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Biomedical subjects

D K Hossfeld

Publications and source records attributed to D K Hossfeld.

At least 55 records · Page 3Linked to original sources
PubMed2000

Derivation of a new hematopoietic cell line with endothelial features from a patient with transformed myeloproliferative syndrome: a case report.

BACKGROUND: During embryonal development primitive hematopoiesis can be observed first in the yolk sac, in which both hematopoietic and endothelial cells are derived from a common precursor, the hemangioblast. Whether cells with this dual differentiation potential persist during postnatal life is unknown. METHODS: A cell line was derived from a patient with secondary acute leukemia. Because of its ability to grow in soft agar and in SCID mice, this cell line was analyzed for expression of differentiation antigens by fluorescence-activated cell sorter analysis, immunocytochemistry, fluorescent in situ hybridization (FISH) analysis with simultaneous cell surface staining, and polymerase chain reaction (PCR). RESULTS: A new cell line was established from a patient with essential thrombocytosis that transformed into acute leukemia. The patient's initial clinical presentation included skin and lymph node infiltrations that were taken for an angiosarcoma due to positivity for CD34, CD31, and von Willebrand factor on immunohistology. In addition to hematopoietic markers, leukemic cells expressed endothelial antigens such as CD62E, CD105, and bound Ulex europäeus lectin-1. Immunocytochemistry revealed positive staining for vascular endothelial growth factor receptor type 2 (KDR), Tie-2/Tek, the angiopoietin receptor, and vascular endothelial cadherin. These results were confirmed by PCR analysis. Simultaneous staining for CD62E and FISH analysis showed that cells with endothelial characteristics belonged to the leukemia. FISH analysis of histologic sections of the lymph node infiltration confirmed this manifestation as part of the leukemic process. The derived cell line, UKE-1, forms colonies in soft agar and is tumorigenic in SCID mice. CONCLUSIONS: This new cell line, UKE-1, appears to combine hematopoietic and endothelial features, indicating the close ontogenic relation of both lineages.

Adult↗
PubMed2000

Genetic abnormalities in marginal zone B-cell lymphoma.

Marginal zone B-cell lymphoma (MZBCL) including extranodal mucosa-associated lymphoid tissue (MALT)-type lymphoma, nodal, and splenic MZBCL represents a distinct subtype of B-non-Hodgkin's lymphoma. Recently, important progress in the elucidation of the genetic mechanisms underlying the pathogenesis and disease progression of these lymphomas has been made. The API2 gene, an inhibitor of apoptosis, and the novel MLT gene have been found to be altered by the t(11;18)(q21;21), which represents the most frequent structural chromosomal abnormality in extranodal low-grade MALT lymphoma. Another gene involved in the regulation of apoptosis, the BCL10 gene, has been cloned from a MALT lymphoma cytogenetically characterized by the t(1;14)(p22;q32). Along the same lines, inactivating mutations of the proapoptotic FAS gene have been detected in a relatively high proportion of extranodal MZBCLs. Considering these data and the fact that at least some MALT lymphomas show low levels of apoptosis and seem to escape from FAS-mediated apoptosis one may speculate that abrogation of apoptosis constitutes a central pathogenetic mechanism in the development of these lymphomas. The pathogenetic role of trisomy 3, the most frequent numerical chromosomal change of MZBCL, is not known. The minimal overrepresented region has been delineated to 3q21-23 and 3q25-29 using comparative genomic hybridization. The BCL6 proto-oncogene, located on 3q27, which is rearranged in some MZBCL and a high proportion of large cell B-cell lymphomas with extranodal localization, represents one of the candidate genes residing in these critical regions.

Chromosome Aberrations↗
PubMed2000

ASHAP--an effective salvage therapy for recurrent and refractory malignant lymphomas.

