Biomedical subjects

B Wörmann

Publications and source records attributed to B Wörmann.

At least 73 records · Page 4Linked to original sources

PubMed1997

TGF-beta inhibits growth and induces apoptosis in leukemic B cell precursors.

The uncontrolled proliferation of malignant lymphoblasts is the pathobiological hallmark in B cell precursor-ALL (BCP-ALL). Identification of inhibitory growth factors is of great importance for the understanding of growth control of leukemic B cell precursors and the development of novel therapeutic approaches in BCP-ALL. The aim of our study was the analysis of the effect of TGF-beta on cell survival and apoptosis of B cell precursors (BCP) from patients with acute lymphoblastic leukemia in vitro. Experiments were performed in a coculture system with cloned murine fibroblasts, which efficiently block spontaneous ex vivo apoptosis of BCP and thus allows the assessment of cytokine-induced growth inhibition. TGF-beta significantly reduced cell viability of highly purified, FACS isolated CD10+/CD19+ leukemic BCP by a mean of 53% (P = 0.0001). The loss of cell viability was accompanied by a significant increase of apoptosis with a mean of 70% (P = 0.0028). The TGF-beta effect was blocked specifically by a monoclonal anti-TGF-beta antibody. Induction of apoptotic cell death by TGF-beta was not accompanied by reduction of bcl-2 protein expression. TGF-beta transcription was not detected in the leukemic pre-B cell line BLIN-1, but in the murine fibroblasts. The growth inhibitory effect of TGF-beta was not restricted to leukemic BCP. The cytokine also increased apoptosis of normal, highly purified BCP by a mean of 58%. The data identify TGF-beta as a potent growth inhibitory cytokine for leukemic BCP.

Animals↗

PubMed1997

Differential effect of GM-CSF pretreatment on intracellular Ara-C metabolism in normal bone marrow mononuclear cells vs acute myeloid leukemia (AML) blasts.

The effect of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) on the intracellular metabolism of cytosine arabinoside (Ara-C) was comparatively analyzed in normal bone marrow mononuclear cells (NBMMC) from eight healthy volunteers and in leukemic blasts from 50 patients with acute myeloid leukemia (AML). Pretreatment with GM-CSF (100 U/ml) for 48 h resulted in a significant enhancement of DNA synthesis in both cell types: 21 of 35 AML specimens were found to be responsive to GM-CSF as defined by an increase of 3H-TdR incorporation into the DNA > 1.5-fold while NBMMC from normal donors were responsive in all cases. In GM-CSF responsive AML blasts, overall DNA polymerase and DNA polymerase alpha activity increased from a median of 84.4 to 96.1 and from 3.45 to 5.2 pmol/min x mg as compared to a median of 96.7 to 189.9 and 1.2 to 2.2 pmol/min x mg in NBMMC (P < 0.05). Median Ara-C-mediated inhibition of DNA synthesis was significantly more effective in AML blasts as compared to NBMMC (76.5 vs 55.0% at 0.05 microM and 99.0 vs 96.0% at 5.0 microM Ara-C, P < 0.01) but was not influenced by GM-CSF pretreatment. Similarly, intracellular Ara-CTP levels were higher in AML blasts as compared to NBMMC (median of 46.9 vs 18.7 at 1 microM, 167.8 vs 48.0 at 10 microM and 337.5 vs 59.5 ng/10(7) cells at 100 microM extracellular Ara-C, P < 0.01) but showed no enhancement in the presence of GM-CSF. Median deoxycytidine (DCK) and thymidine kinase (TK) activity were only slightly increased in AML blasts after GM-CSF priming. In contrast, NBMMC revealed a significant increase in TK activity after GM-CSF pretreatment (from a median of 1.9 to 3.6 pmol/min x mg, P = 0.039). At low; intermediate and high extracellular Ara-C concentrations GM-CSF pretreatment resulted in a significant enhancement of the 3H-Ara-C incorporation into the DNA in both GM-CSF responsive AML blasts and NBMMC (median of 1.3 to 2.1- and 1.4 to 1.6-fold, P < 0.05). GM-CSF non-responsive AML blasts showed no change in 3H-Ara-C incorporation into the DNA in response to GM-CSF at low Ara-C concentrations but significant increases at intermediate and high extracellular Ara-C concentrations (median increases of 1.63-fold at 1.06 microM with P = 0.01 and 1.37-fold at 10 microM extracellular Ara-C with P = 0.0+005). NBMMC revealed significantly lower GM-CSF-induced increases of the 3H-Ara-C incorporation into the DNA as compared to the effect of GM-CSF priming on DNA synthesis (median increases of 1.4 to 1.7-fold vs 2.6-fold, P < 0.05). These data reveal a different effect of GM-CSF priming on the metabolism of Ara-C in normal vs leukemic cells which may cause a preferential increase in the antileukemic cytotoxicity of Ara-C in the presence of GM-CSF.

