摘要:

Purpose: This review summarizes the molecular genetics of childhood leukemias, with emphasis on pathogenesis and clinical applications.Design: We first describe the most common genetic events that occur in pediatric acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). We then illustrate how these molecular alterations may be used to alter therapy.Results: In childhood ALL, the TEL-AML1 fusion and hyperdiploidy are both associated with excellent treatment outcomes and therefore identify patients who may be candidates for less intensive therapy. In contrast, MLL gene rearrangements and the BCR-ABL fusion confer a poor prognosis; these patients may be best treated by allogeneic bone marrow transplantation in first remission.Conclusions: Although clinical features are important prognostic indicators, genetic alterations of leukemic blasts may be better predictors of outcome for acute leukemia patients. We therefore favor risk-adapted therapy based on classification schemes that incorporate both genetic and clinical features.

ISSN:1077-4114    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Purpose: Langerhans cell histiocytosis (LCH) is a disorder of unknown etiology involving the proliferation and accumulation of cells with the phenotype of a bone marrow-derived antigen-presenting cell of the skin, the Langerhans cell. We have studied p53 expression, an element in the control of cell proliferation, to determine whether it plays a role in the pathogenesis of LCH.Patients and Methods: LCH lesions from 10 patients with either localized (n = 5) or multisystem disease (n = 5) were studied. p53 protein expression was assessed by immunohistochemistry, and p53 gene mutation by the single strand conformation polymorphism (SSCP) technique.Results: p53 protein expression was detected in all 10 LCH biopsy specimens examined. It was restricted to Langerhans cells (LCH cells), absent from adjacent cells, and localized to the cell nuclei. No mutations of the p53 gene were detected, nor was there abnormal expression of the p53 binding protein, mdm2.Conclusions: p53 is readily detectable in LCH cells but not in normal cells. This is either caused by an unusual mechanism (given the absence of mutations in the p53 gene and of mdm2 expression in LCH cells) or by overexpression or posttranslational changes of normal p53 in response to an as yet unidentified cellular stress. Stabilization and inactivation of p53 could lead to the uncontrolled proliferation of LCH cells, or the abnormality could lead to the induction of programmed cell death.

ISSN:1077-4114    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Purpose: The purpose of this study was to determine the incidence of c-Myc protein expression in medulloblastoma/primititive neuroectodermal tumor (MB/PNET) and to identify mechanisms in addition to c-myc gene amplification that lead to increased protein expression.Methods: We analyzed c-myc gene copy number, mRNA level and protein expression in a panel of MB/PNET cell lines. C-Myc protein levels were assessed in tumor specimens and cell lines using immunohistochemical staining with a c-Myc-specific monoclonal antibody.Results: Southern analysis confirmed c-myc gene amplification in the D425 MED cell line and re-arrangement of one allele in D283 MED, which was analyzed further and appeared to represent a small deletion 3′ of exon 3. C-myc transcript levels were dramatically elevated in both lines. Using a c-myc probe, fluorescence in situ hybridization (FISH) showed c-myc present in 3 tandem copies at 8q24 in D283 MED and multiple copies as double minutes in D425 MED. Immunohistochemistry showed c-Myc protein expression in 9 of 10 tumors and all cell lines, regardless of gene amplification status or level of mRNA expression.Conclusions: c-Myc protein expression is common in MB/PNET tumor specimens and cell lines. Elevated protein levels are observed in the absence of amplification, suggesting that multiple mechanisms of c-myc dysregulation may be involved in MB/PNET. These studies support a role for c-Myc in the development of this common childhood tumor.

ISSN:1077-4114    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Purpose: Hydroxyurea therapy reduces clinical complications in sickle cell disease. While evaluating the clinical and laboratory responses to hydroxyurea in children with sickle cell disease, we concurrently objectively monitored, for the first time during such treatment, compliance with therapy. Because most deaths in affected children are related to infection, we also evaluated the impact of hydroxyurea on splenic function, estimated by the percentage of red cells containing endocytic vacuoles (“pitted” cells) over 1 year of therapy.Patients and Methods: Seventeen children with a history of ⩾3 hospital admissions in the previous year, aged (mean ± standard error of mean) 12.3 ± 1.2 years, were treated with hydroxyurea. Clinical and laboratory assessments monitored efficacy and toxicity. Compliance was monitored using computerized pill bottles containing cap microprocessors which monitor the frequency of bottle openings.Results: Over 18.5 ± 2.1 months, compliance with hydroxyurea (as determined by percent of the perscribed drug actually taken) was 96 ± 2%, resulting in increases in mean fetal hemoglobin from 7.7 ± 1.6% to 16.7 ± 1.8% (p <0.005). In 11 patients who reached maximum tolerated doses, an increase to 18.8 ± 2.5% (p = 0.0001) was observed. Pitted red cell counts did not change. Annual rates of vaso-occlusive crisis (p = 0.0105), acute chest syndrome (p = 0.0417), transfusions administered (p = 0.0168), and days in hospital (p = 0.0017) all decreased significantly.Conclusions: Hydroxyurea in children is associated with sustained excellent compliance and monitoring this compliance is uncomplicated. Splenic function in most hydroxyurea-treated children did not change over 1 year of therapy.

