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D K Hossfeld

Publications and source records attributed to D K Hossfeld.

At least 19 recordsLinked to original sources
PubMed1998

Indirect radiation leukemogenesis in DBA/2 mice: increased expression of B2 repeats in FDC-P1 cells transformed by intracisternal A-particle transposition.

We have previously reported that granulocyte-macrophage colony-stimulating factor (GM-CSF)- and interleukin-3 (IL-3)-dependent FDC-P1 cells undergo leukemic transformation when injected into sublethally irradiated DBA/2 mice. Transformation is related to aberrant activation of growth-regulatory genes by insertion of intracisternal A-particle (IAP) genomes. To elucidate the transformation process further, a subtracted cDNA library was constructed from a factor-independent leukemic FDC-P1 variant and the parental FDC-P1 cells. Screening for clones that were preferentially recognized by a total cDNA probe from the transformed cell line (in comparison to a similar probe from untransformed FDC-P1 cells) led to the isolation of 14 clones, of which six contained cDNA inserts encoding so-called B2 repeats, a class of short interspersed nucleotide elements. The expression of B2 repeats was significantly increased not only in the cell line from which the subtracted library was constructed, but also in all other leukemic FDC-P1 variants analyzed. B2 repeats can act as insertional mutagens and may have a role in the stabilization of certain oncogene and cytokine mRNAs. Interestingly, B2 repeats contain a 14-nucleotide region that is almost completely complementary to an AU-rich sequence in a region of the IAP mRNA encoding the enzyme reverse transcriptase. Although preliminary experiments to demonstrate stabilization of IAP mRNA by hybridization to B2 repeat sequences remained inconclusive, it is intriguing to speculate that B2 repeat sequences may have a causative role in the transformation process.

Animals↗
PubMed1998

Fotemustine and interferon alpha2b in metastatic malignant melanoma.

The efficacy of treatment with fotemustine and interferon (IFN) alpha was evaluated in metastatic melanoma. A group of 50 patients with metastatic malignant melanoma were treated with a combination of IFNalpha2b and the nitrosourea fotemustine. The patients received 10 MU IFN three times weekly for 3 weeks and fotemustine at a dose of 100 mg/m2 on days 8, 15 and 22. After a 5-week rest period, patients with stabilized or responding disease received a maintenance therapy consisting of 10 MU IFN three times a week for 1 week followed by administration of fotemustine (100 mg/m2) on day 8. This cycle was repeated every 4 weeks until progression occurred. If there was complete remission (CR), treatment was stopped after an additional three cycles. Toxicity and clinical response were scored according to WHO criteria. Objective response was seen in 14 patients (28%; 95% confidence interval 15.6%-40.4%) with four CR and ten partial responses (PR). The median duration of CR was 73 weeks, that of PR 26 weeks. Toxicity was acceptable, enabling treatment on an outpatient basis. The combination of fotemustine with IFNalpha is effective and well tolerated, but there is no evident advantage over fotemustine monotherapy in the treatment of metastatic melanoma.

Adult↗
PubMed1998

No evidence of significant activity of the multidrug resistance gene product in primary human breast cancer.

