Biomedical subjects

H Gisslinger

Publications and source records attributed to H Gisslinger.

At least 55 records · Page 3Linked to original sources

PubMed1997

Interferon alpha in the therapy of multiple myeloma.

Response rates of 20% were achieved when interferon alpha (IFN) was applied as single agent treatment for multiple myeloma. A synergistic activity was observed when IFN was combined with chemotherapeutic agents in vitro and in vivo. These observations led to a series of randomized trials comparing chemotherapy alone with the combination of IFN and chemotherapy which yielded controversial results. Ludwig et al have analyzed presently available data of randomized trials in a systematic overview. In 16 trials, 2286 patients were randomized either for induction therapy with chemotherapy or IFN combined with chemotherapy. The IFN dose ranged between 4.8 and 18.7 MU/week. The overall response rate was 45.9% for patients treated with chemotherapy alone compared to 54.4% for patients treated with IFN alpha and chemotherapy. The gain of relapse-free survival was 6 months and the gain of overall survival was 5 months for IFN-treated patients. Advances in treatment were due to the expense of more severe side-effects in IFN-treated patients expressed by hematological side-effects, fever, nausea and neurological as well as psychological alterations. IFN maintenance therapy was evaluated from eight trials comprising 929 patients randomized for IFN-treatment or 'wait and see'. IFN maintenance treatment prolonged the average relapse-free survival by 7 months and prolonged the average overall survival by 5 months. Younger patients, patients in good performance status and patients with lower tumor burden seem to benefit most from the addition of IFN to chemotherapy or from IFN maintenance therapy. In conclusion, IFN shows a minor beneficial effect on response rates, progression-free and overall survival in the above mentioned patient group and might be applied when high-dose chemotherapy with transplantation is not feasible. IFN has been shown to be effective for maintenance therapy in patients with lower tumor burden who have responded to induction therapy.

Clinical Trials as Topic↗

PubMed1996

Duration of second complete remission in patients with acute myeloid leukemia treated with chemotherapy: a retrospective single-center study.

A total of 168 patients with de novo AML were retreated with chemotherapy at relapse following first CR; 66 patients (39%) achieved a second complete remission (CR). The probability of achieving a second CR was highly dependent on the duration of the first remission. Patients who received no or conventional postremission chemotherapy after second CR had a median remission duration of 7.5 months, and the probability of remaining in remission at 3 years was 24%. Patients with a first CR of more than 12 months had a median second remission duration of 18 months. The probability of a second CCR was 35% at 3 years and 24% at 5 years, whereas none of the patients with a first CR of less than 12 months was in remission at 3 years. Only a poor correlation (p = 0.31) was found when the durations of the first and second CR were compared in patients with a second relapse. Patients with long-lasting remissions and long-term survivors after second CR are characterized by a first CR duration of > 12 months and favorable or normal cytogenetics. The type of salvage treatment seems to be less important for achievement of long-term remission, but it is probably important to administer consolidation chemotherapy after second CR. Other so-far ill-defined factors may be responsible for the suppression of the leukemic clone in patients with long-lasting remissions following chemotherapy for relapse after second CR.

Adolescent↗

PubMed1996

FLAG (fludarabine, cytosine arabinoside, G-CSF) for refractory and relapsed acute myeloid leukemia.

Twenty-two patients with refractory or relapsed AML were treated with FLAG [25 mg/m2 fludarabine daily (days 1-5), 2 g/m2 daily Ara-C (days 1-5) and 400 micrograms/m2 daily G-CSF (day -1 till the absolute neutrophil count was > 500/microliter)]. Median age was 46 years (range 24-63). Eight patients had leukemia which was primarily refractory to conventional regimens, six were in first, seven were in second, and one was in third relapse. Overall, 11 of 22 (50%) patients achieved complete remission (CR), three had a partial response (PR), and seven did not respond (NR). One patient died of an early cerebral hemorrhage. The median remission duration from achievement of CR after FLAG was 9.9 months and median survival was 13.0 months. One patient is alive in CR at 31.9 months. Hematological toxicity of the regimen was severe. The median time to neutrophil recovery (ANC > 500/microliter) was 21 days (range 18-33). A median of seven red cell units (range 0-22) and of six platelet concentrate units (range 3-28) had to be given. Median duration of febrile neutropenia was 2 days (range 0-20 days) and patients were on i.v. antibiotics for a median of 16 days (range 0-51). There was no death from infection. Nonhematological toxicity was remarkably low, with almost no neurotoxicity and no major hepatotoxicity. In conclusion, FLAG seems to be an efficient and well tolerated regimen. It may be particularly useful for patients who have a sibling or unrelated donor for subsequent allogeneic bone marrow transplantation.

