Biomedical subjects

Ching-Hon Pui

Publications and source records attributed to Ching-Hon Pui.

At least 109 records · Page 6Linked to original sources

PubMed2002

A mathematical model of in vivo methotrexate accumulation in acute lymphoblastic leukemia.

Methotrexate (MTX) is one of the most widely used drugs for the treatment of childhood acute lymphoblastic leukemia (ALL). Interindividual differences in lymphoblast accumulation of MTX and its active metabolites, methotrexate polyglutamates (MTXPG), may contribute to the effectiveness of treatment among ALL subtypes. To better understand these differences in MTXPG accumulation, we developed a model to characterize the cellular influx and efflux of MTX, formation of MTXPG by the addition of glutamyl residues catalyzed by FPGS (folylpolyglutamate synthetase), and cleavage of glutamyl residues from MTXPG by GGH (gamma-glutamyl hydrolase). The model was fitted to in vivo intracellular MTXPG concentrations measured serially in leukemic blasts from 20 newly diagnosed patients with ALL treated with 24-h intravenous infusions of MTX. The observed median concentrations of total MTXPG at 44 h was higher in B-lineage than in T-cell ALL (1706 vs 518 pmol/10(9) cells, P<0.025), consistent with the higher estimated Vmax for FPGS activity in B-lineage vs T-lineage blasts (414 vs 93 pmol/10(9) cells/h, P<0.008). Simulations based on the model-estimated parameters indicated greater accumulation of MTX, MTXPGs (MTXPG(2-7)) and total MTX (MTXPG(1-7)) with longer MTX infusions and with higher MTX doses, with the highest concentrations in hyperdiploid B-lineage, intermediate in non-hyperdiploid B-lineage, and lowest in T-cell ALL. These differences provide mechanistic and treatment insights for lineage and ploidy differences in MTXPG accumulation in human leukemia cells in vivo.

Aneuploidy↗

PubMed2002

De novo purine synthesis inhibition and antileukemic effects of mercaptopurine alone or in combination with methotrexate in vivo.

Methotrexate (MTX) and mercaptopurine (MP) are widely used antileukemic agents that inhibit de novo purine synthesis (DNPS) as a mechanism of their antileukemic effects. To elucidate pharmacodynamic differences among children with acute lymphoblastic leukemia (ALL), DNPS was measured in leukemic blasts from newly diagnosed patients before and after therapy with these agents. Patients were randomized to receive low-dose MTX (LDMTX: 6 oral doses of 30 mg/m(2)) or high-dose MTX (HDMTX: intravenous 1 g/m(2)) followed by intravenous MP; or intravenous MP alone (1 g/m(2)), as initial therapy. At diagnosis, the rate of DNPS in bone marrow leukemia cells was 3-fold higher in patients with T-lineage ALL compared with those with B-lineage ALL (769 +/- 189 vs 250 +/- 38 fmol/nmol/h; P =.001). DNPS was not consistently inhibited following MP alone but was markedly inhibited following MTX plus MP (median decrease 3% vs 94%; P <.001). LDMTX plus MP and HDMTX plus MP produced greater antileukemic effects (percentage decrease in circulating leukocyte counts) compared with MP alone (-50% +/- 4%, -56% +/- 3%, and - 20% +/- 4%, respectively; P <.0001). Full DNPS inhibition was associated with greater antileukemic effects compared with partial or no inhibition (-63% +/- 4% vs -37% +/- 4%; P <.0001) in patients with nonhyperdiploid B-lineage and T-lineage ALL. HDMTX plus MP yielded 2-fold higher MTX polyglutamate concentrations than LDMTX plus MP (2148 +/- 298 vs 1075 +/- 114 pmol/10(9) cells; P <.01) and a higher percentage of patients with full DNPS inhibition (78% vs 53%; P <.001). Thus, the extent of DNPS inhibition was related to in vivo antileukemic effects, and a single dose of intravenous MP produced minimal DNPS inhibition and antileukemic effects, whereas MTX plus MP produced greater antileukemic effects and DNPS inhibition, with full inhibition more frequent after HDMTX.

