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S J Lauer

Publications and source records attributed to S J Lauer.

At least 55 records · Page 3Linked to original sources
PubMed1989

Identification of leukemic cells in the cerebrospinal fluid from children with acute lymphoblastic leukemia: advances and dilemmas.

As more children survive acute lymphoblastic leukemia, new challenges face the pediatric oncologist. One is the need for early recognition of subclinical nonsymptomatic disease, or occult meningeal leukemia. By obtaining spinal fluid specimens, one can frequently monitor the central nervous system (CNS) for the presence of residual or recurrent leukemia. Methods for identifying small numbers of lymphoblasts in the spinal fluid have progressed from subjective descriptions of nucleated cells to assignment of objective methods for labeling the cells in question. These more sensitive methods of detection have challenged the "old" definitions of remission. The unequivocal identification of lymphoblasts in the spinal fluid of a child with less than 5 cells/mm3 of fluid is an example of such a dilemma. Does this finding herald overt CNS relapse or hematologic relapse? Does it warrant further, more aggressive treatment beyond giving standard prophylactic CNS therapy? It can be suggested that the finding of even a small number or proportion of leukemic cells in the spinal fluid in a child being given continuation/maintenance therapy has a high probability of being followed by an adverse event (relapse). If this is true, then the definition of CNS leukemia needs refinement and the methods for unequivocally identifying leukemic cells in a spinal fluid sample depend on techniques of cytologic examination beyond routine cytomorphology. Such laboratory methods are now available, but they require more clinical testing and standardization before their sensitivity and specificity in identifying leukemic cells is established.

Child↗
PubMed1989

Comparative biochemical and cytogenetic studies of childhood acute lymphoblastic leukemia with the Philadelphia chromosome and other 22q 11 variants.

We studied the relationship of direct karyotypes, determined at diagnosis and remission, to Abelson-related tyrosine kinase activity and the cytogenetic features of erythroid and myeloid colonies derived from remission marrow of six children with acute lymphoblastic leukemia (ALL). These patients had either the characteristic Philadelphia chromosome (Ph1) [t(9;22)(q34;q11)] or cytogenetically similar variants with a 22q11 breakpoint but no detectable cytogenetic involvement of 9q34. The findings suggested two distinct subtypes of ALL: one defined by t(9;22)(q34;q11) and expression of P185BCR-ABL tyrosine kinase and one with variant karyotypes and no P185BCR-ABL expression. The former comprises cases with Ph1 + marrow cells and Ph1 + erythroid and (or) myeloid colonies in remission marrow and others in which the t(9;22) is undetectable in remission marrow cells. In the latter subgroup, the disease may reflect more extreme mosaicism with a similar stem cell that is cytogenetically undetectable. Variant karyotypes included a del(22)(q11) in one patient and a t(6;22;15;9) (q21;q11;q?22;q21) in another; in both instances, the malignant blast cells lacked P185BCR-ABL expression. Thus ALL with t(9;22)(q34;q11) should be distinguished from ALL with other involvement of the 22q11 breakpoint by molecular studies including protein expression. The diversity of karyotypic findings in cases with involvement of 22q11 suggests at least two mechanisms of leukemogenesis in patients with ALL defined by this breakpoint.

Adolescent↗
PubMed1988

Two copies of the human apolipoprotein C-I gene are linked closely to the apolipoprotein E gene.