BACKGROUND: This study was performed to examine the efficacy and toxicity of the combination of adriamycin (ADR), methylprednisolone (solumedrol), cytarabine (Ara-C), and cisplatin (CDDP) in patients with recurrent and refractory malignant lymphomas. PATIENTS AND METHODS: Sixty-five patients with Hodgkin's disease (HD) (n=14) or non-Hodgkin's lymphomas (NHL) (n = 51) were enrolled in the study. The ASHAP therapy consisted of ADR (40 mg/m2 by continuous infusion (CI) over 96 h), methylprednisolone (500 mg i.v., days 1-5), Ara-C (2 g/m2 as a 2-h infusion on day 5), and CDDP (100 mg/m2 by CI over 96 h). RESULTS: Twenty-five patients (38%) achieved complete remission (CR) and 20 (31%) were taken into partial remission (PR) for an overall response rate of 69%. Thirty-two patients with CR or PR following ASHAP underwent high-dose therapy (HDT) with subsequent hematopoietic stem cell transplantation. After a median follow-up of 52 months, 13 patients are in continuous CR (CCR), the 3-year event-free survival (EFS) was 30% for responders and 21% for all patients. The median overall survival (OS) was 12 months (range 0-70 months), and the OS rate after 3 years was 32%. Unfavorable prognostic factors for EFS and OS by univariate analysis were an elevated value of the serum lactate dehydrogenase and refractory lymphoma. The most frequently observed side effects following ASHAP were leukocytopenia and thrombocytopenia of World Health Organization (WHO) grades III/IV in approximately 80% of all courses. Non-hematological toxicities such as gastrointestinal side effects, infections, mucositis, renal and neurotoxicity occurred more rarely and reached WHO grades III/IV only occasionally. No treatment-related mortality with ASHAP was observed. CONCLUSIONS: ASHAP is an effective and moderately toxic salvage therapy for patients with recurrent or refractory HD and NHL. The results in patients responding to ASHAP and afterwards undergoing HDT with stem cell support are comparable with other established protocols and indicate an improvement in survival if HDT is carried out as intensification.

Adolescent↗
PubMed2000

Polysomy 13 with concomitant deletion of 13q13-14 involving the retinoblastoma gene and the D13S25 locus in a case of acute myeloid leukemia.

We herein describe a case of acute myeloblastic leukemia (AML), FAB subtype M4, with an unfavorable clinical course and a complex karyotype, including 4-9 copies of chromosome 13. Polysomy 13 was a result of clonal evolution. Fluorescence in situ hybridization (FISH) revealed a cytogenetically unrecognizable deletion within 13q13-14 that included the retinoblastoma gene (RB) and the D13S25 locus in all but one copy of chromosome 13. The only chromosome 13 that did not show a deletion affecting the q13-14 region was translocated to chromosome 7, resulting in a dic(7;13)(q21;p11). In this case, the coexistence of polysomy and a partial deletion within the same chromosome point toward a possible formation of a fusion product with oncogenic potential and its consecutive amplification as a critical alteration in this case.

Aged↗
PubMed2000

UFT/leucovorin plus weekly irinotecan in advanced or metastatic colorectal cancer.

This is an open-label, nonrandomized phase I trial to determine the safety and maximum tolerated dose of irinotecan with a fixed dose of UFT plus oral leucovorin in patients with advanced or metastatic colorectal cancer. A secondary objective of the study is to determine the response rate in this patient population. Adult patients with histologically confirmed advanced or metastatic colorectal carcinoma and no prior chemotherapy for advanced or metastatic disease, or those patients who have received adjuvant chemotherapy (> 6 months prior to the study entry) will be eligible to participate. All patients must have measurable or evaluable lesions. Symptoms will be evaluated at baseline and every 6 weeks thereafter. Computed tomography scans will be performed at baseline and every three cycles of treatment to assess tumor response. A total of six cycles of treatment may be given, depending on patient tolerance. Patients will be followed for a maximum of 12 months for time to progression, following the last dose of the study drug. Tumor response will be defined using standard World Health Organization criteria.

Administration, Oral↗
PubMed1999

Interferon-alpha before allogeneic bone marrow transplantation in chronic myelogenous leukemia does not affect outcome adversely, provided it is discontinued at least 90 days before the procedure.

The influence of interferon-alpha (IFN) pretreatment on the outcome after allogeneic bone marrow transplantation (BMT) in chronic myelogenous leukemia (CML) is controversial. One goal of the German randomized CML Studies I and II, which compare IFN +/- chemotherapy versus chemotherapy alone, was the analysis of whether treatment with IFN as compared to chemotherapy had an influence on the outcome after BMT. One hundred ninety-seven (23%) of 856 Ph/bcr-abl-positive CML patients were transplanted. One hundred fifty-two patients transplanted in first chronic phase were analyzed: 86 had received IFN, 46 hydroxyurea, and 20 busulfan. Forty-eight patients (32%) had received transplants from unrelated donors. Median observation time after BMT was 4.7 (0.7 to 13.5) years. IFN and chemotherapy cohorts were compared with regard to transplantation risks, duration of treatments, interval from discontinuation of pretransplant treatment to BMT, conditioning therapy, graft-versus-host disease prophylaxis and risk profiles at diagnosis and transplantation, and IFN cohorts also with regard to performance and resistance to IFN. Outcome of patients receiving related or unrelated transplants pretreated with IFN, hydroxyurea, or busulfan was not significantly different. Five-year survival after transplantation was 58% for all patients (57% for IFN, 60% for hydroxyurea and busulfan patients). The outcome within the IFN group was not different by duration of prior IFN therapy more or less than 5 months, 1 year, or 2 years. In contrast, a different impact was observed in IFN-pretreated patients depending on the time of discontinuation of IFN before transplantation. Five-year survival was 46% for the 50 patients who received IFN within the last 90 days before BMT and 71% for the 36 patients who did not (P =.0057). Total IFN dosage had no impact on survival after BMT. We conclude that outcome after BMT is not compromised by pretreatment with IFN if it is discontinued at least 3 months before transplantation. Clear candidates for early transplantation should not be pretreated with IFN.

