PubMed Health⌕ Search

Biomedical subjects

C H Pui

Publications and source records attributed to C H Pui.

At least 289 records · Page 16Linked to original sources
PubMed1987

Nuclear translocation of lymphoblast glucocorticoid receptors in childhood leukemia does not predict steroid responsiveness.

Nuclear translocation of glucocorticoid receptors (GR) was measured in lymphoblasts from 45 children with acute lymphoblastic leukemia (ALL). The percent of total GR translocated to the nucleus ranged from 0 to 100% (mean, 59%) and was independent of the total GR level. Neither the extent of GR nuclear translocation nor the absolute amount of GR translocated at 4 or 25 degrees C correlated with glucocorticoid response in 13 patients with single-agent glucocorticoid trial. These results indicate that defects in nuclear translocation of GR are not a common cause for steroid resistance in childhood ALL.

Adolescent↗
PubMed1987

High risk lymphoblastic leukemia in children: prognostic factors and management.

Most of the presenting clinical and biological features that have prognostic significance in childhood acute lymphoblastic leukemia are closely related, although they are not equally important. The predictive value of these factors can vary with the efficacy of the therapy delivered. Although there are no uniform criteria to define a high-risk group, an initially high leukocyte count and an age less than 1 or greater than 10 years at diagnosis are universally accepted as the most powerful indicators of a poor outcome. With advances in immunology and genetics, blast cell immunophenotypes and karyotypic abnormalities have emerged as independently significant prognostic factors. With this information, therapy can be tailored for patients at various risks of treatment failure. Using early aggressive therapy, more than 60% of patients are expected to be long-term survivors, but better therapy is still needed for those at high risk of relapse. Innovative approaches, such as bone marrow transplantation, phenotype-specific treatment, or pharmacokinetic-directed therapy, are being tested.

Child↗
PubMed1987

Pharmacokinetics and toxicity of methotrexate in children with Down syndrome and acute lymphocytic leukemia.

Children with Down syndrome and acute lymphocytic leukemia (ALL) have poor tolerance to antineoplastic drugs, including methotrexate (MTX). We evaluated MTX pharmacokinetics and toxicity in five patients with Down syndrome and ALL who had received multiple high doses of MTX (1 g/m2). Three control patients without Down syndrome were matched to each case according to sex, race, age, and initial leukocyte count. Median MTX plasma concentrations, measured 42 hours after infusion, were significantly higher in patients with Down syndrome versus control patients (average 0.47 vs 0.24 mumol/L, respectively, P = 0.03). When a 42-hour MTX concentration of 0.5 mumol/L was used to identify patients at risk for toxicity, more courses were considered at high risk for toxicity among patients with Down syndrome (31 of 62, 50%) than in control patients (13 of 214, 6.1%, P less than 0.0001). The average MTX clearance was 64.1 mL/min/m2 in Down syndrome vs an average control value of 80.6 mL/min/m2 (P = 0.13). Toxicity after each high-dose MTX course was graded according to standardized criteria. Grades 2 through 4 gastrointestinal toxicity and grades 3 and 4 hematologic toxicity occurred more frequently in the patients with Down syndrome (36% and 13.4% of courses, respectively) vs the control patients (3.6% and 0.9% respectively, P less than 0.0001 for both). This higher frequency of toxicity occurred despite higher doses and prolonged duration of leucovorin given to all patients with Down syndrome. We conclude that altered MTX pharmacokinetics may contribute to the higher incidence of MTX-induced toxicity seen in patients with Down syndrome.

Adolescent↗
PubMed1987

Acute lymphocytic leukemia in childhood: immunologic marker, cytogenetic, and molecular studies.

Remarkable progress has been achieved in our understanding of the biology of acute lymphoblastic leukemias (ALL) occurring in childhood. Morphologic, immunologic, and cytogenetic studies of ALL have resulted in more accurate classification and risk assessment, permitting tailoring of therapy in this heterogeneous group of diseases. Studies of tumor cell biology have begun to pinpoint genes whose altered functions may be etiologically linked to cancer, and have provided insights into the biochemical processes involved in leukemogenesis.

Antibodies, Monoclonal↗
PubMed1987

Height at diagnosis of malignancies.

Studies of the presenting height of children with malignancies have produced conflicting results, from an excess of taller patients to an excess of shorter patients. The problems of measurement bias, inadequate comparison populations, small numbers of patients, subgroup analyses, and overreliance on simple significance tests are all possible reasons for the variation in results. To clarify this issue, we studied heights at diagnosis of 3657 children and adolescents aged under 18 years. Their malignancies included acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin's disease, acute non-lymphoblastic leukaemia, osteosarcoma, retinoblastoma, neuroblastoma, Wilms' tumour, rhabdomyosarcoma, and Ewing's sarcoma. Compared with published standards for the heights of children in control populations, no significant deviation from population norms was found for patients in any of the 10 disease categories after proper adjustment for multiple significance testing.