BACKGROUND: The discovery of the multidrug resistance (MDR1) gene product P-glycoprotein (P-gp) has been widely seen as an important milestone in our understanding of the mechanisms underlying the clinical phenomenon of the emergence of resistant cells. MDR1 expression has been shown for numerous solid tumors and for virtually all hematologic malignancies. Nevertheless, results regarding MDR1/P-gp expression in human breast cancer have been controversial and the results of clinical trials on modulation of P-gp activity have not been encouraging. PATIENTS AND METHODS: MDR1/P-gp expression and the function of the P-gp pump were investigated in 61 tumor samples from patients with primary breast cancers by multiparameter analysis using MDR1-RT-PCR, immunohistochemistry with two MAbs (UIC2 and MRK16) and the rhodamine 123 (Rh123) efflux assay. The cellular composition of the tumor cell suspension was analyzed by using specific MAbs against the P-gp expressing lymphocyte subsets CD4, CD8 and CD56, as well as against the HER-2/neu gene product, which was used to identify breast carcinoma cells. RESULTS: UIC2 and MRK16 revealed a staining positivity in 72% and 75% of samples, respectively. A positive MDR1-RT-PCR signal was detected in 62% of the samples. Nevertheless, no correlation between immunohistochemistry and RT-PCR could be established. Furthermore, there was no correlation between HER-2/neu expression and MDR1-RT-PCR or P-gp immunohistochemical assays. A contamination by CD8+ and CD4+ lymphocytes was established in 100% and 84% of tumor cell suspensions, respectively. As assessed by the Rh123 efflux assay CD8+ and the CD4+ lymphocytes exhibited marked P-glycoprotein activity, whereas such activity was not detectable in a single instance for the breast carcinoma cells. In MDR1-RT-PCR positive samples, contamination by CD8 lymphocytes averaged 4.3%, while the contamination of CDS cells in the MDR1 mRNA-negative samples was only 2.4% (P = 0.007). This signal vanished after elimination of the lymphocyte subpopulations by T-cell rosetting. CONCLUSIONS: In primary breast cancer detection of MDR1 gene expression by means of RT-PCR or immunohistochemical assays is not indicative for the MDR phenotype, since there is no evidence of significant activity of the P-gp pump.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

The ESMO programme of certification and training for medical oncology.

ESMO has designed a programme of certification and training in medical oncology. In this paper the background of these programmes is given, and the programme of graduate education is described in greater detail. The standard requirements are a total training period of six years, beginning with a common internship in internal medicine of at least two years, followed by a training programme in oncology for three to four years, which must include at least one year of full-time clinical training in the diagnosis and management of neoplastic diseases, accompanied by one year of experience in an ambulatory care setting.

Certification↗
PubMed1998

Combination of aclarubicin and etoposide for the treatment of advanced acute myeloid leukemia: results of a prospective multicenter phase II trial. German AML Cooperative Group.

In order to develop new strategies for the treatment of relapsed or refractory acute myeloid leukemia, the German AML Cooperative Group performed a prospective multicenter phase II study to evaluate the antileukemic efficacy of aclarubicin 60 mg/m2/day and etoposide 100 mg/m2/day each given for 5 days. Of 37 heavily pretreated evaluable patients (median age 42 years, range 18-81) 15 (40%) achieved a remission after one or two courses of treatment consisting of nine complete (24%) and six partial remissions (16%). Fourteen (38%) cases were non-responders and eight (22%) patients suffered from early deaths. Disease-free survival for patients in remission and overall survival were 3.2 months each. The median duration of critical neutropenia <500/microl was 27 days. The most frequent non-hematologic side-effects were stomatitis (WHO III/IV, 48%), infections (40%), nausea/vomiting (26%) and diarrhea (24%). Cardiac toxicity was mild. This study suggests a substantial antileukemic efficacy and an acceptable toxicity of aclarubicin in combination with etoposide in heavily pretreated patients with advanced acute myeloid leukemia, and warrants further evaluations in a more favorable stage of the disease.

Aclarubicin↗
PubMed1998

The use of dose-intensified chemotherapy in the treatment of metastatic nonseminomatous testicular germ cell tumors. German Testicular Cancer Study Group.

