24 research outputs found
Prognostic Factors in Children With Extragonadal Malignant Germ Cell Tumors: A Pediatric Intergroup Study
Detection of MYCN Gene Amplification in Neuroblastoma by Fluorescence In Situ Hybridization: A Pediatric Oncology Group Study
To assess the utility of fluorescence in situ hybridization (FISH) for analysis of MYCN gene amplification in neuroblastoma, we compared this assay with Southern blot analysis using tumor specimens collected from 232 patients with presenting characteristics typical of this disease. The FISH technique identified MYCN amplification in 47 cases, compared with 39 by Southern blotting, thus increasing the total number of positive cases by 21%. The major cause of discordancy was a low fraction of tumor cells (≤30% replacement) in clinical specimens, which prevented an accurate estimate of MYCN copy number by Southern blotting. With FISH, by contrast, it was possible to analyze multiple interphase nuclei of tumor cells, regardless of the proportion of normal peripheral blood, bone marrow, or stromal cells in clinical samples. Thus, FISH could be performed accurately with very small numbers of tumor cells from touch preparations of needle biopsies. Moreover, this procedure allowed us to discern the heterogeneous pattern of MYCN amplification that is characteristic of neuroblastoma. We conclude that FISH improves the detection of MYCN gene amplification in childhood neuroblastomas in a clinical setting, thus facilitating therapeutic decisions based on the presence or absence of this prognostically important biologic marker
Phase II/III trial of a pre‐transplant farnesyl transferase inhibitor in juvenile myelomonocytic leukemia: A report from the Children's Oncology Group
BackgroundJuvenile myelomonocytic leukemia (JMML) is not durably responsive to chemotherapy, and approximately 50% of patients relapse after hematopoietic stem cell transplant (HSCT). Here we report the activity and acute toxicity of the farnesyl transferase inhibitor tipifarnib, the response rate to 13-cis retinoic acid (CRA) in combination with cytoreductive chemotherapy, and survival following HSCT in children with JMML.ProcedureEighty-five patients with newly diagnosed JMML were enrolled on AAML0122 between 2001 and 2006. Forty-seven consented to receive tipifarnib in a phase II window before proceeding to a phase III trial of CRA in combination with fludarabine and cytarabine followed by HSCT and maintenance CRA. Thirty-eight patients enrolled only in the phase III trial.ResultsOverall response rate was 51% after tipifarnib and 68% after fludarabine/cytarabine/CRA. Tipifarnib did not increase pre-transplant toxicities. Forty-six percent of the 44 patients who received protocol compliant HSCT relapsed. Five-year overall survival was 55 ± 11% and event-free survival was 41 ± 11%, with no significant difference between patients who did or did not receive tipifarnib.ConclusionsAdministration of tipifarnib in the window setting followed by HSCT in patients with newly diagnosed JMML was safe and yielded a 51% initial response rate as a single agent, but failed to reduce relapse rates or improve long-term overall survival
The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease
Germ line PTPN11 mutations cause 50% of cases of Noonan syndrome (NS). Somatic mutations in PTPN11 occur in 35% of patients with de novo, nonsyndromic juvenile myelomonocytic leukemia (JMML). Myeloproliferative disorders (MPDs), either transient or more fulminant forms, can also occur in infants with NS (NS/MPD). We identified PTPN11 mutations in blood or bone marrow specimens from 77 newly reported patients with JMML (n = 69) or NS/MPD (n = 8). Together with previous reports, we compared the spectrum of PTPN11 mutations in 3 groups: (1) patients with JMML (n = 107); (2) patients with NS/MPD (n = 19); and (3) patients with NS (n = 243). Glu76 was the most commonly affected residue in JMML (n = 45), with the Glu76Lys alteration (n = 29) being most frequent. Eight of 19 patients with NS/MPD carried the Thr73Ile substitution. These data suggest that there is a genotype/phenotype correlation in the spectrum of PTPN11 mutations found in patients with JMML, NS/MPD, and NS. This supports the need to characterize the spectrum of hematologic abnormalities in individuals with NS and to better define the impact of the PTPN11 lesion on the disease course in patients with NS/MPD and JMML. (Blood. 2005;106:2183-2185
Intensified Platinum Therapy Is an Ineffective Strategy for Improving Outcome in Pediatric Patients With Advanced Hepatoblastoma
Phase II Randomized Comparison of Topotecan Plus Cyclophosphamide Versus Topotecan Alone in Children With Recurrent or Refractory Neuroblastoma: A Children's Oncology Group Study
Development of an allele-specific minimal residual disease assay for patients with juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia is an
aggressive and frequently lethal myeloproliferative disorder of childhood. Somatic mutations in NRAS, KRAS, or
PTPN11 occur in 60% of cases. Monitoring disease status is difficult because of
the lack of characteristic leukemic blasts
at diagnosis. We designed a fluorescently
based, allele-specific polymerase chain
reaction assay called TaqMAMA to detect
the most common RAS or PTPN11 mutations. We analyzed peripheral blood
and/or bone marrow of 25 patients for
levels of mutant alleles over time. Analysis of pre–hematopoietic stem-cell transplantation, samples revealed a broad distribution of the quantity of the mutant
alleles. After hematopoietic stem-cell
transplantation, the level of the mutant
allele rose rapidly in patients who relapsed and correlated well with falling
donor chimerism. Simultaneously analyzed peripheral blood and bone marrow
samples demonstrate that blood can be
monitored for residual disease. Importantly, these assays provide a sensitive
strategy to evaluate molecular responses
to new therapeutic strategies