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Ching-Hon Pui

Publications and source records attributed to Ching-Hon Pui.

At least 37 records · Page 2Linked to original sources
PubMed2006

Cancer survivorship--genetic susceptibility and second primary cancers: research strategies and recommendations.

Cancer survivors constitute 3.5% of the United States population, but second primary malignancies among this high-risk group now account for 16% of all cancer incidence. Although few data currently exist regarding the molecular mechanisms for second primary cancers and other late outcomes after cancer treatment, the careful measurement and documentation of potentially carcinogenic treatments (chemotherapy and radiotherapy) provide a unique platform for in vivo research on gene-environment interactions in human carcinogenesis. We review research priorities identified during a National Cancer Institute (NCI)-sponsored workshop entitled "Cancer Survivorship--Genetic Susceptibility and Second Primary Cancers." These priorities include 1) development of a national research infrastructure for studies of cancer survivorship; 2) creation of a coordinated system for biospecimen collection; 3) development of new technology, bioinformatics, and biomarkers; 4) design of new epidemiologic methods; and 5) development of evidence-based clinical practice guidelines. Many of the infrastructure resources and design strategies that would facilitate research in this area also provide a foundation for the study of other important nonneoplastic late effects of treatment and psychosocial concerns among cancer survivors. These research areas warrant high priority to promote NCI's goal of eliminating pain and suffering related to cancer.

Antineoplastic Agents↗
PubMed2006

Natural history of thyroid nodules in survivors of pediatric Hodgkin lymphoma.

BACKGROUND: Survivors of Hodgkin lymphoma and other patients who receive neck irradiation are at increased risk of thyroid cancer. Ultrasonography provides an inexpensive and non-invasive method of thyroid screening, but the clinical significance of thyroid nodules detected by ultrasound screening is uncertain. PROCEDURE: We reviewed the demographics, clinical characteristics, method of detection, and outcome of patients who developed thyroid nodules after treatment for pediatric Hodgkin lymphoma at our institution. One radiologist reviewed all imaging studies. RESULTS: Sixty-seven children treated for Hodgkin lymphoma from 1962 to 2001 developed thyroid nodules. The study group represented 9,024 person-years of follow-up after the diagnosis of Hodgkin lymphoma and 581 person-years after diagnosis of a thyroid nodule. A median of 10.5 years (range, 0.2-24.8 years) elapsed between the diagnoses of Hodgkin lymphoma and thyroid nodule(s). All but one patient had received neck irradiation for Hodgkin lymphoma, with a median thyroid radiation dose of 35 Gy (range, 12-45 Gy). Thyroid nodules were found to be malignant in seven patients (10%), at a median of 16.2 years (range, 8.4-23.7 years) after diagnosis of Hodgkin lymphoma. Only one malignancy was found through screening ultrasonography. All patients with thyroid cancer remained disease-free at 0.4-16.2 years of follow-up. CONCLUSIONS: Thyroid nodules are common in Hodgkin lymphoma survivors treated with neck irradiation, but the majority of these lesions have an indolent clinical course and do not undergo malignant transformation. Only patients with a palpable mass or clinical symptoms need more extensive evaluation, including Doppler-flow ultrasonography and fine-needle aspiration.

Disease-Free Survival↗
PubMed2006

Changes in bone mineral density in survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: There is little information about factors modulating bone mineral density (BMD) in survivors of childhood acute lymphoblastic leukemia (ALL). PROCEDURE: We analyzed data from 57 survivors (26 male, 52 Caucasian) who underwent two serial quantitative computed tomography (QCT) studies of BMD. Using multiple linear regression, we evaluated the association of BMD change with demographic variables, treatment history, hormone therapy, exercise, and tobacco and alcohol use. RESULTS: The median age was 3.4 years (range, 0.9-17.4 years) at diagnosis of ALL; the median age at the first QCT (Study I) was 15.0 years (range, 10.6-31.0 years) and at the second QCT (Study II) was 18.2 years (range, 14.2-35.3 years). Mean height increased 4.7 cm and mean weight increased 8.8 kg between Studies I and II. While the mean BMD increased 9.33 mg/cc (P = 0.003), the BMD Z-score increased only slightly (0.21 SD, P = 0.035). Cortical bone density increased significantly (approximately 25.3 mg/cc; P = 0.001), but the ratio of trabecular to cortical BMD decreased significantly (P = 0.045). Factors independently associated with unfavorable BMD changes included older age at diagnosis (P = 0.001), female sex (P = 0.018), and nutritional supplementation (0.032). Alcohol (P = 0.009) was an unfavorable factor in a univariable analysis. CONCLUSIONS: Bone mineral accretion during adolescence is attenuated in childhood ALL survivors by a comparative deficit in trabecular versus cortical bone deposition. BMD is influenced favorably by exercise in early adolescence and unfavorably by the use of nutritional supplements and alcohol. These results provide new information about behavioral factors that affect bone accrual in survivors of childhood ALL and warrant definitive evaluation in a larger cohort.

