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Biomedical subjects

C H Pui

Publications and source records attributed to C H Pui.

At least 271 records · Page 15Linked to original sources
PubMed1988

Non-Hodgkin's lymphoma in children younger than 3 years.

The distribution of histologic subtypes of non-Hodgkin's lymphoma (NHL) in children is known to differ from that in adults, but the histologic characteristics of NHL in very young children have seldom been investigated. The authors retrospectively studied 331 patients with NHL, of whom 16 were younger than 3 years old and found that the distribution of histologic subtypes in the very young patients was similar to that in older children. Six patients had small noncleaved cell lymphomas, five diffuse large cell immunoblastic, four lymphoblastic, and one had a diffuse large noncleaved cell lymphoma. The complete remission rate was 62.5% and six (37.5%) patients are long-term disease-free survivors, although remissions in the six children with large cell lymphomas were relatively brief, lasting no more than 7 months. These cases illustrate that NHL should be included in the differential diagnosis of tumors in infants and young children and that the distribution of histologic subtypes is similar to that in older children.

Child, Preschool↗
PubMed1988

Phase I clinical trial of orally administered 4-demethoxydaunorubicin (idarubicin) with pharmacokinetic and in vitro drug sensitivity testing in children with refractory leukemia.

Fifteen children with acute leukemia in relapse, refractory to conventional therapy, were treated with idarubicin administered orally for 3 consecutive days in dosages ranging from 30 to 50 mg/m2 per day at 19- to 21-day intervals. Gastrointestinal complications, including nausea, vomiting, abdominal pain, diarrhea and stomatitis, were the major forms of dose-limiting toxicity, affecting the majority of patients at all levels of idarubicin dosage. Two patients who had received total-body irradiation for bone marrow transplantation developed life-threatening gastrointestinal toxicity suggestive of a radiation "recall" phenomenon. Echocardiographic evidence of depressed cardiac function, without clinical symptoms or signs, was noted in six of 11 patients, although the changes were judged to be significant in only one child. The maximal tolerated oral dose of idarubicin was 40 mg/m2 per day. The medium terminal plasma half-life of idarubicin was 9.2 h (range, 6.4-25.5 h). Both idarubicin and its metabolite, idarubicinol, accumulated during the 3 days of therapy. Among the five patients with acute nonlymphoblastic leukemia whose cells were tested for drug sensitivity in vitro, the idarubicin concentration resulting in 50% inhibition (IC50) of cluster and colony formation ranged from 1.6 x 10(-10) M to 5 x 10(-7) M. There was no obvious relationship between the IC50 for idarubicin and that for epirubicin or daunorubicin. Oral idarubicin produced definite antileukemic effects, clearing blast cells from the circulation in 13 of the 14 evaluable patients. Future studies should define an optimal dose schedule to circumvent the limiting gastrointestinal complications associated with this agent.

Acute Disease↗
PubMed1988

Vertebral compression fracture as a presenting feature of acute lymphoblastic leukemia in children.

Twenty-four (1.6%) of 1466 children with acute lymphoblastic leukemia (ALL) treated at St. Jude Children's Research Hospital had vertebral compression fractures at diagnosis. When compared with patients without this complication, they were more likely to have good prognostic features, including a leukocyte count of greater than 25 X 10(9)/l, a leukemic cell DNA index of greater than 1.15, and hyperdiploidy (greater than 50 chromosomes). Complete remission of ALL was induced in all patients, and symptoms of vertebral compression fractures abated following antileukemia therapy. Although the diagnosis of ALL was delayed for some patients because this unusual presenting complication was not recognized as such, their treatment outcome was as good as that for other children with "standard-risk" ALL.

Adolescent↗
PubMed1988

Cyclic combination chemotherapy for acute lymphoblastic leukemia recurring after elective cessation of therapy.