Adolescent↗

PubMed2002

Prognostic importance of measuring early clearance of leukemic cells by flow cytometry in childhood acute lymphoblastic leukemia.

Early clearance of leukemic cells is a favorable prognostic indicator in childhood acute lymphoblastic leukemia (ALL). However, identification of residual leukemic cells by their morphologic features is subjective and lacks sensitivity. To improve estimates of leukemia clearance, we applied flow cytometric techniques capable of detecting 1 leukemic cell in 10,000 or more normal cells and prospectively measured residual leukemia in bone marrow samples collected on day 19 of remission-induction chemotherapy from 248 children with newly diagnosed ALL. In 134 samples (54.0%), we identified at least 0.01% leukemic cells (0.01%-< 0.1% in 51 samples [20.6%], 0.1%-< 1% in 36 [14.5%], and > or = 1% in 47 [19.0%]). Among 110 children treated within a single chemotherapy program, the 5-year mean +/- SE cumulative incidence of relapse or failure to achieve remission was 32.2% +/- 6.5% for the 59 patients with 0.01% residual leukemic cells or greater on day 19 and 6.0% +/- 3.4% for the 51 patients with less than 0.01% leukemic cells (P <.001). The prognostic value of day-19 bone marrow status defined by flow cytometry was superior to that defined by morphologic studies and remained significant after adjustment for other clinical and biologic variables. Lack of detectable leukemic cells on day 19 was more closely associated with relapse-free survival than was lack of detectable residual disease at the end of remission induction (day 46). Thus, approximately half of the children with ALL achieve profound clearance of leukemic cells after 2 to 3 weeks of remission-induction chemotherapy, and these patients have an excellent treatment outcome.

Antigens, CD↗

PubMed2002

Persistence of lymphoblasts in bone marrow on day 15 and days 22 to 25 of remission induction predicts a dismal treatment outcome in children with acute lymphoblastic leukemia.

We determined the prognostic importance of morphologically identifiable persistent disease at day 15 and days 22 to 25 of remission induction in childhood acute lymphoblastic leukemia (ALL). Among 546 patients entered on 2 consecutive protocols, 397 patients had evaluable bone marrow (BM) examinations on day 15 (+/- 1 day) and 218 on days 22 to 25 (+/- 1 day). Fifty-seven patients (14%) had persistent lymphoblasts (> or = 1%) in the BM on day 15 and 27 patients (5.5%) had persistent lymphoblasts on days 22 to 25. The 5-year event-free survival (EFS) was significantly worse for patients with lymphoblasts on day 15 (40% +/- 6%) or on days 22 to 25 (4% +/- 3%) as compared to those without lymphoblasts on these dates (78% +/- 2% and 76% +/- 2%, respectively, P <.001 for both comparisons). A worse prognosis was observed even for patients with a low percentage of lymphoblasts (ie, 1%-4%) at either day 15 (5-year EFS = 56% +/- 8%) or days 22 to 25 (5-year EFS = 0%) compared to those without morphologically identifiable persistent lymphoblasts at these times (P <.001 for both comparisons). The prognostic impact of persistent lymphoblasts on both dates remained significant after adjusting for other known risk factors, including treatment protocol, age, white blood cell count, DNA index, cell lineage, and central nervous system status, and National Cancer Institute/Rome criteria simultaneously. Hence, persistence of lymphoblasts (even 1%-4%) on day 15 of remission induction was associated with a poor prognosis and on days 22 to 25 signified a particularly dismal outcome; these very high-risk patients require novel or more intensive therapy to improve outcome.

Blast Crisis↗

PubMed2002

Outcomes of growth hormone replacement therapy in survivors of childhood acute lymphoblastic leukemia.

