Biomedical subjects

D K Hossfeld

Publications and source records attributed to D K Hossfeld.

At least 91 records · Page 5Linked to original sources

PubMed1997

The significance of trisomy 8 in de novo acute myeloid leukaemia: the accompanying chromosome aberrations determine the prognosis. German AML Cooperative Study Group.

Trisomy 8 is the most frequent numerical chromosome aberration in acute myeloid leukaemia (AML). It occurs either as the sole anomaly or together with other clonal chromosome aberrations. We investigated whether accompanying chromosome anomalies influence the clinical outcome in patients with trisomy 8 and de novo AML. Since 1986, in 713 AML cases treated according to the protocols of the German AMLCG trials, chromosome analyses have been successfully performed. The overall incidence of trisomy 8 was 7.6%. Complete clinical follow-up data were available for 51 patients who were divided into three different categories: group 1: trisomy 8 as the sole cytogenetic anomaly (n = 20); group 2: trisomy 8 in addition to favourable chromosome aberrations (t(8;21)(q22;q22), t(15;17)(q22;q21), inv(16)(p13q22)) (n = 10); and group 3: trisomy 8 accompanied by other anomalies, in most cases of complex type (n = 21). Complete remission (CR) rates were 70%, 90% and 67% for groups 1, 2 and 3, respectively. Event-free survival (EFS) at 3 years differed significantly between patients with trisomy 8 only (37.5%), patients with trisomy 8 in combination with favourable aberrations (55.0%) and patients with trisomy 8 and other accompanying anomalies, mostly complex chromosome aberrations (9.0%) (group 1 v group 2: P=0.12; group 1 v group 3: P=0.005; group 2 v group 3: P=0.05). In this study patients with +8 as the sole cytogenetic anomaly had an intermediate prognosis, patients with +8 in addition to favourable chromosome aberrations maintained a good clinical outcome, and patients with +8 in combination with other abnormalities showed the worst prognosis.

Acute Disease↗

PubMed1997

Allogeneic transplantation with CD34+-selected cells.

We report the outcome of eight patients with different hematological malignancies who were transplanted with allogeneic CD34-selected mononuclear cells following myeloablative therapy. Four patients received G-CSF mobilized CD34-enriched peripheral blood progenitor cells (PBPC) together with CD34-enriched bone marrow (BM), two patients were transplanted with allogeneic G-CSF mobilized CD34-enriched PBPC alone, and two patients received only allogeneic CD34-enriched BM cells. On average, patients received 2.66 x 10(6) CD34+-cells/kg BW (range: 0.53-8.40 x 10(6) CD34+-cells/kg body weight) and 0.57 x 10(6) CD3+-cells/kg BW (range: 0.20-1.10 x 10(6) CD3+-cells/kg BW), respectively. Seven of the eight patients engrafted (ANC > 0.5 x 10(9)/L median: day +19 (range: 16-23 days); platelets > 20 x 10(9)/L median: day +34 (range: 21-47 days); one patient died on day +16 after transplantation and was not evaluable for engraftment. Three of seven patients evaluable for acute graft-versus-host disease (GvHD) developed acute GvHD grade II which resolved upon steroid treatment. Five of the eight patients are still alive and in remission with a median follow-up of 215 days (range: 80-420 days). Causes of death included fungal infection, cerebral bleeding and sepsis. These preliminary data suggest that CD34-enriched cells can be successfully given during for allogenic transplantation following myeloablative therapy in hematological malignancies. The impact of T-cell depletion by enrichment for CD34+-cells in an attempt to reducing the incidence and/or severity of acute and/or chronic GvHD still remains to be determined.

Adult↗

PubMed1997

Whole-body positron emission tomography (PET) for diagnosis of residual mass in patients with lymphoma.

