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Biomedical subjects

C H Pui

Publications and source records attributed to C H Pui.

At least 19 recordsLinked to original sources
PubMed2006

The Eighth International Childhood Acute Lymphoblastic Leukemia Workshop ('Ponte di legno meeting') report: Vienna, Austria, April 27-28, 2005.

The International Acute Lymphoblastic Leukemia Working Group, the so-called 'Ponte di Legno Workshop' has led to substantial progress in international collaboration in leukemia research. On April 27-28, 2005, the 8th Meeting was held in Vienna, Austria, to continue the discussions about special common treatment elements in randomized clinical trials, ethical and clinical aspects of therapy. Furthermore, collaborative projects of clinical relevance with special emphasis on rare genetic subtypes of Childhood ALL were established. The following report summarizes the achievements and aspects of possible future cooperation.

Austria↗
PubMed2005

No prognostic effect of additional chromosomal abnormalities in children with acute lymphoblastic leukemia and 11q23 abnormalities.

This study characterized the additional chromosomal abnormalities (ACA) associated with 11q23 rearrangements in 450 infants and children with acute lymphoblastic leukemia (ALL) and examined the impact of these ACA on survival. Overall, 213 (47%) cases had ACA but the incidence varied according to patient age and 11q23 subgroup. Infants and patients with t(4;11)(q21;q23) had the lowest incidence of ACA (50/182 (27%) and 57/216 (26%) respectively), whereas patients with del(11)(q23) had the highest incidence (66/93 (71%)). Del(11)(q23) abnormalities were heterogeneous and occasionally secondary to t(9;22)(q34;q11.2). Thus, patients with del(11)(q23) comprised a separate biological entity, which was clearly distinct from those with an 11q23 translocation. The most frequent specific ACA were trisomy X (n = 38), abnormal 12p (n = 32), abnormal 9p (n = 28) and del(6q) (n = 19). The presence of ACA did not change the 5 year event-free survival estimates among children (56% (95% Cl 46-65%) vs 62% (54-69%)) or infants (22% (15-29%) vs 18% (9-29%)), nor when the different 11q23 subgroups were analyzed separately. This study has conclusively demonstrated that there is no prognostic effect of secondary chromosomal changes in association with 11q23 abnormalities in childhood ALL. However, characterization of these ACA is important to determine their potential role in initiation of MLL driven leukemogenesis.

Child↗
PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗
PubMed2004

Quality of life as conveyed by pediatric patients with cancer.

Quality-of-life instruments have provided important advances in measuring the quality of life of pediatric patients receiving treatment for cancer. However, the bases of these instruments have not included first-hand reports from the patients; thus, these instruments may be conceptually incomplete. We directly solicited from pediatric patients their perspectives regarding their quality of life during treatment for cancer. We conducted two pilot studies: 23 patients (aged 8-15 years) participated in the first, a cross-sectional study; and 13 patients (aged 10-18 years) participated in the second, a 2-year longitudinal study. Data were analyzed by using a semantic-content method, and the following six domains were recognized in data from both of the studies: symptoms, usual activities, social/family interactions, health status, mood, and the meaning of being ill. These domains were compared with those of seven established pediatric oncology quality-of-life instruments, none of which included all six of these domains; the domain most frequently missing was the meaning of being ill domain. Here we present a new definition of the quality of life of pediatric oncology patients that is based on six domains; this definition may ensure the completeness and sensitivity of these important instruments.

Adolescent↗
PubMed2004

Expression of the adaptor protein BLNK/SLP-65 in childhood acute lymphoblastic leukemia.

Deficient expression of BLNK, an adaptor molecule crucial for normal B-cell development, is associated with increased pro-B/pre-B-cell expansion in mice. It has been proposed that BLNK deficiency is a primary cause of B-lineage acute lymphoblastic leukemia (ALL). We studied BLNK expression in the leukemic cells from 352 patients with childhood ALL (309 B-lineage; 43 T-lineage). By HG_U95Av2 Affymetrix GeneChip analysis, BLNK was expressed in 275 of 284 (96.8%) B-lineage ALL samples but in only one of 43 (2.3%) T-lineage ALL samples. Of 118 B-lineage ALL samples analyzed with the HG_U133A GeneChip, 117 (99.2%) expressed BLNK. All 30 primary B-lineage ALL samples studied by RT-PCR expressed BLNK transcripts; all 19 samples studied by Western blotting or flow cytometry expressed BLNK protein. Levels of BLNK in B-lineage ALL were as high as those of their normal counterparts; they were not related with genetic subgroups or differentiation stage. These results indicate that BLNK deficiency is a rare occurrence in childhood B-lineage ALL and is unlikely to be a common leukemogenic event as previously proposed.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Lactic acidosis: a metabolic complication of hematologic malignancies: case report and review of the literature.

