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M Shtalrid

Publications and source records attributed to M Shtalrid.

At least 55 records · Page 3Linked to original sources
PubMed1988

Significance and correlations of molecular analysis results in patients with Philadelphia chromosome-negative chronic myelogenous leukemia and chronic myelomonocytic leukemia.

PURPOSE: Several investigators have documented a rearrangement of the breakpoint cluster region (bcr) in selected patients with a morphologic diagnosis of chronic myelogenous leukemia (CML) but no abnormality of the Philadelphia chromosome (Ph) by cytogenetic studies. Our intention was to systematically investigate the incidence of the bcr rearrangement in such patients, and to correlate the findings with patient characteristics, response to therapy (especially alpha interferon treatment), and overall prognosis. PATIENTS AND METHODS: Molecular analysis studies were performed in 40 patients with Ph-negative CML (23 patients) and myelomonocytic leukemia (CMML; 17 patients). RESULTS: Rearrangement of the breakpoint cluster region (bcr) was detected in 11 of the 23 patients with Ph-negative CML (48 percent), indicating the presence of the abnormal molecular events in Ph-positive CML without documentation of the Ph cytogenetic abnormality. None of the 17 patients with CMML had the bcr rearrangement. Patients with Ph-negative CML and the bcr rearrangement had characteristics similar to those of patients with Ph-positive disease. These included a younger age, higher white blood cell counts, a higher incidence of thrombocytosis and basophilia, and a lower occurrence of thrombocytopenia. The leukocyte alkaline phosphatase score was not a helpful distinguishing feature. Among 21 patients receiving alpha interferon-based regimens, response to therapy was significantly better among patients with Ph-negative disease and the bcr rearrangement (seven of seven, 100 percent), compared with those without the bcr rearrangement (one of six, 17 percent), or patients with CMML (two of eight, 25 percent) (p less than 0.01). At this time of follow-up, only one of the 11 patients with Ph-negative CML and the bcr rearrangement had died from complications of allogeneic bone marrow transplantation, compared with three deaths among the 12 patients with Ph-negative CML and no bcr rearrangement, and 11 deaths among the 19 patients with CMML. CONCLUSION: We conclude that molecular studies help in better understanding the nosology of Ph-negative CML, and define a subgroup of patients with clinical, therapeutic, and prognostic correlations similar to those of patients with Ph-positive CML.

Adolescent↗
PubMed1988

Philadelphia-negative chronic myelogenous leukemia with breakpoint cluster region rearrangement: molecular analysis, clinical characteristics, and response to therapy.

We have detected rearrangement in the breakpoint cluster region (bcr) on chromosome 22 in cells derived from seven chronic myelogenous leukemia (CML) patients who had no cytogenetic evidence of a chromosome abnormality. These Philadelphia (Ph)-negative, bcr rearrangement-positive CML patients had clinical features and laboratory parameters that bore a strong resemblance to those of Ph-positive CML; all patients have shown a favorable response to hydroxyurea, busulphan, or alpha interferon (IFN-alpha) therapy. In one patient, because of the deletion of distal 3' sequences, detection of bcr rearrangement required a large probe that recognized proximal 5' sequences. Cells obtained from five patients were studied by Northern blotting and showed an aberrant 8 kilobase (kb) mRNA indistinguishable from the bcr-abl transcript that is felt to be a pathogenetic factor in Ph-positive CML. In three patients with a normal karyotype, bcr rearrangement was detected at the time of hematologic remission, and represented the only evidence for persistent malignancy. Our results suggest that: (1) the presence of bcr rearrangement in CML is associated with clinical features of Ph-positive disease, even in the absence of the Ph chromosome; (2) deletions occur within bcr and necessitate the use of probes covering both 5' and 3' DNA segments for accurate diagnosis; (3) molecular analysis may provide a useful approach to the follow-up of leukemia therapy in some patients; and (4) these patients respond to hydroxyurea, busulphan, and IFN-alpha therapy.

Adolescent↗
PubMed1988

Analysis of breakpoints within the bcr gene and their correlation with the clinical course of Philadelphia-positive chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation between chromosomes 9 and 22. The breakpoints on chromosome 22 are clustered within a 5.8-kilobase (kb) DNA fragment known as the breakpoint cluster region (bcr), which encodes part of a functionally active gene. We analyzed the bcr in DNAs from 108 consecutive, unselected Philadelphia chromosome-positive CML patients by Southern blot and determined five restriction enzyme fragments within which breaks occur on chromosome 22. The exact sublocalization was determined in the DNA of 100 patients. It was found to be within the 5.8-kb in 99 patients and outside the bcr in only one. Within the bcr, most of the breakpoints occurred in fragments 1, 2, and 3. Overall, laboratory and clinical features of CML did not correlate with specific breakpoint fragments, but chronic-phase duration was longer in patients with a breakpoint in fragment 2 of the bcr. Large 3' bcr deletions were found in nine patients but did not influence clinical outcome. DNA from one of six patients analyzed both during chronic phase and blastic crisis showed an additional aberrant fragment, which suggested that a second abnormal clone developed in blastic crisis.