BACKGROUND: PET using 18fluorodesoxyglucose (FDG) may offer the possibility of differentiating vital from necrotic residual masses. PATIENTS AND METHODS: Seventeen patients with HD and 17 patients with NHL underwent FDG-PET following therapy. According to staging by routine methods at diagnosis, 7 patients presented stage I, 13 stage II, 5 stage III, and 9 stage IV. A dose of 250-400 MBq FDG was injected and whole-body PET was performed 30-60 minutes later. RESULTS: Residual mass was found in 32 patients with routine methods. FDG-PET was negative in 17 patients, who were considered to be in CR. None of them relapsed (median follow-up 63 weeks ). FDG-PET was positive in 17 patients. Sixteen patients had residual mass with routine methods. Four patients received radiation after PET. Their median follow-up is 58 weeks without relapse. Two other patients with lasting CR had FDG uptake outside the residual mass--one with confirmed pneumonia. Five patients had histologically confirmed lymphoma, 2 patients relapsed according to routine methods. One patient is likely to be false positive because of fracture at lymphoma site. Seven of 10 patients with FDG uptake in the residual mass after completed therapy relapsed. According to routine restaging, 2 patients achieved CR. In 1 patient an additional focus was found in the humerus in spite of normal scintigraphy with histologically confirmed lymphoma. There were no false-negative results, but 3 false-positive results inside and 2 false-positive results outside the residual mass after completed therapy. CONCLUSIONS: PET performed for evaluation of residual mass after treatment of lymphoma has a high predictive value.

Adult↗

PubMed1997

Randomized studies with interferon in chronic myelogenous leukemia (CML) and comparative molecular aspects. German CML Study Group.

Four randomized prospective studies on interferon alpha (IFN) in CML report varying degrees of prolongation of the chronic phase of CML and of survival as compared to conventional therapies. There is agreement that IFN prolongs survival as compared to standard busulfan. There is disagreement, however, as to which degree IFN is superior to hydroxyurea. Whereas the randomized studies of the Italian cooperative group and of the British MRC find a statistically significant survival advantage of IFN over hydroxyurea of about 20 months, this difference is only 10 months in the German randomized study and not significant. One reason for this difference might be the more intensive treatment schedule for the hydroxyurea control group in the German study. Other reasons might be differences in risk profiles between the patient groups studied and in strategies of IFN therapy. About 1% of the human genome consists of retroviral or retroviral-like sequences. By analogy to animal models, endogenous retroviruses might also have pathogenic potential in human disease. The transposon-like structure of retroviruses that enables them to integrate at almost any position in the host genome and the capability of retroviruses to serve as efficient vehicles of cellular genes are in support of a pathogenic potential. Furthermore, particles resembling retroviruses have been observed long ago in human embryonic and malignant tissues and cell lines. Sequence information and the transcriptional activity of the endogenous sequences argue against the possibility that these sequences are only fossil relics of early evolutionary periods. Most of the sequences appear to be inactivated by stop codons or frameshifts, making the genomic localization of open reading frames with biological activity difficult. Up to now, mutagenesis by insertion of retroviral-like sequences in sporadic cases of human disease appears to be the only example of pathogenic relevance of retroviruses in man.

Antineoplastic Agents↗

PubMed1996

[Immunosuppressive treatment of a spontaneous inhibitor hemophilia A using cyclophosphamide, vincristine and prednisone following prior Factor VIII stimulation].

A 59-year-old patient who presented with hematuria and recurrent soft tissue bleeding was found to have a factor VIII inhibitor level of 52 Bethesda units (BU)/ml and acquired hemophilia was diagnosed. After treatment with immunoglobulins (0.4 g IgG/kg per day for one week) the factor VIII inhibitor titer decreased to 12 BU/ml. Because of another episode of retroperitoneal hemorrhage, the patient was put on an immunosuppressive combination therapy which was first described by Lian et al. (1988). Our patient was infused with a factor VIII concentrate followed by cyclophosphamide, vincristine and prednisone. This regimen was repeated every 3-4 weeks. After 6 courses a further decline in the factor VIII inhibitor concentration, but no complete eradication of the autoantibody, was achieved. The factor VIII inhibitor level has remained at 2.5 BU/ml for more than 7 weeks without further bleeding episodes. The pathophysiology and treatment of acquired hemophilia are discussed.