PURPOSE: Little is known about the long-term efficacy or adverse effects of growth hormone (GH) replacement therapy in survivors of childhood acute lymphoblastic leukemia (ALL) who have GH deficiency. We investigated the adult height of patients who had received GH and estimated their risk of leukemia relapse or development of a second malignancy. PATIENTS AND METHODS: Of 910 patients treated for ALL at a single institution, 47 had received GH replacement therapy. The linear growth of these 47 patients was retrospectively evaluated. Their risk of leukemia relapse or second malignancy was compared with that of survivors who did not undergo GH therapy. RESULTS: The median height SD score at the start of GH therapy had decreased by 1.0 since the time of diagnosis of ALL. After a median duration of 4.5 years of GH therapy, adult height SD scores improved and approached height SD scores at the time of diagnosis of ALL. The median adult height for male patients was 173.2 cm (range, 157 to 191.9 cm), and for female patients, it was 158.1 cm (range, 141 to 168 cm). None of the patients developed adverse effects requiring discontinuation of GH treatment. At the 7-year and 11-year landmarks in continuous hematologic remission, there was no statistical evidence that GH therapy was associated with leukemia relapse or development of a second malignancy. CONCLUSION: This study suggests that GH replacement therapy is safe and efficacious for the correction of GH deficiency in survivors of childhood ALL.

Adolescent↗

PubMed2002

Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region.

BACKGROUND: The prognosis and optimum treatment of childhood acute lymphoblastic leukaemia (ALL) with abnormalities of chromosomal band 11q23 are controversial. We aimed to identify prognostic factors that might help in planning future therapy, and to assess the effectiveness of haemopoietic stem-cell transplantation in patients with the t(4;11) translocation, which is associated with a particularly poor outcome. METHODS: We reviewed data on 497 children and young adults who had ALL with various 11q23 abnormalities, including the translocations t(4;11), t(9;11), and t(11;19). All patients were treated with intensive chemotherapy, with or without haemopoietic stem-cell transplantation in first complete remission, by 11 study groups and single institutions from 1983 to 1995. FINDINGS: Age was the most important prognostic factor. In a Cox's proportional-hazard model stratified by 11q23 abnormalities, infants younger than 1 year fared significantly worse than patients 1 year of age or older (hazard ratio for event-free survival 1 84 [95% CI 1 38-2 47], p=0 0001). Among infants, any category of 11q23 abnormality conferred a dismal outcome, whereas in older patients, t(4;11) and t(9;11) were associated with a worse outcome than were other 11q23 changes. In the largest subgroup--256 patients with t(4;11)--any type of transplantation was associated with significantly worse disease-free survival (1 61 [1 10-2 35], p=0 014) and overall survival (1 76 [1 08-2 45], p=0 004) compared with chemotherapy only. Even transplantation with stem cells from HLA-matched related or HLA-matched unrelated donors tended to be associated with a worse outcome than chemotherapy alone. INTERPRETATION: The prognosis of acute lymphoblastic leukaemia with an 11q23 abnormality is particularly dismal in infants. Allogeneic transplantation with haemopoietic stem cells from an HLA-matched related donor does not seem to improve the clinical outcome in patients with t(4;11)-positive leukaemia.

Age Distribution↗

PubMed2002

Favorable impact of the t(9;11) in childhood acute myeloid leukemia.

PURPOSE: To determine the impact of MLL rearrangements on the outcome of children with acute myeloid leukemia (AML). PATIENTS AND METHODS: We analyzed the clinical and biologic features of 298 infants and children with primary AML treated on four consecutive institutional clinical trials. The Kaplan-Meier method was used in survival analysis and the Cox proportional-hazards model was used to analyze the effect of potential prognostic factors on event-free survival (+/- 1 SE). RESULTS: Molecular studies of 152 cases detected 42 with MLL rearrangements. The karyotypes of these 42 revealed the t(9;11) (15 cases), abnormalities of chromosomes 10 and 11 (nine cases), the t(11;19) (four cases), other abnormalities of 11q23 (seven cases), and miscellaneous rearrangements (seven cases). Among these 42 patients, the 15 whose leukemic cells carried the t(9;11) had a better outcome (66% +/- 15%) than the other 27 (25.9% +/- 11.2%; P =.004). Cases with the t(9;11) were also characterized by M5 AML morphology (21 of 23 cases). Of the 63 patients with M5 AML, the 21 whose leukemic cells demonstrated the t(9;11) had a better outcome (71.1% +/- 11%) than the other 42 (25.8% +/- 7.9%; P =.0004). The only independent factors indicating a favorable prognosis were presenting leukocyte count less than 50 x 10(9)/L (relative risk of relapse, 0.73; 95% confidence interval, 0.55 to 0.97; P =.03) and the t(9;11) (relative risk of relapse, 0.32; 95% confidence interval, 0.16 to 0.64; P =.002). CONCLUSION: We conclude that the t(9;11) is the most favorable genetic factor for patients with AML treated at our institution.

