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Ching-Hon Pui

Publications and source records attributed to Ching-Hon Pui.

At least 55 records · Page 3Linked to original sources
PubMed2005

Global gene expression as a function of germline genetic variation.

Common, functional, germline genetic polymorphisms have been associated with clinical cancer outcomes. Little attention has been paid to the potential phenotypic consequences of germline genetic variation on downstream genes. We determined the germline status of 16 well-characterized functional polymorphisms in 126 children with newly diagnosed acute lymphoblastic leukemia (ALL). We assessed whether global gene expression profiles of diagnostic ALL blasts from the same patients differed by these germline polymorphic genotypes. Gene expression values were adjusted for ALL-subtype-specific patterns. Of the 16 loci, only the UGT1A1 promoter repeat polymorphism [A(TA)nTAA] (UGT1A1*28) and GSTM1 deletion were significant predictors of global gene expression in a supervised approach, which divided patients based on their germline genotypes [UGT1A1: 124 probe sets, false discovery rate (FDR)=13%, P< or =0.0031; GSTM1: 112 probe sets, FDR=42.5%, P< or =0.0084]. Genes whose expression distinguished the UGT1A1 (TA) 7/7 genotype from the other UGT1A1 genotypes included HDAC1, RELA and SLC2A1; those that distinguished the GSTM1 null genotype from non-null genotype included NBS1 and PRKR. In an unsupervised approach, the gene expression profiles using the entire array delineated two major clusters of patients. The only germline genotype frequency that differed between the two clusters was UGT1A1 (P=0.002; Fisher's exact test). Although their expression is limited to specific tissues, both GSTM1 and UGT1A1 are involved in the conjugation (and thus transport, excretion and lipophilicity) of a broad range of endobiotics and xenobiotics, which could plausibly have consequences for gene expression in different tissues.

Child↗
PubMed2005

Pharmacogenetics of outcome in children with acute lymphoblastic leukemia.

Acquired genetic characteristics of acute lymphoblastic leukemia (ALL) cells are used to individualize therapy, whereas germ line genetic characteristics generally are not. We determined whether ALL outcome was related to 16 genetic polymorphisms affecting the pharmacodynamics of antileukemic agents. Of 246 children, 116 were treated on the lower-risk (LR) and 130 on the higher-risk (HR) arms of a St Jude protocol. Patients in the HR group with the glutathione S-transferase (GSTM1) non-null genotype had greater risk of hematologic relapse (P = .03), which was further increased by the thymidylate synthetase (TYMS) 3/3 genotype (P = .03). These genotypes remained predictive in multivariate analyses (P < .001 and .003, respectively). No genotypes were predictive in the LR arm. Expression of these 2 genes in ALL blasts was lower in those with low-activity genotypes. For central nervous system relapse, among the HR group, the vitamin D receptor start site (P = .02) and intron 8 genotypes (P = .04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (P = .04). The GSTM1 non-null and TYMS 3/3 genotypes are plausibly linked to drug resistance. Polymorphisms interact to influence antileukemic outcome and represent determinants of response that can be used to optimize therapy.

Alleles↗
PubMed2005

Bone marrow recurrence after initial intensive treatment for childhood acute lymphoblastic leukemia.

BACKGROUND: The authors studied the clinical outcome of 106 children with acute lymphoblastic leukemia (ALL) who developed a bone marrow recurrence as the first adverse event after contemporary intensified therapy. METHODS: Endpoints were the rates and lengths of second remission, the cumulative incidence of second hematologic recurrence, second event-free survival (EFS), and survival. RESULTS: Bone marrow recurrences were isolated in 79 patients, and combined with an extramedullary site in 27 patients. The median time to recurrence was 2.6 years (range, 0.3-11.6 years). Seventy-six patients (71.7%) attained a second remission (median length, 0.7 year; range, 0.03-13.3 years). The 5-year survival probability among all patients was 24.2% +/- 4.2% (standard error). On multivariate analysis, time to first disease recurrence and blast cell lineage were found to be independent predictors of a second EFS (P = 0.008 and P = 0.028, respectively). The 5-year EFS estimate in patients with an initial disease remission of >/= 36 months was 42.6% +/- 7.8% but was only 12.5% +/- 3.9% among children with a short duration of disease remission (< 36 months). These estimates were 28.7% +/- 4.9% and 5.0% +/- 3.4%, respectively, for B blast and T blast cell lineages. CONCLUSIONS: Despite acceptable long-term second EFS rates for certain subgroups, overall bone marrow recurrence after intensified first-line therapy for childhood ALL signals a poor outcome.

Adolescent↗
PubMed2005

Lymphoid gene expression as a predictor of risk of secondary brain tumors.

