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D Catovsky

Publications and source records attributed to D Catovsky.

At least 235 records · Page 13Linked to original sources
PubMed1993

Splenectomy in lymphoproliferative disorders: a report on 70 cases and review of the literature.

Between February, 1970 and September, 1991, we performed splenectomies on 70 patients with chronic lymphoproliferative disorders including primary leukemias: 19 B-cell chronic lymphocytic leukemia, 1 B-cell prolymphocytic leukemia, 22 hairy cell leukemias, 4 large granular lymphocytic leukemias, 1 T-cell prolymphocytic leukemia, and non-Hodgkin's lymphomas (NHL): 10 splenic lymphomas with villous lymphocytes, 4 follicular lymphomas, 5 mantle cell lymphomas, 3 lymphoplasmacytic and 1 large cell NHL. The primary indications for surgery in this series were therapy-resistant disease (40%) and therapeutic splenectomy (38%). Postsplenectomy, 70% of patients had a complete hematological response, 23% had a partial response, and 7% were nonresponsive. Median treatment-free survival correlated with the hematologic response postsplenectomy and the underlying diagnosis. Better treatment-free survivals were seen in patients with lesser degrees of anemia and thrombocytopenia. Overall, improvements were more pronounced in the B-cell than in the T-cell disorders. Indications for further therapy, postoperative morbidity and mortality, and survival times are discussed along with a review of the literature. These findings advocate a continuing role for splenectomy in symptomatic lymphoid malignancies running with splenomegaly and hypersplenism.

Adult↗
PubMed1993

In vitro activation of leukaemic B cells by interleukin-4 and antibodies to CD40.

Chronic lymphocytic leukaemia (CLL) B cells have the phenotype of mature, partially activated B cells, but are relatively resistant to stimulation through cell-surface receptors with agents such as antibodies to immunoglobulin M. In the present study we have shown that culture of CLL cells with interleukin-4 (IL-4) and antibodies to CD40 caused significant DNA synthesis as assessed by incorporation of thymidine. This effect was largely mediated by antibody binding to CD40, a molecule known to induce B-cell activation and to mediate survival signals to germinal centre B cells. Epstein-Barr virus (EBV) infection of CLL cells stimulated with IL-4 and anti-CD40 did not affect the state of differentiation of the cell, augment the proliferative capacity, prolong cell survival or cause virus-driven immortalization.

Antibodies↗
PubMed1993

Infection of leukaemic B lymphocytes by Epstein Barr virus.

Epstein-Barr virus (EBV) infection of B lymphocytes in vitro gives rise to immortalized lymphoblastoid cell lines. Previous reports have shown that chronic lymphocytic leukaemia (CLL) cells, although infectable by EBV, are resistant to immortalization (1-4), although a small number of CLL cell lines have been reported (5-7). In the present study we have analysed early events occurring after EBV infection in 16 CLL samples. Out of 16 samples, 15 could be infected by the virus and expressed the full EB viral nuclear antigen (EBNA) complex but only one out of 16 expressed the latent membrane protein (LMP). The five CLLs in which we could investigate the presence of viral episomes showed circularized EBV by 16 hours after infection. The sequence of EBNA expression and genome circularization mirrored that seen in normal B cells, although genome amplification was not detected. The only CLL sample which expressed LMP after EBV infection was induced to proliferate for 2-3 weeks, but no cell line was established. Immortalized cell lines were obtained from three out of 16 samples tested, but all were polyclonal for light chain expression and had arisen from the CD5-negative, normal B-cell population. Thus the inability of EBV to induce proliferation of most CLL cells correlated with the absence of LMP expression which is invariably expressed during immortalization of normal B cells. This novel type of restricted gene expression could be compatible with evasion of host immune responses and consequent long-term survival of the cell in vivo.

Antigens, Viral↗
PubMed1993

Feasibility and efficacy of maintenance chemotherapy following autologous bone marrow transplantation for first remission acute lymphoblastic leukaemia.