Cyclic combination chemotherapy was administered to 26 patients with acute lymphoblastic leukemia who had relapsed in the bone marrow greater than or equal to 6 months after elective cessation of therapy. Each patient had been in initial continuous complete remission for 36-111 months (median, 47 months). Prednisone, vincristine, and doxorubicin induced second complete remissions in all patients within 1 month. Continuation therapy consisted of alternating 6-week courses of 6-mercaptopurine/methotrexate and vincristine/cyclophosphamide with intervening reinforcement courses of prednisone/doxorubicin, for a total of 18 months. All patients received 4 weeks of late intensification therapy with the same agents used for remission reinduction. Periodic intrathecal methotrexate was given as reprophylaxis for subclinical central nervous system leukemia. The estimated rate of continuous failure-free survival at 5 years is 31% +/- 17% (2 SE). Eight patients remain free of leukemia for 42 + to 65+ months after completing therapy a second time. Adverse second events included 11 hematologic, 1 testicular, and 3 meningeal relapses. Patients who relapsed at more than 12 months after the completion of initial treatment have had significantly longer second remissions than patients whose first remissions were shorter (p = .04). None of the other six factors we analyzed showed predictive strength. These end results indicate that intensive cyclic continuation chemotherapy, as described here, will secure durable second remissions in approximately one-third of the children with late bone marrow relapses.

Adolescent↗
PubMed1988

High-dose methotrexate improves clinical outcome in children with acute lymphoblastic leukemia: St. Jude Total Therapy Study X.

High-dose methotrexate (HDMTX, 1,000 mg/m2) and cranial irradiation/sequential chemotherapy (RTSC) were compared for ability to extend complete remission durations in children with acute lymphoblastic leukemia (ALL). Three hundred thirty patients were enrolled in the study, according to our criteria for standard-risk ALL: a leukocyte count less than 100 X 10(9)/L, no mediastinal mass, no leukemic involvement of the central nervous system (CNS), and blast cells lacking sheep erythrocyte receptors and surface immunoglobulin. Prednisone-vincristine-asparaginase induced complete remissions in 95% of the patients, who were then randomized to receive either HDMTX (n = 154) or RTSC (n = 155). HDMTX was administered with intrathecal MTX for the first 3 weeks following remission induction, and then every 6 weeks with daily mercaptopurine (MP) and weekly oral MTX for a total of 18 months. The RTSC regimen consisted of 1,800 cGy cranial irradiation and intrathecal MTX for 3 weeks, followed by MP/MTX, cyclophosphamide/doxorubicin, and teniposide/cytarabine administered sequentially over 18 months. The final 12 months of treatment for both groups was MP and oral MTX; all patients received intrathecal MTX every 12 weeks. With a median follow-up of 5 years, complete remission durations have been significantly longer among children treated with HDMTX, compared with RTSC (P = .049) or historical institutional control regimens (P = .002). Approximately 67% of the patients receiving HDMTX and 56% of those receiving RTSC are expected to be in continuous complete remission at 4 years. Overall, isolated CNS relapse rates were similar (P = .17) in the two treatment groups, although by newer risk criteria cranial irradiation could be expected to provide better protection in patients with an unfavorable prognosis. These findings indicate that addition of intermittent HDMTX infusions to conventional chemotherapy is an effective method for extending complete remissions in children with ALL.

Child↗
PubMed1988

Sequelae of thrombotic or hemorrhagic complications following L-asparaginase therapy for childhood lymphoblastic leukemia.

Thirty-four cases of childhood lymphoblastic leukemia that were complicated by CNS and peripheral thrombosis or hemorrhage associated with L-asparaginase (L-asp) therapy were reviewed to determine the effect of the events on the subsequent clinical status. There was no predilection for any site in the CNS cases; all but one of the peripheral events occurred in the lower extremities. The median time for 28 CNS and eight peripheral events from the beginning of L-asp therapy was 17 and 16 days, respectively. One patient died as a result of the CNS event. Twenty-six patients were surviving with a median follow-up of 27 months at the close of the study. Of the patients with peripheral thromboses, only the patient with a dorsal pedal artery occlusion had a significant problem (autoamputation of a toe). Although eight patients received L-asp subsequently without recurrence of the complication, two had transient neurological deterioration associated with the repeat administration of L-asp. Twenty-two patients received CNS prophylaxis consisting of intrathecal methotrexate, CNS radiation, or both, following the CNS event without deterioration. In general, clinical status was not compromised after thrombotic or hemorrhagic events. Although most patients had gross recovery of their neurological impairment, detailed neurological and neuropsychological testing is needed to elucidate possible defects.