Age Factors↗
PubMed1987

An analysis of leukemic cell chromosomal features in infants.

Leukemic cell chromosomal findings in 27 infants were analyzed. Among the 18 cases of acute nonlymphoblastic leukemia (ANLL), all but two were classified as monocytic or myelomonocytic. The remaining nine cases were acute lymphoblastic leukemia (ALL), seven lacking the common ALL antigen and two having cytoplasmic immunoglobulin (pre-B phenotype). Twenty-five cases (93%) had an abnormal karyotype, 21 (84%) being pseudodiploid. Chromosomal translocations were detected in 67% of the ANLL cases and in 78% of the ALL cases. Nonrandom chromosomal abnormalities included the t(9;11)(p21-22;q23) in three cases of monocytic leukemia, inversion of chromosome 16 in three cases of myelomonocytic leukemia with bone marrow eosinophilia, and t(4;11)(q21;q23) in one case of ALL. Chromosomal regions preferentially involved in infant leukemia included 11q23-25 (13 cases), 9p21-22 and 10p11-13. All but one of the 24 cases with chromosomal breakage or rearrangement had breakpoints that corresponded to known fragile sites, half of which were at 11q23-25, a finding that may have pathogenetic importance. The CALLA- or pre-B phenotype and the presence of chromosomal translocations in most infants with ALL provide a biological explanation for their poor prognosis.

Acute Disease↗
PubMed1987

Clinical significance of low levels of myeloperoxidase positivity in childhood acute nonlymphoblastic leukemia.

The clinical significance of a low percentage of myeloperoxidase-positive blast cells in childhood acute nonlymphoblastic leukemia was determined. Of 155 consecutive cases studied by cytochemical staining methods, 14 were characterized by 4% to 15% (median 6%) myeloperoxidase-positive blasts. All 14 cases showed reactivity to Sudan black B stain, and 7 had Auer rods. The morphological subtypes of leukemia were M1 (8 cases), M2 (3), M4 (1), and M5 (2). Immunological marker studies disclosed the lymphoid-associated T11 antigen on cells from 8 of the 11 cases tested. Other lymphoid-related findings in these 8 cases included the T3 antigen and E rosette formation in 1 case each. Among cases that were prospectively studied for the expression of lymphoid-associated markers, 6 of 8 with low levels of myeloperoxidase positivity compared with only 1 of 44 with higher levels (greater than 15%) possessed such features (P less than 0.001). We conclude that low levels of myeloperoxidase reactivity distinguish cases of acute leukemia in which the blast cells coexpress lymphoid (T11 antigen) and myeloid markers.

Acute Disease↗
PubMed1987

High serum interleukin-2 receptor levels are related to advanced disease and a poor outcome in childhood non-Hodgkin's lymphoma.

The clinical usefulness of serum interleukin-2 receptor (IL2R) measurements was determined in 59 children with non-Hodgkin's lymphoma (NHL) and six with B cell acute lymphoblastic leukemia (B-ALL). Levels of the receptor showed a clear relationship to disease stage, as follows: B-ALL greater than stage III or IV diffuse small noncleaved-cell NHL greater than stage III or IV lymphoblastic NHL greater than stage I or II NHL. Soluble IL2R levels were also closely correlated with serum lactic dehydrogenase levels (r = 0.7, P = .0001), a recognized indicator of tumor cell burden. Children with higher soluble IL2R levels (greater than 1,000 U/mL) were significantly more likely to fail treatment (P = .001), even when the analysis was limited to those with more advanced disease: stages III and IV NHL and B-ALL (P = .02). In a multivariate analysis, soluble IL2R level was found to have greater predictive strength than either serum lactic dehydrogenase level or disease stage. Thus, the measurement of soluble IL2R in children with NHL could be expected to improve existing methods of risk assignment in this disease.

Acute Disease↗
PubMed1987

Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia.