Adolescent↗
PubMed2006

Outcome of hematopoietic stem cell transplantation for pediatric patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome.

BACKGROUND: Therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) carry a poor prognosis. We analyzed the results of allogeneic HSCT in 38 children to determine which factors, if any, affected outcome. PROCEDURE: The effects of demographic, donor, and disease-related factors were analyzed to determine their effects on overall and disease-free survival (OS, DFS), relapse, and non-relapse mortality (NRM). RESULTS: OS and DFS for t-AML and t-MDS were similar. Three-year OS and EFS were the same (15.4 +/- 5.8%) and the 3-year NRM was 59.6 +/- 8.4%. The 1-year cumulative risk of grade III-IV acute graft-versus-host disease (GVHD) and relapse were 23.7 +/- 7.0% and 18.7 +/- 6.5%, respectively. The percentage of pre-transplant bone marrow (BM) blasts was positively associated with relapse (P = 0.05), while the percentage of BM blasts at diagnosis of therapy-related disease tended to associate with NRM (P = 0.07). Alternative donor and matched sibling donor grafts had similar outcomes. NRM was higher among patients who did not develop acute GVHD as compared to those with grade 1-2 acute GVHD (69.2 +/- 14.2% vs. +/- 12.7%, respectively), while NRM was 100% in patients with grade III-IV acute GVHD (P = 0.007). CONCLUSIONS: The percentage of BM blasts is associated with relapse in these disorders. High rates of NRM negatively impact the outcome of allogeneic HSCT for children with t-AML and t-MDS. Future studies should focus on reducing NRM.

Adolescent↗
PubMed2006

Near-triploidy and near-tetraploidy in childhood acute lymphoblastic leukemia: association with B-lineage blast cells carrying the ETV6-RUNX1 fusion, T-lineage immunophenotype, and favorable outcome.

The prognostic significance of near-triploidy (68-80 chromosomes) and near-tetraploidy (>80 chromosomes) in childhood acute lymphoblastic leukemia (ALL) is unclear. Therefore, we retrospectively evaluated the incidence of and outcome associated with these subtypes of ALL. In 620 children with ALL diagnosed between 1988 and 1999, the leukemic cells were near-triploid (DNA index, 1.50-1.73) in 4 and near-tetraploid (DNA index, 1.79-2.28) in 14. Of 15 patients with B-lineage ALL, 11 (73.3%) had an ETV6-RUNX1 (previously TEL-AML1 and then ETV6-CBFA2) fusion. No differences in age (P = 0.99), leukocyte count (P = 0.99), or immunophenotype (P = 0.99) were observed between patients with near-triploidy and those with near-tetraploidy. Patients with near-triploidy or near-tetraploidy were more likely than those with high-hyperdiploidy (51-67 chromosomes) (n = 159) to be female (P = 0.05) and have T-lineage ALL (P = 0.02), L2 morphology (P < 0.0001), or the ETV6-RUNX1 fusion (P < 0.0001). The median follow-up period was 10.4 years. The 5-year event-free survival estimates (+/- SE) were 75% +/- 19% for patients with near-triploidy, 93% +/- 7% for those with near-tetraploidy, and 84% +/- 3% for those with high-hyperdiploidy. Although near-triploidy and near-tetraploidy are biologically different from high-hyperdiploidy, the favorable outcomes of patients with any one of these abnormalities suggest that patients with B-lineage ALL and a DNA index >or= 1.16 can be included in the low-risk arm of treatment protocols. We cannot make similar recommendations for patients with T-lineage ALL because of the small number of cases (n = 3) in this study.

