Stephen D. Smith

Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor

The gene (E2A) for enhancer binding transcription factors E12 and E47 maps to the t(1;19) chromosomal translocation breakpoint in pre-B cell leukemias. Altered E2A transcripts lacking sequences coding for the helix-loop-helix DNA binding motif were detected in several t(1;19)-carrying cell lines. Fusion cDNAs that crossed the t(1;19) breakpoint were cloned and shown to code for an 85 kd protein consisting of the amino-terminal two-thirds of E2A fused to a chromosome 1-derived protein. The fusion protein has the features of a chimeric transcription factor in which the DNA binding domain of E2A is replaced by the putative DNA binding domain of a homeoprotein from chromosome 1 for which the name Prl (pre-B cell leukemia) is proposed. Identical E2A-prl mRNA junctions were detected by PCR in three t(1;19)-carrying cell lines, indicating that the fusion transcripts and predicted chimeric protein are a consistent feature of this translocation.

lyl-1, a novel gene altered by chromosomal translocation in T cell leukemia, codes for a protein with a helix-loop-helix DNA binding motif

We have characterized a transcription unit at chromosome band 19p13 that lies at the site of a chromosomal translocation breakpoint in T cell acute lymphoblastic leukemia. The lyl-1 gene is structurally altered following a t(7;19) translocation, resulting in its head-to-head juxtaposition with the T cell receptor C beta gene and truncation of lyl-1 RNA. The predicted protein product of the lyl-1 gene contains a potential helix-loop-helix DNA binding motif also found in several proteins involved in the control of cellular proliferation and differentiation: all members of the Myc family, MyoD1, myogenin, the Drosophila achaete-scute, twist, and daughterless proteins, and two recently described immunoglobulin enhancer binding proteins. The implication of lyl-1 in cellular transformation suggests that other proteins containing similar DNA binding motifs may also be involved with neoplastic transformation in various cellular lineages.

A reliable method for evaluating drug compliance in children with cancer

Poor drug compliance may cause a decreased survival of children with malignancies. Children who fail to take their medications are not receiving optimum amounts of chemotherapy and suboptimal therapy causes a shortened survival in children with cancer. This is a study of prednisone compliance in 52 children with cancer during three distinct phases of therapy. The patients were either known to be taking prednisone (on‐therapy group), off prednisone (off‐therapy group), or their compliance was unknown (unknown group). Evaluation of prednisone compliance was attempted by measuring hemoglobin level changes, weight changes, and random urinary 17‐ketogenic steroids. The results obtained show that while hemoglobin and weight changes are not helpful, a random urine 17‐ketogenic steroid assay is able to differentiate clearly those patients who are taking their prednisone. By the use of this assay it was found that 33% of patients who by protocol and instruction were supposed to be receiving prednisone were not complying. Separate analysis of adolescents revealed an even more alarming 59% noncompliance rate. This striking level of noncompliance strongly suggests that the survival of patients may be threatened by noncompliance.

Fludarabine, Melphalan, and Alemtuzumab Conditioning in Adults With Standard-Risk Advanced Acute Myeloid Leukemia and Myelodysplastic Syndrome

PURPOSE This prospective phase II study evaluated toxicity, relapse rate, progression-free survival, and overall survival after allogeneic transplantation and conditioning with fludarabine, melphalan, and alemtuzumab in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS Fifty-two consecutive adults with AML and MDS were enrolled onto the study. Median age was 52 years (range, 17 to 71 years) and the majority of patients had high-risk disease, comorbidities, and/or modest reduction in performance status. Fifty-six percent of patients had unrelated or mismatched related donors. RESULTS After a median follow-up of 18 months (range, 2 to 34 months), 1-year survival was 48% (95% CI, 34% to 61%), progression-free survival was 38% (95% CI, 25% to 52%), relapse rate was 27% (95% CI, 15% to 40%), and treatment-related mortality was 33% (95% CI, 20% to 46%). The cumulative probability of extensive chronic graft-versus-host disease (GVHD) was only 18% (95% CI, 8% to 40%); extensive chronic GVHD was only observed in recipients of unrelated donor transplants. Performance score and disease status were the major predictors of outcome. High-risk disease (ie, active AML or MDS with > 5% blasts) or even modest decreases in performance status were associated with poor outcomes. Patients with standard-risk leukemia (first or second complete remission) or MDS (< 5% blasts) had excellent outcomes despite unfavorable disease characteristics. CONCLUSION Fludarabine and melphalan combined with in vivo alemtuzumab is a promising transplantation regimen for patients with AML or MDS and low tumor burden. For patients with active disease, this regimen provides at best modest palliation. Despite a low incidence of GVHD, transplantation is still associated with considerable nonrelapse mortality in patients with decreased performance status.

Congenital anaemia after transplacental B19 parvovirus infection.

We report three children with congenital anaemia after intrauterine infection with B19 parvovirus. All the fetuses developed hydrops fetalis that was treated by blood transfusion. After delivery the infants had hypogammaglobulinaemia. In all three, sera lacked B19 but viral DNA was found in bone marrow. All were treated with immunoglobulin. One child died and B19 was found in various tissues. In the other two cases, virus could no longer be detected after therapy but the patients remain persistently anaemic. Persistent B19 infection should be suspected in infants with congenital red-cell aplasia.

