High dose mitoxantrone with thiotepa, cyclophosphamide and autologous stem cell rescue for high risk stage II and stage III breast cancer. German GABG-4/EH-93-Study.
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Adult↗
Biomedical subjects
D K Hossfeld
Publications and source records attributed to D K Hossfeld.
[Treatment of thrombotic thrombocytopenic purpura (Moschcowitz's disease) with vincristine].
A 64-year old female had been diagnosed as having thrombotic thrombocytopenic purpura (TTP; Moschcowitz syndrome) in 1984. The initial episode and one recurrence 5 years later were successfully treated with fresh plasma transfusions without plasmapheresis. Two days before the present admission, she noticed pain in the knee and haematomas in both legs. Marked thrombocytopenia (9000/microliters), haemolytic anaemia (lactate dehydrogenase 1800 U/l, haemoglobin 7.8 g/dl, haptoglobin 5 mg/dl) and skin haemorrhages suggested a second recurrence of TTP. The blood film showed a massive increase in fragmented cells (more than 30 per field), microspherocytes and normoblasts. Thrombocyte values initially rose on daily treatment with plasmapheresis using membrane separation and fresh plasma exchange. However, after two attempts at stopping therapy, plasmapheresis and fresh plasma replacement failed to normalise thrombocyte values. The patient had a total of 44 plasmaphereses. Intravenous administration of three doses of 1.5 mg vincristine at intervals of 7 and 5 days combined with further plasmapheresis treatment soon led to normalisation of the thrombocyte count (320,000/microliters), a fall in lactate dehydrogenase (120 U/l) and a disappearance of fragment cells in the blood smear. The patient is still in complete remission 6 months after stopping treatment. Treatment with vincristine should be considered for TTP refractory to treatment.
Bone Marrow Examination↗
Role of mature leukemic cells in the amplification of leukemic stem cells in a murine model.
The recently described PGM-2 leukemia displays a hierarchical structure with bipotential stem cells, B-lymphocyte and macrophage progenitor cells, and post-mitotic end cells. Because the different cell types can easily be identified in vitro by clonal culture assays and simple staining procedures, this leukemia is a useful model for the study of the interactions between different cell compartments in a leukemic clone. Our analysis of the impact of mature leukemic macrophages on the proliferation of stem cells was facilitated by the establishment of long-term cultures producing new stem cells over prolonged periods of time. A prerequisite was the development of an adherent layer of fibroblasts and leukemic macrophages. Enumeration of adherent cells revealed a good correlation between the number of macrophages and the number of stem cells generated, and expansion of the macrophage population by treatment with interleukin 3 (IL-3) resulted in a significant improvement of the culture conditions. Leukemic macrophages were also able to induce the formation of stem-cell colonies in agar culture, suggesting a role for humoral mediators. Antibody neutralization experiments and bioassays identified IL-7 and IL-6 as factors cooperating in the stimulation of stem-cell self-renewal. Feed-back stimulation of leukemic stem cells by mature leukemic cells may also be relevant to human leukemias and have implications for differentiation therapy.
Animals↗
Systemic therapy of disseminated soft tissue sarcomas.
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Adult↗
Chimaeric cultures of human marrow stroma and murine leukaemia cells: evidence for abnormalities in the haemopoietic microenvironment in myeloid malignancies and other infiltrating marrow disorders.
PGM-1 is a transplantable C3H/HeJ leukaemia which is not viable in unstimulated in vitro culture, differentiates into mature granulocytes and macrophages in response to soluble cytokines, and undergoes self-renewing cell divisions in coculture with selected human bone marrow stromal cell lines. When PGM-1 cells were cultured on pre-established adherent layers from primary human marrow samples, their fate depended on the source of the human marrow. Adherent layers from healthy marrow donors or patients with reactive marrow alterations had no or very little capacity to maintain PGM-1 cells in an immature colony-forming state. However, in coculture with adherent layers from patients with myeloid leukaemia or, to a lesser extent, lymphoblastic leukaemia or marrow-infiltrating lymphoma the colony-forming potential was retained. There was no correlation between the remission status of the patient and the PGM-1 activity of the adherent layer. Consistent morphological differences between active and inactive stromal layers were not observed. The PGM-1 coculture system enables the detection of a hitherto undescribed regulatory abnormality in bone marrow malignancies. Whether the PGM-1 supporting activity is mediated through differences in the production of a cytokine with close homology to complement factor Bb which has recently been shown to induce self-renewal in immature PGM-1 cells, requires further investigation.