Acute Disease↗

PubMed2002

Endocrine complications in pediatric patients with acute lymphoblastic leukemia.

Endocrine complications of therapy for acute lymphoblastic leukemia (ALL) are common and are potentially debilitating both during and after therapy. Growth velocity slows during therapy for ALL, especially during the first year; however, children who do not receive cranial irradiation usually reach normal adult height. While growth hormone deficiency generally occurs in patients who have received 24Gy of cranial irradiation, it may also develop in those treated with lower doses (18Gy) of cranial radiation or with only high-dose methotrexate. Obesity commonly occurs during therapy and persists after completion of therapy. Osteopenia can occur early during therapy for ALL and can persist for many years. Adrenal insufficiency should be suspected in any child who has recently received glucocorticoid therapy, and stress doses of steroid should be administered in the event of metabolic stress. Screening of urine is useful for early detection of hyperglycemia during therapy with glucocorticoids and L-asparaginase. The syndrome of inappropriate secretion of anti-diuretic hormone is usually associated with vincristine therapy and may be aggravated by concurrent use of azole antifungals. Finally, patients who have received 18 or 24Gy of cranial irradiation may have clinical or subclinical deficiencies of thyroid hormones.

Child↗

PubMed2002

Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.

Treatment of pediatric acute lymphoblastic leukemia (ALL) is based on the concept of tailoring the intensity of therapy to a patient's risk of relapse. To determine whether gene expression profiling could enhance risk assignment, we used oligonucleotide microarrays to analyze the pattern of genes expressed in leukemic blasts from 360 pediatric ALL patients. Distinct expression profiles identified each of the prognostically important leukemia subtypes, including T-ALL, E2A-PBX1, BCR-ABL, TEL-AML1, MLL rearrangement, and hyperdiploid >50 chromosomes. In addition, another ALL subgroup was identified based on its unique expression profile. Examination of the genes comprising the expression signatures provided important insights into the biology of these leukemia subgroups. Further, within some genetic subgroups, expression profiles identified those patients that would eventually fail therapy. Thus, the single platform of expression profiling should enhance the accurate risk stratification of pediatric ALL patients.

Algorithms↗

PubMed2002

Limited and optimal sampling strategies for etoposide and etoposide catechol in children with leukemia.

Etoposide is used to treat childhood malignancies, and its plasma pharmacokinetics have been related to pharmacodynamic endpoints. Limiting the number of samples should facilitate the assessment of etoposide pharmacokinetics in children. We compared limited sampling strategies using multiple linear regression of plasma concentrations and clearance with Bayesian methods of estimating clearance using compartmental pharmacokinetic models. Optimal sampling times were estimated in the multiple linear regression method by determining the combination of two samples which maximized the correlation coefficient, and in the Bayesian estimation approach by minimizing the variance in estimates of clearance. Clearance estimates were compared to the actual clearances from Monte Carlo-simulated data and predicted clearances estimated using all available plasma concentrations in clinical data from children with acute lymphoblastic leukemia. Multiple linear regression poorly predicted clearance (mean bias 8.3%, precision 17.5%), but improved if plasma concentrations were logarithmically transformed (mean bias 1.4%, precision 12.5%). Bayesian estimation methods with optimal samples gave the best overall prediction (mean bias 2.5%, precision 6.8%) and also performed better than regression methods for abnormally high or low clearances. We conclude that Bayesian estimation with limited sampling gives the best estimates of etoposide clearance.