Adult↗

PubMed1997

Cytogenetic analysis of CD34+ subpopulations in AML and MDS characterized by the expression of CD38 and CD117.

It has been supposed in de novo AML that malignant transformation occurs at the level of committed progenitors. Recent data of our group and others provide evidence that in AML malignant transformation may regularly occur at the level of stem cells. These cells can be discriminated by function and specific surface molecules. CD34, a glycophosphoprotein, is a cellular surface antigen characteristically expressed by stem cells. CD34+ stem cells can be further subdivided by the expression of additional surface molecules like CD38 and CD117. In this article we present results from cytogenetic examinations of FACS-isolated stem cell subpopulations in eight patients (four AML and four MDS). Six of them displayed clonal karyotype abnormalities at the time of first diagnoses in the native bone marrow (5q-; 5q- and complex abnormalities; +8; inv(16) and +8; i(17q) and -21; i(21q)). We used CD117, the receptor for the stem cell factor (also KIT oncogene) as a new cellular surface marker. CD34+/CD117+/- stem cell subpopulations were examined in two patients with AML and three patients with MDS. We found leukemic stem cells in every type of stem cell subpopulation examined (CD34+/CD38-, CD34+/CD38+, CD34+/CD117-, CD34+/CD117+). Secondary, progression-associated chromosome abnormalities likewise were demonstrable in CD34+ cells. In three patients a mosaic of normal and abnormal metaphases was found in the highly purified stem cell subpopulations. We conclude that in AML and MDS stem cells are the target of leukemogenic genetic defects. CD117 as a new marker to isolate different CD34+ subpopulations was not sufficient to discriminate between normal and leukemic stem cells. Our findings have implications for autologous stem cell transplantation, high-dose chemotherapy and the pathogenetic concept of leukemogenesis.

ADP-ribosyl Cyclase↗

PubMed1997

In vitro activation of low-grade non-Hodgkin's lymphoma by murine fibroblasts, IL-4, anti-CD40 antibodies and the soluble CD40 ligand.

The in vitro analysis of growth regulation in low-grade B non-Hodgkin's lymphoma (B-NHL) is hampered by the rapid apoptotic death of the malignant B cells ex vivo. A complex culture system, using murine CDw32 transfected fibroblasts (LTK-cells), IL-4 and anti-CD40 mAb, has been established for the propagation of normal mature B cells in vitro. We investigated the influence of the different components of this coculture system on cell survival and apoptosis of B-NHL cells. Nine samples from patients with follicular lymphoma and from eight patients with immunocytoma were analyzed. No cell proliferation of B-NHL cells could be induced in the culture system. However, CDw32-transfected murine fibroblasts most efficiently supported cell viability of B-NHL cells with an increase in cell survival by 114% compared to the control (P = 0.047). IL-4 alone also had a stimulatory effect on cell survival of B-NHL cells after 6 days. In contrast, the soluble recombinant CD40 ligand gp39 and the anti-CD40 mAbs mAb89 and EA-5 did not prolong cell survival. CDw32 transfectants blocked apoptosis of B-NHL cells efficiently from 67% in the control to 16% (P = 0.001). Reduction in apoptosis was accompanied by an elevated bcl-2 protein expression. IL-4 or mAb89 did not further reduce apoptotic cell death in CDw32 transfectant-dependent cocultures. Our data underline the pivotal role of LTK- cells for cell survival of B-NHL cells in vitro. The efficient blockage of apoptosis associated with increased bcl-2 protein expression causes prolonged cell viability of the B-NHL cells.