BACKGROUND: Lactic acidosis (LA) associated with hematologic malignancies is rare, ominous, and generally occurs in adults. Its pathogenesis is poorly understood. METHODS: The authors present one case of childhood lymphoma and two cases of childhood leukemia associated with LA, and they review the available literature. Plasma concentrations of insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and tumor necrosis factor (TNF)-alpha were retrospectively measured to elucidate the pathogenesis of LA. RESULTS: Lactic acidosis has been reported to date in 28 cases of lymphoma and 25 cases of leukemia, including the authors' cases. Ongoing rapid cellular proliferation was indicated in all leukemia cases. The liver was involved in 43 of the 53 cases, and hypoglycemia was present in 20. The acidosis improved only if the disease responded to chemotherapy. Remission was achieved in only five of the reported cases. In the authors' three cases, LA was associated with altered concentrations of IGFs, IGFBPs, and TNF-alpha, although causality was not established. CONCLUSIONS: Lactic acidosis in association with hematologic malignancies carries an extremely poor prognosis. Because cancer cells have a high rate of glycolysis and produce a large quantity of lactate, this condition may result from an imbalance between lactate production and hepatic lactate utilization. The authors speculate that the IGF system is involved in the pathophysiology of LA in these patients. Only chemotherapy so far has been effective in correcting the acute acidosis in a few patients; however, it has not necessarily improved ultimate outcome.

Acidosis, Lactic↗
PubMed2001

Second malignancy after treatment of childhood non-Hodgkin lymphoma.

BACKGROUND: The objective of this report was to determine the cumulative incidence of and risk factors for second malignancy and the competing risk of death due to any other cause among patients who were treated for childhood non-Hodgkin lymphoma (NHL). METHODS: The authors retrospectively reviewed a cohort of 497 patients with NHL who were treated at St. Jude Children's Research Hospital between 1970 and 1997. RESULTS: A second malignancy developed in 16 patients (9 patients with solid tumors and 7 patients with secondary acute myeloid leukemia [AML]). This number was 10.8-fold (95% confidence interval, 6.1-16.9) higher than the 1.48 patients projected for the general population by SEER Cancer Statistics. The estimated cumulative incidence rate of second malignancy was 2.1% +/- 0.7% at 10 years after diagnosis of NHL and increased to 4.8% +/- 1.3% at 20 years after diagnosis. The cumulative incidence rate of second malignancy was least among patients with small noncleaved cell lymphoma (0.5% +/- 0.5% at 20 years), higher among patients with large cell lymphoma (5.8% +/- 3.3% at 20 years), and highest among patients with lymphoblastic lymphoma (10.9% +/- 3.6% at 20 years; P = 0.002 for overall comparison). Exposure to epipodophyllotoxins was a risk factor for the development of secondary AML (P < 0.001). The cumulative incidence rate of death due to other causes was significantly less for patients who were treated after June 1978 (19.9% +/- 2.2% at 10 years) compared with patients who were treated earlier (55.6% +/- 4.2% at 10 years; P < 0.001), whereas the risk of second malignancy was similar for these two eras. CONCLUSIONS: Survivors of childhood NHL, especially those with lymphoblastic histology, are at a greater risk of developing a second malignancy compared with the general population. The incidence rate of second malignancy has remained unchanged despite a recent decline in the risk of death related to primary NHL or earlier treatment complications.

Adolescent↗
PubMed2001

Molecular emergence of acute myeloid leukemia during treatment for acute lymphoblastic leukemia.