B-Lymphocytes↗
PubMed2006

Central nervous system disease in acute lymphoblastic leukemia: prophylaxis and treatment.

Improved treatment for acute lymphoblastic leukemia (ALL) has virtually eliminated testicular relapse. However, the control of central nervous system (CNS) leukemia remains a therapeutic challenge in childhood ALL, partly because of the late complications arising from cranial irradiation. In most current pediatric protocols, cranial irradiation (12 to 18 Gy) is given to 5% to 25% of patients--those with T-cell ALL, overt CNS disease (CNS3 status) or high-risk cytogenetics. CNS control is a less urgent concern in adults with ALL, in whom systemic relapse remains the major problem. With current approaches, approximately 2% to 10% of patients can be expected to develop CNS relapse. Children with B-cell precursor ALL who have a late CNS relapse (after an initial remission of 18 months or more) and did not receive cranial irradiation have an excellent outcome after retrieval therapy, with a 5-year event-free survival (EFS) rate approaching that in newly diagnosed patients. Innovative treatment options are needed for children who develop CNS relapses after a short initial remission or after receiving cranial irradiation, and in any adults with CNS leukemia at diagnosis or relapse.

Central Nervous System Neoplasms↗
PubMed2006

MRI of knee osteonecrosis in children with leukemia and lymphoma: Part 2, clinical and imaging patterns.

OBJECTIVE: This aim of this study was to explore the relationship between MRI findings and clinical symptoms of knee osteonecrosis in children and to determine the significance of this relationship. Such information is important for early diagnosis of this frequent complication and for choosing an appropriate treatment strategy. MATERIALS AND METHODS: Osteonecrotic lesion size and location were determined in a retrospective analysis of MR images of the knee obtained in our institution during the past 10 years. Association between MRI findings and clinical symptoms expressed by the knee scores was tested for a subgroup of our patient population who had clinical evaluation of the knees in the orthopedic clinic within 6 weeks of their MRI studies. RESULTS: In 80% of patients, osteonecrosis was bilateral. Lesions were distributed as follows: femur and tibia, 66% of the knees; femur alone, 26%; and tibia alone, 8%. Clinical symptoms of knee osteonecrosis were associated with lesions involving the articular surface of the distal femur, large lesions, and involvement of any part of the tibia. MR images showed milder osteonecrosis in patients who were less than 10 years old at the time of primary diagnosis. CONCLUSION: Osteonecrosis affecting the knees of children treated for leukemia and lymphoma is mostly asymptomatic. Children who are 10 years old or older have signs of more advanced osteonecrosis. Clinical symptoms often lag MRI presentation and may develop late in the course of the disease. Routine MRI evaluation is recommended for timely diagnosis of treatment-induced osteonecrosis.

Adolescent↗
PubMed2005

Risk of adverse events after completion of therapy for childhood acute lymphoblastic leukemia.

PURPOSE: We studied the frequency, causes, and predictors of adverse events in children with acute lymphoblastic leukemia (ALL) who had completed treatment on contemporary clinical protocols between 1984 and 1999. Our goal was to use the information to further refine therapy and advance cure rates. METHODS: Cumulative incidence functions of any post-treatment failure or any post-treatment relapse were estimated by the method of Kalbfleisch and Prentice and compared with Gray's test. The Cox proportional hazards model was used to identify independent prognostic factors. RESULTS: Of the 827 patients who completed all treatment while in initial complete remission, 134 patients subsequently had major adverse events, including 90 leukemic relapses, 40 second malignancies, and four deaths in remission. The cumulative incidence of any adverse event was 14.0% +/- 1.2% (SE) at 5 years and 16.9% +/- 1.4% at 10 years. The risk of any leukemic relapse was 10.0% +/- 1.1% at 5 years and 11.4% +/- 1.2% at 10 years. Male sex was the only independent predictor of relapse (hazard ratio, 1.74; 95% CI, 1.11 to 2.74; P = .02). CONCLUSION: Further treatment refinements for children with ALL should aim not only to decrease the leukemic relapse rate, but also to reduce the risk of development of second malignancies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes.