Autoantibodies↗

PubMed1996

ider(9)(q10)t(9;22)(q34;q11) is a recurrent chromosomal abnormality in acute lymphoblastic leukemia and lymphatic blastic phase of chronic myelogenous leukemia.

We report on two cases, one with acute lymphoblastic leukemia and a second with lymphatic blastic phase of Philadelphia chromosome-positive chronic myelogenous leukemia, cytogenetically characterized by ider(9)(q10)t(9;22)(q34;q11). Our findings and the data of the 4 cases previously published indicate that ider(9)(q10)t(9;22)(q34;q11) represents a rare but recurrent chromosomal abnormality occurring in hematological malignancies with lymphoid differentiation, namely acute lymphoblastic leukemia and lymphatic blastic phase of chronic myelogenous leukemia, and most likely evolves from a preexistent der(9) involved in the standard t(9;22).

Adult↗

PubMed1996

Trisomy 8 preceding diagnosis of acute nonlymphocytic leukemia by 2 years in a patient with multiple myeloma without cytological evidence of myelodysplasia.

A case of acute nonlymphocytic leukemia (ANLL) occurring 2 years after the diagnosis of multiple myeloma (MM) that had been treated by only one course of melphalan/prednisone chemotherapy is reported. Cytogenetic and fluorescence in situ hybridization analysis of peripheral blood cells revealed trisomy 8 as the sole cytogenetic defect at the time of diagnosis of ANLL. Two years earlier, when MM was diagnosed without any cytological evidence of co-existent myelodysplasia, chromosomal analysis of bone marrow cells showed the same pathological karyotype 47, XY, +8 in 14 of 20 mitoses studied. Our interpretation of this unusual cytogenetic finding is that at the time of diagnosis of MM, in spite of lacking cytological signs of myelodysplasia, an unrecognizable myelodysplastic syndrome must have been present which then evolved to ANLL.

Aged↗

PubMed1996

Lactic acidosis and hypoglycemia in a patient with high-grade non-Hodgkin's lymphoma and elevated circulating TNF-alpha.

A 71-year-old patient with high-grade non-Hodgkin's lymphoma stage IVB, severe lactic acidosis and tumor-associated hypoglycemia is described. Endocrine causes of hypoglycemic episodes were excluded because of low serum concentrations of insulin and "insulin-like growth factor 1", and normal concentrations of growth hormone and thyroid hormone. Clinical conditions associated with lactic acidosis such as diabetes mellitus, biguanide intoxication, septicemia, acute hypoxemia, or circulatory insufficiency were ruled out. Enhanced glucose metabolism within the tumor was visualized by positron emission tomography employing 2-fluro-2-deoxy-D-glucose (FDG) as a tracer. A markedly elevated tumor necrosis factor-alpha (TNF-alpha) level was found which decreased after cytoreductive therapy paralleling the normalization of serum lactate. In contrast to the majority of cases of lymphoma-associated lactic acidoses reviewed to date, in our case lactate elimination was not reduced.

Acidosis, Lactic↗

PubMed1996

The MDR phenotype in hematologic malignancies: prognostic relevance and future perspectives.

The multidrug resistant (MDR) phenotype has been suspected as a major cause of treatment failure in hematologic malignancies. Numerous studies have investigated the expression of the MDR1 gene product, P-glycoprotein, in leukemia, lymphoma and myeloma. Studies in myelogenous leukemia and myeloma have so far provided best evidence for a significant correlation between P-glycoprotein expression and response to chemotherapy, although large discrepancies in the proportion of positive cells limit any definite conclusion. Differences in P-glycoprotein detection techniques and methodology may account for the divergent results thus emphasizing the necessity for standardized methods of detection. Despite this, encouraging clinical results have been obtained using MDR modulators in combination with conventional chemotherapy to inhibit the activity of the P-glycoprotein pump. The paper summarizes currently available clinical data and provides guidelines for future trials aimed to reverse the MDR phenotype. The potential of idarubicin to overcome the MDR phenotype is also discussed.

Drug Resistance, Multiple↗

PubMed1996

Stromal abnormalities in neoplastic bone marrow diseases.

