Biomedical subjects

H Gisslinger

Publications and source records attributed to H Gisslinger.

At least 37 records · Page 2Linked to original sources

PubMed1999

[Polycythaemia vera--diagnosis and therapy].

Polycythaemia vera is a clonal myeloproliferative disorder mainly involving proliferation of the erythropoiesis. The symptoms are varied and usually unspecific. The most serious complications of the disease are a thrombotic tendency and myeloid metaplasia. Thromboses mainly (2/3) occur in the arterial and less often (1/3) in the venous system and are the most common cause of death. Criteria have been established for the diagnosis of polycythaemia vera which should be strictly observed in order to distinguish between this disease, spurious polycythaemia, essential thrombocythaemia and secondary erythrocytosis. The goal of treatment is the prevention of thromboembolic complications and of myeloid metaplasia. The initial treatment always consists of phlebotomies until a hematocrit < 45% is achieved. The decision regarding maintenance therapy is difficult. While hydroxyurea or radiophosphorus is the treatment of choice in older patients (> 70 years of age), it is more difficult to select the appropriate therapy for younger patients (< 60 years), since recent studies have indicated that hydroxyurea treatment might increase the risk of leukemia. Interferon is effective but its role in the treatment of polycythaemia vera has not been established.

Humans↗

PubMed1999

Effect of high-dose melphalan and peripheral blood stem cell transplantation on renal function in patients with multiple myeloma and renal insufficiency: a case report and review of the literature.

Multiple myeloma with IgG-lambda monoclonal gammopathy and severe renal impairment with light-chain deposit disease was diagnosed in a 51-year-old man. Following conventional therapy with VAD (vincristine, adriamycin, dexamethasone) a partial remission was achieved. Peripheral blood stem cells (PBSC) were then collected following mobilization with cyclophosphamide and recombinant human granulocyte colony-stimulating factor and enriched for CD34-positive cells by immunoaffinity column. Fourteen months after diagnosis high-dose melphalan was given, followed by infusion of CD34-positive PBSC. Aside from mild oral mucositis and trigonitis, high-dose therapy was tolerated well. After he underwent PBSC transplantation his renal function improved, and the patient has been in in continuous complete remission for 1 year. Thus, high-dose chemotherapy can be safely administered to patients with multiple myeloma and severe renal impairment. Our findings confirm previous reports summarized in the current presentation.

Antineoplastic Agents, Alkylating↗

PubMed1999

Granulocyte colony-stimulating factor-supported combined immunosuppressive therapy (antilymphocyte globulin, cyclosporine, and methylprednisolone) in patients with aplastic anemia: tolerability, efficacy, and changes in the progenitor cell compartment.

Neutropenic infections are the major cause of morbidity and mortality in the treatment of aplastic anemia (AA) with antilymphocyte globulin (ALG), cyclosporin A (CSA), and methylprednisolone (MP). Recent data suggest a beneficial effect of administering G-CSF as an adjunct to immunosuppression. We have treated 11 consecutive patients with AA using a combined immunosuppressive regimen including ALG, CSA, and MP plus G-CSF at a dose of 5 microg/kg/day until neutropoietic recovery. In addition to measuring routine hematological parameters we have performed serial determinations of reticulocyte counts and in vitro progenitor cell cultures before and after therapy in order to assess their predictive value for treatment response and to determine the impact of therapy on early hematopoiesis. One patient died on day 34 of neutropenic septicemia. At 1 year, 81% of patients showed response to treatment. The median time to ANC values >0.5 and >1.0 x 10(9)/l were 19 and 35 days, respectively. Reticulocyte counts started to recover after 6 weeks, and transfusion independence was observed on day 52 for red blood cell transfusions and on day 53 for platelet concentrates. All patients with detectable colony formation in peripheral blood achieved a complete hematological remission, as compared with only one of five patients without progenitor cell growth. Although normal ranges were rarely achieved, there was a small but definitive improvement in progenitor cell numbers as compared with baseline values in most patients. Our results confirm the good tolerability and high efficacy of this G-CSF-supported combined immunosuppressive therapy for AA. Detectable colony growth at diagnosis seems to predict a high chance for complete hematological response.

Adult↗

PubMed1999

Massive disseminated intravascular coagulation and hyperfibrinolysis in alveolar rhabdomyosarcoma: case report and review of the literature.

