Specific extra chromosomes occur in a modal number dependent pattern in pediatric acute lymphoblastic leukemia

Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (>50 chromosomes) are considered to have a relatively good prognosis. The specific extra chromosomes are not random; extra copies of some chromosomes occur more frequently than those of others. We examined the extra chromosomes present in high hyperdiploid ALL to determine if there were a relation of the specific extra chromosomes and modal number (MN) and if the extra chromosomes present could differentiate high hyperdiploid from near-triploid and near-tetraploid cases. Karyotypes of 2,339 children with ALL and high hyperdiploidy at diagnosis showed a distinct nonrandom sequential pattern of gain for each chromosome as MN increased, with four groups of gain: chromosomes 21, X, 14, 6, 18, 4, 17, and 10 at MN 51-54; chromosomes 8, 5, 11, and 12 at MN 57-60; chromosomes 2, 3, 9,16, and 22 at MN 63-67; chromosomes 1, 7 13, 15, 19, and 20 at MN 68-79, and Y only at MN >or=80. Chromosomes gained at lower MN were retained as the MN increased. High hyperdiploid pediatric ALL results from a single abnormal mitotic division. Our results suggest that the abnormal mitosis involves specific chromosomes dependent on the number of chromosomes aberrantly distributed, raising provocative questions regarding the mitotic mechanism. The patterns of frequencies of tetrasomy of specific chromosomes differs from that of trisomies with the exception of chromosome 21, which is tetrasomic in a high frequency of cases at all MN. These results are consistent with different origins of high hyperdiploidy, near-trisomy, and near-tetrasomy.     

Microdeletions and Microduplications in Patients with Congenital Heart Disease and Multiple Congenital Anomalies

Objective. Multiple genetic syndromes are caused by recurrent chromosomal microdeletions or microduplications. The increasing use of high‐resolution microarrays in clinical analysis has allowed the identification of previously undetectable submicroscopic copy number variants (CNVs) associated with genetic disorders. We hypothesized that patients with congenital heart disease and additional dysmorphic features or other anomalies would be likely to harbor previously undetected CNVs, which might identify new disease loci or disease‐related genes for various cardiac defects. Design. Copy number analysis with single nucleotide polymorphism‐based, oligonucleotide microarrays was performed on 58 patients with congenital heart disease and other dysmorphic features and/or other anomalies. The observed CNVs were validated using independent techniques and validated CNVs were further analyzed using computational algorithms and comparison with available control CNV datasets in order to assess their pathogenic potential. Results. Potentially pathogenic CNVs were detected in twelve of 58 patients (20.7%), ranging in size from 240 Kb to 9.6 Mb. These CNVs contained between 1 and 55 genes, including NRP1, NTRK3, MESP1, ADAM19, and HAND1, all of which are known to participate in cardiac development. Conclusions. Genome‐wide analysis in patients with congenital heart disease and additional phenotypes has identified potentially pathogenic CNVs affecting genes involved in cardiac development. The identified variant loci and the genes within them warrant further evaluation in similarly syndromic and nonsyndromic cardiac cohorts.     

Evolving applications in the use of bone-anchored hearing aids

The bone-anchored hearing aid (BAHA) is an effective means of intervention, its use being well documented in persons with chronic conductive pathology and congenital aural anomalies. This article describes the standard guidelines (both auditory and extraauditory aspects) for patient selection and expands the criteria to include bilateral BAHA implantation, unilateral conductive hearing loss, and unilateral profound sensorineural hearing loss. The BAHA's development, design features, and patient outcomes are also reviewed. Suggestions are presented for fitting, counseling, and following BAHA users.     

A phase II study of weekly Edatrexate (10-EDAM) in metastatic melanoma: A National Cancer Institute of Canada Clinical Trials Group Study

BACKGROUND: Phase I and II clinical trials have demonstrated acceptabletoxicity and promising activity of Edatrexate (10-EDAM). Theobjective of this multicentre phase II study was to determinethe efficacy and toxicity of this agent in patients with metastaticmelanoma. PATIENTS AND METHODS: Sixteen previously untreated patients with metastatic melanomareceived 10-EDAM, 80 mg/m²/week intravenously. Patients wereevaluated for response and toxicity. RESULTS: There were no objective responses. The median dose intensityof 10-EDAM actually delivered was 56.25 mg/m²/week (70% of projected).Mucositis of any degree was encountered in 93.8% of patients.Grade 3 or 4 mucositis, skin rash, nausea, abdominal pain, neutropenia,thrombocytopenia, anemia and hyperbilirubinemia each were encounteredin 1–2 patients. There was 1 toxic death due to 10-EDAM. CONCLUSION: 10-EDAM is an inactive agent in metastatic melanoma.     