The gene for human apolipoprotein (apo) C-I was selected from human genomic cosmid and lambda libraries. Restriction endonuclease analysis showed that the gene for apoC-I is located 5.5 kilobases downstream of the gene for apoE. A copy of the apoC-I gene, apoC-I', is located 7.5 kilobases downstream of the apoC-I gene. Both genes contain four exons and three introns; the apoC-I gene is 4653 base pairs long, the apoC-I' gene 4387 base pairs. In each gene, the first intron is located 20 nucleotides upstream from the translation start signal; the second intron, within the codon of Gly-7 of the signal peptide region; and the third intron, within the codon for Arg39 of the mature plasma protein coding region. The upstream apoC-I gene encodes the known apoC-I plasma protein and differs from the downstream apoC-I' gene in about 9% of the exon nucleotide positions. The most important difference between the exons results in a change in the codon for Gln-2 of the signal peptide region, which introduces a translation stop signal in the downstream gene. Major sequence differences are found in the second and third introns of the apoC-I and apoC-I' genes, which contain 9 and 7.5 copies, respectively, of Alu family sequences. The apoC-I gene is expressed primarily in the liver, and it is activated when monocytes differentiate into macrophages. In contrast, no mRNA product of the apoC-I' gene can be detected in any tissue, suggesting that it may be a pseudogene. The similar structures and the proximity of the apoE and apoC-I genes suggest that they are derived from a common ancestor. Furthermore, they may be considered to be constituents of a family of seven apolipoprotein genes (apoE, -C-I, -C-II, -C-III, -A-I, -A-II, and -A-IV) that have a common evolutionary origin.

Amino Acid Sequence↗
PubMed1987

Cytosine arabinoside/cyclophosphamide pulses during continuation therapy for childhood acute lymphoblastic leukemia. Potential selective effect in T-cell leukemia.

One hundred seventy-seven children with acute lymphoblastic leukemia (ALL) were admitted to a study designed to determine whether pulses of cytosine arabinoside (ara-C) and cyclophosphamide (cyclo) would improve disease-free survival (DFS). All patients received vincristine, prednisone, and asparaginase for remission induction, CNS prophylaxis with cranial irradiation and intrathecal methotrexate, and continuation therapy with 6-mercaptopurine plus methotrexate. Forty-seven of 101 patients with non-T ALL and 18 of 26 patients with T-cell ALL received ara-C/cyclo pulses every eight weeks during continuation therapy. The age, sex, and initial white cell count distributions were similar in both treatment groups. Patients with non-T-cell ALL had similar DFS with or without ara-C/cyclo pulses (36% versus 48%; P = 0.32). Ara-C/cyclo pulses significantly improved DFS in children with T-cell ALL (36% versus 0%; P = 0.015). Toxicities of the ara-C/cyclo pulses included reversible pancytopenia, drug induced fever, fever associated with neutropenia, and death in one patient from systemic candidiasis while neutropenic. This is the first clinical evidence to indicate that the combination of ara-C/cyclo used during continuation therapy is selectively beneficial in T-cell ALL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Expression of GD3 ganglioside in childhood T-cell lymphoblastic malignancies.

Lymphoblasts from seven children with T-cell lymphoblastic malignancies and three children with non-T, non-B acute lymphoblastic leukemia (ALL) were analyzed for ganglioside content. Nonmalignant T-cells from thymus served as controls. Both ganglioside and glycoprotein sialic acid were increased approximately 3-3.5-fold in T-cell disease compared to thymic tissue when expressed on a per cell basis, but not on a per milligram protein basis. Thin-layer chromatography of the isolated ganglioside fraction from T-cell lymphoblasts revealed two major resorcinol-positive bands. One ganglioside comigrated with II3-alpha-N-acetylneuraminosyllactosylceramide (GM3), the major ganglioside in normal lymphoid tissue, and the other ganglioside comigrated with authentic II3-alpha-N-acetylneuraminosyl-alpha 2----8-N-acetylneuraminosyllactosylceramide (GD3) in three different solvent systems. Neuraminidase treatment of the latter ganglioside yielded GM3 and lactosyl ceramide, hydrolysis products of GD3. Scanning densitometry revealed that whereas thymus cells contained 97% GM3 and 3% GD3, T-cell lymphoblasts contained from 22 to 86% GD3 and a corresponding decrease in GM3. The shift to increased GD3 was observed in the blasts from all seven T-cell patients, but not in the blasts from the non-T, non-B patients studied. Only trace quantities of GD3 were detected from two continuous T-ALL cell lines, HSB2 and RPMI 8402. The results demonstrate a consistently significant increase in ganglioside GD3 in uncultured, patient-derived T-cell ALL lymphoblasts when compared to non-T-cell ALL and normal lymphoid tissue. Therefore, GD3 may represent a tumor-associated antigen for the T-cell subclass of childhood lymphoblastic malignancy.