Aged↗

PubMed1997

Combination chemotherapy with CHOP for recurrent thrombotic thrombocytopenic purpura.

We report the case of a 42-year-old woman with chronic recurrent thrombotic thrombocytopenic purpura. Therapy with corticosteroids, high-dose immunoglobulins, plasma exchange and cyclophosphamide only induced short-lasting remissions during a course of almost 3 months. Following a severe relapse on day 90 after the start of symptoms, polychemotherapy with cyclophosphamide. adriamycin, vincristine and prednisolone (CHOP) was begun. After two cycles of CHOP the patient has stayed in complete remission, with normal platelet counts for more than 9 months to date.

Adult↗

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

Comparison of CD34+ cell numbers and colony growth before and after cryopreservation of peripheral blood progenitor and stem cell harvests: influence of prior chemotherapy.

BACKGROUND: Quantitative determination of hematopoietic progenitor cells is a major issue in peripheral blood progenitor and stem cell collection and transfusion, although the extent is still an object of discussion. STUDY DESIGN AND METHODS: In 116 leukapheresis collections from 42 patients, immunophenotyping for CD34+ cells, evaluation of in vitro proliferative capacity by a colony-forming unit-granulocyte-macrophage (CFU-GM) assay, and viability assessment by trypan blue exclusion were performed before and after storage in liquid nitrogen at -196 degrees C. RESULTS: Before storage, the median number of CD34+ cells was 1.46 x 10(6) (range, 0.01-54.05 x 10(6)) per kg of body weight (BW). There was no significant difference between precryopreservation and postcryopreservation numbers. The median number of CFU-GM was 2.25 x 10(5) (range, 0.02-157.49 x 10(5)) per kg of BW before cryopreservation and significantly (p < 0.001) lower, 0.83 x 10(5) (range, 0-220.36 x 10(5)) per kg of BW, after cryopreservation. The correlation coefficient of prestorage and poststorage values was 0.92. The median ratio of poststorage and prestorage values was 42.3 percent (0-304.8%). Male patients who underwent intense chemotherapy (> 5 cycles) showed a significantly lower ratio of postcryopreservation and precryopreservation CFU-GM values than other patients (p = 0.0047). A strong linear correlation was determined between the number of CD34+ cells per kg of BW and the number of CFU-GM per kg of BW before and after cryopreservation. A viability below 50 percent predicted a high loss of in vitro proliferative capacity, while a viability above 50 percent did not correlate with a high ratio of CFU-GM from after and before cryopreservation. CONCLUSION: A good correlation between the variables used for characterization of peripheral blood progenitor cells--the number of CD34+ cells and the number of CFU-GM--was observed. Viability assessment by trypan blue exclusion does not seem to be a substitute for assays evaluating in vitro proliferative capacity.

Adult↗

PubMed1997

A phase-II study with idarubicin, ifosfamide and VP-16 (IIVP-16) in patients with refractory or relapsed aggressive and high grade non-Hodgkin's lymphoma.

We report a phase-II study of idarubicin, ifosphamide and etoposide (IIVP-16) in heavily pretreated patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. The IIVP-16 regimen consisted of idarubicin (10 mg/m2 i.v. days 1 + 2 or days 1 + 8), ifosfamide (1000 mg/m2 i.v. days 1-5) and VP-16 (150 mg/m2 i.v. days 103). 40 patients were enrolled. Of 38 evaluable patients, 26 had centroblastic subtype, followed by lymphoblastic (6), immunoblastic (2), and other entities (4). 18 patients were primary resistant; 14 patients had early relapse (CR less than 12 months) and 8 patients late relapse (CR longer than 12 months). The median number of different prior chemotherapy regimens was 2 (range 1 to 6). 20 patients had received additional radiotherapy. The response-rate was 47.4% including 8 CR (21.1%) and 10 PR (26.3%). IIVP-16 was more effective in patients with relapsed disease when compared with patients with primary resistant disease (response rate 65% vs. 27.8%, p < 0.025). Leukopenia and thrombocytopenia were the major toxicities occurring in 73/107 (68.2%) and 57/107 (53.3%) of cycles (WHO grade IV). IIVP-16 is an effective regimen particularly in patients with unfavorable relapsed NHL.

