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Biomedical subjects

W Hunstein

Publications and source records attributed to W Hunstein.

At least 91 records · Page 5Linked to original sources
PubMed1988

Deficiency in interferon production of peripheral blood leukocytes from patients with non-Hodgkin lymphoma.

In search for a rationale for the use of interferons (IFNs) in treatment of non-Hodgkin lymphoma (NHL), we have investigated the IFN system of 13 patients with low-grade NHL, 15 patients with high-grade NHL, and 20 patients with chronic lymphocytic leukemia or leukemic immunocytoma (CLL/IC). Production of IFN induced by phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), Corynebacterium parvum, Herpes simplex virus (HSV), Newcastle disease virus (NDV), and interleukin 2 (IL-2) were studied in the peripheral leukocytes from the patients and from 21 control persons by means of a whole blood technique. All three groups of patients with NHL had significantly reduced production upon stimulation by NDV (p ranged between 0.0038 and less than 0.0001) compared to controls. Similarly, C. parvum also induced lower titers of IFN in the leukocytes of patients with non-leukemic NHL (p = 0.0015 for low-grade NHL and p = 0.0038 for high-grade NHL). When stimulated by PHA, the IFN response of all groups of patients was within normal range. With the exception in low-grade NHL, Con A also induced normal titers of IFN in the patients with NHL. The levels of IFN induced by PWM, HSV, and IL-2 were very low and no differences between controls and patients could be found. As NDV and C. parvum induce mainly IFN-alpha and the mitogens PHA and Con A mainly IFN-gamma, our results suggest that there is a deficiency in the IFN-alpha response in the patients with NHL but normal response in IFN-gamma. This deficiency may have implications for the choice of subtypes of IFN in the treatment of NHL.

Adult↗
PubMed1988

Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia--an active and well-tolerated regimen.

Both mitoxantrone and etoposide have been shown to be active in monotherapy trials of relapsed and refractory acute myelogenous leukemia (AML). This phase II study was undertaken to assess the antitumor activity and toxicity of the combination in refractory and poor-risk AML. The regimen consisted of mitoxantrone, 10 mg/m2/d intravenously (IV), and etoposide, 100 mg/m2/d as short infusion, both on days 1 to 5. Sixty-one patients are evaluable for response and toxicity. Twenty-one were primarily refractory to conventional courses of cytarabine, daunorubicin, and thioguanine; 20 patients had poor-risk first relapse (relapse within 6 months of first complete remission [CR] or relapse under continuous maintenance therapy); 11 had second or subsequent relapses; and nine developed secondary AML after myelodysplastic phase or myelofibrosis. Twenty-six patients (42.6%) attained a CR and seven (11.5%) a partial remission (PR). The median duration of continuous CR was 4.7 months, with a range of 21 days to 14 months, excluding four patients who underwent autologous bone marrow transplantation. Severe myelosuppression was observed in all patients, with a median time to CR of 49 days. Nonhematologic toxicity included stomatitis (mainly grade 1 and 2) in 41 patients, nausea (mainly grade 1 and 2) in 44, infections (mainly grade 3) in 33, and fever of unidentified origin in 11. Other than transient, mild cardiac failure in nine patients, in some of them combined with grade 1 to 2 tachyarrhythmia, no other drug-related cardiac events were observed. Two cases of early death within the first 6 weeks of treatment were registered. Thus, the combination of mitoxantrone and etoposide is a highly active and well-tolerated regimen for refractory and poor-risk AML.

Adolescent↗
PubMed1988

B-cell proliferative and differentiative responses after autologous peripheral blood stem cell or bone marrow transplantation.

In this study the authors have evaluated B-cell function after autologous peripheral-blood stem cell transplantation (ABSCT) and autologous bone marrow (ABMT) transplantation. The B-enriched fractions of peripheral blood from ten normal subjects and 22 autografted patients (11 patients after ABMT, eight patients after ABSCT, and three patients after ABSCT followed by ABMT) were investigated. Time postgrafting ranged from 1 to 34 months. Proliferative responses to anti-mu antibody, Staphylococcus aureus Cowan 1 (SAC), and low molecular weight (mol wt) 12-Kd B-cell growth factor (BCGF) were measured. Differentiative responses to the same factors were assessed by quantifying in vitro immunoglobulin (IgG/IgM) production. The authors found no difference in B-cell function between the ABMT and the ABSCT patient groups. Compared to the B cells of normal subjects, only five out of 22 autografted patients showed a normal proliferative response to all agents used, while nine out of 22 did not respond to any signals. Eight out of 22 patients displayed various defects of B-cell response. However, in vitro IgG/IgM secretion of predominantly IgG subclass was normal in 19 out of 22 patients. This in vitro ability to produce Ig was reflected by the patients' normal serum IgG/IgM levels, whereas serum IgA levels were low. The authors speculate that there may be 2 B-cell populations: the normal in vitro Ig production and in vivo serum IgG may come from the stimulation of a small number of re-infused pre-committed memory B cells while, in parallel, immature B cells develop from autografted hematopoietic progenitor cells.