With the use of a cisplatin-based chemotherapy, metastatic testicular cancer has become a model for a highly curable malignant disease. Current data show that 70% to 80% of patients with this disease will achieve long-term survival following cisplatin/etoposide/bleomycin therapy. The role of high-dose chemotherapy with autologous stem cell support is being investigated in metastatic germ cell cancer in attempts to improve outcome for patients whose disease relapses after standard-dose chemotherapy and for those who present initially with advanced metastatic disease. Prognostic categories for patients receiving high-dose salvage chemotherapy have recently been developed: cisplatin-refractory disease, beta-human chorionic gonadotropin values greater than 1,000 U/L, and primary mediastinal germ cell tumors are factors characterizing patients who will derive less benefit from high-dose chemotherapy than those with chemosensitive disease at relapse. While standard-dose salvage chemotherapy achieves only a 20% long-term survival rate, high-dose salvage chemotherapy may yield a cure rate of approximately 40%. A randomized study comparing high-dose therapy with conventional-dose therapy (IT94 coordinated by the European Group for Blood and Marrow Transplantation) in patients with relapsed disease is ongoing to substantiate this observation. The use of dose-intensive therapy as first-line treatment is currently being studied by several institutions. High-dose therapy may be better tolerated when used first line compared with its use in the salvage situation, and may also achieve a rapid initial cell kill before cytostatic drug resistance develops. The German Testicular Cancer Study Group has developed a sequential high-dose combination regimen of cisplatin/etoposide/ifosfamide given with granulocyte colony-stimulating factor and peripheral blood stem cell support for four cycles every 3 weeks. This ongoing study, started in 1990, had accrued 218 patients with advanced testicular germ cell tumors as of June 1997. Of 141 evaluable patients receiving dose levels 1 through 5, 82 (58%) have achieved complete remission with no evidence of disease and 32 (23%) have achieved partial remission with marker normalization. The early death rate was 8%. Overall and event-free survival rates at 2 years are 78% and 73%, respectively, with a projected 5-year overall survival rate of 74%. Despite favorable preliminary results, this approach cannot be considered standard treatment. Currently, high-dose chemotherapy with peripheral blood stem cell transplantation should be administered to patients with testicular cancer only within controlled clinical trials to allow long-term cure rates and treatment-related late side effects to be evaluated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Long-term survival of patients with acute myeloid leukemia: a third follow-up of the Fourth International Workshop on Chromosomes in Leukemia.

BACKGROUND: In 1982, the Fourth International Workshop on Chromosomes in Leukemia reviewed data prospectively collected on 716 patients with acute myeloid leukemia (AML) diagnosed between 1980 and 1982. The present study examined the extended follow-up on these patients. METHODS: The analyses included cytogenetic and clinical data, with a median follow-up of 14.7 years, from 54 patients with treatment-associated AML and 628 with de novo AML. Of these patients, 291 received induction therapy that would be considered standard by today's criteria; no patient received high-dose cytarabine (HiDAC) intensification. RESULTS: Among the patients with treatment-associated AML, the only long-term survivor in retrospect appears to have had de novo AML. Among the patients with de novo AML, achievement of complete remission and survival varied significantly based on cytogenetic classification among all 628 patients as well as among those who did and did not receive standard induction therapy. The remission rate and survival were significantly better with standard induction therapy for patients with t(15;17) and normal cytogenetics. Multivariate analyses showed that karyotype was an independent predictor of survival for all patients and those receiving standard induction therapy. Only 8.9% of patients were alive 5 years following diagnosis, but 5 years of continuous remission was synonymous with cure. Even among 5-year survivors who had suffered a previous relapse, 41% appeared to be cured. Survival among patients in continuous remission for > or = 10 years varied significantly by cytogenetic classification. In the absence of HiDAC intensification, no complete responders with t(8;21) and only 7% with normal cytogenetics survived continuously 10 years disease free. CONCLUSIONS: Cure of AML following specific therapies must be evaluated in the context of cytogenetics. A meta-analysis incorporating cytogenetic data is indicated for patients with > or = 10 years of follow-up.

Acute Disease↗
PubMed1997

[Transplantation of hematopoietic stem cells. II: Indications for transplantation of hematopoietic stem cells after myeloablative therapy].