Thirty-eight patients with poor risk ALL in first remission received maintenance chemotherapy following ABMT. Patients were conditioned for ABMT with high-dose melphalan and single fraction total body irradiation. Maintenance chemotherapy was commenced in a total of 26 patients and was tolerated to a median daily dose of 6-mercaptopurine of 40.5 mg/m2 and a median weekly dose of MTX 8.3 mg/m2. Twenty patients remain alive in first remission with a projected disease-free survival of 50% and a median follow-up in survivors of 200 weeks (range 48-387 weeks). Eleven patients have relapsed at a median of 4.5 months from ABMT. These patients were compared with remission patients with ALL receiving conventional chemotherapy on the United Kingdom Medical Research Council trials UKALL X and XA. After stratifying for major risk factors and allowing for the delay from remission to transplant, we have shown a significant reduction in the risk of relapse after ABMT (p = 0.04). Disease-free survival was not significantly increased due to transplant-related toxicity. This study suggests that maintenance chemotherapy to prevent relapse after ABMT for ALL is well tolerated and warrants assessment in a formal controlled trial.

Adolescent↗
PubMed1993

Lineage commitment in biphenotypic acute leukemia.

Acute leukemias (ALs) with phenotypic and genotypic features of several hematopoietic lineages are difficult to classify and may represent the transformation of multipotent stem cells. We have studied immunological features of 200 cases of acute leukemia (109 acute myelogenous leukemia, AML, and 91 acute lymphoblastic leukemia, ALL, according to FAB criteria), including 17 (8.5%) classified as biphenotypic by a scoring system based on the number and specificity of unexpected lineage antigens and which gives more weight to cytoplasmic markers such as myeloperoxidase, CD3, and CD22, and less to other membrane markers. Sixty-eight AML and 42 ALL cases were also examined for rearrangements of the immunoglobulin (Ig) and T-cell receptor (TCR) beta, gamma, and delta genes, and these included 12 biphenotypic AL. The expression of myeloid antigens in ALL was seen in 25% of the cases. All B-lineage ALL had rearrangements and/or deletions of the Ig genes whereas TCR beta, gamma, and delta genes were rearranged in 21%, 52%, and 71%, respectively. TCR delta, gamma and/or beta were rearranged in T-ALL and four out of 13 cases had Ig gene rearrangement. Lymphoid-associated antigens were expressed in 40% of AML cases; those most frequent expressed were CD7 (17%), CD2 (15%), CD19 (10%), and CD10 (7.5%). Evidence of Ig and/or TCR gene rearrangements was detected in 12% of AML cases. There was no correlation between the isolated expression of terminal deoxynucleotidyl transferase (TdT), B, and T-cell antigens with Ig and TCR gene rearrangements. However, in cases of AML defined as biphenotypic because they expressed two or more lymphoid antigens there was a statistically significant correlation between gene rearrangements and lymphoid score (p < 0.001). Our findings support the concept of biphenotypic leukemia as a distinct entity in which there is frequent correspondence between phenotypic and genotypic changes.

Acute Disease↗
PubMed1992

Translocation t(11;14)(q13;q32) in chronic lymphoid disorders.

The translocation t(11;14)(q13;q32) has been described in a spectrum of B-lymphoproliferative diseases and involves a putative oncogene, BCL1, which maps to chromosome band 11q13. Recent evidence indicates that this abnormality may delineate particular subtypes of lymphoma, such as intermediate lymphocytic and centrocytic lymphomas. Thus the possible significance of the t(11;14) within B-cell disorders should be reexamined in the light of a more objective approach to classifying these diseases by morphology, histology, and immunophenotype. We describe 16 patients with t(11;14)(q13;q32) from a series of 90 patients with chronic lymphoid disorders in whom clonal chromosome abnormalities were detected. All the cases were leukemic: prolymphocytic (B-PLL; 4/15 cases), chronic lymphocytic leukemia (CLL) with increase in prolymphocytes (2/9 cases), or non-Hodgkin lymphoma in leukemic phase, intermediate (3/4 cases), lymphoplasmacytic (2/2 cases), splenic lymphoma with villous lymphocytes (4/18 cases), and follicular (1 case). None of the CLL (25) or hairy cell leukemia cases (15) had t(11;14). Our findings showed that t(11;14) occurred in leukemias of mature B cells with lymphoplasmacytic features as judged by morphology and immunophenotype.

