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Biomedical subjects

W D Ludwig

Publications and source records attributed to W D Ludwig.

At least 163 records · Page 9Linked to original sources
PubMed1992

Cytotoxicity of interleukin 2-induced lymphokine-activated killer (LAK) cells against human leukemia and augmentation of killing by interferons and tumor necrosis factor.

Adoptive immunotherapy with interleukin 2-induced lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TIL) and the induction of anti-tumor responses by IL-2 alone having proven to be promising approaches in cancer therapy. The present study investigated the cytotoxicity of LAK cells towards human leukemia cells. LAK cells were generated by culturing peripheral blood mononuclear cells from normal donors for six days in the presence of recombinant interleukin 2 (IL-2). Cytotoxicity was evaluated using a standard 4-h chromium-release assay. A significant lysis of fresh uncultured leukemia cells by IL-2-activated killer cells could be detected in 77 of 150 leukemias examined. The mean Cr-release was 35.7 +/- 12.9% in the LAK cell-sensitive vs 9.9 +/- 5.9% in the resistant leukemias. With a view to the therapeutic utilization of the LAK-cell system, we attempted to improve the efficiency of its cytotoxic mechanisms. Combined application of IL-2 and interferon-alpha, interferon-gamma, or tumor necrosis factor-alpha in cultures for generation of activated killer cells significantly improved the effectiveness of cytotoxic mechanisms. Our results suggest that the performance of adoptive immunotherapy with ex vivo-activated LAK cells and the in vivo induction of cytotoxic immune responses by IL-2 alone or combined with different lymphokines or cytokines may be of value in treating human leukemia, especially when the tumor burden is low, e.g. during maintenance therapy or after bone marrow transplantation to eliminate minimal residual disease or in early relapse.

Cytokines↗
PubMed1992

Characterisation of insulin-like growth factor I receptors of human acute lymphoblastic leukaemia (ALL) cell lines and primary ALL cells.

The expression of insulin-like growth factor I (IGF-I) receptors (IGR-IR) on human B-lineage and T-lineage acute lymphoblastic leukaemias (ALL) representing different maturational stages has been studied. Immature (stage I) and mature (stage II) T ALL as well as pre-B ALL cell lines expressed high numbers of IGF-IR with high affinity for IGF-I. In contrast, on T ALL, stage II and B ALL only low specific binding of 125I-IGF-I was detected. No binding of 125I-IGF-I to Burkitt lymphoma cells was found. Primary human T, pre-B and cALL cells also expressed IGF-IR with Kd for IGF-I and IGF-IR number per cell in the same range as the investigated cell lines. Crosslinking of 125I-IGF-I to T and pre-B ALL cells revealed IGF-IR alpha-subunits of 135 and 116 kD for HSB2. Gene expression of IGF-IR could be detected in all T ALL cell lines but was undetectable in SKW6, a B ALL cell line.

Antibodies, Monoclonal↗
PubMed1992

Nonsegmental vitiligo: decrease of the CD45RA+ T-cell subset and evidence for peripheral T-cell activation.

Peripheral T-lymphocytes from 16 randomly selected patients with nonsegmental vitiligo were labeled with monoclonal antibodies recognizing T-cell receptor (TCR) alpha/beta, TCR gamma/delta, CD3, CD4, CD8, CD45RA, CD45RO, CD11b, CD11c, CD16, CD56, CD25, CD54, and HLA-DR antigens. In comparison with matched controls, a significant decrease of the CD45RA+ subset (P less than 0.03) together with significant increase of the circulating HLA-DR+ cells (P less than 0.02) was found. No other alterations were detected. These findings may point to some autoimmune phenomena involved in the pathogenesis of the disease. The increased HLA-DR expression indicates the presence of activated peripheral T-cells. Thus, our data provide new and further evidence for T-cell dysregulation in nonsegmental vitiligo.

Adolescent↗
PubMed1992

Rearrangements of T-cell receptor delta, gamma and beta genes in acute myeloid leukemia coexpressing T-lymphoid features.

In order to investigate the role of T-cell receptor (TcR)-delta and TcR-gamma gene rearrangements and/or deletions in acute myeloid leukemia (AML) coexpressing T-cell-associated antigens (i.e. CD2 and/or CD4 and/or CD7), we examined blasts from a selected group of 56 AML cases (25 children, 31 adults) coexpressing either of these antigens without cytoplasmic CD3 expression. Forty-four typical AML cases (7 children, 37 adults) without T-cell associated antigens were further studied as controls. Germline configuration of the TcR-delta gene was observed in 91 out of the total of 100 AML cases investigated. Eight of nine cases with rearranged or deleted TcR-delta genes coexpressed T-cell-associated antigens. Blast cells of 7/9 cases were classified as FAB M1, two as FAB M2. In six of these cases TcR-gamma gene rearrangements were also detected. TcR-delta alterations were predominantly found in children whose blasts coexpressed T-lymphoid associated antigens (6/25, 24%), but were rarely detected in adult AML with or without coexpression of T-cell antigens (2/31 and 0/37, respectively).