Animals↗
Leukemic nodules at the site of G-CSF injection in acute myelomonocytic leukemia.
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Female↗
Infusion of tumor-contaminated bone marrow for autologous rescue after high-dose therapy leading to long-term remission in a patient with relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia.
We report a female patient with relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia remaining in long-term second remission after high-dose radiochemotherapy followed by autologous stem cell rescue with bone marrow showing evidence of residual disease. The Philadelphia chromosome and a positive signal for the BCR/ABL p185 translocation by the polymerase chain reaction were detected in the harvested marrow. After mafosfamide-purged marrow failed to engraft, her unpurged 'back-up' bone marrow was also infused. Control marrow examinations after recovery were repeatedly positive for the BCR/ABL translocation on PCR analysis turning negative 30 months after high-dose therapy. She remains in unsustained complete clinical remission for 48+ months showing no evidence of leukemia by cytological and cytogenetic analyses.
Adult↗
Absence of point mutations in the extracellular domain of the alpha subunit of the GM-CSF receptor in a series of patients with acute myeloid leukemia (AML).
The GM-CSF receptor belongs to the cytokine receptor superfamily. The high-affinity receptors of this class are lacking intrinsic tyrosine kinase domains. The GM-CSF receptor consists of alpha and beta subunits. The beta subunit is shared with the receptors of IL-3 and IL-5. In addition to the membrane bound forms the receptors have been found to possess soluble isoforms. Since retroviral infection of the human GM-CSF dependent cell line, TF-1, leads to factor independent growth by increased expression of the GM-CSF receptor alpha chain in a subgroup of infected clones, we were interested in studying the role of this chain in human AML. Further considering that a point mutation in the extracellular domain of the erythropoietin receptor, also a member of the cytokine receptor superfamily, resulted in constitutive activation of a murine cell line, we investigated the possibility that a point mutation of the GM-CSF receptor was responsible for autonomous growth of AML cells. We sequenced a segment of the receptor coding for the extracellular domain of the alpha subunit. cDNA was prepared from peripheral blood or bone marrow cells from 24 patients with AML, from four patients with MDS and from three human myeloid cell lines. The region of interest was amplified with two rounds of PCR reactions with nested primers, covering five overlapping fragments, and directly sequenced using a non-radioactive technique. No point mutations were found in the investigated samples. Thus, point mutations in this segment of the GM-CSF receptor gene do not seem to play an important role in the transformation process of human acute leukemia.
Base Sequence↗
Correlations between karyotype and cytologic findings in multiple myeloma.
In multiple myeloma, correlations between cytogenetic and morphologic findings are hampered by the relatively scarce chromosomal data and the lack of a widely accepted morphologic classification. The aim of the analysis, comprising 111 patients with multiple myeloma, was to study possible correlations between karyotype and a morphologic classification proposed by Bartl et al. Grade of plasma cell infiltration, predominant cell types (Marschalko, small, cleaved, polymorphous, asynchronous, blastic) and grade of malignancy are the basis of this classification. A pathologic karyotype was found in the bone marrow of 39/111 patients (35%). The incidence of chromosomal anomalies closely correlated with the grade of infiltration, plasma cell type and grade of malignancy. Chromosomal anomalies were rarely detected in patients with low infiltration (16%), but they were frequently found in high-grade infiltration (69%). A low incidence was found in Marschalko (25%) or small cell type (15%); the incidence was much higher in cleaved (75%), asynchronous (65%) and basic cell types (71%). An abnormal karyotype was more frequently found in high (71%) than in intermediate (53%) or low (23%)-grade malignant multiple myeloma. The most consistent structural chromosomal aberration found in five patients was translocation t(11;14)(q13;q32). In four of the five patients small, often cleaved plasma cells were the predominant cell types. These reported correlations between morphological and cytogenetic findings must be confirmed by future studies.
Bone Marrow↗
Randomized comparison of interferon-alpha with busulfan and hydroxyurea in chronic myelogenous leukemia. The German CML Study Group.