Adult↗
PubMed1992

The role of an anti-myeloperoxidase antibody in the diagnosis and classification of acute leukaemia: a comparison with light and electron microscopy cytochemistry.

The enzyme myeloperoxidase (MPO) is the hallmark of the myeloid lineage. We have analysed the presence of MPO in blasts from 180 cases of acute leukaemia (103 acute myeloid leukaemia (AML) and 77 acute lymphoid leukaemia (ALL) by means of monoclonal antibodies anti-MPO and immunocytochemistry (alkaline phosphatase anti-alkaline phosphatase method). The aim of the study was to investigate the specificity and sensitivity of this marker compared with MPO cytochemistry by light (LM) and electron microscopy (EM), and with the expression of myeloid antigens. Anti-MPO was positive (greater than 3% blasts) in all but one of the 90 AML positive by LM cytochemistry. Of 13 AML cases negative by MPO cytochemistry, six showed 3-10% blasts reactive with anti-MPO and were also positive with antibodies to CD13 and/or CD33. The presence of MPO was confirmed in four of these by EM. The overall positivity of anti-MPO in AML was 92%. Anti-MPO was negative in all but two ALL (6% and 8% positive blasts). The blasts in these two cases were also CD13, CD33 and MPO positive by EM; both were thus reclassified as biphenotypic. Another two ALL reinterpreted as biphenotypic were negative by MPO cytochemistry and anti-MPO but were MPO positive by EM and with CD13 and/or CD33. We conclude that anti-MPO is a sensitive and specific early marker of myeloid blasts and should be incorporated in the routine immunophenotyping of acute leukaemia.

Acute Disease↗
PubMed1992

Increase in 2',5'-oligoadenylate synthetase caused by deoxycoformycin in hairy cell leukaemia.

2',5'-oligoadenylate synthetase (2-5OAS) has been studied in peripheral blood mononuclear cells from nine patients with hairy cell leukaemia (HCL) receiving therapy with the adenosine deaminase inhibitor deoxycoformycin (dCF) or alpha interferon (alpha-IFN). 2-5OAS mRNA was assayed by dot-blot hybridization. Increase of 2-5OAS mRNA level was seen in six patients with HCL treated with dCF and in one patient treated with alpha-IFN who responded to therapy. A patient with a variant form of HCL treated with dCF and the second patient treated with alpha-IFN did not show an increase of 2-5OAS mRNA and neither responded to therapy. The 15 other patients with T or B-chronic lymphoblastic leukaemia (CLL), T-acute lymphoblastic leukaemia (ALL), adult T-cell leukaemia lymphoma (ATLL), non-Hodgkins lymphoma (NHL), Sezary and T or B-prolymphocytic leukaemia (PLL) treated with dCF did not show an increase in 2-5OAS, though four patients, all with T-cell tumours, responded clinically. 2-5OAS activity is known to be stimulated by alpha-IFN and recent work suggests that this rise in 2-5OAS may result in increased cleavage of mRNA for tumour necrosis factor (TNF) and other cytokines on which autocrine growth and proliferation of the tumour cells are dependent. By analogy, we suggest that one mechanism of action of dCF in hairy cell leukaemia may be to break down an autocrine growth loop for TNF or other cytokines. An alternative explanation for these observations is that cytokines released from hairy cells in the bone marrow killed by dCF induce a rise in 2-5OAS in circulating leucocytes.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Characterisation of normal peripheral blood cells in cycle identified by monoclonal antibody Ki-67.