Blast Crisis↗
PubMed1988

Lack of breakpoint cluster region rearrangement in marrow fibroblasts of patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

Involvement of marrow fibroblasts in myeloproliferative disorders such as chronic myelogenous leukemia (CML) is controversial. We examined the blood leukocytes and bone marrow fibroblasts of four patients with Philadelphia chromosome- (Ph1) positive CML for evidence of rearrangement in the breakpoint cluster region (BCR). Fibroblasts were obtained by growing bone marrow in long-term culture, disposing of nonadherent cells, and passaging three times before final trypsinization and analysis. DNA from fibroblasts and peripheral leukocytes was digested with Bg1II, Bc1I, EcoRI, and HindIII restriction endonucleases and hybridized to both 3' and 5' BCR probes. Southern blot analysis of the DNA from the peripheral leukocytes in all four patients demonstrated rearrangement in the BCR. However, analysis of DNA from marrow fibroblasts showed only the normal BCR restriction fragments in all patients. This study demonstrates the absence of the Ph1 -associated molecular events in the fibroblasts of patients with CML. It is consistent with previous studies using G6PD isoenzymes to show polyclonality in CML fibroblasts and with most cytogenetic studies that did not show the Ph1 in these cells. In summary, we present further evidence that involvement of CML fibroblasts is a secondary event in the leukemogenic process.

Bone Marrow Cells↗
PubMed1987

Molecular characteristics of chronic myelogenous leukemia in blast crisis.

We have studied the expression of c-abl and c-myc in leukemic cells of patients in all clinical phases of chronic myelogenous leukemia. We demonstrate that an aberrant 8-Kb c-abl related transcript is present in the RNA of the leukemic cell from all patients with Ph+ CML and that the loss of both normal chromosome #9 is associated with the loss of the normal c-abl related transcripts. This represents direct evidence that the normal c-abl related transcripts derive from the normal c-abl gene locus on the normal chromosome #9, while the aberrant c-abl related transcript in Ph+ CML derives from the hybrid bcr-abl gene formed as a result of the t(9;22). We further demonstrate that trisomy 8 in some instances is associated with enhanced expression of the c-myc oncogene.

Blast Crisis↗
PubMed1987

Molecular analysis of chromosome 22 breakpoints in adult Philadelphia-positive acute lymphoblastic leukaemia.

The Philadelphia (Ph) translocation, t(9:22)(q 34:q11), is found in the majority of patients with chronic myelogenous leukaemia (CML) as well as in approximately 20% of adult acute lymphoblastic leukaemia (ALL) patients. The chromosome 22 breakpoint in CML has been localized within a restricted 5.8 kb segment of DNA known as the breakpoint cluster region (bcr). To investigate the chromosome 22 breakpoint in ALL, we analysed five adult Ph-positive ALL patients for bcr rearrangement. Rearrangement was detected within bcr in two patients. However, in one patient the break occurred 5' to the first exon of bcr and in two patients the bcr region was not involved. We conclude that the identical cytogenetic marker, t(9:22), may yield a different genomic configuration in ALL and CML.

Acute Disease↗
PubMed1987

Review of clinical and haematological response to low-dose cytosine arabinoside in acute myeloid leukaemia.

15 patients with acute myeloid leukaemia (AML) were treated with low-dose cytosine arabinoside (LD ARA-C). 2 patients had complete remissions, which lasted for 8 and 3 months, and 5 patients had a partial remission. 46% of the patients thus responded to LD ARA-C. This included 1 responding patient who had not previously responded to therapy with 6-mercaptopurine, thioguanine, or vinblastine. The 2 patients with complete remission did not show LD ARA-C-induced hypoplasia of bone marrow, although 1 had hypoplastic AML before therapy. Leukaemic cells from 1 patient showed in vivo maturation from M1 to M3 after LD ARA-C treatment. The present results, together with the published data, indicate that: a. LD ARA-C treatment, although it may have some toxic effects, is an effective treatment for some patients with AML, especially those with hypoplastic AML; b. Response to LD ARA-C can be obtained after one or several courses of treatment; c. LD ARA-C-induced remissions are sometimes obtained even in patients who fail in more conventional treatments; d. LD ARA-C-induced remissions can be achieved without bone marrow hypoplasia, and induction of hypoplasia by itself does not always result in complete remission; e. LD ARA-C can induce in vivo maturation of leukaemic cells. It is suggested that induction of remission in AML patients by LD ARA-C may result from either differentiation of leukaemic blast cells, cytotoxicity to leukaemic blasts, or both mechanisms acting together.