Adult↗

PubMed1997

Somatostatin receptor scintigraphy in the staging of lymphomas.

In this prospective study we evaluated the somatostatin receptor scintigraphy in the initial staging of 19 patients suffering from Hodgkin's (HD) and non-Hodgkin's lymphomas (NHL) and in the restaging of 16 patients. Scintigraphy was compared to the results of the methods applied for adequate staging of lymphoma patients in the large multicentre trials. Planar imaging and SPECT was performed after intravenous injection of 110 or 220 MBq of 111In-pentetreotide. The patient-based analysis yielded an overall sensitivity of 88%, contrasting lesion-based sensitivities of 57%, 35%, and 43% in HD, low-grade NHL and high-grade NHL, respectively. The best results were obtained in the head-and-neck region and the worst in the abdomen (sensitivities of 61% and 24%, respectively). Bone marrow infiltration was visible in 1/12 cases only. There was no significant difference between the outcomes of patients in the initial staging and restaging and no influence of the amount of injected radiopharmaceutical on the results. In terms of the Ann-Arbor classification, 10/35 patients were concordant whereas 22 were understaged and 3 overstaged scintigraphically. In conclusion, somatostatin receptor scintigraphy is not useful in the initial staging or restaging of malignant lymphomas, especially NHL, due to low lesion detection rates most probably because of low receptor densities. In addition, intraindividual heterogeneity of somatostatin receptor expression has to be considered.

Adult↗

PubMed1997

Hematopoietic growth factors in acute myeloid leukemia: supportive and priming effects.

Hematopoietic growth factors (GFs) are administered to patients who have acute myeloid leukemia (AML) in order to overcome two limitations of chemotherapy: (I) myelotoxicity, and (2) the chemoresistance of minimal residual disease. GFs have been used after chemotherapy in 11 clinical studies, 8 on older age or otherwise high-risk AML. The GFs used were granulocyte-macrophage colony-stimulating factor (GM-CSF) in 7, G-CSF in three and macrophage-CSF in one of the studies. Beneficial effects could be shown on the duration of neutropenia in 8 studies, frequency of infections or fever in 4 studies, mortality or survival in 2 studies and remission rate in 1 study. The benefits in remissions and survival were all found among high-risk patients. One study in younger patients found disadvantages in the remission rate and event-free survival, whereas there was no adverse effect of GF on therapy resistance, leukemic regrowth, or disease-free survival in the other studies. GF priming strategies are based on their stimulation of AML blasts in vitro, their modulation of cellular cytarabine (ARA-C) metabolism and enhancement of clonogenic cell kill by ARA-C. Protective effects of GF against clonogenic cell kill or apoptosis were also described. There are data from 10 clinical studies using GFs before or simultaneously with chemotherapy. One study showed significance, two others a tendency to longer disease-free survival, and two studies showed a trend toward more remissions. A disadvantage in the remission rate and survival was found in one study and prolonged thrombocytopenia in two studies. Nine of ten studies did not find evidence for an adverse effect of GF priming on the course of the disease. In most studies, GF priming was only administered in one or two chemotherapy courses. One study giving four to five courses found a reduction in relapses during the first 6 months. In conclusion, a supportive use of GF may have a place in high-risk, but not standard-risk AML. GF priming approaches may not have been adequately investigated and an extension of this strategy to more treatment courses now appears more promising. Based on the clinical data available, all administration of GF in AML should be regarded as investigational.

Acute Disease↗

PubMed1997

Stimulation of B-chronic lymphocytic leukemia cells by murine fibroblasts, IL-4, anti-CD40 antibodies, and the soluble CD40 ligand.

