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Evidence for monoclonal proliferation in prolymphocytic leukemia of T-cell orgin. A cytogenetic and Quantitative immunoautoradiographic analysis.

B- and T-cell markers were studied in a patient with prolymphocytic leukemia, a rare variant of chronic lymphocytic leukemia. Thymus-derived features were identified on the membrane of the neoplastic lymphocytes using the following cellsurface markers: Heterologous T-cell antigen, sheep erythrocyte receptor, surface immunoglobulin, complement receptor, Fc receptor and mouse erythrocyte receptor. Cytogenetic studies of leukemic cells from unstimulated and mitogen-stimulated cultures revealed a consistent karyotype characterized by marker chromosomes and a decreased chromosome number, whereas chromosomal analysis of hair root cells yielded a normal karyotype. A uniform expression of T-cell antigens measured on single leukemic cells by quantitative microphotometric immunoautoradiography correlated with the cytogenetic findings which are compatible with a descent from one progenitor cell.

Aged↗

Molecular analysis of an ataxia telangiectasia T-cell clone with a chromosomal translocation t(14;18)--evidence for a breakpoint in the T-cell receptor delta-chain gene.

We established a clonal T-cell line with a reciprocal chromosomal translocation t(14;18)(q11;q23) from a patient with ataxia telangiectasia (AT) and T-cell chronic lymphocytic leukemia (T-CLL). The tumor cells and the derived T-cell line were compared with respect to phenotype, karyotype, and rearrangement pattern. Restriction fragment analyses of the T-cell receptor (TCR)-delta gene, which is located within the TCR-alpha gene on chromosome 14q11, indicated that the breakpoint is located within the TCR-delta locus, splitting the TCR-delta gene between the variable and joining segments. This specific chromosomal translocation was only detected in the derived T-cell line and may be involved in the genesis of T-cell malignancies in AT.

Ataxia Telangiectasia↗

Successful treatment of chronic adult T-cell leukemia with ubenimex.

A 38-year-old Japanese man had suffered from trichophyton infection for several years. The white blood cell count was 20,300/mm3, including 54% abnormal lymphocytes with irregularly convoluted nuclei. Adult T-cell leukemia (ATL) was diagnosed based on proliferation of CD4-positive lymphocytes, positive anti-HTLV-I antibody and monoclonal integration of proviral DNA. By 30 mg/day of ubenimex (Bestatin), the abnormal lymphocytes positive for CD4 in the peripheral blood were gradually reduced. Complete remission was maintained for 9 months without any antineoplastic agents. Ubenimex may have suppressed the growth of ATL cells in this patient. Accordingly, ubenimex may prove useful for treating some patients with chronic-type ATL.

Adult↗

Glutathione depletion in chronic lymphocytic leukemia B lymphocytes.

Glutathione (GSH) content may be the major determinant of a cell's sensitivity to cytotoxic alkylating agents. In the present study, the GSH concentration was determined in lymphocytes isolated from the blood of normal subjects and patients with chronic lymphocytic leukemia (CLL). Comparable levels were found in both types of cells. Incubation for 20 hours led to a decrease in GSH to 51% of baseline values in CLL B cells. Under the same conditions, normal B- or T-lymphocyte GSH content remained constant. GSH depletion was shown to be a characteristic of the B-CLL B lymphocyte. It was not found in the T cells of patients with B-CLL or in cells from patients with T-CLL. Chlorambucil (CLB) contributes to the decrease in GSH in B-CLL lymphocytes; after incubation with the drug, lower levels of GSH were found than in the normal B or T lymphocytes, B-CLL T cells, or T-CLL (CD4 or CD8) cells. GSH depletion of CLL B lymphocytes may be related to the greater therapeutic efficacy of CLB in B-CLL than in T-CLL.

B-Lymphocytes↗

Immunological features in chronic lymphocytic leukaemia (CLL) of T cell origin.

Peripheral blood lymphocytes from a patient with chronic lymphocytic leukaemia of T cell origin were studied. The thymus derived nature of these lymphocytes was confirmed by surface markers, mitogen cultures, mixed lymphocyte reaction, cytotoxicity studies, and cytochemical stains. This case is notable for several clinical and laboratory findings. Among these, the benign clinical course, the reduced rate of serum immunoglobulins, the elevated number of active E rosettes, the increased PHA-induced response to low mitogen doses, the absence of PHA mediated cellular cytotoxicity, and the thy-like positivity to ANAE should be pointed out. Emphasis should be placed, however, on the loss of stimulatory ability in MLR. This last feature supports the hypothesis that these cells proliferate as a clone.

Aged↗

Atypical T-cell leukemia terminating Hodgkin's disease.