Adolescent↗
PubMed1988

Correlation of karyotype and immunophenotype in childhood acute lymphoblastic leukemia.

To correlate leukemic cell karyotype with immunophenotype, we studied 364 children with acute lymphoblastic leukemia (ALL). A prognostically favorable cytogenetic feature, hyperdiploidy greater than 50 chromosomes, was found in 33% of cases classified as common ALL antigen positive (CALLA+) early pre-B (common) ALL, in contrast to 18% of pre-B cases (P = .012), 5% of T cell cases (P less than .001), and none of the B cell cases (P less than .001) or cases of CALLA negative (CALLA-) early pre-B ALL (P = .002). The frequency of translocations, an adverse cytogenetic feature, was significantly lower in CALLA+ early pre-B ALL cases (35%) than in B cell (100%; P less than .0001), pre-B (59%; P less than .001), or CALLA- early pre-B (62%; P = .016) cases. Thus, patterns of chromosomal change differ widely among the major immunophenotypic groups of ALL and may account for reported differences in responsiveness to treatment.

Antigens, Neoplasm↗
PubMed1988

Acute nonlymphoblastic leukemia in infants: clinical presentation and outcome.

The presenting features and clinical outcome of acute nonlymphoblastic leukemia (ANLL) in infants and older children were compared to identify any differences that might suggest methods to improve therapy. Twelve of the 29 infants were boys and 17 were girls, with ages ranging from two days to 12 months (median, 7 months). By comparison with 222 patients greater than 1 year of age, infants were significantly more likely to have monoblastic or myelomonoblastic leukemia (P less than .0001), chloroma (P less than .0001), marked hepatomegaly (P = .001), and high leukocyte count (P = .005) and were less likely to have Auer rods (P less than .001). Each of these features except leukocyte count showed an association with infant ANLL in a multivariate analysis. Twenty-four (83%) of the infants attained a complete remission, a rate that was not significantly different from that of the older children. Even though infants had a significantly higher CNS relapse rate (P = .003), their event-free survival times were no different than those of older children (P = .74). Ten of the infants remain in initial complete remission for 5+ to 112+ months (median, 52+ months). Infants with ANLL did not have a poorer prognosis than older patients in our study; future protocols for this age group should emphasize more effective systemic therapy, preferably including an epipodophyllotoxin, as well as improved treatment for subclinical CNS leukemia.

Acute Disease↗
PubMed1988

Serum levels of CD8 antigen in childhood lymphoid malignancies: a possible indicator of increased suppressor cell activity in poor-risk patients.

Serum concentrations of CD8 antigen were measured at diagnosis with an enzyme-linked immunoassay in children with acute lymphoblastic leukemia (n = 344) or non-Hodgkin's lymphoma (n = 65). All patients had detectable levels of the serum antigen, which in its soluble nonreduced form appeared to be a 52-Kd homodimer as compared with the 66-Kd surface membrane component on most thymocytes and on a subset of functionally distinct T cells (suppressor/cytotoxic). Increased serum levels of CD8 in leukemia patients were significantly related to recognized high-risk prognostic features: high leukocyte count, large liver and spleen size, high serum lactic dehydrogenase level, T-cell immunophenotype, presence of a mediastinal mass, pseudodiploid karyotype, DNA index less than 1.16, and chromosomal translocation. Children with serum CD8 levels greater than or equal to 450 U/mL were more likely to fail treatment than were those with lower levels (P = .002), even in the group with non-T-cell leukemia (P = .003). In a multivariate analysis, serum CD8 antigen contributed independent prognostic information beyond that conveyed by age, leukocyte count, and race (P = .02). High serum CD8 antigen levels also correlated with advanced stages of disease in children with non-Hodgkin's lymphoma or B-cell leukemia. Children with higher serum CD8 antigen levels (greater than or equal to 700 U/mL) had a poorer treatment outcome (P = .003), even after results were adjusted for disease stage and serum lactic dehydrogenase level (P = .05). Measurement of serum levels of CD8 antigen not only has important prognostic value in childhood lymphoid malignancies but also could be useful in assessing the immunoregulatory role of T cells in patients with cancer.