Acute Disease↗

PubMed1995

[Interferon-alpha-induced disorders of thyroid function. A retrospective analysis of the literature and personal experiences].

This paper tries to evaluate the importance of IFN-alpha induced thyroid dysfunction. Based on our own experience and reported data we present the results obtained in a total of 588 patients, in whom thyroid function and thyroid antibody occurrence was monitored during therapy with IFN-alpha: About 10% of these patients developed thyroid dysfunction during IFN-alpha treatment. Half of them reacted with hypothyroidism, 3% with hyperthyroidism and in 2% a biphasic (hyperthyroidism followed by hypothyroidism) pattern of reaction was observed. The frequency of these thyroid dysfunctions was increased in female patients and in patients with preexisting thyroid antibodies. The risk to develop thyroid dysfunction is reduced to 7% in patients with no pretherapeutic thyroid antibodies. The evolution of the thyroid ailment is variable and therefore unpredictable. In many patients there is no need to stop treatment with IFN-alpha nor to treat the thyroid dysfunction specifically. IFN-alpha induced autoimmune- phenomena seem to be etiologically important for the development of thyroid disease during IFN-alpha. The reported data allow in our view some basic recommendations for the clinician: thyroid function and thyroid antibodies should be evaluated before the start of treatment with IFN-alpha. During therapy with IFN-alpha these parameters should be regularly (eg every 4 months) monitored. In patients with thyroid autoantibodies or dysfunction already before IFN-alpha the control intervals should not be longer than every two months.

Female↗

PubMed1994

Altered levels of interleukin-1 beta and interleukin-1 receptor antagonist in chronic myelogenous leukemia: clinical and prognostic correlates.

We have recently demonstrated that interleukin (IL)-1 beta levels are elevated in advanced chronic myelogenous leukemia (CML) and that IL-1 inhibitors can suppress CML clonogenic growth. To further assess the clinical implications of increased IL-1 beta expression in CML, we analyzed IL-1 beta and IL-1 receptor antagonist (IL-1RA) levels in leukocyte lysates from a series of CML patients and from normal volunteers. Both IL-1 beta and IL-1RA were measured by enzyme-linked immunosorbent assays (ELISAs), with the lower limits of sensitivity of the assays being 20 pg/mL and 6.5 pg/mL, respectively. The median IL-1 beta level in the 81 CML patients tested was higher (115.8 pg/2.4 x 10(7) cells; range, 0 to 2,000 pg/2.4 x 10(7) cells) than the median level in 25 control samples (10.8 pg/2.4 x 10(7) cells; range, 0 to 95.5 pg/2.4 x 10(7) cells) (P < .01). IL-1 beta was bioactive, as demonstrated with a bioassay based on cytotoxicity to a melanoma cell line (A375). For survival analysis, elevated IL-1 beta levels were defined as those exceeding the mean + 2 SD of normal levels (83 pg/2.4 x 10(7) cells). The survival of the 44 patients with elevated IL-1 beta levels was significantly shorter than that of those who had low IL-1 beta levels (median, 44 v 58 months; P = .049 by Wilcoxon-Gehan method). An association between IL-1 beta and CML prognostic criteria shows that IL-1 beta levels were significantly higher in patients in accelerated/blastic crisis phases of the disease (364.0 pg/2.4 x 10(7) cells) compared with patients in chronic phase (102.0 pg/2.4 x 10(7) cells) (P < .01), and that high IL-1 beta levels correlated with increased blasts in the marrow and peripheral blood (P < .01). In contrast, while IL-1RA levels did not differ between chronic-phase CML patients (median, 471.7 pg/2.4 x 10(5)) and healthy volunteers (median, 454.4 pg/2.4 x 10(5)), patients with accelerated/blast crisis disease had significantly lower levels of IL-1RA (median, 218.7 pg/2.4 x 10(5); P = .03). Finally, although IL-1 beta has been previously shown to increase IL-1RA levels, there was no correlation between IL-1 beta and IL-1RA levels in our CML patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone Marrow↗

PubMed1994

Granulocytic sarcoma of the prostate as the first manifestation of a late relapse of acute myelogenous leukemia.

