Biomedical subjects

A T Look

Publications and source records attributed to A T Look.

204 records · Page 12Linked to original sources

PubMedDate not supplied

The v-fms oncogene induces factor independence and tumorigenicity in CSF-1 dependent macrophage cell line.

The McDonough strain of feline sarcoma virus (SM-FeSV) transforms fibroblast cell lines in culture and produces fibrosarcomas in domestic cats. SM-FeSV does not induce haematopoietic malignancies in spite of the fact that its viral oncogene, v-fms, codes for a glycoprotein related to the receptor for the mononuclear phagocyte colony stimulating factor, CSF-1. The v-fms-coded polypeptide includes the complete extracellular domain of the c-fms proto-oncogene product and retains the ability to bind CSF-1 specifically. The two molecules have very similar sequences except at their extreme carboxyl terminal ends where 40 amino acids of the c-fms-coded glycoprotein are replaced by 11 unrelated residues in the v-fms product. Autophosphorylation of the c-fms gene product on tyrosine is enhanced by CSF-1 addition, whereas phosphorylation of the v-fms-coded glycoprotein appears to be constitutive. We now show that introduction of the v-fms gene into simian virus-40 (SV40)-immortalized, CSF-1 dependent macrophages renders them independent of CSF-1 for growth and tumourigenic in nude mice. These factor-independent cell lines express unaltered levels of the c-fms product which is down-modulated in response to either CSF-1 or the tumour promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The induction of factor independence by a non-autocrine mechanism suggests that the v-fms product is an unregulated kinase that provides growth stimulatory signals in the absence of ligand.

Animals↗

PubMedDate not supplied

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 (< or =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.

Blotting, Southern↗

PubMedDate not supplied

Molecular genetics of childhood leukemias.

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.

Child↗

PubMedDate not supplied

Natural history and biology of stage A neuroblastoma: a Pediatric Oncology Group Study.

PURPOSE: To prospectively analyze the outcome of patients with Stage A neuroblastoma (NB) treated with surgery alone, especially with regard to the prognostic significance of age, tumor site, MYCN copy number, tumor cell ploidy, and histology. PATIENTS AND METHODS: The clinical course of 329 patients with Stage A disease registered on the POG NB Biology Study #9047 between February, 1990 and October, 1997 were evaluated. Age, tumor site, MYCN copy number, tumor cell ploidy, and histology were analyzed for their impact on event-free survival (EFS) and survival (S). RESULTS: The 5-year estimated EFS and S rates for the 329 patients were 91% (+/-3%) and 96% (+/-2%), respectively. The EFS rate was similar for infants younger than 12 months and children age 12 months or older, but age older than 12 months was predictive of lower S rates (P = 0.044). Patients with adrenal, abdominal non-adrenal, thoracic, and cervical tumors had similar S rates. The majority of patients had tumors with favorable biologic features, and only 3% had MYCN amplification. For infants with diploid tumors, the EFS rate was 82% (+/-16%), but effective therapy yielded an S rate of 100%. Rate of S was 80% (+/-26%) and 64% (+/-27%) for patients with unfavorable tumor histology and MYCN-amplified tumors, respectively. CONCLUSION: The outcome for patients with Stage A NB treated with surgery alone is excellent. Although EFS and S rates were significantly worse for patients with MYCN-amplified tumors, a subset achieved long-term remission after surgery alone. For patients with Stage A and MYCN amplification, additional factors are needed to distinguish the patients who will achieve long-term remission with surgery alone from those who will develop recurrent disease.

Abdominal Neoplasms↗

PubMedDate not supplied

Cyclophosphamide/etoposide: effective reinduction therapy for children with acute nonlymphocytic leukemia in relapse.

Reinduction therapy consisting of cyclophosphamide (250 mg/m2 orally daily for 4 days) followed by etoposide (250 mg/m2 iv daily for 3 days) was administered to 14 children with refractory or recurrent acute nonlymphocytic leukemia. Five complete remissions were achieved in eight patients who had relapsed in the bone marrow 1-27 months after cessation of initial therapy, which included anthracyclines, cytarabine, etoposide, and 5-azacitidine. Reinduction attempts were unsuccessful in patients who had failed to achieve an initial remission and in those whose relapses occurred while receiving therapy. Toxicity, including myelosuppression and mucositis, was within acceptable limits. This drug combination deserves further assessment in therapeutic protocols for patients with acute nonlymphocytic leukemia.

Acute Disease↗

PubMedDate not supplied

Effective remission induction of refractory childhood acute nonlymphocytic leukemia by VP-16-213 plus azacitidine.

Thirty-eight children and young adults with advanced acute nonlymphocytic leukemia (ANLL) in relapse were treated with VP-16-213 plus azacitidine (5AZ). Each patient had previously received many chemotherapeutic drugs, including anthracyclines and cytarabine. Initially, 16 patients received a 5-day course of VP-16-213 (100 mg/m(2)) daily x 3 days and 5AZ 9150 mg/m(2)) daily x 2 days, repeated after 9-16 days. Since this treatment produced marrow hypoplasia and complete remission (CR) in only one of 16 patients, a more intensive regimen was devised: the remaining 22 patients received a course of VP-16-213 (200 mg/m(2)) daily x 3 days, followed by 5AZ (300 mg/Fm(2)) daily x 2 days, repeated after 1-2 days until the bone marrow became hypoplastic. After two to four courses, 18 patients had marrow hypoplasia and ten of these achieved CR. The proportion of patients achieving CR with the higher doses was significantly greater than that with the initial doses )P less than or equal to 0.05). The toxicity also increased with the higher doses, with major problems due to prolonged pancytopenia. Supportive therapy was required for severe bleeding and infections. We conclude that the intensive treatment with VP-16-213 plus 5AZ can effectively induce remission in patients with refractory advanced acute nonlymphocytic leukemia.

Acute Disease↗