Acute Disease↗
PubMed1992

Combined effect of very early intensification and prolonged post-remission chemotherapy in patients with AML.

The study combines the effects of prolonged postremission chemotherapy with that of very early intensification. 900 adult patients at all ages with newly diagnosed AML uniformly received TAD for induction and consolidation followed by monthly myelosuppressive maintenance for 3 years. In patients of 60+ years with persistent bone marrow blasts a second TAD course was given. In all patients of less than 60 years a second induction course started on day 21 even in aplasia with no blasts. Second induction was randomly either TAD or HAM. In the younger age group 69% attained CR and similar in the two arms the CR rate after 5 years is 35%. Including the 50% patients attaining CR in the higher age group the CR rate after 5 years is 32%. In 40 patients receiving allogeneic BMT and 21 patients receiving autologous BMT in first CR relapse free survival is similar to that from chemotherapy alone in a matched pair analysis. We conclude that age adapted very early intensification followed by prolonged postremission chemotherapy represents a therapeutic progress.

Adolescent↗
PubMed1992

GM-CSF-mediated proliferation induction improves the susceptibility of leukemia cells to lymphokine-activated killer cells.

Our studies on the susceptibility of fresh noncultured leukemia cells to interleukin-2 (IL-2)-induced lymphokine-activated killer (LAK) cells have shown that about two thirds of the leukemias are susceptible to the LAK-cell-mediated cytolysis. Analysis of 214 acute leukemias revealed considerable variation in the degree of cytotoxicity achieved. Cytolysis was substantially lower in fresh noncultured acute leukemia samples than in K562 and Daudi cell lines (mean Cr-release 21.0 +/- 16.0% versus 69.2 +/- 6.6% and 70.8 +/- 7.9%). Augmentation of susceptibility to LAK-cell lysis is desirable in connection with therapeutic application of IL-2-induced effector mechanisms. We observed a relationship between the LAK-cell susceptibility of leukemia cells and their spontaneous proliferation rate, which is significantly higher in LAK-cell-sensitive than in LAK-cell-resistant leukemias. It was therefore considered useful to examine the possibility of augmenting LAK-cell sensitivity by proliferation induction. These studies demonstrate that incubation of blast cells from acute myeloid leukemia (AML) and chronic myelogenous leukemia in myeloid blast crisis (CML-BC) with recombinant granulocyte-macrophage colony stimulating factor (GM-CSF) significantly augments LAK-cell susceptibility and that this is associated with an increased cell proliferation.

Cell Cycle↗
PubMed1992

Acute myelogenous leukaemia in children under 2 years--experiences of the West German AML studies BFM-78, -83 and -87. AML-BFM Study Group.

Clinical, morphological, immunological, cytogenetical and prognostic features of 84 children under 2 years of age with AML in studies AML-BFM-78, -83 and -87 were retrospectively analysed. There was a high incidence of acute monoblastic leukaemia (FAB M5) (41 patients--49%) and acute megakaryoblastic leukaemia (FAB M7) (study AML-BFM-87: five patients--13%) in this age group. Acute monoblastic leukaemia was associated with hepatosplenomegaly, extramedullary organ manifestations and chromosomal abnormalities involving 11q23. The probability of an 11-year event-free survival of all patients under 2 years of the three studies combined was 39% (SD 6%). While the event-free survival rates of patients aged 2 years and older could be improved in studies AML-BFM-83 and -87 compared with study AML-BFM-78, overall prognosis in children under 2 years in the three consecutive studies remained unchanged. The event-free survival rate of children with acute monoblastic leukaemia in both age groups was comparable (7 yr-EFS (AML-BFM-83 and -87): much less than 2 years--43% (SD 9%), =/much greater than 2 years--33% (SD 9%); P much greater than 0.5). This also applied to other risk groups. In conclusion, taking the high incidence of acute monoblastic and megakaryoblastic leukaemia in children under 2 years into account, no significant differences between children under 2 years or older children concerning response to therapy and overall prognosis could be evaluated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Longterm effects of prolonged maintenance and of very early intensification chemotherapy in AML: data from AMLCG.