Gene expression profiles are tissue-specific but may also reflect germ-line-driven expression patterns across tissue types. Previously, using a targeted pharmacologic approach, we identified germ-line polymorphisms in a single gene (thiopurine methyltransferase) associated with the risk of irradiation- and chemotherapy-induced secondary brain tumors in children with acute lymphoblastic leukemia (ALL). To identify additional candidate genetic risk factors, in identically treated patients, we compared the gene expression profiles of diagnostic ALL blasts of those who did develop irradiation-associated brain tumors (n = 9) with the profiles from those who did not (n = 33). Weighted rank regression was used to identify 33 probe sets associated with the time-dependent development of brain tumors; k-means clustering (k = 2) identified 2 groups that differed significantly in cumulative incidence of brain tumors (P = 0.012). Permutation analysis was used to estimate the probability (P = 0.18) of obtaining 2 such clusters by chance. Linear discriminant analysis (time-independent categorization of outcome) was used to identify 70 probe sets whose expression differentiated between the 2 groups of patients. Permutation analyses (n = 1,000) was used to estimate the probability of selecting these probe sets by chance (P = 0.055). Five probe sets were in common between the time-independent and time-dependent methods. The distinguishing genes are involved in neural growth (FGFR1) and in nuclear trafficking (HNRPL, KPNB1). These data suggest that gene expression profiling from accessible tissues may identify targets involved in therapy-related malignancies in unrelated tissues.

Adolescent↗
PubMed2005

Lack of benefit of early detection of relapse after completion of therapy for acute lymphoblastic leukemia.

BACKGROUND: Although most pediatric oncologists obtain routine blood counts in patients who have completed treatment for acute lymphoblastic leukemia (ALL), the value of this practice is unproven. We therefore sought to determine if detection of relapse by blood counts before the onset of symptoms provided any clinical benefit. PROCEDURES: We performed a retrospective review of 72 patients with ALL who suffered isolated or combined hematologic relapses after the completion of therapy. We compared attainment of second remission and survival after relapse among patients who were asymptomatic and diagnosed by routine blood count, those who had symptoms suggestive of relapse and were diagnosed at the time of a scheduled follow-up, and those whose relapse was diagnosed because of the appearance of symptoms. RESULTS: Only 11% of patients who suffered a relapse were asymptomatic at the time of relapse and diagnosed solely by routine blood counts. There were no significant differences in the survival distributions for the three groups of patients. CONCLUSIONS: In this cohort of patients with relapsed ALL, we found no evidence that detection of relapse by routine blood counts before the onset of symptoms leads to a better outcome.

Adolescent↗
PubMed2005

Early complications in children with acute lymphoblastic leukemia presenting with hyperleukocytosis.

BACKGROUND: The optimal management of childhood acute lymphoblastic leukemia (ALL) with hyperleukocytosis is unclear, largely because the risk of leukostasis-related complications is poorly characterized. PROCEDURE: We reviewed the presenting characteristics, initial management, and frequency and type of complications in all children seen at St. Jude Children's Research Hospital with previously untreated ALL and an initial leukocyte count >200 x 10(9)/L. RESULTS: A total of 178 children, representing 8% of all children with ALL, had an initial leukocyte count >200 x 10(9)/L; 67 patients had a leukocyte count >400 x 10(9)/L. Sixteen patients (9%) had neurological complications with 12 of these patients experiencing symptoms at presentation. Four patients (2%), all with initial leukocyte counts >400 x 10(9)/L, suffered a CNS hemorrhage. Pulmonary leukostasis occurred in 11 patients (6%). The degree of hyperleukocytosis was significantly predictive of neurological (P = 0.006) and respiratory (P = 0.014) complications. The majority of complications occurred at presentation. Cytoreduction (94 patients) decreased the leukocyte count but delayed initiation of chemotherapy (P = 0.013). CONCLUSIONS: Serious leukostasis-related complications are relatively uncommon in childhood ALL and most occur at presentation. Their incidence increases in proportion to the leukocyte count. A large subset of cases can be managed successfully without cytoreduction. Cytoreduction may be considered for patients with leukocyte counts >400 x 10(9)/L or patients who have complications at presentation.

Acute Kidney Injury↗
PubMed2005

Severe cardiopulmonary complications consistent with systemic inflammatory response syndrome caused by leukemia cell lysis in childhood acute myelomonocytic or monocytic leukemia.