A case of Hodgkin's disease is described which developed into a terminal illness characterized by a malignant proliferation of T-cells. The leukemic cells, after optical and ultrastructural analysis, were distinct from those of myelomonocytic, acute lymphoblastic, chronic lymphocytic as well as prolymphocytic leukemia. Their relationship with the T-cell lineage seemed to be confirmed by a highly positive E-rosette test and by cytochemistry which showed focal positivity of acid phosphatase. The importance of this T-cell malignant proliferation is discussed, especially with regard to cellular interactions in Hodgkin's disease.

Acid Phosphatase↗

[Chronic T-cell lymphocytic leukemia. Report of two cases (author's transl)].

Two patients with chronic lymphocytic leukemia of T-cell immunological origin are studied. One case was of the prolymphocytic variety, and the other corresponded to the "classical" type of chronic T-cell lymphocytic leukemia. From a morphological point of view what stood out was the hyperchromatic aspect of the cytoplasm of the lymphocytic proliferation. The high increase of acid hydrolases localized preferentially in the centrosomic area was the main cytochemical characteristic. Isoenzymatic study of leukocytic acid phosphatase showed a noticeable increase of band 3 and the absence of supernumerary band 3b. Immunological analysis revealed a significant decrease of the surface immunoglobulins and a rise in absolute terms in the number of lymphocytes forming spontaneous rosettes. In the case of the prolymphocytic variety what was particularly noticeable was the great number of lymphocytes bearing complement receptors. The combination of cytomorphologic, isoenzymatic and immunological data make it possible to differentiate between lymphoproliferative diseases of T and B-cell origin at the present time.

Acid Phosphatase↗

Molecular analysis of a new translocation, t(X;14)(q28;q11), in premalignancy and in leukaemia associated with ataxia telangiectasia.

The disease ataxia telangiectasia (A-T) is a multifaceted disorder in which patients have an increased chance of developing a T-cell leukaemia, often with abnormalities of chromosome 14, but sometimes with rare translocations, like t(X;14)(q28;q11). We describe the cloning of the breakpoint of one such novel t(X;14) from an A-T patient. The translocation breaks within the T cell receptor alpha chain gene on chromosome 14 at band q11 and in a region of the X chromosome, within about 1 Mb of the telomere of the long arm. The patient subsequently developed T-cell prolymphocytic leukaemia (T-PLL), and molecular examination showed that the tumour cells carried the same t(X;14) breakpoint as that cloned from the premalignant cells. The same breakpoint could be detected in blood samples taken as much as 5 years prior to diagnosis of T-PLL. This suggests a role for the abnormality in the tumour development in this patient but implies that other mutational events were necessary for overt disease to become manifest.

Adult↗

[Membrane receptors of lymphoreticular cells in hyperplastic and neoplastic diseases of the lymphatic system].

The results of T- and B-cell determinations are described in 105 cases of lymphoreticular and lymphoepithelial neoplasia, and are compared to similar investigations of 582 cases as published in the literature. In addition, T- and B-cell values are determined in blood of 35 healthy individuals, in 12 normal lymph nodes, as well as in hyperplastic conditions of lymph nodes from 30 patients and of tonsils from 85 patients. Cell characterizations are done by immunofluorescence and use of monospecific anti-immunoglobulin antisera (H chain specific), anti-thymus antiserum, as well as by the E-rosette test. While normal blood and normal and hyperplastic tissues show a polyclonal distribution or proliferation of lymphoreticular cells, neoplastic conditions are often characterized by an exuberant, possibly monoclonal proliferation of one cell type. According to this, lymphoreticular neoplasias are immunologically grouped into four main classes: B-cell neoplasias comprising most of the chronic lymphocytic leukemias, well differentiated lymphocytic lymphomas, BURKITT's tumor, follicular lymphoma BRILL-SYMMERS, and hairy cell leukemia. T-cell lymphomas represent a large part of poorly or undifferentiated leukemias of children, poorly differentiated lymphocytic lymphomas, prolymphocytic leukemia, and Sézary's syndrome. Monocytic neoplasias are malignant histiocytoses and leukemic reticuloendothelioses. A fourth group, which probably is not homogeneous and might be further classified in the future by use of more sophisticated methods, consists of tumors with T- and B-cell lack. Such tumors are histologically classified as Hodgkin's lymphomas, a certain number of histiocytic lymphomas, and mycosis fungoides. The prognostic and pathogenetic implications of a combined morphological and immunological classification of lymphoreticular neoplasias are briefly outlined.

B-Lymphocytes↗

Prolymphocytic leukemia: clinical, histopathological, and cytochemical observations.

