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F Katz

Publications and source records attributed to F Katz.

At least 19 recordsLinked to original sources
PubMed1998

Absence of expression of the Wiskott-Aldrich syndrome protein in peripheral blood cells of Wiskott-Aldrich syndrome patients.

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency that is usually associated with thrombocytopenia and eczema. The very variable phenotype of WAS results from defects in the WAS protein (WASP), the function of which is not well understood. In many cases causative mutations have now been identified in the WAS gene. Attempts have been made to correlate the nature of the mutations with the severity of the disease. In this study we investigated mutations in 13 patients with WAS and analyzed the expression of WASP in patient blood samples by immunoblot analysis. We found that despite extensive variation in the nature of the mutations in patients with severe WAS symptoms, none express the protein. However, in 1 patient with a mild clinical phenotype WASP expression was detected. Such an analysis could be used as an initial screening procedure for the diagnosis of WAS prior to genotypic analysis.

Base Sequence↗
PubMed1997

B-cell-negative severe combined immunodeficiency associated with a common gamma chain mutation.

Severe combined immunodeficiency (SCID) is caused by a variety of underlying defects. Approximately 40% of cases are thought to be of the X-linked type (SCIDX1), which is phenotypically characterised by the absence, or very low numbers, of T cells, but normal or even high B cell numbers. The gene responsible for SCIDX1 is that coding for the common gamma chain (gamma c), a component of multiple cytokine receptors. Mutations in this gene have been demonstrated in a large number of boys affected by typical SCIDX1. We describe a sporadic case of a boy who had SCID with absent B cells and absent T cells, but in whom a mutation in the gamma c gene has been demonstrated. In the absence of a typical X-linked pedigree, the phenotype in this boy suggested an autosomal recessive form of SCID and the family would usually have been counselled accordingly. This family raises the question of the true frequency of SCIDX1 amongst sporadic male cases of SCID and highlights the need to screen these boys for gamma chain mutations.

Antigens, CD↗
PubMed1996

Mutation analysis in CD40 ligand deficiency leading to X-linked hypogammaglobulinemia with hyper IgM syndrome.

Mutations in the gene encoding CD40 ligand have been shown to be the cause of X-linked hypogammaglobulinemia with hyper IgM (HIGM1). We have used the technique of single strand conformational polymorphism (SSCP) analysis to screen for mutations in this gene in affected boys from nineteen unrelated families. Sixteen novel mutations were identified in patients, comprising six patients with single base substitutions, two patients with single base insertions, six patients with deletions ranging from one to seven bases and two patients with large deletions at the 5' end of the gene. These mutations were distributed throughout the gene SSCP band shifts and/or alterations in restriction enzyme digestion sites could be used for unambiguous determination of carrier status in at-risk female relatives of most of the affected boys and, in some cases, prenatal diagnosis also can be offered.

Agammaglobulinemia↗
PubMed1996

Improving performance with clinical decision support.

BACKGROUND: CADU/CIS (Clinical and Administrative Decision-support Utility and Clinical Information System) is a clinical decision-support workstation that allows large volumes of clinical information systems data to be analyzed in a timely and user-friendly fashion. CARE PROCESS MEASUREMENT: For any given disease, subgroups of patients are identified, and automated, customized "clinical pathways" are generated. For each subgroup, the best practice norms for use of test and therapies are identified. Practice style variations are then compared to outcomes to focus inquiry on decisions that significantly affect outcomes. CASE STUDY: INTESTINAL OBSTRUCTION: Graduate Health Systems, a multisite integrated provider in the Philadelphia area, has used CADU/CIS to improve quality problems, reduce treatment-intensity variations, and improve clinical participation in care process evaluation and decision making. A task force selected intestinal obstruction without hernia as its first study because of the related high-volume and high-morbidity complications. Use of a ten-step method for clinical performance improvement showed that the intravenous administration of unnecessary fluids to 104 patients with intestinal obstruction induced congestive heart failure (CHF) in 5 patients. Task force members and other practicing physicians are now developing guidelines and other interventions aimed at fluid use. Indeed, the task force used CADU/CIS to identify an additional 250 patients in one year whose conditions were complicated by CHF. CONCLUSION: A clinical decision support tool can be instrumental in detecting problems with important clinical and economic implications, identifying their important underlying causes, tracking the associated tests and therapies, and monitoring interventions.