The destruction of hematopoiesis and lymphopoiesis by total body irradiation or high dose chemotherapy for the treatment of malignancy can be reversed by the transplantation of allogeneic or autologous hematopoietic stem cells. In primary disorders of bone marrow or immune system, allogeneic stem cells replace deficient cells. Acute leukemias can be cured, with in 50 to 80% disease free survival after 5 to 8 years. The allogeneic graft versus leukemia effect by immunoreactive cells reduces the relapse rate in myeloid and lymphoid malignancies. 40 to 70% of patients with chronic myeloid leukemia remain disease free after more than 5 years. Patients with malignant lymphoma have a 40 to 70% chance of cure with autologous transplantation, which is not increased by allogeneic cells, because of a higher incidence of severe complications. An increasing number of patients without option for cure is treated with the aim of prolonging remission or retarding disease progression, such as in chronic myeloid leukemia, multiple myeloma and certain solid tumors. New studies suggest in breast cancer with axillary lymph node metastases, that adjuvant high dose chemotherapy with autologous stem cell support will significantly improve disease free survival from 30 to over 60% after 3 to 5 years. In congenital metabolic and storage diseases deficient enzymes are substituted by the allogeneic cells. Clinical trials explore the use of stem cell transplantation after myeloablative therapy in autoimmune disorders as well as in gene therapy with transfected hematopoietic stem cells.

Combined Modality Therapy↗
PubMed1997

[Transplantation of hematopoietic stem cells. I: Definitions, principle indications, complications].

The transplantation of hematopoietic and lymphopoetic stem and progenitor cells has become a standard procedure for the treatment of many malignant diseases. Autologous stem cells are derived from the patient himself, allogeneic cells from an HLA-identical or HLA-compatible family or unrelated donor. Hematopoietic stem cells can be obtained from bone marrow, blood and fetal cord blood. After 3 to 5 days treatment, the granulocyte-colony stimulating factor (G-CSF) mobilizes stem- and progenitor cells from the marrow into the blood. This method is now standard in autologous transplantation and is increasingly preferred in allogeneic transplantation. The time to hematopoietic recovery is shorter with blood stem cells than with bone marrow cells. With myeloablative high dose therapy followed by stem cell transplantation, long term disease free survival is possible in many cases and great proportions of patients can be cured (see part II). Improvements of supportive care have reduced toxicity of treatment substantially, however severe complications still occur at oropharynx, gastrointestinal tract, liver, lung, skin, kidney, urinary tract and nervous system. After allogeneic transplantation immunocompetent donor cells can react with the recipients tissue. In HLA-identical donor and recipients differences in the minor histocompatibility antigens account for this graft-versus-host-reaction (GvH), which is mainly mediated by transplanted T-cells. The GvH-reaction can affect skin, liver, gut and other organs and cause clinically relevant GvH-disease (GvHD). The GvHD is more severe in HLA-mismatched or unrelated transplantations. Immunodeficiency and organ dysfunction due to GvHD may predispose infections and impair the outcome of transplantation. Unrelated cord blood stem cells may have a minor risk of inducing acute GvHD, as stem and T-cells are immature. After allogeneic stem cell transplantation, the relapse rate of leukemia or lymphoma is significantly reduced by immunoreactive cells:graft-versus-tumor (GvT) or graft-versus-leukemia effect (GvL).

Graft vs Host Disease↗
PubMed1997

Chromosomal abnormality inv(3)(q21q26) associated with multilineage hematopoietic progenitor cells in hematopoietic malignancies.

We have identified ten patients with acute myeloid leukemia (AML) and one patient with chronic myeloid leukemia with megakaryocytic crisis who displayed an inv(3)(q21q26). Seven of them had an additional monosomy 7. Most of them had a myelodysplastic syndrome (MDS) preceding AML, normal or increased platelet counts, increased number of megakaryocyte, megakaryocytic dysplasia, and erythroid dysplasia. There was a high incidence of resistance to induction chemotherapy, short remission time, and early relapse. Seven patients were immunologically analyzed. The main immunophenotypes were as follow: CD7+, CD34+, HLA-DR+, CD38+, CD13+, CD33+, CDw65+, CD2-, CD3-, CD4-, CD8-, CD19+, CD20-, CD11b-. Our results suggest that the leukemia with inv(3)(q21q26) represents a new cytogenetic-clinicopathologic subtype, characterized by 1) abnormal megakaryopoiesis and multiple hematopoietic lineage involvement; 2) an antecedent MDS; 3) poor response to conventional chemotherapy; and 4) expression of CD7, CD34, CD38, HLA-DR, CD13, and CD33 antigens. We propose that the malignant transformation in patients with inv(3)(q21q26) occurs in an early stem cell prior to lineage commitment.