Analysis of Variance↗

PubMed2002

Vincristine-induced vocal cord paralysis in an infant.

We report the development of stridor and dysphagia in a 5-month-old-infant with acute lymphoblastic leukaemia after the administration of four weekly doses of vincristine during induction therapy. Because direct laryngoscopy revealed bilateral vocal cord paralysis, the patient underwent elective intubation. Extubation was performed 7 days later, after direct laryngoscopy confirmed recovery of vocal cord mobility. Vincristine-induced bilateral recurrent laryngeal nerve paralysis is a rare but potentially life-threatening complication. Therefore, it should be suspected when stridor is present, and clinicians should consider visualization of the airway to establish the cause of upper airway compromise in infants receiving vincristine.

Antineoplastic Agents, Phytogenic↗

PubMed2002

Childhood acute lymphoblastic leukemia.

As cure rates in childhood acute lymphoblastic leukemia reach 80%, emphasis is increasingly placed on the accurate identification of drug-resistant cases, the elucidation of the mechanisms involved in drug resistance and the development of new therapeutic strategies targeted toward the pivotal molecular lesions. Pharmacodynamic and pharmacogenomic studies have provided rational criteria for individualizing therapy to enhance efficacy and reduce acute toxicity and late sequelae. Currently, assessment of the early response to treatment by measurement of minimal residual disease (MRD) is the most powerful independent prognostic indicator. MRD is affected by both the drug sensitivity of leukemic cells and the pharmacodynamic and pharmacogenetic properties of the host cells. Rapid advances in biotechnology and bioinformatics should ultimately facilitate the development of molecular diagnostic assays that can be used to optimize antileukemic therapy and elucidate the mechanisms of leukemogenesis. In the interim, prospective clinical trials have provided valuable clues that are further increasing the cure rate of childhood acute lymphoblastic leukemia.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Genetic polymorphisms in CYP3A5, CYP3A4 and NQO1 in children who developed therapy-related myeloid malignancies.

Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-ML) are serious complications that affect some patients after acute lymphoblastic leukemia (ALL) treatment. Genetic polymorphisms in the promoter of CYP3A4 (CYP3A4*1B) and in NAD(P)H:quinone oxidoreductase (NQO1609C-->T substitution) have been associated with the risk of t-ML. A polymorphism in CYP3A5 (CYP3A5*3) affects CYP3A activity and the wild-type allele (CYP3A5*1) is in partial linkage with the CYP3A4*1B allele. We compared the genotype frequencies for the CYP3A5*3, the CYP3A4*1B and the NQO1609C-->T substitution in 224 children with ALL who did not develop t-ML (controls) and in 53 children with ALL who did develop the complication. The allele frequencies differed significantly among whites, blacks and Hispanics (P < 0.001 for CYP3A5*3, P < 0.001 for CYP3A4*1B and P = 0.004 for NQO1609), thus we performed the comparisons between ALL controls and t-ML patients after accounting for race. We found no differences in the CYP3A4*1B allele distribution between ALL controls and t-ML patients in whites (P = 0.339, 6.6% vs. 9.8%), blacks (P = 0.498, 93.8% vs. 87.5%) or Hispanics (P = 0.523, 39.1% vs. 25.0%). The frequencies for the NQO1609C-->T allele did not differ between control and t-ML groups in whites (P = 0.191, 35.0% vs. 44.9%), blacks (P = 0.664, 37.5% vs. 37.5%) or Hispanics (P = 0.447, 65.2% vs. 50.0%). We found no differences between the control and t-ML group in the incidence of homozygous CYP3A5*3 genotypes: 82.0% vs. 85.4% in whites (P = 0.403), 6.5% vs. 12.5% in blacks (P = 0.508), and 69.6% vs. 75.0% in Hispanics (P= 0.663). Our data do not support an association between common CYP3A4, NQO1 or CYP3A5 polymorphisms and the risk of t-ML in children treated for ALL.

Acute Disease↗

PubMed2002

Acute lymphoblastic leukemia.