A 68-year-old woman presented with profuse hemorrhage and other signs suggesting an acute leukemia. Histologic and cytogenetic evaluation of her bone marrow revealed alveolar rhabdomyosarcoma as the underlying cause of massive disseminated intravascular coagulation and hyperfibrinolysis. A review of the literature reveals that coagulopathy appears to be a common feature of alveolar rhabdomyosarcoma.

Aged↗

PubMed1999

The role of interferon-alpha in the treatment of idiopathic myelofibrosis.

Idiopathic myelofibrosis (IMF) is a chronic myeloproliferative disorder characterized by fibrosis of the bone marrow, varying degrees of extramedullary hematopoiesis, splenomegaly, anemia, and a leukoerythroblastic peripheral blood smear. Bone marrow fibrosis develops as a secondary phenomenon and is caused by increased intramedullary activity of mitogens such as platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and calmodulin. Because of the variable clinical course of IMF, attempts have been made to define prognostic parameters that can be helpful in detecting patients with a shortened life expectancy. The most important adverse prognostic parameters that have been reported are hemoglobin concentration, age, leukocyte count, number of thrombocytes, and cytogenetic abnormalities. However, no standardized prognostic score for IMF has yet been established. Therapeutic strategies in IMF remain predominantly supportive. The most common are blood transfusions, androgens, and cytoreductive agents such as hydroxyurea. Bone marrow transplantation is increasingly being taken into consideration, but it still has to be regarded as an experimental approach. Interferon-alpha (IFN-alpha) has shown promising results in early hyperproliferative stages of IMF but has no or only very little effect in more advanced stages of the disease. Whether IFN-alpha is able to postpone marrow fibrosis if administered in early disease stages remains to be determined in future clinical trials.

Humans↗

PubMed1999

Clonality analysis using X-chromosome inactivation at the human androgen receptor gene (Humara). Evaluation of large cohorts of patients with chronic myeloproliferative diseases, secondary neutrophilia, and reactive thrombocytosis.

Chronic myeloproliferative diseases (MPDs) are not associated with consistent cytogenetic or molecular abnormalities. Demonstration of clonal cell growth by analysis of X-chromosome inactivation (XCI) patterns in females provides a promising tool for diagnosis. However, this technique can be complicated by excessive lyonization of normal cells mimicking clonal cell growth: We analyzed XCI patterns at the human androgen receptor (HUMARA) locus in 146 healthy females, 65 women with secondary neutrophilia, 31 women with reactive thrombocytosis, and 86 women with chronic MPDs. A skewed XCI pattern with greater than 75% amplification of 1 allele (allele ratio > 3:1) was found in 22 (9.1%) of 242 control subjects. The incidence of skewing was statistically significantly lower in women younger than 30 years (2/73) compared with women older than 60 years (10/53). Of 86 patients with a chronic MPD, 71 (82%) exhibited an allele ratio greater than 3:1, whereas only 10 (12%) of 86 age-matched control subjects showed a skewed XCI pattern. Although statistical evaluation of the data showed a significant difference between patients with a chronic MPD and control subjects, proof of clonality in individual, especially elderly, patients is difficult.

Adolescent↗

PubMed1999

The effect of interferon alpha on myeloproliferation and vascular complications in polycythemia vera.

The effect of interferon alpha (IFN) on myeloproliferation and vascular complications was studied in 32 patients (17 female, 15 male; median age 60.5 yr) with polycythemia vera (PV). IFN therapy was initiated at a median time of 19 months after diagnosis. Ten patients were pretreated with chemotherapy in addition to phlebotomy. IFN dose was 12 megaU/wk during the first year, 9 megaU/wk during the second year and 12 megaU/wk thereafter. During IFN alpha treatment hematocrit level was 45.7% and remained at this level after the second year of treatment, compared to 46.5% before IFN. The frequency of phlebotomy before IFN was 0.49/month and dropped to 0.19/month (p <0.0005) during the first year of IFN treatment. IFN normalized high platelet and leukocyte counts in a majority of patients. The incidence of deep venous thromboses was 3.6%/yr before IFN alpha and 1.8%/yr during the first year of treatment. IFN-induced side-effects were mainly flu-like symptoms, fever, fatigue and arthralgia. In conclusion, IFN allowed the reduction of the dose of chemotherapy and decreased the need of phlebotomy. Despite improvement of hematological parameters, it is still uncertain whether IFN alpha can improve clinical symptoms in PV.