Adolescent↗
PubMed1999

Novel Philadelphia variant t(Y;9;22)(q12;q34;q11) in a case of chronic myeloid leukemia.

A novel Philadelphia (Ph) variant translocation, t(Y;9;22)(q12;q34;q11), was detected in a 63-year-old man with a newly diagnosed chronic myeloid leukemia (CML). Reverse transcription polymerase chain reaction (RT-PCR) analysis revealed a b3a2 fusion transcript. Fluorescence in situ hybridization (FISH) utilizing library probes, subtelomeric cosmid probes, and probes hybridizing to the ABL and BCR genes showed a reciprocal three-way translocation involving Yq12, 9q34, and 22q11, and a BCR-ABL fusion signal on der(22). The subtelomeric Yq probe hybridizing centromerically to the IL9 receptor gene and covering the centromeric portion of the SYBL1 gene was found to be translocated to der(9).

Adult↗
PubMed1999

The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas.

Marginal zone cell lymphomas of the mucosa-associated lymphoid tissue (MALT) are the most common subtype of lymphoma arising at extranodal sites. The t(11;18)(q21;q21) appears to be the key genetic lesion and is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphomas. We show that the API2 gene, encoding an inhibitor of apoptosis also known as c-IAP2, HIAP1, and MIHC, and a novel gene on 18q21 characterized by several Ig-like C2-type domains, named MLT, are recurrently rearranged in the t(11;18). In both MALT lymphomas analyzed, the breakpoint in API2 occurred in the intron separating the exons coding respectively for the baculovirus IAP repeat domains and the caspase recruitment domain. The breakpoints within MLT differed but the open reading frame was conserved in both cases. In one case, the translocation was accompanied by a cryptic deletion involving the 3' part of API2. As a result, the reciprocal transcript was not present, strongly suggesting that the API2-MLT fusion is involved in the oncogenesis of MALT lymphoma.

Amino Acid Sequence↗
PubMed1999

Origin of stroma cells in long-term bone marrow cultures from patients with acute myeloid leukemia.

Bone marrow stroma cells from patients with acute myeloid leukemia (AML) display a variety of functional abnormalities. In order to determine whether this is related to an imbalance in the proportion of different stroma cell types or to integration of leukemic progeny into the regulatory cell network, stroma layers were established in mycophenolic acid-treated long-term marrow cultures from 16 patients with AML and 42 controls and analyzed by means of simultaneous membrane immunofluorescence and interphase cytogenetics. Macrophages were identified by CD14 expression, fibroblasts by staining with the AS02 antibody, and malignant cells by leukemia-specific numerical chromosome aberrations, including monosomy 7 and trisomy 8. Compared with normal controls, there was a slight decrease in the proportion of stroma fibroblasts (52+/-27% versus 77+/-5%) in 10-week-old cultures from patients with AML. Two of five AML patients with trisomy 8 and both patients with monosomy 7 had evidence of leukemic stroma cells. Most malignant cells were CD14+ macrophages (3.8-98.1% of all CD14+ cells), but some were AS02+ (2.8-5.2%). AML stroma layers showed a reduced capacity to support the growth of normal hematopoietic cells in standard two-stage long-term cultures, but this was unrelated to the presence or absence of leukemic stroma elements. In conclusion, AML populations vary with respect to their ability to produce a malignant microenvironment. Functional defects in the hematopoietic microenvironment, however, are not limited to AML patients with cytogenetically abnormal stroma cells, but extend to cases without evidence of malignant stroma cells.

Acute Disease↗
PubMed1999

Melanoma-associated expression of vascular endothelial growth factor and its receptors FLT-1 and KDR.