Adult↗
PubMed1988

The effect of human recombinant GM-CSF on the myelopoiesis in a long-term bone marrow culture (LTBMC).

The long-term bone marrow culture (LTBMC) allows continuous self-renewal of a myeloid precursor population from an adherent stromal cell layer. We investigated the effect of human recombinant GM-CSF (100 ng/ml) on the in vitro hemopoiesis in a LTBMC. After a culture period of 14 days we observed a 2.3-fold increase in the total number of non-adherent cells in the cultures containing GM-CSF. Whereas the total cell number in the cultures without GM-CSF decreased after 28 days, proliferation continued in the cultures with GM-CSF. During the first 14 days there was a slight decrease of the number of CFU-GM in the cultures with GM-CSF. Thereafter no significant difference in the numbers of committed progenitors present in two culture systems could be observed.

Bone Marrow Cells↗
PubMed1988

[A new approach in the treatment of metastatic melanoma: adoptive immunotherapy using lymphokine-activated killer cells and interleukin 2].

The treatment of metastatic malignant melanoma remains unsatisfactory. Recently, immunological approaches have been examined. In this respect, therapy with interleukin 2 (Il 2) and Lymphokine-activated killer cells (LAK-cells) is of special interest. In the present paper, the results from the literature are reviewed, and the first patient is reported, who was treated in our department with this therapeutic regimen in a phase-one study to examine the toxicity of a new Il 2 preparation.

Humans↗
PubMed1988

Clinical response to deoxycoformycin in chronic lymphoid neoplasms and biochemical changes in circulating malignant cells in vivo.

Deoxycoformycin (DCF), an adenosine deaminase (ADA) inhibitor, has been shown to be active in lymphoid neoplasms. The mechanism of cytotoxicity might involve accumulation of deoxyadenosine triphosphate (dATP), depletion of the nicotinamide adenine dinucleotide (NAD) and ATP pool, induction of double-stranded DNA strand breaks, or inhibition of S-adenosyl homocysteine hydrolase (SAH-hydrolase). We have investigated the biochemical changes in the circulating malignant cells of patients with chronic leukemia/lymphoma who were treated with DCF (4 mg/m2 weekly). Blood samples were taken from 17 patients with 60% or more circulating leukemic cells before, 4, 24, and 48 hours and five days after the first administration of DCF. Leukemic cells were separated and studied for changes in ADA, dATP, ATP, NAD, and SAH-hydrolase levels and DNA strand breaks and the data analyzed according to clinical response. Inhibition of ADA activity was found in all except one patient at 4 to 24 hours after the first administration of DCF. dATP started to accumulate at four hours, reached a maximum level between 24 and 48 hours, and returned to base values on the fifth day. Intracellular ATP and NAD levels were transiently reduced in some of the patients. However, no correlation between these changes and a clinical response could be found. DNA strand breaks could be studied in 13 patients. A significant increase in DNA breaks at 24 to 48 hours was found in six of the seven responders but only in one of the six nonresponders. At 24 hours, SAH-hydrolase levels were reduced in all seven responders studied, but only in two of the seven nonresponders. The difference in inhibition of SAH-hydrolase was statistically significant (P = .0023). These results suggest that DNA strand breaks and inhibition of SAH-hydrolase correlate with clinical response.

Adenosine Deaminase Inhibitors↗
PubMed1987

2'-Deoxycoformycin (Pentostatin) in hairy cell leukemia: response in patients refractory to interferon alpha.