Adolescent↗
PubMed1988

Biology and staging of childhood non-Hodgkin lymphoma.

Childhood non-Hodgkin lymphomas are relatively common childhood cancers composed of malignant B lymphocytes or thymocytes at various stages of maturation, usually intermediate or late. Most often, they have a diffuse pattern of infiltration and are high grade, lymphoblastic, small noncleaved-cell (undifferentiated, Burkitt or non-Burkitt types) or large cell types. Primary site correlates with immunophenotype and histopathology. For example, most abdominal tumors are B cell and non-lymphoblastic types, and most thoracic primary tumors are of thymocytic origin. Skin presentations are rare, usually lymphoblastic in histology and often of the pre-B cell phenotype. An appropriate work-up and adequate staging is mandatory, since the selection of therapy depends heavily on disease stage. Histopathologic findings are additionally important in determining appropriate therapy for advanced-stage disease. Finally, cytogenetic studies of B and T cell malignancies have defined nonrandom abnormalities in many of these neoplasms and, together with molecular analyses, hold exciting promise for an improved understanding of tumor pathogenesis.

Adolescent↗
PubMed1988

Clinical and biological features predict relapse hazard in childhood acute lymphoid leukemia.

Remarkable progress has been made in understanding the immunobiology, cytogenetic features and potential molecular pathogenetic mechanisms of childhood acute lymphoid leukemias (ALL). Studies of the expression of certain lineage restricted molecules on the surface of or within normal lymphoid cells and their malignant counterparts have been largely responsible for this advance, which has markedly improved the classification of ALL. These studies have disclosed previously unrecognized biologic heterogeneity and have shown that there are several different immunophenotypic subsets of ALL. Some of these subsets differ in their clinical and cytogenetic features, as well as in their responsiveness to modern therapy, underscoring the clinical relevance of such studies. A consideration of all of these features of ALL permits a more accurate assessment of prognosis for children with newly diagnosed disease and has permitted tailoring therapy based on expected relapse hazard. Recent cytogenetic studies have disclosed that clonal abnormalities are present in the blast cells of most children with ALL. Furthermore, such studies have demonstrated increasing numbers of non-random structural anomalies of chromosomes, some of which are specific for certain immunophenotypic species of ALL. Finally, molecular studies of some of these particularly informative cytogenetic anomalies in leukemic cells have suggested that proto-oncogenes are altered and/or activated as a consequence of chromosomal rearrangements.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗
PubMed1988

Serum interleukin 2 receptor levels in childhood acute lymphoblastic leukemia.

The clinical significance of interleukin 2 receptor (IL2R) concentrations in serum was determined for 344 children with newly diagnosed acute lymphoblastic leukemia (ALL). Serum levels of IL2R in patients (267 to 80,000 U/mL, median 2,007 U/mL) were significantly higher than normal control values (170 to 738 U/mL, median 347 U/mL) (P less than .0001). Measurements in cases of T cell ALL were lower than in the non-T, non-B cases (P = .02). Among the 264 patients with non-T, non-B ALL, but not in those with T cell disease, higher serum IL2R levels (greater than 2,000 U/mL) were associated with a poorer treatment outcome (P = .04). In a multivariate analysis, serum IL2R level contributed independent prognostic information beyond that conveyed by leukocyte count, race, and age (P = .04). One explanation for these results is that soluble IL2R competes with normal lymphocyte-integrated IL2R for the ligand and thus could suppress host antitumor immunity.