Adult↗

PubMed1999

Neurological function during long-term therapy with recombinant interferon alpha.

In 14 patients with myeloproliferative disorders associated with thrombocytosis, neurological and neuropsychological function were monitored prior to therapy with recombinant human interferon alpha (rIFN; dose 25 mU/week; range 10-35 mU/week) and after 3, 6, 9, and 12 months of treatment. No overt neurological side effects were observed except 1 case of cerebral insult, probably not treatment-related. Attention, memory function, and tapping improved significantly. The P2-N3 amplitudes of visually evoked potentials increased during normalization of platelet counts. Muscular strength and the amplitude of the compound muscle action potential of the median and peroneal nerves increased significantly in an inversely dose-related fashion. In patients with myeloproliferative disorders, long-term therapy with low to intermediate doses of rIFN does not seem to impair neurological function, but rather is associated with enhanced muscle power and the level of mental arousal.

Aged↗

PubMed1999

Persisting bone marrow aplasia following interferon-alpha combined with ara-C for chronic myelogenous leukemia.

A 37-year-old man with a newly diagnosed chronic myelogenous leukemia received induction therapy with hydroxyurea and interferon-alpha, and maintenance therapy with low-dose ara-C and interferon-alpha. Subsequent to a rapid hematological remission, a continuously aggravating pancytopenia with bone marrow aplasia developed which persisted after withdrawal of maintenance therapy. Bone marrow examination exhibited aplastic areas and residual hematopoiesis with impaired maturation; cytogenetically, there was a 100% persistence of Philadelphia chromosome-positive metaphases. By allogeneic bone marrow transplantation, a complete reconstitution of hematopoiesis was achieved.

Adult↗

PubMed1999

Homocysteine levels in polycythaemia vera and essential thrombocythaemia.

Patients with polycythaemia vera (PV) or essential thrombocythaemia (ET) have an increased risk of arterial and venous thromboembolic complications. Since hyperhomocysteinaemia (HHC) is a risk factor for vascular disease, we investigated the frequency of HHC in these disorders and analysed a possible association of elevated plasma homocysteine levels with vascular complications. In the cohort of 134 patients from Vienna (69 female, 65 male, median age 65.5 years, range 21-91 years) with PV (n = 74) or ET (n = 60), plasma homocysteine levels were significantly higher compared to 134 healthy controls. Median homocysteine level was 12.3 micromol/l (range 3.5-48.4 micromol/l) in patients with PV or ET and 8.9 micromol/l (range 4.8-30.5 micromol/l) in normal controls (P < 0. 0001). In addition to the 134 patients from Vienna, 48 patients (28 female, 20 male; median age 66.5 years, range 24-82) from Vicenza with PV (n = 25) or ET (n = 23) were included to evaluate the impact of HHC on the risk of thrombosis. Of 59 patients with HHC (44 from Vienna and 15 from Vicenza) 18 (31%) had a history of arterial and 10 (17%) of venous thrombosis. Of 123 patients with normal homocysteine levels, 30 (24%) had arterial and 16 (13%) had venous thromboses. The difference between the two groups was statistically not significant. Even though mild to moderate HHC occurred in a larger number of patients with PV or ET and thrombosis, it can presently not be regarded as an additional risk factor for thrombosis.

Adult↗

PubMed1999

Expression of the lung resistance protein predicts poor outcome in patients with multiple myeloma.

Expression of the lung resistance protein (LRP) is associated with resistance to various anticancer drugs including melphalan and, therefore, may affect the clinical outcome in multiple myeloma (MM). To determine the clinical significance of LRP, we have compared LRP expression in bone marrow plasma cells with clinical parameters including response to chemotherapy and survival of previously untreated patients with MM (n = 72). LRP expression immunocytochemically assessed by means of the LRP-56 monoclonal antibody was positive (> or =10% staining plasma cells) in 44 (61%) samples. There was no correlation between LRP expression and age, sex, type of the paraprotein, serum creatinine, stage, beta2-microglobulin, serum lactate dehydrogenase, or C-reactive protein. However, LRP expression was more frequently observed in patients with a p53 deletion than in those without such a deletion (P = 0.01). The overall response rate for all of the patients evaluable for response to induction chemotherapy (n = 58) was 67%. The response rate was 87% for patients without LRP expression but only 54% for patients with LRP expression (P = 0.01). Kaplan-Meier analysis revealed that patients with LRP expression had a shorter overall survival (median, 33 months) than those without LRP expression (median not reached; P = 0.04). These data show that LRP expression is an important marker for clinical drug resistance and predicts a poor outcome in MM.

