Biomedical subjects

C H Pui

Publications and source records attributed to C H Pui.

At least 325 records · Page 18Linked to original sources

PubMed1985

Altered von Willebrand factor molecule in children with thrombosis following asparaginase-prednisone-vincristine therapy for leukemia.

Eleven consecutive leukemia patients with thrombosis induced by asparaginase-prednisone-vincristine therapy were studied to gain insight into the pathogenesis of this complication. Measurement of anti-thrombin III, plasminogen, factor V, and fibrin degradation products as well as platelet aggregation sensitivity to adenosine diphosphate disclosed no consistent abnormalities that would explain pathologic thrombus formation. A decrease in platelet counts observed in nine of 11 patients, prompted us to investigate the possible involvement of factor VIII in this disorder. Levels of factor VIII procoagulant activity, von Willebrand factor (vWF) and ristocetin cofactor were similar to findings for an identically treated comparison group who remained free of thrombotic complications. However, qualitative examination of vWF by crossed immunoelectrophoresis (CIE) revealed a distinct right shift of the immunoprecipitin lines in each of three thrombotic patients tested, whereas a normal profile was found in three similarly treated patients without the complication. This altered pattern had reverted to normal when CIE was repeated 2 to 7 months later. We postulate that the abnormal vWF is related to the development of thrombosis.

Adolescent↗

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

Central nervous system leukemia in children with acute nonlymphoblastic leukemia.

Factors contributing to the development of central nervous system (CNS) leukemia, and the impact of leukemic involvement of this site on subsequent remission length, were determined in 184 children with acute nonlymphoblastic leukemia who had been treated in two successive clinical trials. Preventive CNS therapy in both studies consisted of intrathecal methotrexate (12 mg/m2) given monthly during the first six months of therapy and then every three months until all treatment was stopped. Children with CNS leukemia at diagnosis or relapse were given intrathecal chemotherapy weekly for four weeks and then monthly throughout the remainder of the treatment course. Those continuing in complete remission received 2,400 rad cranial irradiation plus five doses of intrathecal methotrexate before cessation of therapy. The 38 children (20.7%) with CNS leukemia at diagnosis were more likely to have an initial leukocyte count greater than or equal to 25 X 10(9)/L (P = .01) and age less than 2 years (P = .03). The presence of CNS leukemia at diagnosis did not adversely affect the remission induction rate (P = .13) or the length of complete remissions (P = .73). CNS relapse ended initial remissions in 11 patients only and did not preclude subsequent long-term survival, as four of these children are off therapy and in second complete remission for 33+ to 78+ months. Three features at diagnosis were predictive of CNS relapse: monocytic or myelomonocytic leukemia (P = .002); age less than 2 years (P = .0001); and leukocyte count greater than or equal to 25 X 10(9)/L (P = .012). By stepwise Cox regression analysis, each factor was found to have independent predictive value. Despite the apparent effectiveness of intrathecal methotrexate as preventive CNS treatment, our findings indicate that more effective prophylaxis is needed for patients with features predisposing to CNS relapse.

Acute Disease↗

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↗

PubMed1985

Acute mixed lineage leukemia: clinicopathologic correlations and prognostic significance.

The frequency and clinical significance of acute leukemia displaying both lymphoid and myeloid characteristics was determined in 123 consecutive children using a panel of lineage-associated markers. The leukemic blasts from 18 of 95 children (19%) with the diagnosis of acute lymphoblastic leukemia (ALL) by standard diagnostic criteria expressed myeloid-associated cell surface antigens. Despite immunological evidence of lymphoid differentiation (17 CALLA + and one T cell-associated antigen +) and findings of immunoglobulin gene rearrangement, blasts from these patients reacted with one to five monoclonal antibodies identifying myeloid-associated cell surface antigens (My-1, MCS.2, Mo1, SJ-D1, or 5F1). Dual staining with microsphere-conjugated antibodies and analysis by flow cytometry confirmed that some blasts were simultaneously expressing lymphoid- and myeloid-associated antigens. Conversely, blasts from seven of 28 patients (25%) with acute nonlymphocytic leukemia (ANLL), diagnosed by otherwise standard morphological and cytochemical criteria, expressed lymphoid-associated surface antigens. Dual staining of individual blasts demonstrated simultaneous expression of myeloperoxidase (MPO) (including Auer rods) in association with either T-11, CALLA, or terminal deoxynucleotidyl transferase. Blasts from one patient with ANLL demonstrated T cell receptor gene rearrangement, while blasts from another patient demonstrated characteristics associated with T (T-11), B (CALLA and heavy-chain immunoglobulin gene rearrangement), and myeloid (MPO) lineage. There were no consistent cytogenetic abnormalities, and no patient demonstrated independent leukemic clones. Each patient with typical ALL, except for myeloid-associated antigens, achieved complete remission with conventional induction therapy for ALL. By contrast, three of the seven children with ANLL whose blasts expressed the T-11 surface antigen failed ANLL induction therapy. These three patients subsequently achieved remission with ALL therapy.