The expression patterns of vascular endothelial growth factor (VEGF) and its two receptors, flt-1 and KDR, were assessed in normal human melanocytes, transformed melanocytes expressing the simian virus 40 Tgene (SV40T), and melanoma cells derived from primary and metastatic lesions. Constitutive expression of VEGF, flt-1, and KDR mRNA and proteins was observed in the majority of primary and metastatic melanoma cell lines, and in SV40T-transformed melanocytes. VEGF expression in melanoma cell lines was further enhanced by exogenous growth factors including insulin and fetal calf serum. By contrast, neonatal melanocytes did not express VEGF or VEGF receptors and VEGF expression could not be induced by exogenous growth factors. Exogenous VEGF had no significant effects on melanoma cell proliferation or on production of a transcriptional target for VEGF, urokinase-type plasminogen activator. Down-regulation of VEGF expression in the metastatic melanoma cell line WM164 through transfection of a VEGF antisense construct similarly did not affect proliferation of the transfected cells in the presence or absence of exogenous VEGF. In summary, coexpression of VEGF and its receptors is a tumor-associated phenomenon in melanoma development. However VEGF production does not support autocrine proliferation of the melanoma cell lines tested.

Antibody Specificity↗
PubMed1999

Unusual clinical course and acquisition of del(11)(q23) in second lymphatic blastic phase of a Ph-positive chronic myeloid leukemia.

We describe unusual clinical and cytogenetic findings of a 29-year-old female with a Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML), who showed a mosaic of apparently normal cells and cells bearing the classical t(9;22)(q34;q11) during the first lymphatic blastic phase (BP). The second lymphatic BP developed 10 years later. In addition to the t(9;22), which was detected in all metaphases, a del(11)(q23) was identified as a subclonal change in 4 of 25 metaphases. Fluorescence in situ hybridization (FISH) analysis using a chromosome 11-specific library probe and a probe covering the breakpoint cluster region of the MLL gene revealed hybridization signals of both probes on the normal and the deleted chromosome 11, indicating that the breakpoint on chromosome 11 occurred telomerically to the breakpoint cluster region of the MLL gene. Chemotherapeutic treatment resulted in reconstitution of the chronic phase with persistence of the Ph translocation as the sole chromosomal abnormality.

Adult↗
PubMed1999

Treatment of mantle-cell lymphomas with intermittent two-hour infusion of cladribine as first-line therapy or in first relapse.

PURPOSE: Cladribine (2-chlorodeoxyadenosine, 2-CdA) has been reported to be effective in the treatment of low-grade lymphomas. The objective of this multicenter study was to evaluate the activity of cladribine in mantle-cell lymphomas as first-line therapy or in first relapse using an intermittent two-hour infusion of cladribine. PATIENTS AND METHODS: A total of 47 courses, or an average of four courses per patient, were administered to 12 patients (seven untreated, five relapsed) with 5 mg/m2 cladribine given as an intermittent two-hour infusion over five consecutive days for a maximum of six cycles every four weeks. RESULTS: Cladribine showed activity in patients with mantle-cell lymphomas, achieving a response rate of 58% (95% confidence interval (95% CI): 28%-85%). Myelosuppression was the major toxicity with 17% of grade 3 and 4 neutropenia. Thrombocytopenia was rare with only 2% of grade 3 and 4. CONCLUSION: These results demonstrate single-agent activity of cladribine in mantle-cell lymphomas using the intermittent two-hour infusion dosage regimen. To further improve treatment results, cladribine should be combined with other agents active in mantle-cell lymphomas.

Aged↗
PubMed1999

Expression of the adhesion molecules CD49d and CD49e on G-CSF-mobilized CD34+ cells of patients with solid tumors or non-Hodgkin's and Hodgkin's lymphoma and of healthy donors is inversely correlated with the amount of mobilized CD34+ cells.