Adolescent↗
PubMed1987

Evidence for a multipotential stem cell disease in some childhood Philadelphia chromosome-positive acute lymphoblastic leukemia.

Children with Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) have a poorer prognosis than do most pediatric patients with ALL. Because of this poor prognosis and the presence of the Ph chromosome, we have asked whether or not Ph + ALL involves a multipotential stem cell. We cultured hematopoietic progenitors from two children with Ph+ ALL and examined individual BFU-E and CFU-GM colonies for the Ph chromosome. We studied cells from two patients after 18 to 34 months of first complete clinical remission; direct cytogenetic analyses showed 26% and 13% Ph+ metaphases in these patients' marrow cells. BFU-E colonies were obtained from light density marrow cells cultured in methylcellulose supplemented with erythropoietin and CFU-GM colonies from agar or methylcellulose cultures stimulated with leukocyte feeder layers. Fifty-seven G-banded metaphases were recovered from 33 colonies. Ten metaphases from seven colonies were Ph+. Ph+ metaphases were found in three of 12 and three of five BFU-E colonies from the two patients. One of 16 CFU-GM colonies from one patient had the Ph+ chromosome; analyzable metaphases were not obtained from CFU-GM of the other patient. No colonies contained both Ph+ and Ph- cells. These results indicate that Ph+ ALL with persistence of Ph+ cells in remission involves a multipotential stem cell for erythroid and granulocyte/macrophage as well as lymphoid lineages. Multipotential stem cell involvement in the pathogenesis of some childhood Ph+ ALL suggests similarities to Ph+ chronic myelocytic leukemia and may contribute to the poor prognosis of these patients.

Bone Marrow↗
PubMed1986

Childhood primary cutaneous non-T/non-B lymphoma followed by acute T-cell leukemia.

An 8-year-old girl presented with cutaneous lymphoma without bone marrow or visceral involvement. The tumor cells displayed convoluted and invaginated euchromatic nuclei. The immunophenotype of these cells was non-T/non-B (Ia+, CALLA-, SIg-, TdT-, E-, Thy-). The skin lesions regressed promptly with chemotherapy including cyclophosphamide, vincristine, methotrexate, doxorubicin, and cytosine arabinoside. Six months after the completion of chemotherapy (18 months postdiagnosis), the patient had a relapse of the skin lesions with concurrent bone marrow involvement. The cutaneous infiltrate at relapse was morphologically and immunophenotypically similar to that at the onset of illness. However, the bone marrow infiltrate, although morphologically similar to the cutaneous tumor, had an immunophenotype consistent with T-cells (Ia+, CALLA-, SIg-, E-, TdT+, Thy+, OKT4+, OKT8+). As in adults, primary cutaneous non-T/non-B lymphomas in children may be derived from T-cells or their precursors.

Acute Disease↗
PubMed1986

Isolated bilateral T-cell renal lymphoblastic lymphoma.

A 3-year-old girl presented with bilateral renal masses. The histologic diagnosis was lymphoblastic lymphoma. Cell surface markers showed a cytotoxic/suppressor T cell phenotype. The patient was treated with APO therapy. She has remained continuously disease-free for 30 months and has been off all therapy for 6 months. This rare case supports the value of precise classification (by histologic and immunologic methods) as a guide to appropriate tumor therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Effectiveness of a six-drug regimen (APO) without local irradiation for treatment of mediastinal lymphoblastic lymphoma in children.

Fourteen children with mediastinal lymphoblastic lymphoma (MLL) were treated with the six-drug APO protocol. This regimen includes aggressive intermittent chemotherapy and prophylactic central nervous system therapy. Mediastinal irradiation was given only for emergency relief of mediastinal compression (two children) or for incomplete resolution of mediastinal widening with chemotherapy (one child). All 14 patients achieved complete remission; only 1 has relapsed. Toxicities were not severe. APO is effective therapy for children with MLL. APO should receive further trials in children and adults with T-cell lymphoblastic lymphomas.

Adolescent↗
PubMed1985

Characterization of initiation factor 3 from wheat germ. 1. Effects of proteolysis on activity and subunit composition.