Aged↗
PubMed1996

The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9.

The t(7;11)(p15;p15) translocation is a recurrent chromosomal abnormality associated primarily with acute myeloid leukaemia (FAB M2 and M4). We present here the molecular definition of this translocation. On chromosome 7 positional cloning revealed the consistent rearrangement of the HOXA9 gene, which encodes a class I homeodomain protein potentially involved in myeloid differentiation. On chromosome 11 the translocation targets the human homologue of NUP98, a member of the GLFG nucleoporin family. Chimaeric messages spliced over the breakpoint fuse the GLFG repeat domains of NUP98 in-frame to the HOXA9 homeobox. The predicted NUP98-HOXA9 fusion protein may promote leukaemogenesis through inhibition of HOXA9-mediated terminal differentiation and/or aberrant nucleocytoplasmic transport.

Amino Acid Sequence↗
PubMed1996

CD40 ligand deficiency presenting as unresponsive neutropenia.

A male child presented with recurrent respiratory infections, otitis media, and oral ulceration and was found to be neutropenic. Investigations showed hypogammaglobulinaemia with normal serum IgM and a novel deletion in the gene for CD40 ligand on his X chromosome. Intravenous gammaglobulin did not lead to resolution of his neutropenia; G-CSF was also necessary.

Agammaglobulinemia↗
PubMed1994

A polymerase chain reaction study of the stability of Ig heavy-chain and T-cell receptor delta gene rearrangements between presentation and relapse of childhood B-lineage acute lymphoblastic leukemia.

Ig heavy-chain (IgH) and partial V delta 2-D delta 3 T-cell receptor (TCR) gene rearrangements were investigated, by polymerase chain reaction (PCR) amplification and sequence analysis, in 52 patients at presentation and first relapse and in 14 at both first and second relapse of B-lineage acute lymphoblastic leukemia. In combination, these techniques amplified one or more clonal markers at presentation in 90% of patients (IgH-PCR, 75%; V delta 2-D delta 3-PCR, 46%; both, 33%). Changes in the pattern of amplification between presentation and first relapse were seen in 31% of patients positive by IgH-PCR at presentation and in 25% of those positive by TCR delta-PCR. Only 3 patients showed complete change in their rearrangements, which is suggestive of relapse with a new clone. Furthermore, despite the high reported rates of oligoclonality and clonal evolution at the IgH locus, the results presented show that false-negative minimal residual disease (MRD) detection can be avoided by designing D-N-J probes to all presentation rearrangements. Using a PCR approach for both gene markers, false-negative testing because of clonal evolution would have only occurred in 3 (8%) of the IgH-positive patients, in contrast to 5 (21%) of V delta 2-D delta 3-positive patients. Combining these two systems increases the proportion of patients open to study to 90%, allows comparative studies of the sensitive of the two methods, and reduces the rate of false-negative assessment of MRD caused by clonal evolution to less than 10%. We conclude that large prospective PCR studies of MRD detection should examine gene rearrangements at multiple loci to maximize their applicability and to minimize false-negative relapse prediction.

Adolescent↗
PubMed1994

PCR assessment of bone marrow status in 'isolated' extramedullary relapse of childhood B-precursor acute lymphoblastic leukaemia.

Approximately one-third of first relapses of childhood ALL occur at an extramedullary site without morphological evidence of bone marrow disease. However, the high incidence of subsequent medullary relapse in these cases strongly suggests that leukaemia is present at submicroscopic levels at the time of 'isolated' relapse. PCR analysis of immunoglobulin heavy chain (IgH) and T-cell receptor (TCR) gene rearrangements now allows detection of leukaemia at levels as low as 0.001%. We have therefore used this technique to reassess bone marrow status at morphologically isolated relapse in 13 children with B-lineage ALL (11 with off-treatment relapses, two on treatment). In 12 of these 13 patients marrow disease was detectable by PCR at the time of this relapse--in all cases at levels below the threshold of light microscopy. Where relapse occurred off-therapy this indicated re-emergence of disease. since MRD has never been detected by PCR at this stage in patients remaining in long-term remission. In both patients who relapsed on-therapy the level of MRD at the time of relapse represented an increase on that seen in their previous marrow sample. We conclude that re-emerging bone marrow disease can be detected in most cases of 'isolated' relapse when investigated by this highly sensitive technique. Our findings at a molecular level confirm a long-held clinical suspicion and indicate that full systemic re-induction as well as local therapy is obligatory for these children.