Acute Disease↗
PubMed1997

Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia.

Vascular endothelial growth factor (VEGF) is a multifunctional cytokine involved in angiogenesis, inflammation, and wound healing. It is secreted by a variety of tumor cell lines, including hematopoietic lines. Therefore, we investigated expression of VEGF and its receptors on fresh leukemic blasts. VEGF-specific transcripts were detected by polymerase chain reaction (PCR) in 20 of 28 patients with de novo acute myeloid leukemia (AML) and in 3 of 5 patients with secondary AML. Using immunocytochemistry, we found VEGF protein in 2 leukemic cell lines and in 8 AML patients, in concordance with PCR results. Supernatants of fresh leukemic cells from 24 AML patients contained significantly more VEGF than supernatants from bone marrow cells of 9 normal donors or of CD34-enriched cells from 3 normal volunteer donors as determined by an enzyme-linked immunosorbent assay. VEGF possesses two high-affinity receptors, KDR and FLT1. Using a sensitive nested PCR assay, we detected expression of FLT1 in 10 of 20 patients with de novo AML and 3 of 5 patients with secondary AML. KDR was expressed in 4 of 22 patients with de novo AML and 1 of 4 with secondary AML. To study possible paracrine growth stimulation of AML blasts, endothelial cells from human umbilical cords were incubated with increasing concentrations of VEGF. A dose-dependent increase of granulocyte-macrophage colony-stimulating factor secretion from endothelial cells was identified.

Acute Disease↗
PubMed1997

Reinterpretation of G-banded complex karyotypes by fluorescence in situ hybridization with chromosome-specific DNA painting probes and alpha-satellite centromere-specific DNA probes in malignant hematological disorders.

In this study, we have performed fluorescence in situ hybridization (FISH) with chromosome-specific DNA painting probes 1, 2, 3, 4, 6, 8, and 12 and centromere-specific DNA probes 7,10,12,17,18, and X after G-banding on the same metaphase spreads from four patients with malignant hematological disorders to more precisely interpret their complex karyotypes. The findings demonstrated that the application of combined G-banding and FISH can more accurately explain complex karyotypes of hematological malignancies. FISH can detect not only the origin of marker chromosomes, but also the complex rearrangements that cannot be identified by routine banding techniques. This approach is very important to complement the cytogenetic analysis of malignant disorders and to evaluate the role of chromosome change in the development, progression, and prognosis of tumors.

Chromosome Banding↗
PubMed1997

Fatal pulmonary hemorrhage in patients with acute leukemia and fulminant pneumonia caused by Stenotrophomonas maltophilia.

Pulmonary hemorrhage is a rare cause of death in patients with acute leukemia. Within a 3-month period we observed three such cases, all of which were associated with the gram-negative opportunistic pathogen Stenotrophomonas maltophilia. Since fatal lung bleeding had previously not been observed in conjunction with this organism, we collected the data from all patients with documented S. maltophilia infections or colonizations of the past year and analyzed the risk factors for a lethal outcome. A total of eight patients were identified. In the three patients with fatal hemorrhage, the interval between first complaints (chest pain, cough, fever) and death from lung bleeding was 36-72 h. A fourth patient with acute leukemia died of nonhemorrhagic respiratory failure 9 days after developing S. maltophilia-associated pneumonia. All four patients had received intensive chemotherapy and were severely neutropenic and thrombocytopenic. Such a combination of predisposing factors was not observed in the four patients with nonfatal infections or colonizations. Pulsed-field gel electrophoresis demonstrated that the infections were unrelated. S. maltophilia was also isolated from a faucet in a patient's room, but the strain isolated was genetically different from the strain causing the patient's pneumonia. Our data suggest that severe bone marrow aplasia and a recent history of intensive chemotherapy are predisposing factors for the development of fulminant hemorrhagic S. maltophilia pneumonia. Since some of the infections and colonizations developed despite prophylactic administration of antibacterial agents with documented in vitro activity against the pathogen and none was controlled by such agents, it is clear an efficient treatment strategy needs to be developed.