We describe a 68-year-old patient who developed granulocytic sarcoma of the prostate 9 years after complete remission following successful treatment of acute myelogenous leukemia (FAB, M2). PCR analysis of bone marrow samples in first remission and at the time of relapse detected an AML1/ETO rearrangement typical for AMLs with t (8;21). The CD56 antigen was not expressed on the leukemic cells. Systemic chemotherapy led to a short-lasting regression of the tumor, but the patient subsequently developed overt bone marrow relapse and died during chemotherapy. While granulocytic sarcoma as a primary manifestation of AML is well known, as the first manifestation of relapse it appears to be very uncommon.

Aged↗

PubMed1994

Successful re-treatment of an anti-interferon resistant polycythaemia vera patient with lymphoblastoid interferon-alpha N1 and in vitro studies on the specificity of the antibodies.

A polycythaemia vera patient who initially responded to recombinant IFN-alpha 2 (rIFN-alpha 2) treatment developed neutralizing antibodies (NA) against it and lost response. Despite raising the dose, clinical resistance persisted and NA increased when two alternative rIFN-alpha 2 preparations were used. When treatment was switched to lymphoblastoid IFN-alpha (lyIFN-alpha N1), clinical response was restored and maintained. During re-treatment, NA specific for the earlier rIFN-alpha 2 preparations redeveloped and cross-reacted extensively with each other but not with 'whole' lyIFN-alpha N1 and only minimally with the lyIFN-alpha 2 subtype within it. These findings demonstrate the relevance of NA specificities in the re-treatment of antibody-compromised patients.

Antibodies↗

PubMed1994

Immunological findings in patients with myelodysplastic syndrome.

Activation of monocytes and granulocytes in vitro by cytokines, in vivo administration of cytokines, as well as in vivo cytokine production due to infectious and inflammatory diseases causes changes of the surface expression density of certain membrane molecules. In recent studies we attempted to determine the feasibility of using flow cytometric immunophenotyping as a tool to develop a sensitive parameter for detecting infections at an early stage of disease when clinical parameters are still negative. Since infections are an important factor determining the clinical course of myelodysplastic syndromes (MDS), early detection of infection might be beneficial for these immunocompromised patients. We indeed found activation-associated immunophenotypic changes of cell surface antigens on monocytes and granulocytes of clinically infection free MDS patients suggesting enhanced immune activity in these patients, most likely due to latent or beginning infections. In particular, analyses of the expression density of receptors for IgG (Fc gamma Rs), complement receptors, and certain activation-associated surface molecules such as the CD67 and the M5 molecule seem to be of clinical relevance. We will also discuss findings concerning changes of cytokine levels and functional alterations of immunologic parameters in MDS patients.

Humans↗

PubMed1994

MDR1 gene expression in chronic lymphocytic leukemia.

In order to assess the clinical role of the MDR1 gene in chronic lymphocytic leukemia (CLL), we determined its expression in the leukemic cells of 39 patients with CLL and compared this with other clinical and laboratory parameters. MDR1 RNA expression was detected in 29 patients. MDR1 RNA transcripts were independent of age, treatment status of the patients and the clinical stage of CLL, but correlated with the white blood cell count and MDR2 RNA transcripts. Expression of the tumor suppressor gene p53 was found in 30 out of 37 patients and was associated with MDR1 RNA expression (P < 0.001). Immunocytochemistry using the monoclonal antibody C219 was performed in 38 patients, and in 28 cases, more than 5% of the leukemic cells were found to express cell surface P-glycoprotein. P-glycoprotein expression correlated with the expression of MDR1 RNA (P = 0.048).