Adolescent↗
PubMed1994

Trisomy X in a female member of a family with X linked severe combined immunodeficiency: implications for carrier diagnosis.

We describe a family affected by X linked severe combined immunodeficiency (SCIDX1) in which genetic prediction of carrier status was made using X chromosome inactivation studies together with limited genetic linkage analysis. Linkage studies in this family showed a confusing pattern of inheritance for the X chromosome. A female with a random pattern of X chromosome inactivation in her T cells appeared to have inherited an X chromosome with four recombinations within 10 cM. The odds of this happening in a single meiotic event make this an unlikely explanation. Data obtained from studying the X chromosomes of her two unaffected sons showed that this could be explained simply on the basis of her having inherited three alleles each of the relevant polymorphic DNA loci. We used fluorescent in situ hybridisation (FISH) to confirm that this person had inherited three complete X chromosomes. Thus, although the results from X chromosome inactivation analysis indicated that this subject was not a carrier of the affected chromosome, FISH and genetic linkage analysis showed clearly that the affected chromosome had been inherited. The implications of this finding for diagnosis of carrier status in this family and for other families with X linked inherited immunodeficiencies is discussed.

Chromosome Mapping↗
PubMed1994

Characterisation of non-concordance in the T-cell receptor gamma chain genes at presentation and clinical relapse in acute lymphoblastic leukemia.

We have analysed the structure of the T-cell receptor gamma chain (TCRG) genes in a panel of biopsies taken from 24 patients with acute lymphoblastic leukemia (ALL) (13 cALL, one pre-B ALL, two null ALL and eight T-ALL) at presentation and at clinical relapse. In the majority of cases (18/24) the structure of these genes was concordant, but in a significant minority of cases (6/24) the TCRG genes were in a different conformation at different clinical stages. In three of these patients (one null ALL, two T-ALL) the clonal TCRG rearrangements detected at presentation were absent at relapse possibly as a result of clonal regression. In one other patient (cALL), the TCRG locus at relapse was rearranged to V genes which are located downstream of the V genes found in the presentation rearrangement. This indicates that the relapse leukemic clone is probably the result of clonal evolution. In two patients (one cALL, one T-ALL) there were no clonally dominant rearrangements of the TCRG genes at presentation, but evidence for clonal rearrangements at relapse, possibly as a result of clonal progression. The structure of the IgH genes were determined in four of the six patients with clonal changes in the TCRG genes and were found to be concordant. The changes in TCRG gene structure were not restricted to ALL of any one particular age group, phenotype or duration of first remission. These data indicate that the assignment of clonal specific markers based upon the sequence of TCRG rearrangements at presentation may not always be useful in the detection of minimal residual disease in ALL.

Adolescent↗
PubMed1993

Leukaemia arising in donor cells following allogeneic bone marrow transplantation for beta thalassaemia demonstrated by immunological, DNA and molecular cytogenetic analysis.

Combined DNA analysis, molecular cytogenetic and immunological techniques have been used to identify the donor origin of common acute lymphoblastic leukaemia (cALL) which arose in a male patient with beta thalassaemia major, 5 years after an allogeneic bone marrow transplant from his HLA-matched sister. The necessity of using multiple techniques in this and similar cases is emphasized and the possible mechanisms for the development of donor leukaemia and the leukaemic transformation of donor cells are discussed.

Bone Marrow↗
PubMed1993

Assessment of graft status following allogeneic bone marrow transplantation for haematological disorders in children using locus-specific minisatellite probes.