Wheat germ initiation factor 3 (eIF-3) is a large (15 S) particle containing 10 subunits with molecular weights ranging from 28 000 to 116 000. Two forms of wheat germ eIF-3 which differ in ability to support polypeptide synthesis in vitro have been obtained by chromatography on carboxymethyl-Sephadex (CM-Sephadex). The less active form is not retained on CM-Sephadex in 50 mM KCl and contains lower amounts of two subunits, the 116 000-dalton polypeptide (pp116) and the 36 000-dalton polypeptide (pp36). The more active form is retained on CM-Sephadex in 50 mM KCl and is eluted by 150 mM KCl. Treatment of the more active form with small amounts of trypsin results in a rapid degradation of four of the subunits (pp116, pp107, pp87, and pp36) and in a rapid loss in the ability to support polypeptide synthesis. Trypsin treatment also diminishes the ability of eIF-3 to support the binding of mRNA to 40S ribosomal subunits. These findings indicate that pp116, pp107, pp87, and pp36 are in exposed positions in the eIF-3 particle and that pp116 and/or pp36 are essential for activity.

Eukaryotic Initiation Factor-3↗
PubMed1985

Characterization of initiation factor 3 from wheat germ. 2. Effects of polyclonal and monoclonal antibodies on activity.

Rabbit polyclonal antibodies to wheat germ initiation factor 3 (eIF-3) were obtained and were shown to react strongly with 4 of the 10 subunits of eIF-3 (pp116, pp87, pp56, and pp36). Two mouse monoclonal antibodies were obtained, one of which reacts specifically with pp87 and one of which reacts specifically with pp36. Highly purified anti-pp87 has no effect on the activity of eIF-3. Highly purified polyclonal antibodies and anti-pp36 inhibit the ability of eIF-3 to support polypeptide synthesis in vitro and the ability of eIF-3 to support mRNA binding to 40S ribosomal subunits. These results provide additional evidence that pp116, pp87, and pp36 are in exposed positions in the eIF-3 particle and that pp36 is essential for activity.

Antibodies↗
PubMed1985

Phosphorylation of wheat germ initiation factors and ribosomal proteins.

The ability of the wheat germ initiation factors and ribosomes to serve as substrates for a wheat germ protein kinase (Yan and Tao 1982 J Biol Chem 257: 7037-7043) has been investigated. The wheat germ kinase catalyzes the phosphorylation of the 42,000 dalton subunit of eukaryotic initiation factor (eIF)-2 and the 107,000 dalton subunit of eIF-3. Other initiation factors, eIF-4B and eIF-4A, and elongation factors, EF-1 and EF-2, are not phosphorylated by the kinase. Quantitative analysis indicates that the kinase catalyzes the incorporation of about 0.5 to 0.6 mole of phosphate per mole of the 42,000 dalton subunit of eIF-2 and about 6 moles of phosphate per mole of the 107,000 dalton subunit of eIF-3. Three proteins (M(r) = 38,000, 14,800, and 12,600) of the 60S ribosomal subunit are phosphorylated by the kinase, but none of the 40S ribosomal proteins are substrates of the kinase. No effects of phosphorylation on the activities of eIF-2, eIF-3, or 60S ribosomal subunits could be demonstrated in vitro.

Journal Article↗
PubMed1985

Terminal transferase surveillance of remission bone marrows in childhood acute lymphoblastic leukemia: improved sensitivity with countercurrent centrifugal elutriation.