As curative bone marrow transplantation is available only to a minority of patients with chronic myelogenous leukemia (CML), drug therapy remains of central interest. Several nonrandomized studies have suggested that interferon-alpha (IFN) may prolong survival in CML. In a randomized multicenter study the influence of IFN versus busulfan or hydroxyurea (HU) on survival of Philadelphia-positive (Ph+) CML was examined. A total of 513 Ph+ patients were randomized for treatment as follows: 133 for IFN, 186 for busulfan, and 194 for HU. IFN-treated CML patients have a significant survival advantage over busulfan-treated (P = .008), but not over HU-treated patients (P = .44). The longer survival is due to slower progression to blast crisis. Median survival of IFN-treated patients is 5.5 years [5-year survival, 59%; 95% confidence interval (CI), 48%-70%], of busulfan-treated patients, 3.8 years (5-year survival, 32%; CI, 24%-40%), and of HU-treated patients, 4.7 years (5-year survival, 44%; CI, 36%-53%). Patients who continue on IFN survive longer than those in whom IFN is discontinued before blast crisis (P = .007). Complete hematologic IFN-responders have a survival advantage over partial responders or nonresponders (P = .02). Cytogenetic IFN-responders have no significant survival advantage over nonresponders (P = .2). Patients who attain white blood cell (WBC) counts of 10 x 10(9)/L or less have a survival advantage in the IFN (P = .007) and HU (P = .05) groups. Whereas toxicity in the IFN group was considerably higher than in the busulfan or HU groups, long-lasting cytopenias necessitating discontinuation of therapy as observed with busulfan have not been seen with IFN or HU. The problems of conventional prognostic scores (Sokal's score, Score 1) that we observed in IFN-treated patients support the idea that IFN changes the natural course of CML. We conclude that, with regard to survival of CML in the chronic phase, IFN is superior to busulfan and as effective as HU. Whether and to what extent IFN is superior to HU appears to depend, at least in part, on the degree of WBC suppression by HU-therapy and on the risk profile of the patients.
Adolescent↗
Pre-pre-B acute lymphoblastic leukemia: high frequency of alternatively spliced ALL1-AF4 transcripts and absence of minimal residual disease during complete remission.
We used the polymerase chain reaction (PCR) to detect ALL1-AF4 rearrangements, the molecular hallmark of t(4;11) in a series of 46 pre-pre-B (CD19+, CD24+, CD10/CD20/cylgM/sIgM-) acute lymphoblastic leukemias (ALL). Eighteen patients (39%) exhibited fusion transcripts including 4 of 12 children and 14 of 34 adults. This genetic defect was associated with hyperleukocytosis (median leukocyte count 176 x 10(9)/L) and expression of myeloid-associated antigens (CDw65+). In contrast, only two patients from a group of 67 common (CD19/CD10+, cylgM/sIgM-) and pre-B ALLs (CD19/cylgM+, CD10 +/-, sIgM-) showed ALL1-AF4 mRNA. All PCR-positive cases showed multiple amplification products representing alternative splicing events. Moreover, reciprocal der (4)-derived AF4-ALL1 transcripts were observed in 65% of the cases analyzed. Eight of the 18 pre-pre-B ALL patients with an ALL1-AF4 recombination are currently in complete continuous remission for up to 54 months (median, 26 months). Twelve remission samples were available from seven cases, and all of them lacked evidence of minimal residual disease. Overall this study documents a similarly high incidence of ALL1-AF4 recombinations in children (infants excluded) and adults with pre-pre-B ALL and demonstrates the decline of the leukemic cell clone below the detection level of PCR in a remarkable proportion of patients under intense treatment protocols.
Adolescent↗
Self-renewal and differentiation of stem cells in a biopotential murine leukemia: an in vitro model for differentiation therapy.