We have examined peripheral blood or bone marrow DNA following allogeneic bone marrow transplantation (BMT) in children suffering from a variety of haematological disorders. Using either locus-specific minisatellite probes separately or in combination with a Y specific probe for sex-mismatched transplants, complete haematological chimaerism, autologous reconstitution, or mixed chimaeric states have been defined immediately post-BMT. We have also been able to identify emerging autologous cells or relapse prior to morphological diagnosis. Forty-two children, mean age 6.4 years (range 9 months to 15 years), received an allogeneic BMT for: acute lymphoblastic leukaemia (ALL), n = 17; acute myeloid leukaemia (AML), n = 5; biphenotypic leukaemia, n = 1; myelodysplastic syndrome (MDS), n = 5; chronic granulocytic leukaemia (CGL), n = 1; severe aplastic anaemia (SAA), n = 7; familial erythrophagocytic lymphohistiocytosis (FEL), n = 2; beta thalassaemia major (beta thal), n = 1; and juvenile chronic myeloid leukaemia (JCML), n = 3. Immediately post-transplant, 78% had achieved complete haematological chimaerism, 12% had failed to engraft (DNA analysis confirmed autologous reconstitution) and 10% had mixed chimaerism. SAA was the underlying disease in two of the chimaeric cases, the third case having had a matched unrelated donor (MUD) BMT for MDS. In 3/4 cases which subsequently relapsed, DNA analysis showed re-emergence of autologous cells (indicative of relapse), prior to their morphological identification. We conclude that DNA analysis using minisatellite probes to assess graft status provides a useful contribution to patient management following allogeneic BMT.

Bone Marrow Transplantation↗
PubMed1993

Successful allogeneic bone marrow transplantation in juvenile CML: conditioning or graft-versus-leukaemia effect?

Allogeneic BMT is the treatment of choice for juvenile CML (JCML). This has been successful following conditioning with cyclophosphamide (120 mg/kg) and total body irradiation (TBI) (10-15.75 Gy). However, busulphan (16 mg/kg) and cyclophosphamide (200 mg/kg) (Bu/Cy) conditioning has been reported to be insufficient to eradicate the malignant clone in JCML. We report successful BMT and eradication of the disease at 18 months follow-up in a child 15 months old at presentation, who was conditioned with busulphan 20 mg/kg and cyclophosphamide 200 mg/kg, with the addition of splenic irradiation. Despite using higher than conventional doses of busulphan, pharmacokinetic analysis revealed very low busulphan peak levels and rapid excretion. As a possible consequence, only partial chimerism was achieved, but full engraftment ensued following the discontinuation of cyclosporin A, rebound donor lymphocytosis and the onset of acute GVHD. We suggest that host resistance to engraftment and tumour elimination was overcome by removing a suppressive effect on donor lymphocytes, allowing a graft-versus-leukaemia effect.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Diagnosis of acute promyelocytic leukaemia by RT-PCR: detection of PML-RARA and RARA-PML fusion transcripts.

Acute promyelocytic leukaemia (APL; AML M3) is identified by a unique t(15;17) translocation which fuses the PML gene to the retinoic acid receptor alpha gene (RARA). Reverse transcription coupled with the polymerase chain reaction (RT-PCR) has been used to develop a diagnostic test for APL based on the PML-RARA fusion message. Separate PCR assays were designed to amplify either PML-RARA (15q+ derived) or RARA-PML (17q- derived) chimaeric transcripts. PML-RARA transcripts were detected in every case from a series of 18 APL patients with cytogenetically confirmed t(15;17) translocations, whereas RARA-PML messages were detected in only 67% (12/18) of these patients. This suggests that it is the 15q+ derivative which mediates leukaemogenesis. Furthermore the PCR approach (or Southern analysis) may be used to identify in which of the alternative PML introns the breakpoint occurs; 52% of cases (15/29 patients) utilize a 5' PML intron and 48% the 3' intron (14/29 cases). Neither the choice of PML intron nor the expression of the 17q- derivative could be correlated with the microgranular variant of APL (M3V), overall survival rate, age, sex or presence of coagulopathy. Finally, the fusion message is undetectable in five remission samples. This indicates a possible use for RT-PCR in monitoring remission patients for evidence of relapse.

Adolescent↗
PubMed1992

Possible evidence for genomic imprinting in childhood acute myeloblastic leukaemia associated with monosomy for chromosome 7.