ISSN:1077-4114    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Purpose: To review the natural history of mild hemophilia (factor VIII or IX level >5% and <50%), including presentation and diagnosis, characteristics of bleeding episodes, and therapy, at two hemophilia treatment centers.Methods: Inpatient and outpatient records of 55 patients <17 years old with factor VIII or IX levels of 5 to 50% were reviewed and bleeding episodes for which medical attention was sought were analyzed.Results: Five of the 55 patients were girls. Girls and patients with no family history of hemophilia were diagnosed at 5.5 and 5.3 years of age, respectively, compared to 2.8 years overall. Thirty-five patients were diagnosed because of a positive family history. No bleeding occurred in 18 patients; 190 bleeding episodes occurred in 37 patients. Most bleeding occurred in muscle/soft tissue (101 episodes) or joints (57 episodes) and were associated with trauma (174 episodes).Conclusions: Mild hemophilia may affect females more often than is appreciated. Delays in diagnosis and treatment may occur unless the variability in presentation is recognized.

ISSN:1077-4114    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Purpose: To examine the relationships among platelet counts, bone marrow megakaryocyte frequency, and circulating thrombopoietin (TPO) levels.Patients and Methods: TPO levels in 17 children and one young adult with chronic or recurrent thrombocytopenia were measured by ELISA and megakaryocyte frequency was analyzed by light microscopy. Three groups of patients were studied: Group I patients had aplastic anemia and absent or decreased magakaryocytes; Group II patients had intermittent periods of chemotherapy-induced thrombocytopenia; and Group III patients had normal or increased megakaryocytes. Controls consisted of 77 healthy adults.Results: Patients in Group I had markedly increased TPO levels compared to normal controls. Their levels were significantly different (p = 0.03) from those of patients in Group III. The latter had normal or only mildly increased TPO levels except for one patient with myelodysplastic syndrome. Patients in Group II had markedly elevated TPO levels. After their bone marrow and platelet counts recovered from chemotherapy, their TPO levels decreased. In all three groups, a transient increase in platelet count (e.g., after platelet transfusion or anti-D immune globulin therapy) was associated with a moderate decrease in TPO.Conclusions: From this study, three conclusions can be made: 1) TPO levels are inversely related to megakaryocyte frequency; 2) platelet counts have a modest influence on TPO level; and 3) TPO levels may have clinical utility in diagnosis and management and further our understanding of the pathobiology of the disorders that cause thrombocytopenia.

ISSN:1077-4114    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Purpose: Bone marrow aspiration is often performed to diagnose childhood acute immune thrombocytopenic purpura (ITP) because no non-invasive investigation to confirm the diagnosis is routinely available. Reticulated platelets (RPs)—young platelets characterized by a high RNA content—increase with increased platelet production and may be useful in the diagnosis of ITP.Methods: To assess the role of RP counts in distinguishing ITP, we compared counts from 15 consecutive patients with ITP with counts from 20 patients with acute lymphoblastic leukemia (ALL), 10 with aplasia, and 27 healthy normal children. Whole blood in edetic acid (EDTA) was labelled with a platelet-specific monoclonal antibody and incubated with thiazole orange (TO). A standard gate was set to achieve a fluorescence value of 1.3 ± 0.5% for control lyophilized platelets.Results: Patients with ITP had a mean (± 1 standard deviation) RP level of 32.9 ± 10.2%; patients with ALL, 6.6 ± 3.1%; patients with aplasia, 3.4 ± 2.0%; and normal patients, 7.9 ± 2.9%. The difference in RPs between the ITP group and the ALL, aplasia, and normal groups was highly significant (p <0.0001 each), with no significant difference between the non-ITP groups (p = 0.12).Conclusions: Measuring RPs by this simple whole-blood cytometric technique discriminated very well between the acute ITP and non-ITP groups. This test has a strong positive predictive value and may prove very useful in the assessment of childhood acute ITP and the screening of candidates for bone marrow aspiration.