AIMS: To investigate the numbers, morphology, and lineage assignment of Ki-67 positive cells in peripheral blood from normal subjects. METHODS: Single and double immunoenzymatic staining procedures, immunoperoxidase, and immunoalkaline phosphatase were used with Ki-67, a monoclonal antibody that recognises a nuclear antigen present in proliferating cells, with markers expressed in B and T lymphocytes and monocytes. RESULTS: In the five healthy donors 2.1% (range 1.6-3.7%) cells of the blood mononuclear fraction and 2.7% (range 2.3-3.9%) lymphocytes were Ki-67 positive. Of these, 88% (range 85-90%) were small cells and 12% (range 10-15%) were medium sized. Forty one per cent of the Ki-67 positive cells were CD3 positive by double immunoenzymatic staining and corresponded to T lymphocytes, and 11.4% were mature B cells expressing kappa or lambda light chains. Monocytes detected by the anti-lysozyme antibody were consistently Ki-67 negative. Half of the Ki-67 positive lymphocytes could not be accounted for by B or T cells with the markers used. Most Ki-67 positive cells were of small size; the B lymphocytes in cycle showed abundant cytoplasm and features suggestive of lymphoplasmacytic differentiation. CONCLUSIONS: The methodology described is useful for the simultaneous detection of nuclear and cytoplasmic antigens. The demonstration that a proportion of normal blood lymphocytes are in cell cycle raises the issue of whether immunophenotypic analysis of Ki-67 positive cells in haemopoietic malignancies with peripheral blood disease should be carried out to define more precisely the proportion of normal and neoplastic cells in cycle.

Adult↗
PubMed1992

Monoclonal antibody Ki-67 identifies B and T cells in cycle in chronic lymphocytic leukemia: correlation with disease activity.

Ki-67 is a monoclonal antibody that recognises a nuclear antigen expressed during most phases of the cell cycle. We have analysed, by immunocytochemistry, the frequency, morphology, and clinical significance of Ki-67+ cells in 108 patients with B-cell chronic lymphocytic leukemia (CLL). Because in normal peripheral blood Ki-67+ cells are mainly T lymphocytes, we have also investigated, by double immunoenzymatic staining, the proportion of Ki-67+ T cells (Ki-67/CD3+) in CLL. Four groups of patients were identified: (i) 47 with stage A, (ii) 32 with stages B + C, (iii) 24 with greater than 10% of circulating prolymphocytes (CLL/PL) and (iv) five with Richter's syndrome. Within stage A CLL, two groups were considered: A' (Hb greater than or equal to 12 g/dl and lymphocytes less than 30 + 10(9)/l) and A" (Hb less than 12 g/dl or lymphocytes greater than or equal to 30 x 10(9)/l). The percentage and absolute number of Ki-67+ leukemic cells was found to increase with the stage of the disease and correlate with the proportion of prolymphocytes. On the other hand, the proportion of Ki-67+ T cells (CD3+) was significantly higher in patients with CLL stage A' (29.3 +/- 4.5), which includes patients with long-standing, stable disease, than in CLL stage A" (9.5 +/- 3.3), B + C (7.1 +/- 4.6), and CLL/PL (6.4 +/- 2.8). Ki-67 seems to identify patients with more aggressive forms of CLL, such as CLL/mu 2PL with more than 10% Ki-67+ cells (25% of the cases) and Richter's syndrome, in which all the large lymphoma cells are Ki-67+. Long-term follow-up will establish whether Ki-67 is a good prognostic marker and can predict disease outcome.

Aged↗
PubMed1992

The classification of acute leukaemia.