Acute Disease↗
PubMed1997

Cytogenetic studies in malignant fibrous histiocytoma.

Among soft tissue sarcomas, malignant fibrous histiocytoma is considered to be the most commonly encountered tumor-type of late adult life. Cytogenetic data are, however, sparse and contradictory, without any specific anomalies. We are describing the results of cytogenetic studies in 20 malignant fibrous histiocytomas of various subtypes and gradings. Although we saw two single and therefore possibly primary rearrangements, t(13;14) and t(5;7), most tumors had complex rearrangements without sharing any characteristic aberrations. In our opinion, the heterogeneity of these findings supports the concept that malignant fibrous histiocytoma is not a distinctive entity but merely a name for a group of as yet poorly defined sarcomas.

Aged↗
PubMed1997

Genetic abnormalities in chronic lymphocytic leukemia and their clinical and prognostic implications.

Clonal chromosome abnormalities can be detected in approximately 50% of patients with chronic lymphocytic leukemia (CLL). The most common changes are trisomy 12, followed by structural abnormalities of 13q, 11q, 6q, and 14q. By fluorescence in situ hybridization (FISH), these aberrations can be demonstrated even in cases with insufficient mitotic yield or a normal karyotype. The biologic consequences of trisomy 12 are unknown, but a gene dosage effect is suspected and studies on partial trisomy 12 indicate that the region 12q13 to 12q22 might be of particular pathogenetic importance. Trisomy 12 is strongly associated with atypical lymphocyte morphology and seems to be a secondary event in leukemogenesis, as shown by combined immunophenotyping and interphase FISH. Structural abnormalities of 13q frequently involve hetero- and homozygous deletions of a region in 13q14, distal to the retinoblastoma gene, which may be the site of a tumor suppressor gene. In contrast to a normal karyotype or structural changes of 13q, complex karyotypic abnormalities, high percentage of abnormal metaphases, trisomy 12 and structural changes involving the P53 tumor suppressor gene on 17p13 are adverse prognostic indicators. Cytogenetic and molecular findings provide important diagnostic, clinical, and prognostic information which can contribute to treatment decisions and follow-up of CLL patients.

Chromosome Deletion↗
PubMed1997

Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia.

FLT4 represents a recently cloned member of class III receptor tyrosine kinases which include receptors for the angiogenic growth factor VEGF, namely FLT1 and KDR. The ligand of FLT4 has been identified as VEGF-C which shares sequence homology with VEGF and P1GF. In the adult FLT4 shows a restricted expression pattern that is limited to lymphatic endothelia and endothelia of some high endothelial venules (HEV). FLT4 has also been detected in some tumor cell lines including the hematopoietic line HEL. We therefore investigated expression of FLT4 and its ligand VEGF-C in fresh samples from patients with AML. Using a sensitive PCR method we detected FLT4 m-RNA in 15 of 41 patients with de novo AML at diagnosis or relapse and in three of 12 patients with secondary AML. FLT4 expression was confirmed by immunocytochemistry in a subgroup of the studied patient population. FLT4 was also found in leukemic cell line U937, but not TF-1 and KG1a. VEGF-C expression was found in leukemic samples of four of seven FLT4-positive and four of six FLT4-negative patients. U937 cells also produced VEGF-C m-RNA. Interestingly, FLT4 expression was not detected in bone marrow samples of 15 normal volunteer donors or in CD34-positive cells from three additional donors. Possible autocrine and paracrine growth stimulation of leukemic blasts by VEGF-C is currently being investigated in our laboratory.

Acute Disease↗