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Granulocyte colony-stimulating factor (G-CSF) as an adjunct to induction chemotherapy of adult acute lymphoblastic leukemia (ALL).

Our purpose was to evaluate the ability of recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) as an adjunct to induction chemotherapy of acute lymphoblastic leukemia (ALL) to ameliorate chemotherapy-induced neutropenia and thus allow patients to receive full doses of chemotherapy on time. Sixteen consecutive patients with adult ALL (13 de novo, three relapsed) were treated with induction chemotherapy according to the BMFT protocol and received in addition r-metHuG-CSF (200 micrograms/m2/day). Patients who were treated with the same induction chemotherapy but without G-CSF between 1982 and 1990 served as controls. Fifteen of the 16 patients achieved complete hematological remission. One patient died because of fungal septicemia. Compared with historical controls, G-CSF-treated patients had a significantly faster neutrophil recovery in phase I, resulting in neutrophil counts > 1000/microliters at day 17 vs day 26 (in median) in controls. In phase II, the onset of severe leukocytopenia (< 1500/microliters) was significantly (p = 0.01) delayed and the degree of leukocytopenia less pronounced (mean nadir 3300/microliters) in G-CSF-treated patients compared with controls (1880/microliters). The number of days of febrile neutropenia was not different in phase I. In phase II it was lower in study patients (0 vs 1.1 days), but the difference did not reach statistical significance (p = 0.09). Full doses of chemotherapy could be given on time to 11/13 (85%) G-CSF patients but to only 7/30 (23%) controls. These data indicate that (a) G-CSF can be given along with chemotherapy in induction treatment of ALL without compromising efficacy; (b) the duration of neutropenia in phase I is markedly shortened and the degree of leukocytopenia in phase II ameliorated; (c) these beneficial effects allow patients to receive full doses of chemotherapy on time.

Adolescent↗

PubMed1993

Atrial natriuretic peptide release in response to different positive end-expiratory pressure levels.

OBJECTIVE: To assess the influence of different positive end-expiratory pressure (PEEP) levels on plasma atrial natriuretic peptide concentrations. DESIGN: Prospective, randomized study. SETTING: Intensive care unit of a university hospital. PATIENTS: Twenty-seven patients who were mechanically ventilated due to acute respiratory failure. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The patients were randomized into three groups: in each group, a defined PEEP level (5, 10, or 15 cm H2O, respectively) was applied, alternating with zero PEEP (0 cm H2O) in consecutive order (reversal experiment). Blood samples for the determination of atrial natriuretic peptide concentrations were drawn from the pulmonary artery and the radial artery catheters. There were no decreases in atrial natriuretic peptide concentrations with a PEEP of 5 cm H2O, but significant decreases could be shown for PEEP values of 10 and 15 cm H2O. The patients of all groups were subjected to PEEP levels of 5, 10, 15, and 20 cm H2O in randomized order (step experiment). The data demonstrated a significant inverse correlation between changes in PEEP levels and changes in plasma atrial natriuretic peptide concentrations. CONCLUSION: The data suggest that the release of atrial natriuretic peptide is influenced by a PEEP of > or = 10 cm H2O, while a PEEP of < or = 5 cm H2O does not disturb this cardiac endocrine function.

Adult↗

PubMed1993

Immunophenotypic characterization of myelomonocytic cells in patients with myelodysplastic syndrome.

Infections, an important determining factor in the clinical course of myelodysplastic syndromes (MDS), result in activation of myelomonocytic cells. In this study we demonstrate activation-associated immunophenotypic changes of cell surface antigens on monocytes and granulocytes observed in two groups of MDS patients, one with low and another one with high clinical risk, and compared them to healthy individuals. Significantly changed expression of the complement receptors 1 (CD35) and 3 (CD11b), the Fc gamma receptor I (CD64), the leucocyte-homing receptor (CD44) and the activation associated membrane proteins CD67 and M5 were found on monocytes and/or granulocytes of MDS patients. In low-risk MDS patients we observed activation-associated phenotypic changes only in monocytes, whereas in high-risk MDS patients, both monocytes and granulocytes showed such changes. Additionally, we performed respiratory burst experiments and observed an impaired response of monocytes and granulocytes derived from MDS patients. Despite the fact that all patients were free of infection by clinical criteria, cell surface phenotyping as well as the reduced respiratory burst capacity of myelomonocytic cells suggests in vivo preactivation of these cells.