Bone marrow malignancies are clonal disorders resulting from neoplastic transformation of hematopoietic stem or progenitor cells. Similar to their normal counterparts, transformed blood-forming cells remain dependent on signals from the hematopoiesis-regulating stromal environment for survival and proliferation. There is increasing evidence that the microenvironment may also take a more active part in the disease process. A review of the literature on stromal abnormalities in the leukemias, the myelodysplastic syndromes, and multiple myeloma reveals three principal mechanisms by which stromal derangements can contribute to the evolution of a neoplastic disease. In the simplest case, neoplastic blood-forming cells induce reversible changes in stroma function or composition which result in improved growth conditions for the malignant cells ('malignancy-induced microenvironment'). In the second setting, functionally abnormal end cells derived from the malignant clone become an integral part of the stroma system, selectively stimulating the neoplastic cells and inhibiting normal blood cell formation ('malignant microenvironment'). In the third condition, the emergence of a neoplastic cell population is the consequence of a primary stroma lesion characterized by inability to control regular blood cell formation ('malignancy-inducing microenvironment'). The perception of different stroma-related disease mechanisms may eventually lead to the development of alternative therapeutic approaches.

Acute Disease↗

PubMed1996

Philadelphia chromosome-positive secondary acute myeloid leukemia following high-dose chemotherapy with peripheral blood progenitor cell support for relapsed low-grade non-Hodgkin's lymphoma.

We report the case of a 47-year-old patient who developed acute myelogenous leukemia (AML) 18 months after receiving high-dose chemotherapy with peripheral blood progenitor cell support (PBPCT) for relapsed low-grade follicular non-Hodgkin's lymphoma (NHL). Cytogenetic analysis of the leukemic cells showed the translocation (9;22)(q34;q11). In three mitoses, an additional Philadelphia chromosome (Ph1) was present. In the literature, Philadelphia chromosome-positive secondary AML has been described only once before in a patient with multiple myeloma.

Acute Disease↗

PubMed1996

Pharmacokinetics and pharmacodynamics of the new podophyllotoxin derivative NK 611. A study by the AIO groups PHASE-I and APOH.

NK 611 is a new podophyllotoxin derivative in which a dimethyl amino group replaces a hydroxyl group at the sugar moiety of etoposide. This results in profound physico-chemical differences: NK 611 is much less hydrophobic than etoposide. Preclinical studies have shown that NK 611 is advantageous in terms of bioavailability and of the potency of its anticancer activity. A clinical phase I study was performed in cancer patients within the framework of the AIO. Additionally, its pharmacokinetics and pharmacodynamics were investigated. NK 611 was given to 26 patients at doses ranging from 60 to 140 mg/m2 [maximum tolerated dose (MTD) 120 mg/m2] in a 30-min infusion. Plasma and urine samples were collected from 25 patients and analyzed using a validated high-performance liquid chromatography (HPLC) assay procedure. The concentration versus time curve of total NK 611 in plasma samples was best described by a three-compartment model. The overall median pharmacokinetic values were as follows (ranges are given in parentheses): mean residence time (MRT) 16.5 (5.4-42.3)h, terminal half-life 14.0 (8.2-30.5)h, volume of distribution at steady state (V(ss)) 11.4 (7.9-18.1) l/m2 and plasma clearance (Cl(p)) 15.1 (3.6-36.4) ml min-1 m-2. The total systemic drug exposure, represented by the area under the curve (AUC), varied between 53.4 and 532.0 micrograms ml-1 h. The mean AUC (+/- SD) increased with the dose from 78.7 +/- 3.7 micrograms ml-1 h at 60 mg/m2 up to 202.8 +/- 157.2 micrograms ml-1 h at 120 mg/m2. The mean urinary excretion (UE) fraction of unchanged drug at 48 h after the end of the infusion varied between 3.0% and 25.8% of the total dose delivered. Analysis of ultrafiltrate samples showed a protein binding of approx.. 99%. The percentage reduction in white blood cells (WBC) and neutrophils (ANC) correlated with the dose, AUC, and AUC(free). The best relationship between the percentage of reduction in ANC and a pharmacokinetic parameter (AUC) took a nonlinear Hill-type form. The laboratory parameter for kidney or liver function did not correlate with the AUC. The variation of pharmacokinetic parameters within each dose level was profound. The reason for this pharmacological behavior remains unclear and should be investigated in further studies.