The clinical, histopathological, and cytochemical features of eight patients with prolymphocytic leukemia, a rare variant of chronic lymphocytic leukemia, were reviewed. Six of the patients had clinical evidence of "massive" splenomegaly at the time of diagnosis, and in four of these this clinical impression was confirmed by splenic weights in excess of 2000 g. No patient had significant lymph node enlargement. The initial leukocyte count was elevated in seven patients and was greater than 100 X 10(9)/1 in four of them. The absolute prolymphocyte count ranged from 16.3 to 378.1 X 10(9)/1 and was greater than 100 X 10(9)/1 in four patients. Splenectomy in four patients had no lasting effect on the peripheral leukocyte count. In the four patients in whom the disease was shown by surface marker or immunocytochemical studies to be of B-cell origin, the histopathologic features were distinctive and were characterized by a pattern of infiltration which was nodular and diffuse in both the splenic red pulp and the bone marrow, whereas involvement of the lymph nodes was pseudonodular. In one patient in whom the prolymphocytes had cytochemical characteristics suggestive of T-cells, the distribution of the abnormal cellular proliferation in the lymph nodes was paracortical and the infiltrations of the spleen and the bone marrow were diffuse.

Aged↗

Prolymphocytic leukaemia of T-cell type: immunological, enzymatic and ultrastructural morphometric characteristics.

A case of prolymphocytic leukaemia with immunological characteristics of T-cell type is reported. Three noteworthy findings can be emphasized: the presence of C3 receptors on the T-prolymphocytes, the study of the acid-phosphatase isoenzymatic pattern, which showed an increased band 3 with absence of band 3b, and the morphometric ultrastructural investigation. Cytochemistry and ultrastructural morphometry may be useful for a more precise characterization of prolymphocytic leukaemia and help to distinguish it from other lymphoproliferative disorders.

Acid Phosphatase↗

[T-cell leukemias of adulthood].

9 adult patients suffering from different forms of T-cell-malignancies were investigated: 4 patients with T-ALL; 1-T-ALL-CLL mixed form (prolymphocytic); 2 T-CLL; 2 Sézary-syndrome. The clinical peculiarities of the different forms of leukemias were compared: involvement of lymph nodes and spleen, of the central nervous system and the skin was frequent; in contrast to the findings in Sézary-syndrome, bone marrow infiltration was prominent. Light and electron microscopic morphology of the malignant cells are described. In all cases a strong activity of acid phosphatase was demonstrated, in one patient prominent deposits of glycogen. The T-cell-quality of the respective malignant cell population as well as the B-T-cell distribution of the remaining "normal" lymphocytes were shown by the following cell markers: demonstration of T-cell-antigen, resp. membrane immunoglobulins with the aid of specific heterologous antisera conjugated with peroxidase, 125iodine or fluoresceine; complement consumtion or cytotoxicity with such antisera; spontaneous rosette formation with sheep red cells or with acrylic acid beads. Usually, there was a good coincidence in results obtained with the different markers. In two patients, however, T-cells demonstrated by anti-T-globulin were not able to form T-rosettes. Responsiveness of the malignant T-cells and also of the remaining "normal" blood lymphocytes to different mitogens usually was depressed, immunoglobulin levels in the blood mostly were normal. Taking all findings into consideration, T-cell-leukemias of the adult represent a special group of hematological malignancies; the different subgroups show similarities; transitional forms occur.

Adult↗

[Classification of non-Hodgkin's lymphomas on the basis of Morphological and immunological features shared by normal and neoplastic lymphatic cells (author's transl)].

A review is given of the new Kiel classification of non-Hodgkin's lymphomas (NHL) and of the findings which led to its development. The Kiel classification of NHL is based on morphological and immunological features shared by normal and neoplastic cells. Therefore, the origin, maturation, and reaction of nonneoplastic T- and B-cells together with their immunological, enzyme-cytochemical and morphological features are discussed first. In the T-cell system T-precursor cells, prothymocytes, T1/T2-cells, and T-immunoblasts can be distinguished on the basis of the given features. The B-system is primarily composed of cells of the two antigen-dependent B-cell reactions, the germinal center reaction, and the plasma cell reaction. These cells can be distinguished both morphologically and through demonstration of the complement receptor in frozen sections. We differentiate the following entities of NHL, divided into six groups for better understanding: 1. lymphocytic lymphomas: chronic lymphocytic leukemia (CLL), prolymphocytic leukemia, hairy cell leukemia, mycosis fungoides, and Sézary syndrome; 2. secretory immunoglobulin-producing lymphomas: plasmacytoma and lymphoplasmacytoid immunocytoma; 3. germinal center cell tumors: centroblastic/centrocytic lymphoma, centrocytic lymphoma, centroblastic lymphoma, Burkitt's lymphoma, and lymphoma of the Burkitt type; 4. lymphoblastic lymphomas: "convoluted cell" type and "unclassified" type; 5. immunoblastic lymphoma; 6. reticulosarcoma. B-cell characteristics are revealed by more than 80% of the NHL, namely by 97% of the cases of CLL, by all secretory immunoglobulin-producing lymphomas, by all germinal center cell tumors, and by most immunoblastic lymphomas. More than 50% of the B-cell tumors are evidently derived from germinal center cells. The following are T-cell tumors: a few rare forms of CLL, mycosis fungoides Sézary syndrome, about 50% of the lymphoblastic lymphomas, and a few immunoblastic lymphomas. It could be shown that the cells of lymphoblastic lymphoma, "convolted cell" type with strong acid phosphatase reactivity have the same features as fetal thymocytes. So far, we have not observed any cases of true reticulosarcoma as described by Roulet and Rappaporti, i.e. tumors of phagocytic reticulum cells. The morphological features which could be defined for the entities distinguished in the Kiel classification of NHL are so characteristic that most of these entities can now be diagnosed on the basis of their histological and cytological pictures alone.