ISSN:1077-4114    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Purpose: We report the results of a phase I/II stem cell rescue trial for patients with high risk neuroblastoma.Patients and Methods: Fifty-one patients with a median age of 2.3 years (range 1 to 20) who were in their first complete remission (CR) (n = 8), very good partial remission (VGPR) (n = 23), partial remission (PR) (n = 5), or subsequent CR/PR (n = 7) after receiving a platinum-based induction regimen were consolidated with high dose chemotherapy and stem cell rescue. They received an ablative regimen of thiotepa (300 mg/m2/day for 3 days) and cyclophosphamide (1500 mg/m2/day for 4 days) followed by either purged marrow (n = 16), unpurged bone marrow (BM) (n = 23), or peripheral blood stem cell (PBSC) rescue (n = 13). The median nucleated cell doses administered were 2.7×108/kg for unpurged marrow (range 1.1 to 13), 1.7×108/kg for purged marrow (range 0.8 to 6.4), and 2.1×108/kg for the PBSC (range 1.1 to 13).Results: Engraftment was achieved for all patients. The time to achieve an absolute neutrophil count (ANC) >500×109/1 was 19 days for patients who received purged BM (range 13 to 18), 17.5 days for patients who received unpurged BM (range 9 to 38), and 13 days for patients who received PBSC (range 9 to 25). An unsustained platelet count >20×109/1 was attained in 33.5 days by patients who received purged BM (range 13 to 100), 35 days for patients who received unpurged BM (range 14 to 128), and 20 days for patients who received PBSC (range 11 to 64). There was one infectious death in the unpurged marrow group caused by aspergillosis pneumonia, but none in the other two groups. Progressive disease (PD) developed in 21 patients at a median of 271 days (range 31 to 1230). The remaining 29 patients are progression-free at a median follow-up of 1190 days (range 530 to 2383).Conclusion: We conclude that this regimen is well tolerated, and that progression-free survival (PFS) with this chemotherapy-only regimen compares favorably with regimens containing total body irradiation (TBI).

ISSN:1077-4114    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Purpose: We report the treatment and outcome of patients with peripheral primitive neuroectodermal tumor (PNET) and extraosseous Ewing's tumor (EOE) using Ewing's-directed therapy, including an ifosfamide and etoposide window.Methods: Seventeen pediatric patients with peripheral PNET (n = 14) or EOE (n = 3) were enrolled between 1988 and 1992 on our institutional Ewing's protocol. Induction therapy comprised a 9-week “window” of ifosfamide and etoposide, followed by 9 weeks of therapy with cyclophosphamide and Adriamycin (Adria Laboratories, Columbus, OH). Response assessment after 17 weeks was followed by surgery and/or radiotherapy (doses based on tumor size and response to induction), repeat evaluation, and maintenance chemotherapy with alternating courses of vincristine/dactinomycin, ifosfamide/etoposide, and cyclophosphamide/Adriamycin for a total of 45 weeks.Results: At diagnosis, 8 patients had large lesions (>8 cm) and 3 had pulmonary metastases (1 with large tumor). Surgical resection was performed at diagnosis for 9 patients and after induction therapy for 5. During window therapy, all of the 9 evaluable patients responded (8 partial, 1 objective), and no patient without measurable disease developed disease progression. Responses were maintained or improved during subsequent induction in six of the patients with residual disease. Fourteen patients received local radiotherapy. At 49 to 94 months after diagnosis, 12 patients are disease-free (1 in second remission), 4 have died, and 1 is alive with disease. The five-year overall and progression-free survival rates are 77 ± 13% and 62 ± 16%, respectively.Conclusion: The use of consistent Ewing's-directed combined-modality therapy for patients with soft tissue peripheral PNET/EOE results in survival similar to that of patients with osseous Ewing's tumor. The combination of ifosfamide and etoposide appears active and should be incorporated in future treatment protocols.

ISSN:1077-4114    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Purpose: To compare the relative hematopoietic protective effects of recombinant human interleukin-1 a (rhuIL-lα), recombinant human granulocyte macrophage colony-stimulating factor (rhuGM-CSF), and PIXY321, a genetically engineered fusion protein combining interleukin-3 and rhuGM-CSF, in children with refractory solid tumors after treatment with ifosfamide, carboplatin, and etoposide (ICE).Patients and Methods: A total of 53 children who had not responded to at least one earlier chemotherapy regimen were enrolled on consecutive trials of ICE chemotherapy alone (n = 14) or with rhuGM-CSF (n = 8), rhuIL-lα (n = 10), or PIXY321 (n = 21). The relative hematopoietic effects of these three cytokines were compared retrospectively to each other and to values for patients who received ICE alone. Because one cannot assume that hematopoietic toxicity and response to a given cytokine are independent of the course of chemotherapy, the analysis was restricted to the first treatment course.Results: In this retrospective comparison, 1000 μg/m2/day of rhuGM-CSF reduced the median duration of grade 4 neutropenia (<500/μ.L) from a median of 17 days (range 3 to 34) in children who received ICE alone to 9 days (range 5 to 11, p = 0.003); it appeared to have a beneficial effect on severe thrombocytopenia (<20,000/μL), reducing the median duration from 4.5 days with ICE alone to 3 days (p = 0.08) and the number of platelet transfusions from a median of 5.75 transfusions (range 0 to 13) to 0 in these two cohorts. No significant improvement in these measures was seen with rhuIL-lα or PIXY321.Conclusions: This analysis suggests that 1000 μg/m2/day of rhuGM-CSF has clinically significant effects on platelet recovery and more effectively ameliorates thrombocytopenia and neutropenia than either rhuIL-1α or PIXY321 in the context of ICE chemotherapy. Further dose-intensification will require a combination of cytokines; the optimal dose and combination of these agents awaits further study.

ISSN:1077-4114    

出版商:OVID    

年代:1998

数据来源: OVID