Adult↗
PubMed1987

Expression of c-abl in Philadelphia-positive acute myelogenous leukemia.

The identical cytogenetic marker, t(9;22)(q34;q11) (Philadelphia [Ph] translocation), is found in approximately 90%, 20%, and 2% of adult patients with chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myelogenous leukemia (AML), respectively. In CML, the molecular events resulting from the Ph translocation include a break within the bcr locus on chromosome 22, transfer of the c-abl protooncogene from chromosome 9 to 22, and formation of an aberrant 210-kD bcr-abl fusion protein (p210bcr-abl). Recently, the absence of bcr rearrangement and expression of a distinct aberrant 190-kd abl protein (p190c-abl) has been described in Ph-positive ALL, with the suggestion that the two abl variants may be pathogenetically associated with myeloid v lymphoid leukemogenesis. Here we report that the genomic configuration and translation product of Ph-positive AML can be similar to that of Ph-positive ALL: the break at 22q11 may occur outside the 5.8 kb bcr region and result in expression of a 190-kD abl protein lacking these bcr sequences. Phosphokinase enzymatic activity, a fundamental property of p210bcr-abl, was also associated with AML-derived p190c-abl. Our current observations indicate that p190c-abl can be found in cells of lymphoid or myeloid lineage and is therefore unlikely to play a specific role in the development of lymphoid leukemias. Formation of p190c-abl instead of p210bcr-abl appears to be a characteristic of the acute rather than the chronic Ph-positive leukemic state.

Cell Line↗
PubMed1985

Chronic T cell lymphocytosis with large granular lymphocytes of helper (OKT4) phenotype.

A 54-year-old asymptomatic male patient was followed for more than 7 y and presented a constant T cell lymphocytosis without skin involvement or bone marrow depression. No clinical or haematological aggravation was noted during this follow-up. Morphologically, the cells were large granular lymphocytes strongly positive for beta-D-glucuronidase, negative for acid phosphatase and with features of T cells on transmission and scanning electron microscopy. The immunological studies of the lymphocytes showed the following parameters: E rosettes+, mouse rosettes-, SmIg-, OKT3+, OKT4+, OKT8-, OKT6-, Ia-, TdT-, NK-, HTLV-, decreased PHA and PWM stimulation, no interleukin 2 production and failure to enhance Ig synthesis in a PWM driven system. The karyotype was normal. This case of chronic T cell lymphocytosis with large granular lymphocytes helper profile and defect of helper function, not reported in the literature, may correspond to a distinct entity in the heterogeneous group of chronic T cell disorders.

Antibodies, Monoclonal↗
PubMed1985

In vitro functions of stromal cells from human and mouse bone marrow.

Human fibroblastoid cell strains obtained from primary bone marrow cultures and continuous stromal cell lines recently derived from mouse bone marrow were studied. The incidence of fibroblastoid precursors (CFU-F) varied considerably in human bone marrow samples, and no differences could be detected between marrows from a group of myelodysplastic patients (age range 70-82 years) and groups of age-matched controls or younger individuals. A lack of direct correlation between initial clonogenicity and ultimate capacity of fibroblastoid cells to grow in continuous culture was observed in both the normal and the myelodysplastic groups. Despite the apparently normal clonogenicity of CFU-F in patients with myelodysplastic syndromes, some of these marrows failed to grow when subcultured. Normal fibroblastoid cells at 10(4) per culture exhibited myelopoietic activities when cocultured with fresh bone marrow cells. At higher concentrations, these cells inhibited myeloid colony formation. Fibroblastoid cells from only one out of four myelodysplastic patients examined exhibited comparable inhibitory activity. The specificity of the inhibitor(s) was demonstrated by the lack of effect of fibroblastoid cells from normal human bone marrow on the clonogenicity of mouse erythroleukemia cells. Moreover, human foreskin fibroblasts were devoid of such inhibitory activity. These functions of cultured stromal cells may correlate with some of their activities in the bone marrow microenvironment.