Therapy-related acute myeloid leukemias (t-AML) with translocations of the MLL gene are associated with the use of topoisomerase II inhibitors. We established the emergence of the malignant clone in a child who developed t-AML with a t(11;19) (q23;p13.3) during treatment for acute lymphoblastic leukemia (ALL). The MLL-ENL and the reciprocal ENL-MLL genomic fusions and their chimeric transcripts were characterized from samples collected at the time of t-AML diagnosis. We used PCR with patient-specific genomic primers to establish the emergence of the MLL-ENL fusion in serially obtained DNA samples. The MLL-ENL fusion was not detectable in bone marrow at the time of ALL diagnosis or after 2 months of chemotherapy (frequency <8.3 x 10(-7) cells(-1)). The genomic fusion was first detected in bone marrow after 6 months of treatment at a frequency of one in 4,000 mononuclear bone marrow cells; the frequency was one in 70 cells after 20 months of therapy. At the first detection of MLL-ENL, the only topoisomerase II inhibitors the patient had received were one dose of daunorubicin and two doses of etoposide. The MLL-ENL fusion was not detectable in blood at the time of ALL diagnosis or after 0.7, 2, 8, 10, and 12 months of therapy but was detectable in blood at 16 months (one in 2.3 x 10(4) cells). Recombinogenic Alu sequences bracketed the breakpoints in both fusions. These data indicate that the malignant clone was not present before therapy, arose early during chemotherapy, and was able to proliferate even during exposure to antileukemic therapy.

Adolescent↗
PubMed2001

Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience.

To describe the clinical and biologic features of pediatric acute megakaryoblastic leukemia (AMKL) and to identify prognostic factors, experience at St Jude Children's Research Hospital was reviewed. Of 281 patients with acute myeloid leukemia treated over a 14-year period, 41 (14.6%) had a diagnosis of AMKL. Six patients had Down syndrome and AMKL, 6 had secondary AMKL, and 29 had de novo AMKL. The median age of the 22 boys and 19 girls was 23.9 months (range, 6.7-208.9 months). The rate of remission induction was 60.5%, with a 48% rate of subsequent relapse. Patients with Down syndrome had a significantly higher 2-year event-free survival (EFS) estimate (83%) than did other patients with de novo AMKL (14%) or with secondary AMKL (20%; P < or =.038). Among patients who had de novo AMKL without Down syndrome, 2-year EFS was significantly higher after allogeneic bone marrow transplantation (26%) than after chemotherapy alone (0%; P =.019) and significantly higher when performed during remission (46%) than when performed during persistent disease (0%; P =.019). The 5-year survival estimates were significantly lower for de novo AMKL (10%) than for other forms of de novo AML (42%; P <.001). Treatment outcome is very poor for patients with AMKL in the absence of Down syndrome. Remission induction is the most important prognostic factor. Allogeneic transplantation during remission offers the best chance of cure; in the absence of remission, transplantation offers no advantage over chemotherapy alone. (Blood. 2001;97:3727-3732)

Bone Marrow Transplantation↗
PubMed2001

Identification of novel markers for monitoring minimal residual disease in acute lymphoblastic leukemia.

To identify new markers of minimal residual disease (MRD) in B-lineage acute lymphoblastic leukemia (ALL), gene expression of leukemic cells obtained from 4 patients with newly diagnosed ALL was compared with that of normal CD19(+)CD10(+) B-cell progenitors obtained from 2 healthy donors. By cDNA array analysis, 334 of 4132 genes studied were expressed 1.5- to 5.8-fold higher in leukemic cells relative to both normal samples; 238 of these genes were also overexpressed in the leukemic cell line RS4;11. Nine genes were selected among the 274 overexpressed in at least 2 leukemic samples, and expression of the encoded proteins was measured by flow cytometry. Two proteins (caldesmon and myeloid nuclear differentiation antigen) were only weakly expressed in leukemic cells despite strong hybridization signals in the array. By contrast, 7 proteins (CD58, creatine kinase B, ninjurin1, Ref1, calpastatin, HDJ-2, and annexin VI) were expressed in B-lineage ALL cells at higher levels than in normal CD19(+)CD10(+) B-cell progenitors (P <.05 in all comparisons). CD58 was chosen for further analysis because of its abundant and prevalent overexpression. An anti-CD58 antibody identified residual leukemic cells (0.01% to 1.13%; median, 0.03%) in 9 of 104 bone marrow samples from children with ALL in clinical remission. MRD estimates by CD58 staining correlated well with those of polymerase chain reaction amplification of immunoglobulin genes. These results indicate that studies of gene expression with cDNA arrays can aid the discovery of leukemia markers. (Blood. 2001;97:2115-2120)

Adolescent↗
PubMed2001

Immediate neurocognitive effects of methylphenidate on learning-impaired survivors of childhood cancer.

