ABSTRACT
The outcome for 82 pediatric patients with Ewing sarcoma (ES) and primitive neuroectodermal tumor (PNET) of bone is reported; the patients were treated at the Dana-Farber Cancer Institute (DFCI) and Children's Hospital (CH) in Boston, MA (USA) from 1971-1988. The charts of all patients with ES/PNET of bone treated during this period were reviewed for disease status, therapy, sites of relapse, information on second malignancies, and survival status. Eighty-two patients with ES/PNET of bone treated at DFCI/CH were identified. The 10-year event-free survival (EFS) rates were 12% (95% confidence interval [CI] 0, 27%) and 38% (95% CI 26, 51%) for patients with and without metastases, respectively (P = 0.002); the overall survival (OS) rates were 17% (95% CI 1, 33%) and 48% (95% CI 35, 61%) for patients with and without metastases (P = 0.001). Median follow-up for surviving patients is 10.2 years. Primary site in the pelvis also was associated with a poor outcome for patients with no metastatic disease (P = 0.006 OS, P = 0.03 EFS). Thirty-one patients survived in first remission at least 5 years from diagnosis, and of these, five experienced relapse of original disease, and five experienced secondary malignancies. Pediatric patients treated for ES/PNET of bone remain at risk for life-threatening events into the second decade of follow-up. After 5 years, the risk of second malignant neoplasm is at least as high as the risk of late relapse. Prolonged follow-up of patients with ES and PNET of bone is indicated.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Neoplasms/drug therapy , Neuroectodermal Tumors, Primitive/drug therapy , Sarcoma, Ewing/drug therapy , Adolescent , Adult , Bone Neoplasms/mortality , Bone Neoplasms/pathology , Child , Child, Preschool , Cyclophosphamide/administration & dosage , Dactinomycin/administration & dosage , Female , Follow-Up Studies , Humans , Male , Neoplasm Metastasis , Neuroectodermal Tumors, Primitive/mortality , Neuroectodermal Tumors, Primitive/pathology , Retrospective Studies , Sarcoma, Ewing/mortality , Sarcoma, Ewing/pathology , Survival Rate , Time Factors , Treatment Outcome , Vincristine/administration & dosageABSTRACT
BACKGROUND: The TEL/AML1 fusion associated with t(12;21)(p13;q22) is the most common gene rearrangement in childhood malignancy, occurring in approximately 25% of pediatric acute lymphoblastic leukemia. The TEL/AML1 rearrangement is cryptic at the cytogenetic level but confers a favorable prognosis. The AML1 gene was first identified by virtue of its involvement in adult and pediatric acute myeloid malignancies associated with t(8;21) and t(3;21)(q26;q22.1). We have therefore determined the frequency of the TEL/AML1 fusion in pediatric myeloid leukemias by RT-PCR analysis. METHODS: Total RNA was isolated from cryopreserved bone marrow samples of 38 pediatric patients with AML. RNA quality was controlled for by amplification of the TEL gene. An RT-PCR assay was then used to test for the presence of the TEL/AML1 fusion. RESULTS: 29 patients had adequate RNA for analysis. Zero out of 29 pediatric AML patients had evidence for the TEL/AML1 fusion by RT-PCR. CONCLUSIONS: The TEL/AML1 fusion does not occur in children with AML and suggests that the TEL/AML1 rearrangement is restricted in pediatric hematologic malignancy to B lineage ALL.