Aged↗
PubMed1984

Kaposi's sarcoma in two lymphoma patients with hepatitis B and other infections.

Kaposi's sarcoma developed in two lymphoma patients previously treated by chemotherapy and chemoirradiation. The histologic picture in the two cases showed a non-Hodgkin's lymphoma with multifocal epithelioid histiocytic reaction. Both patients had Hepatitis-B surface antigen and other infections due to herpes and streptococcus. The European Jewish origin of the two patients, the previous chemotherapy, and their infective state tend to support more the hypothesis of predisposing factors in the occurrence of Kaposi's sarcoma than a coincidental association.

Aged↗
PubMed1984

Platelet aggregation defect in megakaryoblastic leukemia.

Platelet aggregation induced in vitro with ADP, adrenalin and ristocetin was tested in 7 patients with megakaryoblastic leukemia (MKL). All patients had normal or high platelet counts and presented with hemorrhagic diathesis including purpura ecchymosis and epistaxis. Platelet morphology was grossly abnormal and electron microscopy revealed few, or absence of, alpha-granules. Platelet aggregation was reduced in all the cases with at least one aggregating agent. Our studies confirm that MKL is often accompanied by a thrombocytopathy which should be taken into account in the management of these patients.

Aged↗
PubMed1984

Philadelphia chromosome in idiopathic acquired sideroblastic anemia.

In a 70-year-old female patient with idiopathic acquired sideroblastic anemia (IASA) the karyotype revealed the presence of a Philadelphia chromosome in one third of the bone marrow mitoses. The patient was followed for 45 months and no signs of chronic myeloid leukemia or other leukemic transformation developed. In IASA the chromosomal changes are variable. This is the first report showing the presence of a Ph1 chromosome.

Aged↗
PubMed1984

Rosetting index (E rosettes/mouse rosettes): a simple diagnostic and prognostic value in CLL.

The rosetting index (E rosettes/mouse rosettes) was evaluated in 34 controls, 4 chronic benign lymphocytosis and 28 CLL patients, grouped according to the Rai classification: 6 asymptomatic stage 0 patients (lymphocytosis less than 10,000/mm3) with a rosetting index of 0.35 +/- 0.2; 11 asymptomatic stage 1-2 patients (lymphocytosis 10,000-40,000/mm3) with a rosetting index of 0.19 +/- 0.11; 9 symptomatic stage 3-4 patients (lymphocytosis greater than 40,000/mm3) with a rosetting index of 0.09 +/- 0.09 and 2 T-CLL patients post splenectomy and 4 chronic benign lymphocytosis patients with a rosetting index of 25 +/- 15. The average rosetting index for the controls was 10.0 (range 3.5-54). Student's t test was p less than 0.0001 for groups 1, 2 and 3 and p less than 0.02 for group 4. These results show that the rosetting index is helpful for the characterization of B-CLL in all stages, the rosetting index decreases with the proliferative activity of the disease and could be used as a prognostic factor, and the rosetting index is significantly increased in T-CLL and chronic benign T lymphocytosis thus being useful in differentiating these conditions from the early stage of CLL, when the SmIg is not conclusive of a monoclonal proliferation.

Animals↗
PubMed1983

IgM lambda globular cytoplasmic inclusions in chronic lymphocytic leukaemia resembling immunocytoma.

In a 64-year-old female with chronic lymphocytic leukaemia, nearly 50% of the lymphocytes presented one or several globular intracytoplasmic inclusions resembling Russell bodies which were characterized by immunofluorescence as IgM lambda. On electron microscopy, the inclusions looked like cisternae of the rough endoplasmic reticulum. Surface membrane Ig was not detected and the serum IgM was low. The histology of a lymph node showed a lymphocytic proliferation with evidence of Ig synthesis, compatible with immunocytoma. The aggressive course of the disease necessitated polychemotherapy. This case represents an unusual ill-defined lymphoproliferative disorder, lying between the B-CLL and a non-secretory macroglobulinaemia.

Cytoplasm↗
PubMed1983

Autoimmune hemolytic anemia preceding Sjögren's syndrome.

Autoimmune hemolytic anemia (AIHA) in Sjögren's syndrome (SS) is a rare occurrence. A patient presented with severe AIHA that seemed idiopathic, responded to treatment with prednisone and azathioprine but she developed symptoms and signs of the sicca syndrome within 8 months. This is a first report of AIHA preceding SS in an adult and the association is discussed. We believe that primary SS should be included in the differential diagnosis of acquired AIHA.

Adult↗