In an attempt to better define hematologic remission and relapse in children with TdT positive acute lymphoblastic leukemia (ALL), 101 bone marrow (BM) aspirates were obtained from 74 pediatric patients. The mononuclear cell population of these specimens was isolated using countercurrent centrifugal elutriation (CCE) and characterized by an immunofluorescent terminal deoxynucleotidyl transferase (IF-TdT) assay. Twenty-two children with non-leukemic disorders had a median of 8% (range 0-34%) TdT positive mononuclear bone marrow cells. This was similar to values obtained for 25 children with ALL off therapy and in remission (median 10%, range 1-22%) and 16 children with ALL on continuous anti-leukemic therapy and in remission (median 7%, range 1-26%). Twenty-three BM samples were obtained from 11 children in early or high risk to relapse because of increased immature cells on a routine marrow examination or previous relapse(s). Samples from the early and high risk to relapse groups contained a median of 56% (range 25-80%) and 39% (range 25-72%) TdT positive cells. In contrast, the median percent marrow lymphoblasts identified using standard morphologic criteria for these 2 groups was 12.5% (range 9-23%) and 3% (range 0-5%), respectively. All high risk patients relapsed in their BM 1-4 1/2 months after these TdT determinations. Longitudinal studies in 4 patients at increased risk to relapse consistently demonstrated elevated percentages of TdT positive cells while morphologic surveillance was inadequate in establishing a clinical diagnosis of leukemic relapse. CCE in combination with an IF-TdT assay may enhance detection of recurrent and/or residual leukemia in BM samples from children with TdT positive ALL.

Bone Marrow↗
PubMed1984

Purification and characterization of three elongation factors, EF-1 alpha, EF-1 beta gamma, and EF-2, from wheat germ.

Three elongation factors, EF-1 alpha, EF-1 beta gamma and EF-2, have been isolated from wheat germ. EF-1 alpha and EF-2 are single polypeptides with molecular weights of approximately 52,000 and 102,000, respectively. The most highly purified preparations of EF-1 beta gamma contain four polypeptides with molecular weights of approximately 48,000, 46,000 and 36,000, 34,000. EF-1 alpha supports poly(U)-directed binding of Phe-tRNA to wheat germ ribosomes and catalyzes the hydrolysis of GTP in the presence of ribosomes, poly(U), and Phe-tRNA. EF-2 catalyzes the hydrolysis of GTP in the presence of ribosomes alone and is ADP-ribosylated by diphtheria toxin to the extent of 0.95 mol of ADP-ribose/mol of EF-2. EF-1 beta gamma decreases the amount of EF-1 alpha required for polyphenylalanine synthesis about 20-fold. EF-1 beta gamma enhances the ability to EF-1 alpha to support the binding of Phe-tRNA to the ribosomes and enhances the GTPase activity of EF-1 alpha. Wheat germ EF-1 alpha, EF-1 beta gamma, and EF-2 support polyphenylalanine synthesis on rabbit reticulocyte ribosomes as well as on yeast ribosomes.

Kinetics↗
PubMed1984

Treatment of meningeal relapse in childhood acute lymphoblastic leukemia. I. Results of craniospinal irradiation.

Fourteen children were treated for isolated meningeal relapse occurring seven to 44 months (median, 14 months) after prophylactic cranial irradiation (2,400 rad/12 fractions) and intrathecal methotrexate (IT MTX, 12 mg/m2 for four doses during cranial irradiation). Eight had "high-risk" acute lymphocytic leukemia with age less than 2 years, white blood cell counts greater than 20,000, or T cell markers. Treatment for central nervous system leukemia included IT MTX (12 mg/m2 twice weekly until clearance of spinal fluid cytology) followed by craniospinal irradiation (CSI, 3,000 rad/20 fractions to the cranium and 1,800 rad/12 fractions to the spine). No maintenance IT MTX was given. Systemic chemotherapy was continued or reinstituted for a minimum of one year after CSI. No instance of second meningeal relapse has occurred. Five patients remain in secondary complete remission 66+, 54+, 36+, 26+, and 24+ months after meningeal relapse. Disease-free survival was limited by marrow relapse in eight patients (2-20 months after CSI) and testicular relapse in one. No acute toxicities were noted with CSI. Myelosuppression occurred in seven patients. Infections within two months of CSI were noted in five. No neurologic sequelae are apparent. Serial neuropsychometric studies in 10 patients revealed a significant decline in mean values on Global IQ scales. Long-term survival with acceptable toxicity is possible following aggressive, prompt treatment of meningeal relapse occurring after prophylactic cranial irradiation. Hematologic relapse remains the major obstacle to long-term disease-free survival.

Acute Disease↗