In order to further improve the cure rate in AML we investigated the effect of more chemotherapy--in terms of its intensity and its duration--in 2 studies. In our 1981 study patients received TAD 1-2 courses for induction, 1 course for consolidation and randomly no further treatment or monthly myelosuppressive maintenance for 3 years. Evaluating 213 responders remission duration was clearly longer in the maintenance group with 24% CCR after 5 and 10 years. In our 1985 study the same successful strategy was further intensified by a second induction course given regardless of response to the first course to all patients up to 60 years of age while older patients received standard induction as before. This age-adapted concept resulted in a further increase of 5 years CCR in the 461 responders to as much as 34% not achieved for unselected patients in other multicenter trials. 20 patients receiving auto-BMT in first CR show the same relapse free survival as their counterparts receiving chemotherapy according to the 1985 protocol in a matched-pair analysis. We conclude that both very early intensification and prolonged maintenance contribute to a higher cure rate that is not further improved even by a maximum intensity short-term treatment. The limits of chemotherapy in AML may be overcome by modulating its myelotoxicity and antileukemic potency using GM-CSF as shown in 2 studies of our group.

Acute Disease↗
PubMed1992

Polymerase chain reaction analysis of BCR-ABL sequences in adult Philadelphia chromosome-negative acute lymphoblastic leukemia patients.

The Philadelphia (Ph) translocation is the most common cytogenetic abnormality in adult acute lymphoblastic leukemia (ALL) and is associated with an adverse prognosis. Using polymerase chain reaction (PCR) technology we recently observed a remarkably high incidence (55%) of BCR-ABL rearrangements in adult common ALL patients. In the present study we asked whether a subset of Ph-negative cALL, similarly to Ph-negative chronic myelocytic leukemia (CML) patients, exhibit BCR-ABL transcripts. PCR analysis of 58 adult Ph-negative cALL patients, including 47 cases with a normal karyotype revealed no evidence of chimeric BCR-ABL genes. We conclude that Ph-negative BCR/ABL-positive ALL is very rare entity if existing at all.

Adult↗
PubMed1991

Recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse.

To reduce critical neutropenia after chemotherapy (CT) for acute myeloid leukemia (AML) we administered recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) to patients over the age of 65 years with newly diagnosed AML and to patients with early or second relapse. CT was 9-day 6-thioguanine, ara-C, and daunorubicin (TAD9) in newly diagnosed AML and sequential high-dose ara-C and mitoxantrone (S-HAM) for relapse. In patients whose bone marrow was free from blasts a continuous intravenous infusion of GM-CSF 250 micrograms/m2/d started on day 4 after CT. Thirty-six patients entered the study and 30 of them did receive GM-CSF. For comparison, a historical control group of 56 patients was used. Complete remission rate was 50% (18 of 36) versus 32% in controls (P = .09), and early death rate was 14% versus 39% (P = .009). Treatment with GM-CSF was not associated with major adverse events. Two patients showed a marked leukemic regrowth that was completely reversible in one patient and appeared to be GM-CSF independent in the other patient. Remission duration does not seem to be reduced after GM-CSF. Under GM-CSF the blood neutrophils recovered 6 and 9 days earlier in the TAD9 (P = .009) and S-HAM (P = .043) groups associated with a rapid clearance of infections in most patients. We conclude that GM-CSF was of therapeutic benefit to our patients and this provides a basis for larger controlled trials.

Acute Disease↗
PubMed1991

Detection of chimeric BCR-ABL genes in acute lymphoblastic leukaemia by the polymerase chain reaction.

Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL) is most common in adults and is associated with poor prognosis. Since karyotypic identification of the Philadelphia translocation has been hampered by technical difficulties, we used the polymerase chain reaction (PCR) to look for the BCR-ABL rearrangement in stored samples from a selected group of 314 German ALL patients. BCR-ABL transcripts were found in 77 of 179 adults and were restricted to those with B-precursor leukaemias. 55% of adult common ALL patients had BCR-ABL and its presence correlated with poor overall survival and remission duration. Of 135 children with common ALL, 5 (6%) primary cases and 8 (17%) with recurrent neoplasias were PCR-positive. We recommend prospective evaluation of BCR-ABL analysis with PCR in patients with a B-precursor leukaemia.

Adult↗
PubMed1991

Use of polymerase chain reactions to monitor minimal residual disease in acute lymphoblastic leukemia patients.