Three patients with advanced hairy cell leukemia received low-dose deoxycoformycin treatment after failure to respond to therapy with interferon alpha. Patients 1 and 2 had progressive disease after splenectomy and subsequent treatment with recombinant interferon alpha (for 7 and 3 months, respectively). DCF was administered at 4 mg/m2 weekly for 3 weeks, and then once every week for 6 weeks. Patient 1 was in complete remission after 9 weeks of treatment and patient 2 in partial remission with normalization of peripheral blood counts. The third patient, also splenectomized, developed hepatotoxicity after therapy trial with interferon for 24 days and no objective improvement was observed at this stage. She subsequently responded to DCF treatment with improvements in blood counts and bone marrow. This report demonstrates that DCF is highly effective in hairy cell leukemia and non-cross-resistant with interferon alpha.

Adult↗
PubMed1987

Combination of low-dose cytarabine and 13-cis retinoic acid in the treatment of myelodysplastic syndromes.

Responses have been reported in patients with myelodysplastic syndromes (MDS) after low-dose cytarabine (Ara-C) or 13-cis-retinoic acid (13-CRA) therapy. Recently, combination of these two substances in vitro was shown to produce a synergistic effect on differentiation of leukemic cells. We conducted a phase II trial with low-dose Ara-C (5 mg/m2 per 12 h s.c.) and 13-CRA (60 mg/m2 per day orally) in 14 patients with MDS, six of whom had refractory anemia with excess of blasts (RAEB), seven had RAEB in transformation (RAEBt) and one chronic myelomonocytic leukemia (CMML). The drugs were administered from day 1 to 14 and the treatment courses repeated every 4 to 8 weeks. One partial response and one minor response could be achieved. Major toxicity included dry skin, mucositis and cheilitis in 11 of the 14 patients. The response rate is no better than the results reported in the literature with either drugs alone. As yet there is no satisfactory treatment for MDS.

Adult↗
PubMed1987

Reduced production of interferon alpha and interferon gamma in leukocyte cultures from patients with active rheumatoid arthritis.

Tests for lymphoproliferation and interferon induction in normal blood donors and patients with rheumatoid arthritis (RA) were performed in a whole-blood assay. Patients with high inflammatory RA showed significantly reduced lymphoproliferation and interferon gamma production after stimulation with phytohemagglutinin (PHA) and concanavalin A (Con A) when compared with patients with low inflammatory activity, or with normal control individuals. Similarly, patients with high and low inflammatory RA exhibited a significantly reduced interferon alpha production after stimulation with Newcastle Disease Virus (NDV) when compared with normal blood donors. Our findings may point to an important immunodeficiency of the circulating lymphocytes of RA patients and may explain some of the in vitro immunoregulatory abnormalities reported in this disease.

Arthritis, Rheumatoid↗
PubMed1986

Enzymes of purine metabolism in hairy cell leukemia.

Differences in activities of the purine degradative enzymes, adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and 5'-nucleotidase (5'NT), have been observed among different classes of lymphoid malignancies. Recent studies have shown that hairy cell leukemia (HCL) may respond to treatment with the ADA inhibitor, 2-deoxycoformycin. This study demonstrates that the cells of HCL have significantly lower levels of ADA and 5'NT (P always less than 0.01) when compared to levels in normal B- or T-lymphocytes, but have higher levels of PNP (P less than 0.001 for both comparisons). Recent studies have shown that when treated with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), cells of B-cell chronic lymphatic leukemia (B-CLL) acquire phenotypic characters of HCL. The authors have therefore also investigated the changes in enzyme pattern of B-CLL after incubation with TPA B-CLL cells are characterized by low levels of ADA, PNP, and 5'-NT, but TPA caused a marked increase in PNP activity (P less than 0.001, t test for paired samples), a pattern similar to HCL. The results from biochemical studies are thus in accordance with the hypothesis that HCL cells are more mature than B-CLL cells. The special enzyme profile of HCL suggests that a PNP inhibitor might also be effective in the treatment of this disease.

5'-Nucleotidase↗
PubMed1986

[Results with the use of the M-2 protocol in plasmacytoma].

99 patients with multiple myeloma were treated over a period of 6 1/2 years; 62 of these were initially treated with vincristine, carmustine, cyclophosphamide, melphalan and prednisone: M 2-Protocol. Response to this therapy was assessed after three therapy cycles had been completed, which had been given at intervals of 5-6 weeks. In patients responding to the therapy, treatment was continued until a maximum regression of the paraproteins was achieved. By the end of May 1985, the data of 52 patients could be evaluated, in 31 (60%) of whom remission was observed. Median survival time of all patients was 27 months. In 18 patients with "complete" remission the median has not yet been reached after 40 months. In 13 patients with partial remission, the median survival time was 36 months. In patients with complete remission, the median remission period was 26.5 months, in patients with partial remission 13.9 months.