Acute Disease↗

PubMed1984

Seizures in childhood lymphoblastic leukaemia patients.

Features of seizures in children with acute lymphoblastic leukaemia were examined in relation to the type of treatment received for central nervous system prophylaxis. Of the 1289 patients in the study, 132 (10%) had experienced one or more seizures. In 96 the seizures had not been associated with any recognisable aetiology and, with 3 exceptions, had been generalised or focal motor in type. Status epilepticus had occurred in one-third of the group with seizures. Initial seizure rates among patients in continuous complete remission were significantly related to the method of central nervous system prophylaxis. Those who had received intrathecal methotrexate repeatedly with or without moderate doses of methotrexate intravenously or prior prophylactic cranial irradiation had a 20-fold higher seizure risk during remission induction, and a 37-fold higher risk during the 6th to 12th month of therapy, than did those who had received irradiation and only five intrathecal injections of methotrexate early in the course of treatment. Other clinical factors associated with an increased frequency of seizures were escalation of intravenous methotrexate dosage following cranial irradiation and treatment of meningeal leukaemia with intrathecal methotrexate. Parenterally administered methotrexate thus seems to increase susceptibility to seizure development in childhood leukaemia patients.

Central Nervous System↗

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↗

PubMed1984

Impact of treatment efficacy on the prognostic value of glucocorticoid receptor levels in childhood acute lymphoblastic leukemia.

Glucocorticoid receptor (GR) levels were quantitated in leukemic blasts from bone marrow aspirates of 249 children with acute lymphoblastic leukemia (ALL) who were entered on two St. Jude Total Therapy Studies. Of these, 235 were evaluable for analysis of the relation of GR levels to clinical outcome. For the 42 patients in the earlier Total Therapy Study IX, lower GR levels (less than 16,000 sites/cell) were associated with both induction failure and more frequent relapse (p less than 0.01) [Cancer Research, Vol. 42, p. 4801 (1982)]. When patients with 'high-risk' features (leukocyte count greater than 100 X 10(3)/mm3, positive erythrocyte rosette test, central nervous system involvement, and mediastinal mass) were excluded, lower receptor levels were still associated with early and more frequent relapse (p less than 0.02). The other 193 evaluable patients were consecutively admitted to Total Therapy Study X, in which patients with 'standard-risk' or 'high-risk' features were assigned to separate protocols--XS and XH, respectively. Induction chemotherapy in both protocols consisted of prednisone, vincristine and L-asparaginase; patients in the XH protocol received additional epipodophyllotoxin (VM-26) and cytosine arabinoside twice a week for 2 weeks preceding the conventional induction therapy. To compare the prognostic value of GR level in Study X with that of Study IX (which included both 'high-risk' and 'standard-risk' patients but did not separate them into different protocol groups), children in the XH and XS protocols were analysed together. The proportion of patients with 'standard-risk' features was the same in the two studies: 69% in Study IX and 73% in Study X. In Study X, which had a significantly better treatment result (p less than 0.001), lower receptor levels were not associated with induction failure, but were correlated with more frequent relapse (p less than 0.05). When patients in XH and XS protocols were analysed separately, however, receptor levels were no longer related to treatment outcome. Thus, GR level in childhood ALL has prognostic value, but it is not an independent factor and its importance is related to the efficacy of treatment.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1984

Acute leukaemia with mixed lymphoid and myeloid phenotype.

Three children with acute leukaemia had blasts that expressed both lymphoid and myeloid markers. The blasts met immunological criteria for acute lymphoblastic leukaemia (ALL)--common ALL antigen+, HLA-DR+, terminal deoxynucleotidyl transferase+--but their cytochemical features, including positive myeloperoxidase and Sudan black B, were those of acute nonlymphoblastic leukaemia (ANLL) as defined by the French-American-British Group. 30% of the blasts from one of two patients tested reacted with a monoclonal antibody specific for nonlymphoid cells (MCS-2). The wide overlap in the percentages of blasts expressing lymphoid or myeloid markers indicates that some leukaemic cells in each child had a mixed phenotype. There were no consistent cytogenetic findings, and the Philadelphia chromosome was not present. Complete remission was induced by treatment effective for either ALL (two patients) or ANLL. These three cases appear to represent a rare leukaemia subtype that we have designated acute leukaemia with mixed lymphoid and myeloid phenotype. Its recognition may be important in treatment, since two patients achieved remission with standard therapy for ALL. These cases demonstrate further the phenotypic heterogeneity that may be seen in leukaemic cell differentiation.