The nature of mendelian inheritance assumes that all tissues in which a phenotype of interest is expressed have a uniform diploid karyotype, which is often not the case in cancer cells. Owing to nonrandom gains of chromosomes, trisomies are present in many cases of leukemia and other malignances. We used polymorphisms in the genes encoding thiopurine S-methyltransferase (TPMT), gamma-glutamyl hydrolase (GGH) and the reduced folate carrier (SLC19A1) to assess the nature of chromosomal acquisition and its influence on genotype-phenotype concordance in cancer cells. TPMT and GGH activities in somatic cells were concordant with germline genotypes, whereas activities in leukemia cells were determined by chromosomal number and whether the acquired chromosomes contained a wild-type or variant allele. Leukemia cells that had acquired an additional chromosome containing a wild-type TPMT or GGH allele had significantly lower accumulation of thioguanine nucleotides or methotrexate polyglutamates, respectively. Among these genes, there was a comparable number of acquired chromosomes with wild-type and variant alleles. Therefore, chromosomal gain can alter the concordance of germline genotype and cancer cell phenotypes, indicating that allele-specific quantitative genotyping may be required to define cancer pharmacogenomics unequivocally.

Adolescent↗
PubMed2005

Typhlitis in childhood cancer.

BACKGROUND: Typhlitis is increasingly recognized in children undergoing chemotherapy but is poorly characterized. The authors investigated the demographic, clinical, and imaging (ultrasonography and computed tomography [CT] scans) variables related to the diagnosis, risk, and outcome of typhlitis. METHODS: The authors reviewed the records of patients who had typhlitis (bowel wall thickness > or = 0.3 cm plus clinical findings) during treatment at St. Jude Children's Research Hospital (Memphis, TN) between 1990 and 2001. They assessed whether duration of typhlitis was related to bowel wall thickness, extent of colonic involvement, ascites, demographics, primary diagnosis, symptoms of typhlitis, or duration of neutropenia. To identify risk factors for typhlitis, the authors compared the demographic data and previous drug therapy of 78 patients who had typhlitis and 1231 identically treated children who did not. RESULTS: Of 3171 children, 83 (2.6%) developed typhlitis. Frequent symptoms were abdominal pain (91%), fever (84%), abdominal tenderness (82%), and diarrhea (72%). Twelve percent of the patients were not neutropenic. Duration of typhlitis was associated with bowel wall thickness measured by ultrasonography (n = 68; P = 0.05) but not CT scan (n = 48; P = 0.67) and was associated with duration of neutropenia (P = 0.02), fever (P = 0.01), and abdominal tenderness (P = 0.04). Age >16 years at cancer diagnosis was the only demographic factor associated with typhlitis (P = 0.03). Two patients died of typhlitis. CONCLUSIONS: Ultrasonography was a useful imaging modality for children with suspected typhlitis. The classic triad of abdominal pain, fever, and neutropenia may be absent. The severity of typhlitis was related to the duration of neutropenia and the presence of fever or abdominal tenderness.

Adolescent↗
PubMed2005

Gene expression and thioguanine nucleotide disposition in acute lymphoblastic leukemia after in vivo mercaptopurine treatment.

To elucidate interpatient variability in thioguanine nucleotide (TGN) concentrations in acute lymphoblastic leukemia (ALL) cells, we determined the TGN concentrations in leukemic blasts from 82 children with newly diagnosed ALL after intravenous administration of mercaptopurine (MP). Patients treated with MP alone achieved higher TGN concentrations than those treated with the combination of methotrexate plus mercaptopurine (MTX + MP). Analysis of the expression of approximately 9600 genes in ALL cells obtained at diagnosis identified 60 gene probes significantly associated with TGN accumulation in patients treated with MP alone and 75 gene probes in patients treated with MTX + MP, with no overlap between the 2 sets of genes. Genes significantly associated with intracellular TGN accumulation after MP alone included those encoding MP metabolic enzymes and transporters (eg, SLC29A1). Inhibition of SLC29A1 by nitrobenzylmercaptopurine ribonucleoside (NBMPR) caused a 33% to 45% reduction of TGN in ALL cells in vitro (P < .006), consistent with the gene expression findings. Genes associated with TGN concentration after combination therapy included those involved in protein and adenosine triphosphate (ATP)-biosynthesis. Together, these in vivo and in vitro data provide new insight into the genomic basis of interpatient differences in intracellular TGN accumulation and reveal significant differences between treatment with MP alone and treatment with MP and MTX.

Adolescent↗