Antigens, CD↗

PubMed1993

Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro.

The successful therapeutic use of interferon-alpha (IFN-alpha) in myeloproliferative disorders offered the possibility to test its acute and long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis in humans. ACTH and cortisol plasma concentrations were measured in 8 patients hourly starting from 4 p.m. through 12 p.m. on three occasions. The first time all patients were studied before initiation of therapy, when the vehicle was injected alone. The patients were studied again on day 1 of IFN-alpha therapy (5 million units) and once more after 3 weeks of therapy. On the control day, plasma concentrations of ACTH and cortisol were in the range expected for this time of day. In contrast, after the first administration of IFN-alpha a significant stimulation of the HPA axis was observed. After 3 weeks of IFN-alpha therapy, no significant stimulation of the HPA axis occurred after administration of IFN-alpha. IFN-alpha-induced adaptive changes in the HPA axis were also indicated by a significantly enhanced ACTH and cortisol response to exogenously administered supramaximal doses of corticotropin-releasing hormone (CRH) when the patients had been on IFN-alpha treatment for 3 weeks. To determine the exact locus of the IFN-alpha action, in vitro experiments were performed using rat hypothalamic organ and primary pituitary and adrenal cell culture systems. Thereby a significant stimulation of hypothalamic CRH secretion and rat adrenal corticosterone production was observed after INF-alpha at concentrations of 5 x 10(-8) M or 10(-7) M respectively. In contrast, no direct IFN-alpha effect on pituitary ACTH secretion could be observed in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗

PubMed1993

Postpartum factor VIII inhibitors. Report of two cases with special reference to the efficacy of various treatments.

Two cases of postpartum inhibitors to F VIII are described. One patient had a severe bleeding tendency (iliopsoas bleeding, forearm bleeding). The maximum inhibitor titer was 800 BU/ml in case 1 and 120 BU/ml in case 2. Bleeding was controlled by treatment with human and porcine factor VIII concentrate and with activated prothrombin complex concentrate (FEIBA, Immuno AG, Vienna, Austria) in case 1, while no replacement therapy was given in case 2. Prednisone (given in both cases) and high-dose immunoglobulin (given in case 2) was without effect. Cyclophosphamide (100 mg per day), combined with small doses of prednisone led to complete disappearance of the inhibitor and normalization of factor VIII in case 1. In the other patient who refused treatment with cyclophosphamide the inhibitor titer remained high over a period of 13 months.

Adult↗

PubMed1992

Thyroid autoimmunity and hypothyroidism during long-term treatment with recombinant interferon-alpha.

Forty-five patients with myeloproliferative or myelodysplastic syndromes, treated with recombinant interferon-alpha (rIFN-alpha) for a minimum of 1 up to 4 years, were examined for the occurrence of thyroid autoimmunity. During treatment, the rate of thyroid autoimmunity rose to more than 20%. The decrease in severity and frequency of thyroid autoimmunity after withdrawal of IFN shows that this is a potentially reversible side effect. The key determinant for the manifestation of this IFN-related autoimmune phenomenon seems to be a predisposition for autoimmunity, since patients with initially detectable thyroid antibodies are prone to exacerbations of thyroid autoimmunity. Concurrent with thyroid autoimmunity, hypothyroidism occurred but did not correlate with the levels of thyroid antibodies, although severe hypothyroidism in two patients was accompanied by increased levels of thyroid antibodies. This investigation shows that thyroid autoimmunity and consecutively hypothyroidism must be expected in certain patients treated with rIFN-alpha during long periods. Furthermore, it may be assumed that IFN-alpha does not induce the development of autoimmunity, but rather enhances the levels of pre-existent thyroid antibodies.

Adult↗

PubMed1992

Treatment and prophylaxis of chemotherapy-induced gastrointestinal complaints.