Acute Disease↗

PubMed1984

Sudan black B positive acute lymphoblastic leukaemia.

The presence of greater than 3% Sudan black B (SBB) positivity in leukaemic blasts has been considered diagnostic of acute non-lymphocytic leukaemia (ANLL). A rare report has indicated that this finding may not be specific for ANLL. In order to determine whether SBB could be found in acute lymphoblastic leukaemia (ALL) the data on 350 patients with newly diagnosed ALL were reviewed. Six patients (1.6%) were found to have 5% or greater SBB positive blasts. The diagnosis of ALL was supported by morphology, cytochemistries, immunologic markers, therapeutic response, and in one case immunoglobulin gene rearrangement. It is important to recognize the fact that SBB is not specific for AML and may be found in the blasts of patients with ALL.

Adolescent↗

PubMed1984

Failure of late intensification therapy to improve a poor result in childhood lymphoblastic leukemia.

This clinical study, begun in 1975, tested the efficacy of early and delayed intensification treatments in children with acute lymphoblastic leukemia. Regardless of presenting features, all patients received 4 weeks of conventional induction therapy with daily prednisone and weekly vincristine and daunorubicin. One-third were randomized to receive, in addition, two doses of asparaginase during induction therapy, while another one-third received four doses of both asparaginase and cytarabine after remission induction. Preventive central nervous system therapy uniformly included 2400 rads cranial irradiation and five doses of intrathecal methotrexate. Remissions were maintained with daily p.o. mercaptopurine and weekly i.v. methotrexate. Of the 277 assessable patients, 254 (92%) entered complete remission, and 102 (37%) remain clinically free of leukemia for 4.6 to 8.0 years (median, 6.3 years). The three treatment groups showed no significant differences in either remission induction rate or outcome, even when the analysis was based on risk assignment. A "late intensification" phase of therapy, added to the maintenance protocol for 65 patients who had been in continuous complete remission for 14 to 30 months, failed to extend remission durations, as judged from statistical comparison with matched controls (p = 0.84). When tested as a time-dependent covariate in the Cox proportional-hazards model, delayed intensification again showed no important effect on duration of complete remission. We conclude that limited early or aggressive late intensification of therapy, as described here, does not improve outcome in childhood acute lymphoblastic leukemia.

Adolescent↗

PubMed1984

Lineage switch in acute leukemia.

Conversions of leukemic cell lineage (lymphoid or myeloid) have been reported only rarely. Our review of the cytochemical and immunophenotypic features of 89 cases of childhood leukemia in marrow relapse indicated lineage switch (lymphoid to myeloid or the reverse) in six patients (6.7%). Five patients with acute lymphoblastic leukemia (ALL) at diagnosis had converted to acute nonlymphoblastic leukemia (ANLL), and one had converted from ANLL to ALL. Each child received lineage-specific multiagent chemotherapy when initially diagnosed, and all achieved a complete remission. After conversion, four patients readily achieved second remissions with treatment for the phenotype evident at lineage switch. Two patients with ANLL at conversion failed ALL-directed reinduction, while one of the two responded to high-dose cytarabine but died during bone marrow hypoplasia, emphasizing the importance of prompt recognition of lineage switch and selection of an appropriate plan of retreatment. Cytogenetic studies disclosed evidence of clonal selection in one patient and clonal stability in two. These findings indicate an unexpectedly high frequency of lineage switch in patients who relapse in the bone marrow after intensive chemotherapy. Although specific causative factors could not be identified, our observations suggest at least two general mechanisms for lineage switch in acute leukemia. In one, chemotherapy appears to eradicate the dominant clone present at diagnosis, permitting expansion of a secondary clone with a different phenotype. In the second, drug-induced changes in the original clone may either amplify or suppress differentiation programs so that phenotypic shift is possible.

Acute Disease↗

PubMed1983

Hydrocele formation in patients with Hodgkin's disease.