Adult↗

PubMed1996

t(1;19)(q23;p13) in a case of acute monocytic leukemia.

Translocation (1;19)(q23;p13) is considered a specific chromosome aberration in acute lymphoblastic leukemia (ALL). We report a case of M5 acute nonlymphocytic leukemia (ANLL) with t(1;19). In all mitoses studied from peripheral blood (PB) cells, the pathological karyotype 51,XX,t(1;19)(q23;p13),+8, +der(19)t(1;19)(q23;p13), +3mar was detected. No rearrangement of the E2A gene was detected. We believe this case shows that cytogenetically indistinguishable aberrations may be accompanied by quite different molecular events.

Chromosomes, Human, Pair 1↗

PubMed1996

Cytogenetic and clinicobiological features of acute leukemia with stem cell phenotype: study of nine cases.

Morphologic, immunologic, cytogenetic, and clinical features were studied in 9 cases of acute undifferentiated leukemia (AUL). These patients were unclassifiable by FAB criteria, they were CD34+ and did not express myeloid- or lymphoid-associated antigens (CD13, CD33, CD14, CD15, CD61, CD19, CD10, CD22, CD7, CD2, CD5, CD3). Clonal abnormalities were seen in 8 of 9 cases. Del(5q) as the sole anomaly was observed in 3 cases; +13 was the primary change in 3 cases, and isolated trisomy 12 was found in 1 patient. A complex karyotype with trisomy 12q, in association with del 17p and trisomy 21q was detected in 1 case. One patient with 5q- relapsed with refractory anemia with excess of blasts; the presence of dysgranulopoiesis and a few blasts with possible monocytoid morphology in the remaining 2 patients point to a "myeloid nature" of these leukemias. Analysis of cytologic features in our 3 patients with +13, in combination with previously reported cases, suggests the occurrence of immature stem cell involvement with limited differentiation potential, possibly more along the myeloid than the lymphoid lineage. The significance of trisomy 12q in this subset of leukemia remains elusive; some clues of minimal differentiation towards the myeloid lineage in our cases are provided by positivity for the CD117 (c-kit) antigen and by relapse with acute myeloid leukemia without maturation (M1) in one patient. We conclude that, with presently available diagnostic techniques, AUL is a rare subset of leukemia, in which cytogenetic changes are confined to a few chromosomes, with prevalent involvement of 5q and of chromosomes 13 and 12. Chromosome findings may be of value in clinical practice, especially in those cases with "myeloid-oriented" karyotype.

Acute Disease↗

PubMed1996

The pharmacokinetics and toxicity of two application schedules with high-dose VP-16 in patients receiving an allogeneic bone marrow transplantation.

BACKGROUND: Etoposide is one of the few drugs being used in conditioning regimens because of the ease with which its dosage can be escalated by a factor of 6 compared to the normal dose. The best schedule in high-dose chemotherapy is not known. PATIENTS AND METHODS: We evaluated the pharmacokinetics (PK) of high-dose VP-16 during two different schedules (6-hour and 3 x 1-hour infusions) and the toxicity of the two application modes in patients with leukemia who underwent allogeneic bone marrow transplantation. RESULTS: A significant difference (p = 0.008) in the volume of distribution at steady state was observed. The mean Vss was 0.21 L/kg in the 6-hour group and 0.36 in the 3 x 1-hour group. The total drug exposure time with plasma levels > 100 ng/ml is significantly longer in the 'split' group (74 vs. 143 h). Other PK parameters such as plasma clearance and area under the curve were not significantly different. Leukocyte recovery to WBC levels > 0.2 and > 0.5/nl as well as platelet recovery to stable counts > 50/nl was significantly (p = 0.002, 0.009 and 0.04) prolonged in the 'split' group (3.7 vs. 12.3, 8.3 vs. 14.3 and 25 vs. 35 d). The liver toxicity as indicated by bilirubin peak levels was significantly (p = 0.02) more severe in the 'split' group (1.7 vs. 5.4 mg/dl). CONCLUSION: The area under the curve as a measure of total drug exposure cannot be correlated to the observed higher toxicity in the patient group with the 'split' application mode. The drug exposure time as well as the three high peak plasma levels may be more important.