Adult↗

PubMed1998

Presence of a p53 gene deletion in patients with multiple myeloma predicts for short survival after conventional-dose chemotherapy.

In multiple myeloma (MM), previous studies showed that mutations of the p53 gene are rare events in patients with newly diagnosed disease, but it is not known whether deletions of p53 are of any significance in MM. To address this question, we used interphase fluorescence in situ hybridization (FISH) with a DNA probe specific for the p53 locus at 17p13 and investigated bone marrow plasma cells from 72 patients with MM (59 patients = 81.9% before therapy). By FISH, deletions of p53, which were found to be predominantly monoallelic, were detected in 32.8% and 54.5% of patients with newly diagnosed and relapsed MM, respectively. Karyotypes from six of the patients with a p53 deletion by FISH showed a structural abnormality of 17p in only one of them. Additional FISH studies including a distal-17p probe (specific for the D17S34 locus) provided evidence for an interstitial deletion on 17p resulting in loss of p53 hybridization signals in myeloma cells. Among all 59 patients with newly diagnosed MM, presence of a p53 deletion was associated with stage III (P = .054), but not with other laboratory and clinical parameters. Patients with a p53 deletion had significantly shorter survival time compared with those without a deletion, both from the time of diagnosis (median 13.9 v 38.7 months; P < .0001) and from the time of initiation of induction treatment consisting of conventional dose chemotherapy (median 15.9 months v median not reached at 38 months; P < .0002). On stepwise multivariate regression analysis, presence of a p53 deletion was the most significant independent parameter predicting for shortened survival (P = .002). We conclude that a p53 gene deletion, which can be identified by interphase FISH in almost a third of patients with newly diagnosed MM, is a novel prognostic factor predicting for short survival of MM patients treated with conventional-dose chemotherapy.

Adult↗

PubMed1998

[Disseminated intravascular coagulation (DIG) with massive hyperfibrinolysis in metastatic uterine cancer. Observations on the effects on the coagulopathy of various treatments (a case report)].

We report on a 64-year-old patient with a recurrent endometrial carcinoma which was associated with disseminated intravascular coagulation (DIC) and excessive hyperfibrinolysis. The patient presented with severe bleeding due to hypofibrinogenemia. Fibrin degradation products were excessively elevated and there were also increased levels of activation markers of coagulation. Free plasmin was demonstrated in the circulation and alpha 2-antiplasmin was almost completely depleted. No increase in t-PA or u-PA level was demonstrated. Antifibrinolytic treatment led to a decrease of fibrin degradation products, but to an increase of activation markers of coagulation and was not associated with an increase of fibrinogen. Combination chemotherapy led to a rapid decrease of activation markers of coagulation and a sustained increase of fibrinogen. The beneficial effects on DIC/hyperfibrinolysis occurred despite the absence of any measurable effect of chemotherapy on the tumour. The patient finally died due to progression of the tumour, but without recurrence of the DIC/hyperfibrinolysis.

Adenocarcinoma↗

PubMed1998

Low-molecular-weight heparin-induced skin necrosis.

We report a case of low-molecular-weight heparin (LMWH)-induced skin necrosis in a patient with chronic lymphatic leukemia. The patient had heparin-PF4 antibodies and the heparin-induced platelet activation (HIPA) test was positive, but platelet counts remained normal. Analysis of seven cases of LMWH-induced skin necrosis revealed that this complication occurred mostly in patients previously exposed to heparin, and that severe problems such as thrombocytopenia or thromboembolic complications were rare. This is in contrast to skin necrosis induced by unfractionated heparin (UFH), where a substantially higher number of patients suffered from thrombocytopenia and thromboembolism. In addition, most patients with UFH-induced skin necrosis were not pretreated with heparin. Therefore, it is possible that LMWH is less immunogenic than UFH and requires repeated exposure for induction of skin necrosis.

Fibrinolytic Agents↗

PubMed1998

Alveolar rhabdomyosarcoma in a 68-year-old patient identified by cytogenetic analysis of bone marrow.