Adolescent↗
PubMed1988

Isochromosome 17q in childhood acute lymphoblastic leukemia: an adverse cytogenetic feature in association with hyperdiploidy?

Isochromosome 17q is associated with the blastic phase of Philadelphia chromosome-positive chronic myeloid leukemia, but its significance in acute lymphoblastic leukemia (ALL) is unknown. We studied 469 consecutive cases of newly diagnosed ALL with completely banded leukemic cell chromosomes, identifying eight that had the isochromosome. The presenting leukocyte counts of these patients ranged from 1.7 to 130.2 x 10(9)/L (median 7 x 10(9)/L). The morphologic classification of their blast cells was L1 in six cases and L2 in the others; the majority of cases had the common ALL phenotype, whereas two were pre-B. Strikingly, hyperdiploidy greater than 50 chromosomes, a favorable prognostic feature in ALL, characterized all but one of the cases with i(17q), compared with 113 of 461 cases lacking the isochromosome (p less than 0.001). Only four patients, three with relatively brief follow-up times (1, 2, and 8 months), are still in remission. All of the eight previously reported cases of ALL with the i(17q) have failed treatment. These findings suggest that the i(17q) exerts an adverse influence on treatment outcome in ALL, even in hyperdiploid cases with greater than 50 chromosomes.

Child↗
PubMed1988

Intensified chemotherapy for childhood lymphoblastic leukemia: modifications and results of induction treatment in St. Jude Study XI.

The value of intensified chemotherapy for improving event-free survival rates in childhood lymphoblastic leukemia (ALL) is now widely accepted among leukemia therapists. Still to be determined are (1) the optimal method of intensification, (2) the subset or subsets of patients for whom such treatment may be excessive, and (3) whether or not cure rates in ALL can be further improved by alternative approaches to intensification. St. Jude Total Therapy Study XI, based on predictions of the Goldie-Coldmand model of drug resistance, addresses some of these questions by use of rotational "non-cross-resistant" drug pairs throughout the course of therapy. A new method of risk classification has been developed to refine distinctions among prognostic subgroups, especially to identify patients with biologically unfavorable ALL. Unacceptable toxicity noted in the first 134 children enrolled in this study led to two protocol modifications. One hundred thirty-two patients have been treated subsequently without undue toxicity. The treatment is now being delivered safely. Our early experience with this regimen demonstrates some of the hazards of intensive multidrug combination treatment, but gains in leukemia control appear to justify this approach.

Antineoplastic Agents↗
PubMed1988

Cytogenetics of childhood T-cell leukemia.

The karyotypes of 57 cases of childhood T-cell acute lymphoblastic leukemia (ALL) were analyzed to establish the cytogenetic profile in this disease. Three questions were of particular interest. Do the chromosomal changes in T-cell ALL preferentially affect bands where genes encoding the T-cell receptor for antigen (TCR) have been mapped? Do alterations involving the TCR gene regions appear with any notable frequency in B-progenitor ALL? Do chromosomal abnormalities in this disease relate to stage of T-cell ontogeny? A relatively high proportion of cases (65%) had a pseudodiploid karyotype at presentation, the majority (58%) characterized by a translocation. The overall frequency of translocations was 44%, comparable to that among all banded cases of ALL seen in our laboratory. Hypodiploidy and hyperdiploidy were exceedingly rare (only four of 57 cases); 16 cases (28%) had apparently normal karyotypes. In half the cases with a translocation (14 of 24), the breakpoints were in regions to which the alpha and beta chain TCR genes have been mapped. Chromosomal breakpoints that were consistently observed in the vicinity of TCR gene loci were 7q32-q36 (TCR beta chain; n = 8), 14q11-q13 (TCR alpha chain; n = 6); other frequent breakpoints were 9p13-pter (n = 8) and 6q15-qter (n = 9). Chromosomal alterations occurred near TCR gene loci significantly more often in T-cell cases than in a comparison group of 335 patients with B-cell precursor ALL (26% v 1.5%, P = .0001). Stage I thymocyte development (CD7+, CD2+, CD5+, CD1-, CD3-, CD4-, CD8-) was noted in 23 cases, stage II (CD7+, CD2+, CD5+, CD1+, CD3-, CD4 +/-, CD8 +/-) in 25 cases, and stage III (CD9+, CD2+, CD1-, CD5+, CD3+, and either CD4+ or CD8+) in nine cases. The only statistically significant associations between cytogenetic findings and T-cell ontogeny were a higher frequency of normal karyotypes in cases with stage I thymocytes, and of pseudodiploidy in stage II cases. There was no apparent relationship between particular translocations and level of thymocyte maturation. Our findings indicate that most children with T-cell ALL have pseudodiploid karyotypes, although a surprisingly high percentage lack demonstrable abnormal clones. Specific chromosomal changes do not appear to be related to discrete stages of T-cell ontogeny as defined in this study, but they occur preferentially in bands containing TCR genes.