Leukemic cells from 31 (7.6%) of 409 children with newly diagnosed acute lymphoblastic leukemia (ALL) had a hypodiploid karyotype. The patients' ages ranged from 0.8 to 17 years (median, 5 years) and their initial leukocyte counts from 1.0 to 132 X 10(9)/L (median, 12.7 X 10(9)/L). Modal chromosome numbers for the leukemic stem lines were 45 in 26 cases, 28 in two cases, and 26, 36 and 43 in one case each. Seven cases had one to three additional abnormal lines due to clonal evolution. Chromosome 20 was lost most frequently (nine cases). Structural abnormalities--including chromosomal translocations (21 cases), deletions (ten cases), duplications (two cases), or inversions (one case)--were common findings; the nonrandom translocations consisted of the t(1;19)(q23;p13.3) in two pre-B cases and tdic(9;12)(p1?1;p1?2) in three cases of common ALL. When compared with hyperdiploid cases (greater than 50 chromosomes), ALL with hypodiploidy was found to have a poorer outcome and was more likely to be associated with chromosomal translocations, higher serum lactic dehydrogenase levels, and age less than 2 or greater than or equal to 10 years. Moreover, patients with hypodiploid ALL fared as poorly as those with pseudodiploid karyotypes, even though their leukocyte counts and serum lactic dehydrogenase levels were lower and they had a comparable frequency of leukemic cell translocations. Hypodiploidy is therefore an unfavorable karyotypic feature in childhood ALL.

Acute Disease↗
PubMed1987

Clinical pharmacodynamic studies of high-dose methotrexate in acute lymphocytic leukemia.

As the intensity of cancer chemotherapy has been reported to influence clinical response for several drug-sensitive cancers, we have investigated the relation between systemic exposure to high-dose methotrexate (HDMTX) and clinical response in childhood acute lymphocytic leukemia (ALL). A total of 108 consecutive, previously untreated children with "standard-intermediate risk" ALL were randomized to receive postinduction therapy with HDMTX (1000 mg/m2 iv over 24 hours weekly for 3 weeks, then every 6 weeks for 72 weeks), superimposed on conventional therapy with low-dose 6-mercaptopurine (6MP; 50 mg/m2 orally per day) and methotrexate (MTX; 25 mg/m2 orally per week). The systemic clearance of HDMTX ranged from 40 to 131 ml/minute/m2 among these patients, yielding MTX steady-state plasma concentrations (Cpss) ranging from 9.3 to 25.4 microM during the infusion. The group of patients (n = 59) with median MTX Cpss less than 16 microM during the HDMTX infusion had a higher probability of having any relapse than patients (n = 49) with MTX Cpss greater than 16 microM (P less than 0.05). In a previously reported univariate analysis, patients with MTX Cpss less than or equal to 16 microM were 3.2 times more likely to relapse on therapy (P = 0.01) and 6.9 times more likely to have a hematologic relapse on therapy (P = 0.001). Multivariate and stepwise Cox's regression analyses indicated that MTX Cpss retains its prognostic importance even when other prognostic variables (i.e., DNA Index, WBC, hemoglobin) are considered.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗
PubMed1987

7q32-q36 translocations in childhood T cell leukemia: cytogenetic evidence for involvement of the T cell receptor beta-chain gene.

Blast cell chromosomal rearrangements involving the long arm of chromosome 7 were identified in eight of 197 cases of childhood acute lymphoblastic leukemia (ALL). Breakpoints were variable but tended to cluster in either the proximal or the terminal 7q region, depending on the immunophenotype of the cells. The 7q32-q36 region, the locus of the T cell receptor beta-chain gene, was the site of breakpoints in four of 31 cases of T cell ALL but was not involved in any of the 166 cases originating from B cell precursors (P less than .0004). In three of the four T cell cases it was possible to identify the chromosomal segment that had been translocated to the 7q32-q36 region: 1p32, 2p21, and 6p21. The 1p32 and 6p21 bands are particularly interesting, as they contain the sites of two known protooncogenes, c-L-myc and hpim, respectively. Our findings suggest that the locus of the beta-chain gene of the T cell receptor is a preferential site for certain chromosomal rearrangements in leukemic T lymphoblasts, analogous to the T cell receptor alpha-chain gene on human chromosome 14. Translocation of proto-oncogenes to a site near the beta-chain regulatory sequences provides a potential mechanism for oncogene activation.

Adolescent↗
PubMed1986

Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect.