This is a comprehensive overview on the most recent developments in diagnosis and treatment of acute lymphoblastic leukemia (ALL). Dr. Dieter Hoelzer and colleagues give an overview of current chemotherapy approaches, prognostic factors, risk stratification, and new treatment options such as tyrosine kinase inhibitors and monoclonal antibodies. Furthermore the role of minimal residual disease (MRD) for individual treatment decisions in prospective clinical studies in adult ALL is reviewed. Drs. Ching-Hon Pui and Mary Relling discuss late treatment sequelae in childhood ALL. The relation between the risk of second cancer and treatment schedule, pharmacogenetics, and gene expression profile studies is described. Also pathogenesis, risk factors, and management of other complications such as endocrinopathy, bone demineralization, obesity, and avascular necrosis of bone is reviewed. Dr. Fred Appelbaum addresses long-term results, late sequelae and quality of life in ALL patients after stem cell transplantation. New options for reduction of relapse risk, e.g., by intensified conditioning regimens or donor lymphocyte infusions, for reduction of mortality and new approaches such as nonmyeloablative transplantation in ALL are discussed. Drs. Jacques van Dongen and Tomasz Szczepanski demonstrate the prognostic value of MRD detection via flow cytometry or PCR analysis in childhood ALL. They discuss the relation between MRD results and type of treatment protocol, timing of the follow-up samples, and the applied technique and underline the importance of standardization and quality control. They also review MRD-based risk group definition and clinical consequences.

Adult↗

PubMed2002

Rasburicase: a potent uricolytic agent.

Rasburicase (Fasurtec, Elitek, Sanofi-Synthelabo) is a new recombinant urate oxidase developed for the prevention and treatment of hyperuricaemia. It has a half-life of 17-21 h and produces rapid (within 4 h) and pronounced reductions in plasma uric acid concentrations. To date, rasburicase has been tested in four clinical trials conducted in patients with cancer (primarily haematological malignancies). It successfully alleviated hyperuricaemia in 98% of patients and prevented this complication in 99.6% of those who were at risk. In a stratified, randomised trial, rasburicase was more effective than allopurinol. Most patients had improved or stabilised renal function during rasburicase treatment, despite ongoing chemotherapy-induced tumour lysis. Except for occasional instances of haemolytic anaemia and methemoglobinaemia in patients with glucose-6-phosphate dehydrogenase deficiency, rasburicase was well-tolerated, with a low frequency of mild adverse events. Rasburicase is a safe and effective agent in the prevention or treatment of hyperuricaemia in cancer patients.

Animals↗

PubMed2002

HPLC determination of thiopurine nucleosides and nucleotides in vivo in lymphoblasts following mercaptopurine therapy.

BACKGROUND: Mercaptopurine is a prodrug requiring intracellular activation to thiopurine nucleotides to exert antileukemic effect. We developed a reversed-phase liquid chromatographic assay for the quantification of mercaptopurine, thioguanine, and methylmercaptopurine nucleoside and nucleotide concentrations in the target tissue, the leukemic lymphoblast. METHODS: Leukemic blasts were isolated from peripheral blood and bone marrow by a standard Ficoll-hypaque procedure. Proteins were removed by ultrafiltration in the presence of dithiothreitol. Thiopurine ribonucleotides were converted into their respective ribonucleosides by treatment of ultrafiltrate with acid phosphatase. Thiopurine nucleosides and bases were measured by direct injection of ultrafiltrate into the chromatographic system. Thiopurine nucleotide concentrations were calculated by subtracting the thiopurine nucleoside concentrations measured after treatment with acid phosphatase from those measured after direct injection of ultrafiltrate in the chromatographic system. Analytes were separated on a C18 Supelco column with ammonium phosphate-methanol eluent coupled with ultraviolet detection. RESULTS: CVs for intra- and interday precision were 1.1-14% (median, 4.9%), and recovery of added analyte was 89-126% (median, 105%) at low and high concentrations of analytes, except for mercaptopurine riboside. The median signal for each of the five metabolites in lymphoblast samples was 98% (range, 80-106%) of that in water. Detection limits for thiopurine bases and nucleosides ranged from 0.5 to 4.5 pmol/5 x 10(6) cells. CONCLUSIONS: This method is suitable for measurement of thiopurine metabolite concentrations in lymphoblasts in children with acute lymphoblastic leukemia following a single dose of intravenous mercaptopurine.