Adult↗
PubMed1986

An immunoenzymatic staining assay (ISA) for the rapid screening of monoclonal antibodies detecting membrane and cytoplasmic antigens.

We report a rapid and very sensitive immunoenzymatic staining assay (ISA) for the determination of the fine specificity of monoclonal antibodies directed against cellular antigens. Reactivity is analysed at the single cell level by light microscopy using alkaline phosphatase-conjugated second and third antibodies on cells bound to Terasaki plates. Reactive cells can be defined by their morphology even in preliminary screening procedures. Only small numbers of cells are necessary for this assay which is comparable to radioimmunoassays in its sensitivity. Plates with fixed cells can be stored at 4 degrees C so that a permanent 'library' of various cell types is always immediately available for use. The test is also suitable for human blood cell phenotyping. Moreover, a simple modification of the procedure by short pretreatment of the cells with the detergent Brij allows the detection of antigens within the cytoplasm. The importance of evaluating the cytoplasmic compartment in order to define antibody specificity and study the distribution of different cytoplasmic and membrane antigens is emphasized.

Antibodies, Monoclonal↗
PubMed1986

Purine degradative enzymes and immunological phenotypes in chronic B-lymphocytic leukaemia: indications that leukaemic immunocytoma is a separate entity.

Investigations of the purine degradative enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and ecto-5'-nucleotidase (5'NT) have been shown to be of value in defining subsets of lymphoid malignancies. We have studied the activities of these enzymes in the circulating malignant cells of 35 patients with chronic B lymphocytic leukaemia and have correlated the biochemical data with immunological phenotypes. Classification of the cases into those without evidence of secretory activity ('true' CLL, 14 patients) and those with cytoplasmic immunoglobulin (CIg) ('immunocytoma'; 21 patients) revealed that immunocytomas are phenotypically and biochemically associated with more mature features. Malignant cells without CIg were characterized by low activities of ADA, PNP and 5'NT. In malignant cells with evidence of secretory activity (immunocytoma), low activity of ADA was also observed, but the activities of PNP and 5'NT were relatively high and approached the range of normal B lymphocytes. The differences in PNP (P less than 0.05) and in 5'NT (P less than 0.01) between these two groups were significant. Phenotypically the cells without CIg were predominantly associated with IgM (+k light chains) as surface membrane immunoglobulin (SmIg) whereas expression of IgG was more often observed in the leukaemic cells with CIg. No correlation between enzyme patterns and the stage of the disease was apparent. Thus both biochemical and immunological criteria show that cases of CLL vary within a range of maturity and that those with CIg might be more mature in the B cell axis. The present study emphasizes the value of purine enzyme studies in defining subsets of B cell neoplasia.

5'-Nucleotidase↗
PubMed1986

Autologous transplantation of blood-derived hemopoietic stem cells after myeloablative therapy in a patient with Burkitt's lymphoma.

A patient with Burkitt's lymphoma in complete remission received myeloablative consolidation treatment with superfractionated total body irradation (1,320 rad) and cyclophosphamide (200 mg/kg) followed by autologous transplantation of previously harvested and cryopreserved blood-derived hemopoietic stem cells. Seven successive leukaphereses were performed to yield a total of 55.2 X 10(9) mononuclear cells (MNC) comprising 15.1 X 10(6) CFU-GM or 4.34 X 10(6) CFU-GEMM. Following autologous blood stem cell transplantation (ABSCT), reconstitution of all cell lines occurred very rapidly, ie, 1,000 leucocytes per microL were reached after nine days, 500 granulocytes and 50,000 platelets per microL after ten days. B cells reached normal values around day 35 post-transplantation. CFU-GM first appeared in the circulating blood exhibiting an enormous overshoot. Some days later CFU-GM also appeared in the marrow. The kinetics and pattern of hemopoietic reconstitution after myeloablative treatment and ABSCT provide clear evidence that blood-derived hemopoietic stem cells are capable of completely restoring hemopoietic function in man. A possible reconstitutive advantage of blood over marrow-derived stem cells is discussed.

Adult↗