BACKGROUND: Life-threatening pulmonary complications that coincide with cell lysis during early chemotherapy and that mimic systemic inflammatory response syndrome (SIRS) have been reported in patients with acute myeloid leukemia (AML). METHODS: We reviewed the records of patients with de novo AML, excluding M3 and Down syndrome, treated at our institution between 1991 and 2002 to determine the prevalence of severe SIRS with grade 3/4 pulmonary complications and to identify AML subtypes associated with severe SIRS. To examine the role of cell lysis, we compared leukocyte reduction in AML subtypes affected by severe SIRS with that in unaffected subtypes. RESULTS: Of 155 patients, 5 (3 with M4eo and 2 with M5) experienced severe pulmonary complications attributed to tumor lysis, met the criteria for severe SIRS, and showed no clear evidence of infection. Four required pressor support for severe hypotension. Severe SIRS was significantly more common in myelomonocytic or monocytic AML (M4/M4eo/M5) than in other subtypes (P = 0.010) and significantly more common in M4eo than in M4/M5 (P = 0.008). Among 112 cases for which information was available, leukocyte reduction was significantly greater in patients with M4/M4eo/M5 than among others during the first 4 days of chemotherapy (P = 0.015). Leukocyte reduction was significantly more rapid among patients who had severe SIRS than among others (P = 0.008). CONCLUSIONS: Patients with M4/M4eo/M5 AML, especially M4eo, experience life-threatening cardiopulmonary complications of tumor lysis that meet the criteria for severe SIRS. This observation may reflect more rapid cell reduction and the unique biology of this subtype.

Adolescent↗
PubMed2005

Myositis complicating viridans streptococcal sepsis in childhood leukemia.

Hematogenous focal infections are a rare complication of bacteremia or sepsis caused by viridans-group streptococci. We describe two patients with acute leukemia who developed myositis during alpha-hemolytic streptococcal bacteremia. Children complaining of severe muscle pain associated with viridans streptococcal infections should be carefully evaluated for the presence of focal pyogenic complications and rhabdomyolysis. The severity of infectious myositis is highly variable, depending on the etiologic organism and host immunity, making individualized treatment the most effective approach.

Adolescent↗
PubMed2005

Proxy assessment of quality of life in pediatric clinical trials: application of the Health Utilities Index 3.

BACKGROUND: With increased cure rates, pediatric oncology protocols increasingly seek to document the impact of treatment on patients' disease, symptoms, and functional capacity. PROCEDURE: Nurses as proxy respondents used the Health Utilities Index 3 (HUI3) to assess the health-related quality of life (HRQL) in twenty-five patients (age 6 years or older) enrolled on a frontline protocol for leukemia. HRQL observations (n = 70) were made at three different time points to coincide with high-dose methotrexate therapy. Additionally, the proxy respondents evaluated the ease of use of the instrument and the data quality. RESULTS: As patients' health status declined, the number of unassessable HRQL items increased. These missing data made scoring cumbersome and precluded calculation of the overall HRQL scores for nearly 50% of the patients. CONCLUSIONS: Use of the provider proxy-assessed HUI3 in pediatric cancer trials may result in a high proportion of missing data. Trials may benefit more from the use of HRQL measures that consider the acuity of the child's illness, domains specific and sensitive to both disease and treatment, and items that can be proxy-assessed independent of input from parent or patient. Evaluations that combine child self-reports with both parent and provider reports may ultimately provide the most reliable and comprehensive perspective on children's quality of life.

Adolescent↗
PubMed2005

Identification of genes associated with chemotherapy crossresistance and treatment response in childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) can be cured with combination chemotherapy in over 75% of children, but the cause of treatment failure in the remaining patients is unknown. We determined the sensitivity of ALL cells to individual antileukemic agents in 441 patients and used a genome-wide approach to identify 45 genes differentially expressed in ALL exhibiting crossresistance to prednisolone, vincristine, asparaginase, and daunorubicin. We also identified a distinct phenotype of discordant resistance to asparaginase and vincristine and 139 genes whose expression was associated with this novel phenotype. The expression of these genes discriminated treatment outcome in two independent patient populations, identifying a subset of patients with a markedly inferior outcome (37% +/- 13% 5 year DFS).

Age Factors↗
PubMed2005

Clofarabine.

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Adenine Nucleotides↗
PubMed2005

Premedication with acetaminophen or diphenhydramine for transfusion with leucoreduced blood products in children.