PURPOSE: To test if methylphenidate (MPH) has an objective beneficial effect on immediate performance on tests of neurocognitive functions among learning-impaired survivors of childhood acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT). PATIENTS AND METHODS: From July 1, 1997 through December 31, 1998, 104 long-term survivors of childhood ALL or a malignant BT completed neurocognitive screening for learning impairments and concurrent problems with sustained attention. Eligibility criteria for the MPH trial included an estimated intelligence quotient greater than 50, academic achievement in the 16(th) percentile or lower for age in reading, math, or spelling, and an ability to sustain attention on a computerized version of the Conners' Continuous Performance Test (CPT) in the 16(th) percentile or lower for age and sex. Of the 104, 32 (BT, n = 25; ALL, n = 7) were eligible on the basis of these a priori criteria for a randomized, double-blinded, placebo-controlled trial of MPH. The patients ingested a placebo (lactose) or MPH (0.6 mg/kg; 20 mg maximum) and repeated selected portions of the screening battery 90 minutes later. RESULTS: Compared to the 17 patients randomized to the placebo group, the 15 patients randomized to the MPH group had a significantly greater improvement on the CPT for sustained attention (errors of omission, P =.015) and overall index (P =.008) but not for errors of commission (indicative of impulsiveness) nor reaction times. A trend for greater improvement in the MPH group on a measure of verbal memory failed to reach statistical significance. No trend was observed for MPH effectiveness in improving learning of a word association task. No significant side effects from MPH were observed. CONCLUSION: MPH resulted in a statistically significant improvement on measures of attention abilities that cannot be explained by placebo or practice effects.

Administration, Oral↗
PubMed2001

Interleukin-4 variant (BAY 36-1677) selectively induces apoptosis in acute lymphoblastic leukemia cells.

Interleukin 4 (IL-4) suppresses the growth of acute lymphoblastic leukemia (ALL) cells, but its clinical usefulness is limited by proinflammatory activity due mainly to the interaction of cytokine with endothelial cells and fibroblasts. Stroma-supported cultures of leukemic lymphoblasts were used to test the antileukemic activity of an IL-4 variant, BAY 36-1677, in which the mutations Arg 121 to Glu and Thr 13 to Asp ensure high affinity for IL-4Ralpha/IL-2Rgamma receptors expressed by lymphoid cells, without activation of the IL-4Ralpha/IL-13Ralpha receptors mainly expressed by other cells. BAY 36-1677 (25 ng/mL) was cytotoxic in 14 of 16 cases of B-lineage ALL; the median reduction in cell recovery after 7 days of culture was 85% (range, 17%-95%) compared to results of parallel cultures not exposed to the cytokine. Twelve of the 14 sensitive cases had t(9;22) or 11q23 abnormalities; 3 were obtained at relapse. BAY 36-1677 induced apoptosis in leukemic lymphoblasts but did not substantially affect the growth of normal CD34+ cells, thus conferring a growth advantage to normal hematopoietic cells over leukemic lymphoblasts in vitro. BAY 36-1677 had antileukemic activity equal or superior to that produced by native IL-4, but it lacked any effects on the growth of endothelial cells and fibroblasts. The molecular manipulation of IL-4 to abrogate its proinflammatory activity has generated a novel and therapeutically promising cytokine for the treatment of high-risk ALL.

Adolescent↗
PubMed2001

Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma.

PURPOSE: To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys. PATIENTS AND METHODS: We administered Rasburicase intravenously, at 0.15 or 0.20 mg/kg, for 5 to 7 consecutive days to 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens. Blood levels of uric acid, creatinine, phosphorus, and potassium were measured daily. The pharmacokinetics of Rasburicase, the urinary excretion rate of allantoin, and antibodies to Rasburicase were also studied. RESULTS: At either dosage, the recombinant enzyme produced a rapid and sharp decrease in plasma uric acid concentrations in all patients. The median level decreased by 4 hours after treatment, from 9.7 to 1 mg/dL (P =.0001), in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (P =.0001) in the remaining 66 patients. Despite cytoreductive chemotherapy, plasma uric acid concentrations remained low throughout the treatment (daily median level, 0.5 mg/dL). The urinary excretion rate of allantoin increased during Rasburicase treatment, peaking on day 3. Serum phosphorus concentrations did not change significantly during the first 3 days of treatment, decreased significantly by day 4 in patients presenting with hyperuricemia (P =.0003), and fell within the normal range in all patients by 48 hours after treatment. Serum creatinine levels decreased significantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (P =.0003 and P =.02, respectively) and returned to normal range in all patients by day 6 of treatment. Toxicity was negligible, and none of the patients required dialysis. The mean plasma half-lives of the agent were 16.0 +/- 6.3 (SD) hours and 21.1 +/- 12.0 hours, respectively, in patients treated at dosages of 0.15 or 0.20 mg/kg. Seventeen of the 121 assessable patients developed antibodies to the enzyme. CONCLUSION: Rasburicase is safe and highly effective for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.