T-cell receptor (TCR) delta gene rearrangements are observed in more than 80% of acute lymphoblastic leukemia (ALL) patients. Moreover, a preferential usage of specific genetic elements has been shown in different ALL subtypes: V delta 1 DJ delta 1 rearrangements predominate in T-ALL, while most B-precursor ALLs show a recombination of V delta 2 to D delta 3. Recently we have proposed a strategy for the detection of minimal residual disease (MRD) based on the isolation of clonospecific probes following the in vitro amplification of V delta 1 DJ delta 1 junctions by polymerase chain reaction (PCR) and now have adapted this method to the preparation of specific V delta 2 D delta 3 fragments. In the present study, clonospecific probes were generated from 11 T-ALL and 16 cALL patients (21 children, 6 adults). The sensitivity of these 27 probes in detecting residual leukemia cells varied between 10(-4) to 10(-6) as determined by semiquantitative evaluation of dilution experiments. PCR analysis of 55 bone marrow (BM) and peripheral blood (PB) samples obtained from the 27 patients during complete clinical remission showed the following results: (1) Evidence for MRD was obtained in the BM of all patients (eight of eight) investigated 2 to 6 months after remission induction and also in 6 of 11 cases on maintenance therapy 7 to 19 months after diagnosis. (2) In contrast, all patients but one (10 of 11) analyzed 6 to 41 months after the termination of treatment lacked apparent evidence for leukemia DNA; the exception was a girl exhibiting 10(-4) to 10(-5) residual cells in her PB 5.5 years after diagnosis. (3) Longitudinal analysis in nine patients disclosed marked individual differences in the intervals between achievement of clinical remission and complete eradication of the leukemia cell clone. (4) Differences in the duration of MRD were not associated with distinct clinical-hematologic features. (5) Detection of residual disease by PCR proceeded clinical relapse in two cases.

Blotting, Southern↗
PubMed1991

Expression of the c-fes proto-oncogene in granulocyte-macrophage colony-stimulating factor-dependent acute myelogenous leukemia cells grown autonomously.

In the present article, we show that 6 of 69 acute myelogenous leukemia (AML) samples exhibited autonomous in vitro growth that was dependent on endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF). Cytoplasmic RNA harvested from all 6 leukemia specimens contained GM-CSF transcripts easily detectable by mRNA hybridization. All 6 GM-CSF-expressing leukemia samples simultaneously displayed high levels of transcripts for the c-fes proto-oncogene previously shown to be expressed in GM-CSF sensitive myeloid cells, whereas only 2 of the 48 AML samples not expressing GM-CSF accumulated c-fes mRNA. Seven of additional 14 GM-CSF-expressing specimens showed specific signals upon RNA hybridization with the c-fes probe, but failed to grow autonomously. These results suggest that c-fes and GM-CSF genes may be coordinately regulated in AML blasts and that GM-CSF-mediated growth autonomy may be linked to c-fes expression.

Cell Division↗
PubMed1991

Review of the incidence and clinical relevance of myeloid antigen-positive acute lymphoblastic leukemia.

An increasing number of papers document cases of acute leukemia in which individual blast cells co-express markers normally restricted to a single cell lineage. Numerous terms are used to refer to cases with unscheduled expression of lineage-foreign proteins; the best defined categories were hybrid acute leukemia and acute mixed-lineage leukemia. The incidence of phenotypically variant acute leukemia varies with the quality and quantity of parameters used and the stringency of the criteria employed for its definition. Considerable interest has focused on acute lymphoblastic leukemia (ALL) cells expressing one or several myeloid lineage-associated antigens (My+ ALL), CD13, CD14, CD15, CD33, and CDw65. Owing to legitimate and cryptic expression on lymphoid cells, CD11b and CD15 reagents may not be considered as specific indicators of myeloid differentiation. The reported incidence ranged from 5 to 46% in 14 studies on My+ ALL, totalling 3817 patients. Several detailed reports documented a higher incidence of My+ ALL in adults (realistically in the range 10-20%) than in children (5-10%) and in B-lineage ALL as opposed to T-lineage ALL. My+ ALL cases are more likely to display unique cytogenetic [t(9;22), 11q23, 14q32] features than My-neg ALL. There appears to be no predominant expression of a single myeloid-associated antigen among those analyzed. As the morphological diagnosis of a leukemia subtype is often imprecise, some T-neg B-neg My+ ALL cases might actually contain FAB AML-M0 populations. While the expression of myeloid-associated antigens has no apparent prognostic significance in the majority of childhood ALL subtypes, in adults myeloid antigens seem to identify a high risk group of ALL patients with a poorer response to standard ALL therapy.

Adult↗