PGM-2 is a variant of the transplantable PGM-1 leukemia of strain C3H/HeJ. Freshly explanted cells had lymphoid morphology with a CD5+ CD45R (B220)- IgM- phenotype. They were not viable in unstimulated cultures, but formed IgM+ lymphoid colonies in response to interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-7, and Steel factor, and macrophage colonies in response to IL-3. IL-3-stimulated colonies had no recloning potential, but colonies from IL-7 cultures gave rise to large numbers of secondary macrophage colonies in IL-3-stimulated cultures and secondary lymphoid colonies in IL-7-stimulated cultures. The latter ones could be serially transferred in vitro for several months, and formed typical PGM-2 tumors in vivo. IL-7-stimulated colonies could therefore be used to measure leukemic stem cells in vitro. Supramaximal IL-3 stimulation (2,500 U/mL) of suspension cultures was followed by an increase in overall cell numbers and a disappearance of leukemic stem cells, compatible with differentiation induction. This could not be counteracted by simultaneous stimulation with IL-7. However, lower IL-3 concentrations (500 U/mL) induced an expansion of the stem cell pool, possibly by facilitating density-dependent autostimulatory mechanisms involving endogenous production of IL-7. The system described is a simple in vitro model for differentiation therapy. It shows that leukemic stem cells can be induced by hematopoietic growth factors to undergo terminal differentiation, but the concentrations required for differentiation induction in stem cells are much higher than those required for other biologic effects. Submaximal stimulation may favor expansion rather than repression of the leukemic cell population.
Animals↗
[Late relapse following Hodgkin's disease].
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Female↗
Hematopoietic growth factors and the treatment of tumor-associated anemias.
Erythropoietin, alone or in combination with colony-stimulating factors, is a promising agent in the treatment of patients with cancer-related 'anemia of chronic disorders', chemo/radiotherapy-induced anemia, or anemia due to myelodysplastic or myeloproliferative syndromes. In the first two groups, at least half of the patients can be expected to respond to erythropoietin alone, with an average response delay of about 4 weeks and maximal responses at weekly doses of approximately 1000 U/kg. In myelodysplastic syndromes, only 10-20% of patients respond to conventional doses of erythropoietin, but doses exceeding 1000 U/kg weekly in combination with granulocyte colony-stimulating factor yield response rates of about 40%. Although these results show that hematopoietic growth factors can be used successfully to treat cancer-related anemias, economic constraints preclude their use at the present time.
Anemia↗
Demonstration of i(17q) in metaphase and interphase of malignant hematopoietic cells by fluorescence in situ hybridization.
In 10 patients with various hematopoietic disorders, i(17q) has been studied by the technique of fluorescence in situ hybridization (FISH) both in metaphase and interphase cells using an alpha-satellite centromere-specific probe #17. We observed some minor quantitative differences between metaphase and interphase cells with regard to the incidence of i(17q) in individual cases and considerable heteromorphism of the size of signal of i(17q) among different cases. Our results suggest that formation of i(17q) results from a break in the p-arm proximal to the centromere and that the breakpoints vary from case to case.
Aneuploidy↗
Weekly therapy with folinic acid and high-dose 5-fluorouracil 24-hour infusion in previously untreated patients with metastatic colorectal carcinoma.
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Adult↗
Weekly high-dose 5-fluorouracil and folinic acid as salvage treatment in advanced gastric cancer.
BACKGROUND: A weekly schedule of a 24-h high-dose 5-FU infusion in combination with folinic acid was investigated as salvage therapy in patients with advanced gastric cancer. PATIENTS AND METHODS: Seventeen patients with progressive disease after chemotherapy were treated with a weekly schedule of 500 mg folinic acid/sqm by i.v. 2-h infusion followed by an i.v. 24-h infusion of 2.6 g 5-FU/sqm times six. Fourteen of the 17 patients (82%) had been pretreated in regimens which included 5-FU/folinic acid i.v. bolus. RESULTS: Toxicity was mild, with diarrhea, mucositis and nausea; WHO grade III/IV diarrhea was observed in only two patients. Three patients achieved partial remissions (18%; 95% confidence interval: 0%-38%) and 7 patients stable disease (41%; 95% confidence interval: 17%-64%). Their median survival time was five months (range 1.5-10 months) after the onset of salvage therapy. CONCLUSIONS: This schedule of weekly 24-h infusions of high-dose 5-FU and folinic acid is effective, even in patients pretreated with or resistant to regimens including 5-FU/folinic acid i.v. bolus. Based on these data, it appears that this schedule of high-dose 5-FU/folinic acid in first-line combination chemotherapy merits investigation.
Adult↗