The standard methods for classifying acute leukaemias now include morphology, cytochemistry and membrane markers. Major advances in immunology, in particular the development of monoclonal antibodies (McAb) with lineage specificity, have provided objective positive criteria for the diagnosis of acute lymphoblastic leukaemia (ALL). The FAB group has recognised the importance of McAb for the classification of some forms of acute myeloid leukaemia (AML), such as megakaryoblastic leukaemia, AML-M7, in which reactivity with McAb against platelet glycoproteins is a requirement for diagnosis. More recently the group has defined a type of myeloblastic leukaemia with minimal differentiation, AML-MO, in which myeloid cytochemistry is negative and the diagnosis is made by the expression of myeloid antigens and negative lymphoid markers in the blast cells. However, new problems have emerged with the wider use of McAb which now need to be addressed: the most important is the precise evaluation criteria for biphenotypic leukaemia for which we have proposed a scoring system in order to recognise the genuine cases which constitute a distinct disease entity. The role of karyotyping in the classification of acute leukaemia is gradually being defined (MIC proposals) and some forms of acute leukaemia can only be diagnosed by chromosome translocations, e.g. Ph+ ALL, resulting from t(9;22) and t(4;11) in infant ALL. Several translocations can also be demonstrated by molecular techniques. Cases with t(8;16) (p11;p13) are characterised by myelomonocytic features, erythrophagocytosis and fibrinolysis and represent a type of AML which can be defined primarily by its cytogenetic abnormality.

Acute Disease↗
PubMed1992

Low frequency of ras oncogene mutations in Philadelphia-positive acute leukemia and report of a novel mutation H61 Leu in a single case.

Activating ras mutations are frequent (25-60%) in chronic myelomonocytic leukemia (CMML) and in acute myeloid leukemia (AML) (30%), in contrast to chronic myeloid leukemia (CML) in which the incidence is very low (0-3%). This might reflect that the leukemic cell in CML is at a level of differentiation in which ras gene activation is not involved or, alternatively, might be due to the presence in CML of the bcrlabl fused gene. We have analyzed the presence of point mutations in codons 12, 13, 59, 61 and 63 of N-, K-, and H-ras genes, in 26 cases of Philadelphia-chromosome-positive, bcrlabl-positive acute leukemia (Ph+ AL), and in eight CMML cases by using the polymerase chain reaction. Aberrant ras genes were detected in a single Ph+ AL case, and in four out of eight CMML patients. The Ph+ AL showing altered ras allele had an unusual point mutation in H-ras gene, substituting leucine for glutamine. This mutation has not been previously found in any hematological disease. Our findings suggest that ras mutations are probably not involved in the pathogenesis of those leukemias in which blast cells contain bcrlabl oncogene activation.

Codon↗
PubMed1991

Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia.

We describe the clinical and laboratory findings of 78 adult patients with T-prolymphocytic leukemia (T-PLL) studied over the last 12 years. The main disease features were splenomegaly (73%), lymphadenopathy (53%), hepatomegaly (40%), skin lesions (27%), and a high leukocyte count (greater than 100 x 10(9)/L in 75%) with nucleolated prolymphocytes. A variant form with small, less typical cells was recognized in 19%. Membrane markers defined a postthymic phenotype TdT-, CD2+, CD3+, CD5+, CD7+; in 65%, the cells were CD4+ CD8-, in 21%, they coexpressed CD4 and CD8, and, in 13%, they were CD4- CD8+. Serology for human T-cell leukemia/lymphoma virus Type-I (HTLV-I) was negative in the 27 cases investigated. Cytogenetic analysis in 30 cases showed a consistent abnormality of chromosome 14, usually inv (14), with breakpoints at q11 and q32 in 76% of cases. Trisomy 8, including iso8q, was shown in 53%; t (11;14)(q13;q32) was documented in one case; and one had a normal karyotype. The clinical course was progressive with a median survival of 7.5 months. Thirty-one patients were treated with 2' deoxycoformycin and 15 responded (3 complete remissions and 12 partial remissions); the response rate (48%) increased to 58% in patients with a CD4+ CD8- phenotype. The median survival of responders was 16 months and of nonresponders 10 months; other treatments were less effective. T-PLL is a distinct clinico-pathologic entity with aggressive course and characteristic chromosome abnormalities. A subgroup of patients may benefit from deoxycoformycin.

Adult↗