Hydroceles developed in 12 (7.7%) of 155 consecutive male patients who had Hodgkin's disease treated between 1962 and 1981. Except for one patient who had a hydrocele at diagnosis, all developed this complication during remission, 8 months to 7.5 years after inverted-Y or abdominopelvic 60Co irradiation (3000-3800 rad). Hydroceles were bilateral in five patients and on the right side in seven. No tumor was found in the hydrocele sacs of the ten patients who underwent hydrocelectomy. Lymphatic obstruction was evidenced by lymphatic dilation in the hernia sac in six patients. The authors believe postirradiation fibrosis of the lymphatic pathway was the main cause of hydrocele formation.

Adolescent↗

PubMed1983

Immunoregulatory abnormalities in Evans syndrome.

Immune function in six patients with Evans syndrome (Coombs-positive hemolytic anemia and immune thrombocytopenia) was compared to that in seven with chronic ITP. The two groups differed in measurements of T-cell subsets and immunoglobulin production. Evans syndrome patients had decreased T4 (T-helper) (P = 0.025), increased T8 (T-suppressor) (P = 0.008), and a decreased ratio of T4:T8 cells (P = 0.0009) when compared to controls. Results in chronic ITP patients were similar to those in controls. Serum IgG, IgM, and IgA levels and in vitro synthesis of IgG and/or IgM were decreased in most Evans syndrome patients. Diminished in vivo and in vitro immunoglobulin synthesis in Evans syndrome is consistent with the decreased T4:T8 ratio in these patients. The altered T4:T8 ratio may represent an unsuccessful response to an autoimmune process in which the trigger is unknown.

Adolescent↗

PubMed1983

Glucocorticoid receptors in childhood acute non-lymphocytic leukemia.

Using a whole-cell assay, we found glucocorticoid receptors (GR) in all 43 consecutive assessable children with newly diagnosed acute non-lymphocytic leukemia (ANLL). The receptor levels ranged from 2146 to 81,308 sites/cell (median = 18,105); these results were similar to those for acute lymphocytic leukemia. Receptor levels were not related to any of these clinical or biological features at diagnosis: age, sex, race, initial leukocyte count, liver or spleen size, presence of CNS disease or Auer rods, [3H] thymidine ( [3H]TdR) labelling index, French-American-British morphology or terminal deoxynucleotidyl transferase activity. Receptor levels also were not related to the initial treatment response or remission duration after therapy that did not include a glucocorticoid. We conclude that GR level has no clinical utility as a marker protein in childhood ANLL.

Acute Disease↗

PubMed1983

Response of recurrent acute lymphoblastic leukemia to glucocorticoids: serial studies of receptor content, in vivo cytokinetic changes and clinical responses.

The sensitivity of relapsed acute lymphoblastic leukemia (ALL) to treatment with steroids was assessed by measuring bone marrow blast, whole-cell glucocorticoid receptor (GR) levels and serial cytokinetic and clinical responses to steroids, both as single agents and in combination reinduction chemotherapy. GR levels ranged widely, from 1800 to 47,800 sites/cell (median 16,000), and did not differ significantly from levels measured in newly diagnosed patients (p = 0.50). Nineteen of the 48 children studied had GR levels measured both at diagnosis and relapse, and in 14 the values at relapse were either decreased or increased by more than 25%. For nine children, the sensitivity to a three-day oral course of dexamethasone alone (6 mg/m2 per day) was estimated from daily leukocyte counts and serial bone marrow cytokinetic studies. A clinical oncolytic effect of dexamethasone was associated with a reduction in the marrow cell proliferating compartment, as judged from labeling indices, mitotic indices and percent S + G2 + M in five patients. We found, however, that GR levels either alone or combined with clinical or cytokinetic responses to dexamethasone as a single agent did not reliably identify patients who were likely to respond favorably to reinduction with steroid-containing combination chemotherapy. The 35 children who successfully attained subsequent remissions had GR levels similar to those who failed (p = 0.35). While not statistically significant, two observations suggest an association between lower receptor content and drug resistance. Receptor levels from patients with ALL who relapsed while on chemotherapy were appreciably lower (median 15,700, n = 31) than GR levels from patients who relapsed off therapy (median 20,300, n = 17) (p = 0.08). Moreover, three of seven patients with serial studies, whose GR levels at relapse were lower than at diagnosis, failed reinduction--compared to only one of twelve whose levels were either increased or remained unchanged (p = 0.11). Although not having any obvious clinical utility, studies of GR at diagnosis and at relapse may aid in clarifying mechanisms of drug resistance in leukemic blasts.

Acute Disease↗