Antigens↗

Revised seminology of the different mononuclear cells under scanning electron microscopy.

Scanning electron microscopy shows that the thymus cell surface is not smooth but slightly undulated; this type of surface characteristic is found on the cells of several types of T-lymphocyte tumors such as T-cell lymphosarcoma, mycosis fungoides, and T-immunoblastic lymphosarcoma. The cell surface of Frabricius' bursa is covered with numerous short villi. They are found on the cells of several kinds of B-lymphocyte tumors, including B-cell chronic lymphoid leukemia, B-prolymphocytic lymphosarcoma, and B-immunoblastic lymphosarcoma. Mycosis fungoides cells frequently have a characteristic shape. Normal and myeloma plasma cells are similar in shape but their surface is covered with numberous characteristic tiny balls. Immunoblasts are twice the size of so-called small lymphocytes. In the blood and in the lymphocyte population transformed by mitogens, cell surfaces vary from completely smooth (with no undulations as in thymic cells) to villous, with short to very long villi. These variations are visible even when a constant technique and the critical-point drying method are used. Their significance, however, is not known.

Animals↗

Chronic lymphocytic leukaemia of T-cell origin. Immunological and clinical evaluation in eleven patients.

Eleven patients with chronic lymphocytic leukaemia of T-cell origin are reported. The identification of the leukaemic cells was performed with seven different membrane markers for either T or B lymphocytes. The reactivity of the leukaemic T cells with three different heteroantisera to T cells differed from patient to patient but was homogeneous in individual cases. This finding suggests that the leukaemic lymphocytes belonged to a single subset of T cells. These lymphocytes responded to allogeneic cells in some of these patients. In contrast, stimulation by non-specific mitogens was poor in most patients. Two patients were affected with the prolymphocytic type of chronic lymphocytic leukaemia, but a characteristic clinical and haematological pattern was found in nine patients. The blood and marrow infiltration was moderate and the proliferating T lymphocytes had a high content of lysosomal enymes in all patients and cytoplasmic granules in six cases. Other unusual features included massive splenomegaly (five patients), skin lesions (four patients), and major neutropenia (four patients).

Adult↗

Clinical significance and prognostic value of the T-B immunological classification of human primary acute lymphoid leukaemias.

50 cases of primary acute lymphoid leukaemia (A.L.L.) were analysed for the presence of T and B membrane markers on bone-marrow and/or peripheral-blood cells. 26% of cases were predominantly T-cell in type, 4% were B, the remaining 70%, without detectable membrane markers, were classified as "null" cell A.L.L. Of particular interest is the correlation between this immunological classification and the prognosis, since T-cell and B-cell A.L.L. were associated with a poorer prognosis than null-cell A.L.L. in terms of both median length of first complete remission and median survival. With one exception the T-cell cases were, according to the W.H.O. classification, of either the prolymphocytic or macrolymphoblastic type of A.L.L. and were more extensive than the comparable null-cell A.L.L. In contrast, cases of the W.H.O. prolymphoblastic and microlymphoblastic types were all found to be null-cell A.L.L. and were associated with the worst and best prognosis respectively. The correlation found between the immunological classification of A.L.L. and the prognosis means that patients with a poor prognosis can be selected for more intensive therapy.

Adolescent↗

[Prolymphocytic leukaemia (author's transl)].

Prolymphocytic leukaemia occurred in two women aged 75 and 57 years, respectively. In both instances the lymphatic cells fulfilled the morphological criteria of the disease picture. In one patient the disease was characterised by immunological and physical methods as being a B-cell lymphoma, in the other a T-cell lymphoma. Acid phosphatase was of special significance among cytochemical studies. While the patient with the T-cell lymphoma died after three months, the one with B-cell lymphoma is still alive 16 months later. Splenectomy resulted in marked improvement in the latter patient's condition and may turn out to be the treatment of choice in prolymphocytic leukaemia.

Aged↗