Monosomy or deletion of chromosome 7 is a frequent finding in both de novo and secondary acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Based on analysis of deletions of chromosome 7 in such patients, it has been suggested that there is a critical region of the chromosome lying within bands q21-q31. We have examined bone marrow and peripheral blood samples from 10 patients with MDS, AML and biphenotypic acute leukaemia who had monosomy for or rearrangement of chromosome 7, seeking evidence of non-random allele loss that might suggest the presence of imprinted genes on the chromosome. Bone marrow cells from one patient with the infant monosomy 7 syndrome had loss of maternal alleles as did two patients with biphenotypic leukaemia. Five out of five patients with MDS and both patients with de novo AML had loss of paternal alleles. One of the latter patients had a del(7) (q31q36) rather than monosomy 7. These findings suggest that imprinting of a gene(s) on chromosome 7, within the bands q31-q36, may be of importance in MDS and AML. Despite the reported increased incidence of AML amongst relatives of patients with cystic fibrosis (CF) the gene for which lies in chromosome region 7q31, none of the patients nor parents studied here appeared to be carriers of the most common gene mutation seen in patients with CF, the delta F508.

Acute Disease↗
PubMed1991

Analysis of ras gene mutations in childhood myeloid leukaemia.

Previous studies have shown that approximately 30% of adult acute myeloid leukaemias and 20% of adult acute lymphoid leukaemias contain point mutated ras oncogenes. In order to assess whether ras oncogenes are also involved in childhood leukaemias, we have used polymerase chain reaction (PCR) amplification and synthetic oligonucleotide probes to study the nature and frequency of ras gene mutations in childhood leukaemias, concentrating largely on the acute myeloid leukaemias (AML). Thirty-four childhood presentation AML DNAs were screened for mutations in and around codons 12, 61 and 117 of N-, K- and H-ras. Eight of these samples (24%) contained ras mutations. As in the adult disease, the gene predominantly involved was N-ras (6/8), with occasional activation of K-ras (2/6). The most common base change was a G----A transition at codon 12 or 13 (4/8). Of the patients with mutant ras, 4/8 were diagnosed as AML FAB subtype M5. Five of the 34 childhood AMLs analysed displayed abnormalities of chromosome 7. However, none of these cases contained a mutant ras gene. One AML patient was studied at relapse, 14 months after initial presentation. The presentation mutation (N61p3) was not detectable, although a new mutation (N13Cys) was readily identified. This observation extends our original finding with presentation and relapse samples of adult AML, in which it was uncommon for the relapse sample to contain the same ras mutation as the presentation DNA. In addition, two out of five patients diagnosed as juvenile CML, were found to harbour mutant ras.

Acute Disease↗
PubMed1991

Failure of purged autologous bone marrow transplantation in high risk acute lymphoblastic leukaemia in first complete remission.

Patients in first remission of acute lymphoblastic leukaemia (ALL) considered to be at high risk of relapse were offered autologous bone marrow transplantation (ABMT) using purged marrow as a therapeutic alternative to cranial irradiation and maintenance chemotherapy. Twenty-seven bone marrows taken in remission, were purged using monoclonal antibodies (anti CD7 for T lineage and anti CD10 and/or anti CD19 for B lineage leukaemias) plus rabbit complement. Retrospective analysis of 19 purged marrows by immunophenotyping or immunoglobulin gene rearrangement studies demonstrated no evidence of disease. Engraftment was seen in 26 of the patients. No correlation was found between the numbers of infused nucleated cells or colony forming units-granulocyte-macrophage (CFU-GM) and subsequent engraftment kinetics. The actuarial disease-free survival (DFS) is 32% at 7 years (median follow-up 3.4 years). There were two transplant related deaths (actuarial risk 8%); the main cause of treatment failure has been disease recurrence with an overall actuarial risk of 67%; 76% for T-ALL (five of nine), 62% for common ALL (five of 10), two of five pre B and none of three patients with B-ALL. In these 27 high risk patients in vitro purging of remission marrow as part of ABMT appears not to improve patient outcome, although confirmation of this would require a randomized trial.

Adolescent↗