High-dose methotrexate (500 to 33,600 mg per square meter of body-surface area) with leucovorin rescue is a common component of therapy for acute lymphocytic leukemia. To increase understanding of the relation between the serum concentration and the effect of methotrexate, we conducted a randomized, prospective study of 108 children with "standard-risk" acute lymphocytic leukemia who were treated with 15 doses of methotrexate (1000 mg per square meter) that were infused over 24 hours. The median length of follow-up was 3.5 years from diagnosis for patients still in remission. Variability between patients in methotrexate clearance produced steady-state serum concentrations that ranged from 9.3 to 25.4 microM. Patients with median methotrexate concentrations of less than 16 microM (n = 59) had a lower probability of remaining in remission (P less than 0.05) than patients with concentrations of 16 microM or more (n = 49). Multivariate analyses indicated that patients with methotrexate concentrations of less than 16 microM were 3 times more likely to have any kind of relapse during therapy (P = 0.01) and 7 times more likely to have a hematologic relapse during therapy (P = 0.001). Stepwise Cox's regression identified leukemic-cell DNA content, methotrexate concentration, and hemoglobin as significant prognostic variables for hematologic relapse (P = 0.0005). We conclude that there is a concentration-effect relation for high-dose methotrexate in acute lymphocytic leukemia and that 1000 mg per square meter infused over a period of 24 hours may not be optimal for patients with relatively fast drug clearance.

Adolescent↗
PubMed1986

Phagocytic activity and expression of myeloid-associated cell surface antigens by blast cells in acute lymphoblastic leukemia.

The malignant cells of patients with acute lymphoblastic leukemia (ALL) rarely show phagocytic activity. In this retrospective survey, blasts from 7 of 196 patients with newly diagnosed ALL demonstrated phagocytic activity toward platelets and erythrocytes. The morphology and cytochemical staining properties of the cells were typical of ALL. Immunophenotyes were those of common ALL (CALLA+, HLA-DR+) for six patients and of pre-B-cell ALL (positive cytoplasmic immunoglobulin) for one. However, blast cells from six of the seven patients also reacted with myeloid-associated monoclonal antibodies (MCS.2 and/or SJ-D1). The wide overlap in the percentages of blasts expressing CALLA and those expressing myeloid-associated antigens suggests that some cells possessed both lymphoid- and myeloid-associated surface antigens. By a dual staining technique, two patients tested had blasts expressing antigens of both lineages. Each child achieved a complete remission after treatment with agents effective for ALL and remains in remission for 13+ to 20+ months. These morphologic and immunologic findings may define a distinct subtype of acute leukemia.

Acute Disease↗
PubMed1986

Sequential studies of lymphoblast glucocorticoid receptor levels at diagnosis and relapse in childhood leukemia: an update.

For 80 children with relapsed acute lymphoblastic leukemia, glucocorticoid receptor (GR) levels were lower in blast cells from patients who developed relapse while receiving chemotherapy (p = 0.03) and in those who failed reinduction treatment (p = 0.07). Serial determinations of GR at diagnosis and at relapse in blast cells from 41 patients disclosed various changes in receptor content, which were not related to the initial GR levels, the immunophenotype of blast cells or number of relapses. Six of 9 patients for whom reinduction therapy failed and only 7 of 32 patients in whom subsequent remission was induced had decreased GR levels at relapse (p = 0.018). One patient failed reinduction despite a sharp increase in GR level. Although a decrease in GR levels between diagnosis and relapse is associated with steroid resistance, other mechanism(s) can also be responsible for the development of steroid resistance in childhood leukemia.

Child↗
PubMed1986

Unfavorable presenting clinical and laboratory features are associated with CALLA-negative non-T, non-B lymphoblastic leukemia in children.

Twenty-four (5.7%) of 424 children with newly diagnosed acute lymphoblastic leukemia (ALL) were found to have blast cells that expressed HLA-DR antigens but not the common ALL antigen (CALLA), E-rosette receptors, T-cell antigens, or cytoplasmic or surface immunoglobulins. Each of the eight cases tested expressed the B-cell associated antigen B4, but not B1 or B2 antigen. Myeloid-associated antigens were not present in any of the 10 cases tested. By comparison with common (CALLA+ B-cell precursor) ALL, patients having this immunophenotype were more likely to be children less than 2 yr of age (p less than 0.001), to have higher initial leukocyte counts (p less than 0.001), and to have blast cells with a DNA index less than 1.16 (p = 0.05), a pseudodiploid karyotype (p = 0.01) and a chromosomal translocation (p = 0.003). The presence of any chromosomal translocation in these CALLA- ALL was related to measures of increased leukemic cell burden including higher leukocyte counts, larger liver and spleen sizes and higher serum lactic dehydrogenase levels. While the patients were entered into several treatment arms of two protocols, the CALLA- cases appeared to have lower remission rate (p = 0.06) and shorter event-free survival time (p = 0.05) than did those with common ALL. The association with clinical and laboratory features of known adverse prognostic significance provides some explanation for the poor treatment outcome of CALLA- ALL.

Antigens, Neoplasm↗