age between 2 and 9 years (P = .075), and hemoglobin less than 7.0 g/dL (P = .094). DNA index greater than or equal to 1.16 retained its significant prognostic impact even after adjustment for other variables (P = .001). With the combination of DI greater than or equal to 1.16 and WBC less than or equal to 25 X 10(9)/L, one can identify a group of children with ALL who have a low probability of relapse when treated with current therapy. If they remain disease-free after longer follow-up, it may be advisable to treat them with less intensive, hence less toxic, chemotherapy than patients with higher WBC counts or lower DI values.

Antigens, Neoplasm↗
PubMed1985

A novel treatment of childhood lymphoblastic non-Hodgkin's lymphoma: early and intermittent use of teniposide plus cytarabine.

We treated 24 children and adolescents with stage III or IV lymphoblastic non-Hodgkin's lymphoma, using a protocol designed for patients with poor-prognosis acute lymphoblastic leukemia (ALL). Early therapy consisted of teniposide plus cytarabine administered before and immediately after prednisone, vincristine, and asparaginase. The two-drug combination was also given intermittently with continuous 6-mercaptopurine and methotrexate during the first year of continuation chemotherapy. Periodic intrathecal methotrexate and delayed cranial irradiation were used to prevent central nervous system involvement. Anthracycline compounds, alkylating agents, high-dose methotrexate, and involved-field irradiation were not used in any phase of treatment. Twenty-two (96%) of the 23 evaluable patients achieved complete remission. With a median follow-up of 2 1/2 years, only four patients have relapsed; the remainder have been disease-free for eight months to more than five years. The projected four-year continuous complete remission rate is 73% for all patients and 79% for the 19 with mediastinal involvement at diagnosis. These results demonstrate that use of teniposide plus cytarabine with an otherwise conventional plan of ALL therapy is an effective approach to the treatment of childhood lymphoblastic lymphoma.

Adolescent↗
PubMed1985

Serum lactic dehydrogenase level has prognostic value in childhood acute lymphoblastic leukemia.

Serum lactic dehydrogenase (LDH) levels were measured at diagnosis in 293 children with "standard-risk" acute lymphoblastic leukemia (ALL) to determine the prognostic value of this biologic feature. Standard risk assignment was based on an initial leukocyte count of less than 100 X 10(9)/L, the absence of a mediastinal mass, the absence of meningeal involvement, and the presence of lymphoblasts lacking sheep erythrocyte receptors or surface immunoglobulin. Serum LDH levels ranged from 97 to 6,595 U/L, with a mean of 547 U/L. Higher LDH levels were associated with higher leukocyte counts, lower blast cell DNA indices, lower platelet counts, a larger spleen size, and nonwhite race. LDH levels were not related to the percentage of marrow S-phase cells, liver size, French-American-British (FAB) classification, hemoglobin levels, age, sex, or the presence of the common ALL antigen on marrow blasts. Patients with the highest LDH levels (greater than 1,000 U/L) were most likely to fail treatment, whereas those with the lowest levels (less than 300 U/L) had the lowest risk of failure (P less than .0001). The prognostic significance of serum LDH level was retained in a subset of patients that included only those with leukocyte counts less than 25 X 10(9)/L (P = .0018). When 11 presenting characteristics were subjected to multivariate analysis, serum LDH level was found to have independent prognostic strength, contributing clinically important information to that gained from leukocyte count. Early measurement of serum LDH could be useful in identifying a group of standard-risk ALL patients with a high relapse hazard.

Analysis of Variance↗
PubMed1985

Acute megakaryoblastic leukemia. Blast cell aggregates simulating metastatic tumor.

Acute megakaryoblastic leukemia is a rare leukemia that can present diagnostic problems. We describe two children who have this disease and had clumps of blast cells in their bone marrow, a finding usually attributed to metastatic tumor. The megakaryocytic origin of the cells was supported by their cytochemical staining pattern (positive alpha-naphthyl acetate esterase resistant to sodium fluoride inhibition and negative alpha-naphthyl butyrate esterase) and by the presence of factor VIII-related antigen. Ultrastructural studies of blast cells from one patient demonstrated platelet peroxidase. The mechanism of blast cell clump formation in these cases is unknown; nevertheless, awareness that this feature can occur in acute megakaryoblastic leukemia may avoid a misdiagnosis of metastatic solid tumor.

Acute Disease↗
PubMed1984

The plasma pharmacokinetics of high dose (1 g) imipenem coadministered with 1 g cilastatin in six normal volunteers.

The plasma pharmacokinetics of imipenem, a beta-lactam antibiotic of the new class of carbapenems, was evaluated by administering 1 g imipenem plus 1 g of the dehydropeptidase inhibitor cilastatin to six healthy male volunteers over 30 min. Subsequently intensive plasma sampling was done for 5.5 h. The volume of distribution of the central compartment was 0.16 +/- 0.04 1/kg; the volume of distribution (area) was 0.28 +/- 0.07 1/kg; the volume of distribution (steady state) was 0.23 +/- 0.03 1/kg. The mean plasma clearance was 10.1 +/- 1.0 1/h/1.73 m2. Model-independent analysis showed excellent agreement with these values. The terminal excretion half-life was short (1.3 +/- 0.4 h). For approximately 6 h after administration, the observed plasma levels were above those required to inhibit most nosocomial pathogens in vitro.

Adolescent↗
PubMed1984

The relationship of blast cell glucocorticoid receptor levels to response to single-agent steroid trial and remission response in children with acute lymphoblastic leukemia.

Of 263 children with glucocorticoid receptor (GR) levels measured at diagnosis of acute lymphoblastic leukemia (ALL), 27 received single-agent glucocorticoid before combination induction chemotherapy and were evaluable for in vivo clinical response to steroid. Twenty-one were glucocorticoid-responsive and 6 were resistant. There was no difference between the two groups in the distribution of age, sex, white blood cell count, immunophenotype of blasts, initial central nervous system disease or mediastinal mass. The median GR level, however, was appreciably lower in the group of patients with resistant disease (6250 vs 17,800 sites/cell, p = 0.06). Five of 12 patients with GR levels of less than 10,000 sites/cell compared to 1 of 15 with higher levels had glucocorticoid-resistant ALL (p = 0.03). All 21 patients with glucocorticoid-sensitive disease achieved a complete remission after combination induction chemotherapy, but only 3 of 5 evaluable patients in the other group did (p less than 0.04). Two patients were studied both at diagnosis and at relapse; both had decreased GR levels at relapse (below detection in one) and failed to respond to glucocorticoid. We conclude that a lower GR level is associated with glucocorticoid resistance and furthermore that a decrease in the level of GR is a mechanism of acquiring steroid resistance.

Adolescent↗