Cell Differentiation↗
PubMed1988

Efficacy of high-dose methotrexate in childhood acute lymphocytic leukemia: analysis by contemporary risk classifications.

High-dose methotrexate (HDMTX) added to a basic regimen of chemotherapy proved superior to cranial irradiation and sequentially administered drug pairs (RTSC) in prolonging complete remissions in children with "standard-risk" acute lymphocytic leukemia. To extend this result to more contemporary risk groups, we reclassified the patients according to methods of the Pediatric Oncology Group (POG), the Childrens Cancer Study Group (CCG), the Rome workshop, and St Jude Total Therapy Study XI. By life table analysis, 70% to 78% of patients with a favorable prognosis would remain in continuous complete remission (CCR) at 4 years if treated with HDMTX. Uniformly lower CCR rates could be expected with RTSC, especially in St Jude better-risk patients. HDMTX also would show greater efficacy than RTSC in the CCG average-risk and POG poor-risk groups, but the results appear inferior to those being achieved with intensified regimens for high-risk leukemia. Although both therapies would provide adequate CNS prophylaxis in favorable-risk groups, RTSC would offer greater protection in patients classified as being in a worse-risk group by St Jude criteria. We conclude that HDMTX-based therapy, as described in this report, would be most effective in patients with a presenting leukocyte count of less than 25 x 10(9)/L, of the white race, aged 2 to 10 years, and having leukemic cell hyperdiploidy without translocations.

Adolescent↗
PubMed1987

Involvement of von Willebrand factor in thrombosis following asparaginase-prednisone-vincristine therapy for leukemia.

To determine if factor VIII-von Willebrand factor (vWF) complex is involved in the thrombosis associated with asparaginase-prednisone-vincristine induction therapy for acute lymphoblastic leukemia, plasma vWF was analyzed by sodium dodecyl sulfate-agarose gel electrophoresis and crossed immunoelectrophoresis. Five patients with cerebral thrombosis were studied; all had a decreased platelet count following the complication. Sequential studies of three patients disclosed changes in plasma vWF multimer pattern. One patient who was studied serially from 2 days before to 1 day after the event, had an increase in unusually large plasma vWF multimers that disappeared after the complication. The other two patients who were studied at presentation subsequently showed a decrease in plasma large vWF multimers, especially remarkable in the patient having the sharpest decrease in platelet count. No appreciable difference in vWF multimer pattern, when compared to normal pooled plasma, was found in the remaining two patients who were only studied at presentation, or in the seven controls who received the same treatment but did not develop thrombosis. Crossed immunoelectrophoretic analyses of two patients tested disclosed a right shift of immunoprecipitin line in one and a left shift in the other. Our findings suggest that the thrombotic complications resulted from platelet agglutination by plasma vWF.

Acute Disease↗