Antimetabolites, Antineoplastic↗

PubMed2002

Methotrexate intracellular disposition in acute lymphoblastic leukemia: a mathematical model of gamma-glutamyl hydrolase activity.

Methotrexate (MTX) is an antifolate that is widely used for the treatment of childhood acute lymphoblastic leukemia (ALL) and a number of other malignant and nonmalignant diseases. Within cells, MTX is metabolized to more active methotrexate polyglutamates (MTXPG), and these polyglutamates are subsequently cleaved in lysosomes by gamma-glutamyl hydrolase (GGH). GGH is reported to act as either an endopeptidase or an exopeptidase, exhibiting species differences in these functions. To better define the in vivo functions of GGH in human leukemia cells, we characterized GGH activity with different MTXPG substrates (MTX with three to five glutamates) in human T- and B-lineage leukemia cell lines, and in primary leukemia cells from newly diagnosed patients with ALL. Parameters estimated from fitting a series of hypothetical mathematical models to the data revealed that the experimental data were best fit by a model where GGH simultaneously cleaved multiple glutamyl residues, with highest activity at cleaving the outermost or two outermost residues from a polyglutamate chain. The model also revealed that GGH has a higher affinity for longer chain polyglutamates. Together, these findings provide new insights to the intracellular disposition of MTX in human ALL cells, and provides a mechanism-based model for characterizing differences among patients and genetic subtypes of ALL.

Antimetabolites, Antineoplastic↗

PubMedDate not supplied

Risk factors for traumatic and bloody lumbar puncture in children with acute lymphoblastic leukemia.

CONTEXT: Traumatic or bloody lumbar puncture (LP) reduces the diagnostic value of the procedure and may worsen the outcome of patients with acute lymphoblastic leukemia (ALL). Little is known about the risk factors for traumatic and bloody LP. OBJECTIVES: To determine the risk factors for traumatic and bloody LP. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of 956 consecutive patients with newly diagnosed childhood ALL who were treated at a pediatric cancer center between February 1984 and July 1998. INTERVENTIONS: All patients underwent a diagnostic LP followed by a median of 4 LPs to instill intrathecal chemotherapy. MAIN OUTCOME MEASURE: Traumatic LP was defined as an LP in which cerebrospinal fluid contained at least 10 red blood cells (RBCs) per microliter and bloody LP as one in which the cerebrospinal fluid contained at least 500 RBCs per microliter. RESULTS: Of the 5609 LPs evaluated, 1643 (29%) were traumatic and 581 (10%) were bloody. The estimated odds ratios (ORs) and 95% confidence intervals (CIs) for traumatic LP were 1.5 (95% CI, 1.2-1.8) for black vs white race, 2.3 (95% CI, 1.7-3.0) for age younger than 1 year vs 1 year or older, 1.4 (95% CI, 1.2-1.7) for early vs recent (dedicated procedure area and general anesthesia) treatment era, 1.5 (95% CI, 1.2-1.8) for platelet count of 100 x 10(3)/ microL or more vs less than 100 x 10(3 )/ microL, 10.8 (95% CI, 7.7-15.2) for short (1 day) vs longer (>15 days) interval since the previous LP, and 1.4 (95% CI, 1.1-1.8) for the least vs the most experienced practitioners. Analyses for bloody LP yielded similar results. CONCLUSIONS: The unmodifiable risk factors for traumatic and bloody LP include black race, age younger than 1 year, a traumatic or bloody previous LP performed within the past 2 weeks, and a previous LP performed when the platelet count was 50 x 10(3)/ microL or less. Modifiable risk factors include procedural factors reflected in treatment era, platelet count of 100 x 10(3)/ microL or less, an interval of 15 days or less between LPs, and a less experienced practitioner.

Black or African American↗