Fusion of an immunoglobulin variable gene and a T cell receptor constant gene in the chromosome 14 inversion associated with T cell tumors

An inversion of chromosome 14, inv(14)(q11,q32), is frequently observed in human T cell tumors; the cytogenetic breakpoints are of interest because the T cell receptor alpha-chain and immunoglobulin heavy chain genes reside on chromosome bands 14q11 and 14q32, respectively. We have investigated the structure of the alpha-chain genes in a T cell line harboring the chromosome 14 inversion. On the normal chromosome 14, a V alpha segment has rearranged nonproductively with a J alpha segment. In contrast, the inverted chromosome features an unprecedented rearrangement in which an immunoglobulin heavy chain variable gene segment (VH) on chromosome band 14q32 has joined with a J alpha segment from band 14q11. The VH-J alpha C alpha rearrangement is productive at the genomic level and therefore may encode a hybrid immunoglobulin/T cell receptor polypeptide.

ABSENCE OF CELL SURFACE LFA-1 AS A MECHANISM OF ESCAPE FROM IMMUNOSURVEILLANCE

During studies of T-cell recognition of autologous tumour cells, a number of tumour cell lines derived from patients with lymphoma proved to be poor stimulators of both autologous and allogeneic T-cell responses. Analysis of the tumour cell surface molecules indicated that expression of the lymphocyte-function-associated antigen, LFA-1, was lacking, whereas normal leucocytes from these patients expressed normal levels of LFA-1. Examination of other lymphoid tumours revealed that most high grade lymphomas, but not most low or intermediate grade lymphomas, do not express the LFA-1 molecule. Furthermore, in an initial survey, the tumours from 5 of 7 patients with non-relapsing large cell lymphomas expressed LFA-1 whereas only 3 of 18 patients with relapsing lymphomas had tumours that did so. These findings suggest that tumour cells lacking surface LFA-1 cannot initiate an effective immune response in vivo. This lack of immunogenicity might contribute to escape from immunosurveillance.

Statistical Design and Estimation for the National Social Life, Health, and Aging Project

OBJECTIVES The paper discusses the sample design of the National Social Life, Health, and Aging Project (NSHAP) and how the design affects how estimates should be calculated from the survey data. The NSHAP study allows researchers to study the links between sexuality and health in older adults. The goal of the design was to represent adults aged 57-85 years in six demographic domains. METHODS The sample design begins with a national area probability sample of households, carried out jointly with the 2004 round of the Health and Retirement Study. Selection of respondents for NSHAP balanced age and gender subgroups and oversampled African Americans and Latinos. Data collection was carried out from July 2005 to March 2006. RESULTS The survey obtained an overall response rate of 75.5%. DISCUSSION The complex sample design requires that the selection probabilities and the field implementation be accounted for in estimating population parameters. The data set contains weights to compensate for differential probabilities of selection and response rates among demographic groups. Analysts should use weights in constructing estimates from the survey and account for the complex sample design in estimating standard errors for survey estimates.

CLINICAL RECOGNITION AND TREATMENT OF ACUTE POTASSIUM INTOXICATION

Excerpt The toxicity to the living organism of an excess of potassium ion in the extracellular fluid has been recognized for many years.1, 2, 3The accumulation of toxic amounts of potassium may occ...

Treatment of CNS relapse in children with acute lymphoblastic leukemia : a pediatric oncology group study

PURPOSE To assess the efficacy and toxicity of chemotherapy and cranial radiation for the treatment of children with acute lymphoblastic leukemia (ALL) following first isolated CNS relapse. PATIENTS AND METHODS One hundred twenty children were treated on Pediatric Oncology Group (POG) protocol 8304. All children had received prophylactic CNS therapy during their initial treatment. The treatment protocol included a four-drug reinduction and six weekly doses of triple intrathecal therapy (TIT). Cranial radiation, 24 Gy, was followed by monthly TIT. Systemic consolidation and maintenance therapy included 6-week cycles of mercaptopurine/methotrexate (6MP/MTX) and vincristine/cyclophosphamide (VCR/CTX), with randomization to intervening pulses of prednisone/doxorubicin (PDN/DOX) or teniposide (VM26)/cytarabine (Ara-C) for a total of 88 weeks. RESULTS All 120 patients achieved a second complete remission. There have been 61 protocol failures. Thirty-five patients had a bone marrow relapse, four with simultaneous CNS involvement and one with concurrent testicular leukemia. Thirteen patients had a second isolated CNS relapse, 10 a testicular relapse, and two relapsed in other sites. One patient died in remission. Overall event-free survival (EFS) at 4 years was 46% +/- 7%. The toxicity associated with this protocol was minimal except for leukoencephalopathy, which occurred in 20 (17%) patients. The treatment comparison between VM26/Ara-C or PDN/DOX pulses showed a trend toward superior EFS (P = .12) in favor of VM-26/Ara-C. CONCLUSION To date, this represents the largest series of patients with ALL treated uniformly for an isolated CNS relapse. Since marrow relapse remains the primary site of failure, future protocols must intensify systemic therapy.