Adolescent↗
PubMed2001

Urate oxidase in the prophylaxis or treatment of hyperuricemia: the United States experience.

Nonrecombinant urate oxidase (Uricozyme, Sanofi-Synthélabo, Inc, Paris, France) is a highly effective uricolytic agent, but its use is associated with hypersensitivity reaction manifested mainly by bronchospasm in approximately 5% of patients. Recently, several multi-institutional studies have evaluated the efficacy and safety of a recombinant urate oxidase (rasburicase). In a phase I/II study, all 131 patients with newly diagnosed acute lymphoblastic leukemia (ALL) or stage III/IV non-Hodgkin's lymphoma (NHL) experienced rapidly decreased plasma uric acid concentrations after receiving recombinant urate oxidase. Serum creatinine levels also decreased significantly. Toxicity was negligible, and none of the patients required dialysis. In a phase III trial, children with newly diagnosed ALL or stage III/IV NHL were stratified and randomized to receive recombinant urate oxidase or allopurinol. Results showed that the 27 patients who received recombinant urate oxidase had a significantly lower plasma uric acid concentration and a more rapid decline in serum creatinine level than did the 25 who took allopurinol. One patient in the recombinant urate oxidase group had hemolysis of unknown cause, and one in the allopurinol group required hemofiltration for hyperphosphatemia. To further assess the safety profile of recombinant urate oxidase, the data on 245 patients (173 children and 72 adults) who received this agent in a compassionate-use program were reviewed retrospectively. The drug produced dramatic decreases in uric acid concentrations in all patients. Nine patients (four children and five adults) had mild adverse reactions that were drug-related or of unknown etiology. These data suggest that recombinant urate oxidase is safe and effective in the prophylaxis and treatment of hyperuricemia associated with malignancy or chemotherapy.

Allopurinol↗
PubMed2001

Childhood acute lymphoblastic leukaemia--current status and future perspectives.

The current cure rate of 80% in childhood acute lymphoblastic leukaemia attests to the effectiveness of risk-directed therapy developed through well-designed clinical trials. In the past decade there have been remarkable advances in the definition of the molecular abnormalities involved in leukaemogenesis and drug resistance. These advances have led to the development of promising new therapeutic strategies, including agents targeted to the molecular lesions that cause leukaemia. The importance of host pharmacogenetics has also been recognised. Thus, genetic polymorphisms of certain enzymes have been linked with host susceptibility to the development of de novo leukaemia or therapy-related second cancers. Furthermore, recognition of inherited differences in the metabolism of antileukaemic agents has provided rational selection criteria for optimal drug dosages and scheduling. Treatment response assessed by measurements of submicroscopic leukaemia (minimal residual disease) has emerged as a powerful and independent prognostic indicator for gauging the intensity of therapy. Ultimately, treatment based on biological features of leukaemic cells, host genetics, and the amount of residual disease should improve cure rates further.

Child↗
PubMed2001

Allogeneic bone marrow transplantation for infants with acute leukemia or myelodysplastic syndrome.

The objective of this study is to investigate the outcome of children 24 months of age or younger (infants) at the time of allogeneic bone marrow transplantation (BMT) for acute leukemia or myelodysplasia. We analyzed the survival rate, prognostic factors, incidences of late sequelae, and immune reconstitution in 22 infants who underwent allogeneic BMT. The 5-year event-free survival estimate was 45.5% (95% confidence interval (CI), 24.4% to 63.3%). Six patients died of transplant-related complications and six died of disease relapse. Remission status at the time of BMT was the most important prognostic factor (P = 0.005): no patient who received a transplant while their disease was not in remission survived, whereas the 5-year survival estimate for infants who underwent BMT during remission was 56% (95% CI, 31% to 75%). Long-term outcomes in the 10 infant survivors were compared with those of 10 older controls matched for diagnosis, disease status at the time of BMT, calendar year at the time of BMT, and source of stem cells. Immune function 1 year after transplantation and the incidences and spectra of late sequelae were similar for both groups during a median of 3.5 years (range, 1.5 to 7.2 years) of follow-up.

Acute Disease↗