Ninety-eight patients (48 male, 50 female; age median, 56 years; range, 25-85 years) with solid tumors (21 breast cancers, 6 sarcomas, 2 colorectal cancers, 1 pancreatic carcinoma, 1 hypernephroma, and 1 lung cancer) and hematologic neoplasms (24 multiple myelomas, 32 lymphomas, and 10 myeloproliferative syndromes) were recruited into the study. The patients received at least three cycles of chemotherapy with alkylating substances, anthracyclines, antimetabolites, and vinca alkaloids, with or without corticosteroids. A total of 325 cycles of chemotherapy were administered. The symptoms were evaluated by means of a score system on the basis of which heartburn, sensation of repletion, nausea, and cramps were assessed by incidence and degree of severity. Before initiation of concomitant therapy with sucralfate, 47 patients (48%) had symptoms during chemotherapy (heartburn, sensation of repletion, nausea, cramps). After initiation of therapy with sucralfate these symptoms improved in 42 patients (89%); in 6 patients there was a transitory increase in heartburn and nausea. All other patients remained without symptoms in spite of chemotherapy. The evaluation of the patient population as a whole showed a significant decrease of chemotherapy-induced heartburn (p less than 0.01) and nausea (p less than 0.01) during sucralfate therapy. This was tolerated extremely well; side effects were not observed. To summarize, this prospective clinical study shows that sucralfate is an effective and suitable therapeutic principle in long-term therapy for the treatment and prophylaxis of chemotherapy-induced gastrointestinal complaints.

Adult↗

PubMed1991

Phase II study of amonafide in advanced breast cancer.

Twenty-eight patients with advanced breast cancer refractory to prior hormone and/or first-line chemotherapy (with or without anthracycline drugs) were treated with the investigational agent amonafide at a dose of 800 mg/m2 intravenously over 3 hours repeated every 4 weeks. Five objective tumour responses of 5.0 months' median duration were observed in the 20 patients without previous anthracycline exposure, including 1 CR. Leukopenia was the dose-limiting toxicity; though it was generally modest with the 800 mg/m2 amonafide starting dose, an initial dose reduction should be considered in patients with prior radiotherapy and/or bone marrow involvement. Other adverse reactions included nausea/vomiting (53%), phlebitis/erythema along the vein injected (7%), and mild neurotoxic symptoms during the drug administration such as headache, tinnitus, and diaphoresis (21%). Amonafide is an active compound for the treatment of patients with advanced breast cancer and should be considered for further evaluation and incorporation in combination chemotherapy.

Adenine↗

PubMed1991

Interferon in essential thrombocythaemia.

In the present investigation, 20 patients with ET were treated with recombinant interferon alfa-2c (IFN) for up to 4 years. Initially, IFN was administered subcutaneously at a dosage of 6-45 MU/week. The dosage was adjusted according to individual tolerance and response. The median dose during induction was 20 MU/week, 10 MU/week during the remaining first year, 6 MU/week during the second year and 2 MU/week thereafter. 13 patients (65%) achieved complete remission (platelet count less than 440/nl), four patients (20%) had partial remission (greater than 440/nl but a reduction by more than 50% of the initial count). The median platelet count remained steady throughout the 4-year period of treatment, in spite of extreme dose reductions. After withdrawal of IFN, however, platelet counts again increased. The white blood cells showed a marked decrease similar to that of platelet counts, whereas the haemoglobin level remained fairly stable. In the bone marrow, a significant decrease in megakaryocyte density and size could be observed. Concurrently with the improvement of haematological parameters, clinical symptoms improved, but reappeared after withdrawal of IFN. During induction, fever, bone and/or muscle pain, fatigue, lethargy and psychological symptoms were the most prominent side-effects in the majority of patients. In three patients these symptoms led to discontinuation of the treatment. With repeated dose reductions, excellent long-term tolerance was achieved, and during late maintenance treatment the only observed side-effect was an induction of thyroid autoimmunity in three patients. IFN is an effective, well-tolerated alternative in the long-term treatment of symptomatic ET. However, since withdrawal of IFN leads to recurrence of thrombocytosis, continued treatment is to be recommended.

Adult↗