The yield of CD34+ PBPC and colony-forming units-granulocyte-macrophage (CFU-GM) in leukapheresis products and the expression of the adhesion molecules CD11a, CD31, CD49d, CD49e, CD54, CD58, CD62L, c-kit (CD117), Thy-1 (CD90), CD33, CD38, and HLA-DR on CD34+ PBPC were analyzed in patients with cancer of the testis (n = 10), breast cancer (n = 10), Hodgkin's disease (n = 20), high-grade (n = 20) and low-grade (n = 20) non-Hodgkin's lymphoma, and healthy donors (n = 20) undergoing G-CSF (filgrastim)-stimulated PBPC mobilization. For each disease entity, G-CSF was administered in two different doses, 10 microg G-CSF/kg body weight (BW)/day s.c. vs. 24 microg G-CSF/kg BW s.c./day in steady-state condition. Data were compared for each dose group separately. Patients with cancer of the testis and breast cancer mobilized significantly more CD34+ cells than patients with high-grade and low-grade non-Hodgkin's lymphoma and Hodgkin's disease (p<0.05). Correspondingly, expression of CD49d on CD34+ PBPC was significantly lower in the same patients with cancer of the testis compared with high-grade and low-grade non-Hodgkin's lymphoma and Hodgkins' disease and in patients with breast cancer compared with high-grade and low-grade non-Hodgkin's lymphoma, Hodgkins's disease, and healthy donors. Similar results were obtained for CD49e. These data suggest that the expression of the adhesion molecules CD49d and CD49e on G-CSF-mobilized CD34+ cells of patients with solid tumors, non-Hodgkin's lymphoma, Hodgkin's disease, and healthy donors is inversely correlated with the amount of mobilized CD34+ cells.

Adolescent↗
PubMed1999

Intermittent 2-hour-infusion of cladribine as first-line therapy or in first relapse of progressive advanced low-grade and mantle cell lymphomas.

Aim of this multicenter-study was to evaluate rate and duration of remissions and to examine toxicity of cladribine in low-grade lymphomas as first-line therapy or in first relapse using intermittent 2-hour-infusion of cladribine. A total of 294 courses, median of 5 courses per patient, were administered to 66 evaluable patients (53 previously untreated, 13 relapsed) with 5 mg/m2 cladribine given as intermittent 2-hour-infusion over 5 consecutive days for a maximum of 6 cycles every four weeks. Entities: 26 follicle center, 20 lymphoplasmacytoid, 12 mantle cell, 6 T-cell, 2 marginal zone lymphomas. Fifty of 66 patients responded to cladribine corresponding to an overall response rate of 76% (95% confidence interval (95% CI): 64%-85%) with 38% CR (95% CI: 26%-51%) and a median time of remission duration of 23 months (range 6-45+). The overall survival rate at 48 months was 72%. For 49 previously untreated patients with B-cell lymphomas the overall response rate was 86% (95% CI: 73%-94%) with a high CR rate of 43% (95% CI: 29%-58%). Response rate for the group of 23 previously untreated patients with follicle center lymphomas was high with 96% overall response (95% CI: 78%-100%) and 57% CR rate (95% CI: 34%-77%). Cladribine also showed activity in patients with mantle cell lymphomas achieving a response rate of 58% (95% CI: 28%-85%). Myelosuppression was the major toxicity with 17% neutropenia grade 3 and 4. Thrombocytopenia was rare with only 2% grade 3 and 4. A prolonged CD4-lymphocytopenia was observed in all patients. Life threatening complications were not observed. These results confirm the major single-agent activity of cladribine in a large cohort of patients with untreated low-grade lymphomas using the intermittent 2-hour-infusion dosage-regimen. To improve treatment results furthermore, cladribine should be combined with other agents active in low-grade lymphomas.

Adult↗
PubMed1998

Intracisternal A-particle (IAP)-mediated leukemogenesis: levels and stability of IAP mRNA in FDC-P1 cells exposed to the conditions of an irradiated environment.

Following injection into sublethally irradiated DBA/2 or BALB/c mice, factor-dependent FDC-P1 cells undergo leukemic transformation due to oncogene activation by insertion of intracisternal A-particle (IAP) genetic elements. Similar events are observed in vitro during coculture of FDC-P1 cells with irradiated bone marrow stroma cells. To elucidate the mechanism of IAP transposition, we studied the level of IAP expression under the growth conditions preceding cell transformation. In vitro experiments showed that the type of growth factor, FDC-P1 cell density, costimulation with steroid hormones or abrupt growth factor withdrawal had no effect on IAP mRNA levels (major transcripts of 7.4, 4.0 and 1.9 kb). By contrast, stimulation with suboptimal concentrations of GM-CSF or IL-3 induced a mean 2. 5-fold increase in the intensity of the 7.4 kb band, and induction of macrophage differentiation with retinoic acid resulted in an increased stability of the 4.0 kb band. Although suboptimal growth stimulation and incipient macrophage differentiation have previously been shown to occur in the process of FDC-P1 cell transformation, an increase in IAP expression could not convincingly be demonstrated in FDC-P1 cell populations isolated from irradiated BALB/c mice or stroma cell cocultures. Further experiments are required to define the role of suboptimal growth stimulation and/or macrophage differentiation in this transformation model.

Animals↗
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↗