Pancytopenia and fulminant disseminated intravascular coagulation in a 68-year-old woman suggested an acute hematologic malignancy. However, cytogenetic analysis on a bone marrow sample revealed a near-tetraploid karyotype with an isochromosome 1q and a translocation (2;13) (q35;q14), which was suggestive of an alveolar rhabdomyosarcoma (ARMS). This diagnosis was subsequently confirmed by indirect immunohistochemistry. ARMS has not yet been observed in a patient of this age. Thus, our case underlines the importance of cytogenetics, to establish an a priori unexpected tumor diagnosis.

Aged↗

PubMed1998

Hypofibrinogenemia in non-M3 acute myeloid leukemia. Incidence, clinical and laboratory characteristics and prognosis.

Among 379 patients with AML with FAB type M1, 2 and M4-7 diagnosed between 1978 and 1997 in our institution, 19 (5%) had hypofibrinogenemia (HF), ie a fibrinogen level <180 mg/dl. Compared to patients with normal fibrinogen (n = 360) patients with HF had significantly elevated markers of activation of coagulation (TAT, F1.2, FPA) and fibrinolysis (D-dimer, FDP) indicating that disseminated intravascular coagulation/hyperfibrinolysis was the cause of hypofibrinogenemia. Patients with HF had significantly longer prothrombin times, thrombin clotting and reptilase times. Factor X and VIII were significantly lower than in patients without HF. With the exception of M7, HF occurred in all FAB subtypes, but was most common in M5 (12.1%). Patients with HF did not differ from those with normal fibrinogen with regard to age, sex, leukocyte count and other hematological parameters. During induction chemotherapy fibrinogen normalized rapidly (median 5 days) and there was no increased incidence of early hemorrhagic death. The overall and disease-free survival was similar to that of patients without HF.

Adult↗

PubMed1998

Absence of p53 deletions in bone marrow plasma cells of patients with monoclonal gammopathy of undetermined significance.

We have recently shown that presence of a p53 deletion in multiple myleoma is an independent predictor for short survival. We therefore investigated whether or not this chromosomal abnormality can be identified in patients with monoclonal gammopathy of undetermined significance (MGUS). Using a triple staining method combining staining for cytoplasmic immunoglobulins and fluorescence in situ hybridization (FISH) with chromosome 17-centromere and p53-gene specific probes, we studied plasma cells from 15 patients with MGUS. In all patients, concordant signal numbers with both probes were obtained (including one patient with trisomy 17), indicating that allelic loss of p53 does not occur in MGUS.

Bone Marrow Cells↗

PubMed1997

Apoptosis in chronic myelogenous leukemia: studies of stage-specific differences.

In this study we compared rates of apoptosis, survival and metabolic activity from CML peripheral blood neutrophils with peripheral blood and bone marrow neutrophils from healthy volunteer donors and studied the influence of the disease stage and of cytokines including G-CSF, GM-CSF and IL-1beta on these parameters. Quantification of apoptosis by morphology, diphenylamine DNA fragmentation assay and by gel electrophoresis showed similar rates of apoptosis in chronic phase CML and normal peripheral blood neutrophils when the cells were incubated in RPMI + FCS or in serum-free medium. However, there were lower rates of apoptosis in accelerated and blast phase CML neutrophils (p < .001) and in normal bone marrow neutrophils (p < .001) compared to normal peripheral blood neutrophils (incubated in RPMI + FCS). Survival among neutrophils from chronic phase or accelerated/blast phase CML patients was significantly longer (p < 0.002 and p < 0.001, respectively) than among normal peripheral blood neutrophils but neutrophils purified from normal bone marrow had a survival rate which fell between that of normal peripheral blood and chronic phase CML patients. When the cells were incubated in RPMI + autologous sera, neutrophils from chronic phase CML patients showed markedly lower rates of apoptosis (p < 0.001) and maintained higher metabolic activities (p < 0.002) compared to normal neutrophils. G-CSF and GM-CSF were found to considerably decrease the rate of apoptosis in chronic phase CML neutrophils (p < 0.001 and p = 0.008 respectively) while IL-1beta did not show any antiapoptotic effect. It is suggested that the endogenous production of growth factors may therefore participate in delaying apoptotic cell death, during the progression of CML.

Adult↗