Antineoplastic Agents, Phytogenic↗

PubMed1996

3p21 is a recurrent treatment-related breakpoint in myelodysplastic syndrome and acute myeloid leukemia.

In this study we report 11 cases with chromosome abnormalities involving 3p21. Nine cases were diagnosed as myelodysplastic syndrome (MDS), and two as acute myeloid leukemia (AML). Six of nine MDS cases were secondary to a primary malignant disease. In two patients, AML was secondary to breast cancer and polycythemia vera (PV). Seven of eleven patients had a history of intensive polychemotherapy and/or radiation therapy for 3.5 to 5 years. The mean interval from initial therapy to secondary disease was 13.2 years. Complex chromosomal aberrations were found in all 11 cases. Band 3p21 was involved in translocations in 9 patients and in deletions in 2 patients. A t(3;16)(p21;p13) was found in two cases. Additional abnormalities frequently included a -5, -7, as well as deletions or rearrangements of these 2 chromosomes. Data reported in this paper suggest that 3p21 is a recurrent treatment-related breakpoint in MDS and AML and is likely to contain a gene involved in the pathogenesis of this disease.

Acute Disease↗

PubMed1996

Increase of mobilized CD34-positive peripheral blood progenitor cells in patients with Hodgkin's disease, non-Hodgkin's lymphoma, and cancer of the testis.

G-CSF (filgrastim) can effectively mobilize peripheral blood progenitor cells (PBPC) when administered during steady-state hematopoiesis. In this single center study, we compared the effectiveness of two different doses of G-CSF on the mobilization of peripheral blood stem cells in patients with Hodgkin's disease, non-Hodgkin's lymphoma, and cancer of the testis. A first group including 33 patients received 10 micrograms G-CSF/kg BW per day (group A), whereas a second group comprising 34 patients was treated with 24 (2 x 12) micrograms G-CSF/kg body weight (BW) per day (group B) prior to the leukapheresis. A significant difference (P = 0.015) in the total number of CD34+ cells between group A: 11.32 x 10(7) (range 0.34-110.2) and group B: 48.25 x 10(7) (range 1.33-447.4) has been observed in the first leukapheresis product. Moreover, the total number of CFU-GM increased significantly from 34.79 x 10(4) (range 1.07-300.9) to 147.69 x 10(4) (range 1.03- 1204.0) (P < 0.005), and the number of MNC increased from 1.35 x 10(10) (range 0.41-3.09) group A) to 2.93 x 10(10) (range 0.66-9.7) (group B) (P < 0.001). Comparable results were obtained in the second leukapheresis. Our data indicate, that the application of higher doses of G-CSF can significantly improve the effectiveness of mobilizing PBPC during steady-state conditions, and thereby considerably contribute to a safe and fast engraftment as well as a reduced number of leukapheresis procedures to achieve sufficient number of PBPC.

Adolescent↗

PubMed1996

Randomized study of the combination of hydroxyurea and interferon alpha versus hydroxyurea monotherapy during the chronic phase of chronic myelogenous leukemia (CML Study II). The German CML Study Group.

It is the long-term goal of the German CML Study Group and of the Süddeutsche Hämoblastosegruppe (SHG) to improve survival of patients with chronic myelogenous leukemia (CML). In a first randomized study (CML Study I) monotherapies with hydroxyurea or interferon alpha (IFN-alpha) were compared with a standard busulfan regimen with regard to duration of the chronic phase and survival. The main results of this study were published, 1-3 and a long-term follow up is planned. In a second randomized study the effect of the combination of IFN-alpha and hydroxyurea versus hydroxyurea monotherapy on survival is being investigated. This paper provides a first preliminary report on the study concept, patient recruitment, state of documentation and initial patients' characteristics 9 months after closure of the study.

Adult↗