Subject(s)
Leukemia, Myeloid/genetics , Neoplasm Proteins/genetics , Oncogene Proteins, Fusion , Translocation, Genetic/genetics , Acute Disease , Adolescent , Cell Lineage/genetics , Child , Child, Preschool , Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 21 , Core Binding Factor Alpha 2 Subunit , Female , Humans , Leukemia, Myeloid/classification , Male , Polymerase Chain Reaction , RNA/analysisABSTRACT
BACKGROUND: Infants with acute lymphoblastic leukemia (ALL) have a very poor prognosis. Since 1985, we have intensified therapy for infants with ALL by including a month of high dose multiagent chemotherapy after remission induction. METHODS: Between 1985 and 1995, we treated 23 infants (age < 12 months). We compared the presenting characteristics and outcomes of these infants with the 11 infants treated on our protocols between 1973 and 1985, an era prior to the intensification of therapy. Available bone marrow samples from infants treated since 1985 were analyzed for the presence of MLL gene rearrangements by Southern blot analyses and for TEL-AML1 gene fusion by reverse transcriptase-polymerase chain reaction. RESULTS: With a median follow-up of 5.6 years, the 50-month event free survival (EFS) (+/- standard error) for the 23 infants was 54 +/- 11%, a significant improvement (P = 0.001) compared with the outcome for the 11 infants treated on our protocols prior to 1985 (EFS = 9 +/- 9%). Of the seven infants found to have a rearranged MLL gene, three (43%) remained in first complete remission. None of the nine infant bone marrow specimens tested had evidence of TEL-AML1 gene fusion. The intensified therapy was complicated by a high incidence of infections, including septicemia in 52% of patients and Pneumocystis carinii pneumonitis in 22% of patients. Late effects identified in the 13 long term survivors (median age, 6 years) included developmental delay and learning disabilities of varying severity (82% of evaluable patients), asymptomatic cataracts (67%), asymptomatic echocardiographic abnormalities (30%), obesity (27%), and short stature (18%). CONCLUSIONS: Intensification of therapy significantly improved the EFS of infants with ALL compared with previous, less intensive regimens and with the experience of other investigators. Future treatment for infants should attempt to improve efficacy while minimizing toxicity.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Oncogene Proteins, Fusion , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Proto-Oncogenes , Transcription Factors , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Asparaginase/administration & dosage , Asparaginase/adverse effects , Core Binding Factor Alpha 2 Subunit , Cytarabine/administration & dosage , Cytarabine/adverse effects , DNA, Neoplasm/analysis , DNA-Binding Proteins/genetics , Disease-Free Survival , Female , Histone-Lysine N-Methyltransferase , Humans , Infant , Infant, Newborn , Male , Mercaptopurine/administration & dosage , Mercaptopurine/adverse effects , Methotrexate/administration & dosage , Methotrexate/adverse effects , Myeloid-Lymphoid Leukemia Protein , Neoplasm Proteins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Remission Induction , Survival Rate , Treatment Outcome , Vincristine/administration & dosage , Vincristine/adverse effectsABSTRACT
Polymerase chain reaction-based screening of childhood acute lymphoblastic leukemia (ALL) samples showed that a TEL/AML1 fusion transcript was detected in 27% of all cases, representing the most common known gene rearrangement in childhood cancer. The TEL/AML1 fusion results from a t(12;21)(p13;q22) chromosomal translocation, but was undetectable at the routine cytogenetic level. TEL/AML1-positive patients had exclusively B-lineage ALL, and most patients were between the ages of 2 and 9 years at diagnosis. Only 3/89 (3.4%) adult ALL patients were TEL/AML1-positive. Most importantly, TEL/AML1-positive children had a significantly lower rate of relapse compared with TEL/AML1-negative patients (0/22 v 16/54, P = .004). Co-immunoprecipitation experiments demonstrated that TEL/AML-1 formed homodimers in vitro, and heterodimerized with the normal TEL protein when the two proteins were expressed together. The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.
Subject(s)
Biomarkers, Tumor , Chromosomes, Human, Pair 12/genetics , Chromosomes, Human, Pair 21/genetics , Neoplasm Proteins/chemistry , Oncogene Proteins, Fusion , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Translocation, Genetic , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/chemistry , Child , Child, Preschool , Chromosomes, Human, Pair 12/ultrastructure , Chromosomes, Human, Pair 21/ultrastructure , Cloning, Molecular , Core Binding Factor Alpha 2 Subunit , DNA, Neoplasm/genetics , Dimerization , Female , Gene Deletion , Humans , Infant , Life Tables , Male , Neoplasm Proteins/analysis , Neoplasm Proteins/genetics , Polymerase Chain Reaction , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Proto-Oncogenes , Survival Analysis , Treatment OutcomeSubject(s)
Anemia, Sickle Cell/complications , Deferoxamine/administration & dosage , Ilium , Injections, Subcutaneous/adverse effects , Osteomyelitis/etiology , Staphylococcal Infections/etiology , Adolescent , Anemia, Sickle Cell/therapy , Chelation Therapy , Humans , Iron Overload/therapy , Male , Transfusion ReactionABSTRACT
PURPOSE: Hypercalcemia is a known complication of childhood malignancies but has never been reported to be associated with Langerhans cell histiocytosis (LCH) in a pediatric patient. PATIENTS AND METHODS: We describe an infant with multisystem LCH who developed hypercalcemia on two occasions. After being placed on indomethacin, the hypercalcemia did not recur despite disease progression. CONCLUSION: Hypercalcemia may complicate LCH. If it is demonstrated, indomethacin should be considered as a treatment.