Febrile non-haemolytic or allergic reactions occur in 0.1-30% of transfusions; physicians often premedicate patients with acetaminophen or diphenhydramine to prevent these reactions. The effectiveness of this practice has not been demonstrated. In this retrospective review of all transfusions at our institution during 2002, 385 patients received 7900 evaluable leucoreduced, irradiated blood products (4280 single-donor apheresis platelets and 3620 packed red blood cells). Febrile reactions occurred in 0.95% of 4108 transfusions with, and 0.53% of 3792 transfusions without, acetaminophen premedication. Allergic reactions occurred in 0.90% of 4315 transfusions with, and 0.56% of 3585 transfusions without, diphenhydramine premedication. In a multivariate analysis that adjusted for age, patient category, transfusion location, product, transfusion history, and reaction history, premedication with acetaminophen was associated with a statistically non-significant increase in the odds of a febrile reaction (odds ratio 1.74; 95% confidence interval 0.71-4.23; P = 0.22), and diphenhydramine with a non-significant increase in allergic reactions (odds ratio 1.74; 95% confidence interval 0.99-3.06; P = 0.054). Reactions occurred in only 1.3% of the 518 transfusions to patients with a history of two or more prior reactions. Febrile and allergic transfusion reactions were rare in paediatric patients transfused with leucoreduced, irradiated blood products, whether premedication was used or not.

Acetaminophen↗
PubMed2005

Recombinant urate oxidase (rasburicase) in the prophylaxis and treatment of tumor lysis syndrome.

Spontaneous or treatment-induced tumor lysis syndrome (TLS) can cause significant morbidity and potential mortality. Vigorous hydration, alkalinization and inhibition of uric acid synthesis are the most frequently used methods for prevention of TLS. However, this approach requires hospitalization and tedious nursing care, and fails to prevent renal insufficiency in up to 25% of high-risk patients. With increased intensity and efficacy of cancer therapies, and the current trend to deliver treatment in the outpatient setting, novel approaches at management of TLS are needed. Unlike allopurinol, urate oxidase promptly reduces the existing uric acid pool, prevents accumulation of xanthine and hypoxanthine, and does not require alkalinization, facilitating phosphorus excretion. A recombinant form of urate oxidase, rasburicase, is now available. In this chapter we will present an overview of rasburicase development and discuss the impact of rasburicase in the prevention and management of TLS.

Allopurinol↗
PubMed2005

Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics.

The ability of leukemia cells to accumulate methotrexate polyglutamate (MTXPG) is an important determinant of the antileukemic effects of methotrexate (MTX). We measured in vivo MTXPG accumulation in leukemia cells from 101 children with acute lymphoblastic leukemia (ALL) and established that B-lineage ALL with either TEL-AML1 or E2A-PBX1 gene fusion, or T-lineage ALL, accumulates significantly lower MTXPG compared with B-lineage ALL without these genetic abnormalities or compared with hyperdiploid (fewer than 50 chromosomes) ALL. To elucidate mechanisms underlying these differences in MTXPG accumulation, we used oligonucleotide microarrays to analyze expression of 32 folate pathway genes in diagnostic leukemia cells from 197 children. This revealed ALL subtype-specific patterns of folate pathway gene expression that were significantly related to MTXPG accumulation. We found significantly lower expression of the reduced folate carrier (SLC19A1, an MTX uptake transporter) in E2A-PBX1 ALL, significantly higher expression of breast cancer resistance protein (ABCG2, an MTX efflux transporter) in TEL-AML1 ALL, and lower expression of FPGS (which catalyzes formation of MTXPG) in T-lineage ALL, consistent with lower MTXPG accumulation in these ALL subtypes. These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome these potential causes of treatment failure in childhood ALL.

Cluster Analysis↗
PubMed2005

Prevalence of leukoencephalopathy in children treated for acute lymphoblastic leukemia with high-dose methotrexate.

BACKGROUND AND PURPOSE: An effective treatment for acute lymphoblastic leukemia (ALL), intravenous (IV) methotrexate (MTX) has a notable toxic effect on the CNS, with leukoencephalopathy (LE) being the most common form. The purpose of this study was to use objective quantitative MR imaging to prospectively assess potential risk factors on the temporal evolution of LE in patients treated for ALL. METHODS: We evaluated the longitudinal prevalence of LE in 45 children treated for ALL in a single institutional protocol including seven courses of IV MTX and no cranial irradiation. Differences in signal intensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images between hyperintense regions and normal-appearing genu were used to quantitatively detect LE. Cox proportional regression was used to estimate the effect of covariates (e.g., sex, MTX dose, age at diagnosis) on the prevalence of LE. After influential factors were identified, a generalized linear model was determined to predict the probability of LE in new patients. The model was necessary to facilitate statistical testing between examinations. RESULTS: Increasing exposure, which corresponding to more courses and higher doses of IV MTX, influenced the prevalence of LE. The prevalence of LE was significant reduced approximately 1.5 years after the completion of IV MTX. CONCLUSION: Higher doses and more courses of IV MTX placed patients at a higher risk for LE; many of the changes resolved after the completion of therapy. The effect of these changes on neurocognitive functioning and quality of life in survivors remains to be determined.

Adolescent↗