p53 gene mutations in pediatric brain tumors

We investigated the frequency of p53 mutations in 47 pediatric brain tumors of various histologic subtypes that were collected over a period of 5 years. The specimens included 15 primitive neuroectodermal tumors (PNETs), 17 low grade astrocytomas, one anaplastic astrocytoma, three glioblastomas (GBMs), one mixed glial tumor, eight ependymomas, one choroid plexus carcinoma, and one gangliocytoma/ganglioneuroma. Mutations were identified by single strand conformation polymorphism analysis of exons 4–8 and verified by sequencing. Mutations were present in 2 of 3 cases of GBM, but not in 17 low grade astrocytomas (P = 0.02, Fisher's exact test). One GBM demonstrated a germline GGC to AGC transition (gly to ser) at codon 245 with loss of the wild-type allele. A second GBM contained a CGG to TGG transition (arg to trp) at codon 248, also with loss of the wildtype allele, but normal tissue was not available for comparison. In addition, one of 15 PNETs retained heterozygosity but demonstrated a somatic CGT to TGT transition (arg to cys) at codon 273. p53 mutations were absent in other histologic subtypes and in two cases with multiple primary cancers. These data are consistent with earlier findings that p53 mutations are rare in PNETs, which are primarily pediatric tumors. In contrast to adult gliomas, p53 mutations in pediatric gliomas appear restricted to the GBMs. The lack of p53 mutations in pediatric low grade astrocytomas suggests not only histological differences, but also a different molecular pathogenesis in adult and pediatric patients. © 1995 Wiley-Liss, Inc.     

Acute Myeloblastic Leukemia: Management with High-Dose Cytosine Arabinoside, Daunorubicin and Marrow Transplantation; Malignancy; Current Clinical Practice

Combination high-dose cytosine arabinoside (ARA-C) and daunorubicin (DNR) for primary remission induction of patients with acute myeloblastic leukemia (AML) was evaluated in a single institution study. Patients aged 55 or less with an HLA-sibling received an allogeneic bone marrow transplant (alloBMT) in first remission; other responders were offered autologous BMT (autoBMT). For remission induction 93 patients aged less than 60 received DNR 45 mg/m(2) BSA x 3 and ARA-C 2 gm/m(2) BSA every 12 hours for 12 doses; 53 aged 60 or older DNR 25 mg/m(2) daily x 3 and ARA-C 1.5-2.0 gm/m(2) BSA every 12 hours for 12 doses. Consolidation doses of DNR were the same but ARA-C 100 mg/m(2) BSA/day x 5 was given by continuous intravenous infusion. The complete remission rate for patients less than 60 years was 69.9% (95% CI: 59.5-79.0%) and 47.2% (95% CI: 33.3-61.4%) for the older patients. The median duration of first remission for the younger patients was 13.0 months and of overall survival 17.9 months; for patients over 60 years 5.6 and 10.0 months respectively. Disease-free survival and overall survival of the 19 patients receiving alloBMT and the 13 patients undergoing autoBMT aged less than 55 years and in first or second complete remission were significantly increased compared with 22 patients in remission but not having BMT (p < 0.001 and p < 0.013). The results support the effectiveness of high-dose ARA-C for remission induction, a need for intensive consolidation therapy and a role for BMT in the management of AML.     

Role of the bispectral index in sedation monitoring in the ICU

OBJECTIVE: To review and critique evidence for the use of the bispectral index (BIS) in intensive care unit (ICU) patients. DATA SOURCES: A computer search of English-language articles in MEDLINE (1966-July 2005), International Pharmaceutical Abstracts (1971-July 2005), and Scientific Citation Index Expanded (1980-July 2005) was conducted. A manual search of abstracts was also performed using the key search terms BIS, sedation, and critical care. STUDY SELECTION AND DATA EXTRACTION: Case series, letters, editorials, and clinical studies that evaluated BIS in ICU patients were considered for inclusion. DATA SYNTHESIS: Nineteen studies comparing the BIS with sedation scales were evaluated, revealing that the BIS trends lower with increasing sedation. The BIS appeared to correlate better when sedation scores were grouped rather than individual values. However, correlations between BIS and subjective scales were low in most studies (r(2) 0.21-0.93). Additionally, there was poor correlation between drug dosage and the BIS. Randomized, controlled trials demonstrating improved outcomes with BIS monitoring have not been reported. CONCLUSIONS: Interpreting literature on the usefulness of the BIS in the ICU is difficult for reasons that include heterogeneous populations, different methods of collecting BIS data, and use of different versions of BIS software and hardware. Outcomes data are lacking. The 2002 Society of Critical Care Medicine Sedation Guidelines recommendation that more data are needed before the BIS should be used routinely in the ICU remains unchanged. We recommend that further studies be conducted to determine the optimal method of obtaining BIS data and evaluate the impact of the BIS on relevant patient outcomes.