Analysis of growth regulation in B-chronic lymphocytic leukemia (B-CLL) is of pivotal importance for understanding the pathophysiology and the development of new therapeutic approaches. We investigated the effect of soluble ligands and the interaction with fibroblasts in an in vitro system developed for the expansion of normal B lymphocytes. A total of 17 peripheral blood and bone marrow samples from patients with untreated B-CLL were analyzed for survival, apoptosis, and bcl-2 protein expression. The most efficient stimulus for cell survival was cocultivation with CDw32-transfected murine fibroblasts, which achieved a median of 56% surviving CD5 positive B cells with a plateau between Day 3 and Day 13 (p < 0.0001). IL-4 alone had a significant, but less profound, effect on cell survival: cell viability was increased by a factor of 1.7 on Day 3 (p = 0.001), but cell viability continued to decline. In contrast, the soluble recombinant human CD40 ligand and two different anti-CD40 antibodies did not prolong cell survival. In all experiments prolongation of cell survival was accompanied by a significant reduction of apoptosis of the leukemic B cells: in CDw32-transfected fibroblasts apoptosis was reduced by a mean of 90%, in IL-4 by a mean of 55%. Reduction in apoptotic cell death was associated with elevated bcl-2 protein levels. Our results emphasize the critical role of the interaction between B-CLL cells and CDw32-transfected fibroblasts for cell viability in vitro. Prolongation of cell survival is caused by a reduction of apoptosis and correlates with bcl-2 protein expression.

Adult↗

PubMed1997

Detection of trisomy 12 in CD34+ progenitor cells in a patient with B-cell chronic lymphocytic leukemia by fluorescence in situ hybridization.

B-cell chronic lymphocytic leukemia (B-CLL) is a slowly progressive disease resulting from the clonal expansion of mature B lymphocytes. The most frequent chromosomal abnormality is trisomy 12. Recently more aggressive therapeutic approaches using myeloablative therapy and autologous stem-cell support have been developed. Phase I/II studies have resulted in molecular remission and prolonged survival. One cause of relapse may be tumor-cell contamination of the transplant. We asked whether immunophenotypically identified hematopoietic progenitor cells are part of the malignant cell population in B-CLL. In a patient with trisomy 12, two subpopulations of hematopoietic progenitor cells, CD34+/CD38+ and CD34+/CD38- cells, were isolated by fluorescence-activated-cell-sorting; the sort purity was 98%. Trisomy 12 was detected in 13% of CD34+/38+ cells and in 34% of CD34+/38- cells. These data suggest that CD34+ cells are involved in the malignant clone of patients with B-CLL. The results are of significance for future strategies using autologous stem-cell transfusion.

ADP-ribosyl Cyclase↗

PubMed1997

[Brief interdisciplinary oncology: a model for ambulatory, multimodal treatment of tumor patients].

Since 10/1994 the Interdisziplinäre Kurzzeit-Onkologie (IKO) is an outpatient department for the treatment of patients with cancer used by the departments of hematology/oncology and surgery. Between 09/1995 and 02/1997, 818 patients received 2024 cytotoxic therapies with neoadjuvant (15%), adjuvant (65%) or palliative (20%) intention-mostly within multicenter clinical studies. Ambulatory operations like removal of lymph nodes for diagnosis or the implantation of venous catheter systems prepared the way for specialized modalities of cancer therapy. The high compliance and consent of patients, combined with better understanding of cancer therapy, resulted in an enhanced quality of life and optimized therapy. Standardization in diagnostics and fast realisation of interdisciplinary treatment schedules lead to reduction of costs and to enhancement of quality and security in cancer therapy.

Ambulatory Care↗

PubMed1996

[Therapy of low-grade non-Hodgkin lymphomas].

Low-grade non-Hodgkin's lymphomas are characterized by a low proliferative activity and prolonged clinical course. Most of them reveal distinct cytogenetic and molecular aberrations, such as the translocation t (14; 18) in centrocytic/centroblastic or follicular lymphomas, which is combined with an overexpression of the bcl 2 oncogene or the translocation t (11; 14), which is associated with a deregulation of the PRAD 1 gene and is mainly found in centrocytic or mantle-cell lymphomas. The therapy of low-grade non-Hodgkin's lymphoma depends on the extent of the disease. In early stages I and II, in which only 15 to 25% of low-grade lymphomas are diagnosed, radiotherapy represents the treatment of choice and may be applied with curative intention. The appropriate treatment of more advanced stages III and IV is a matter of controversial debates. Currently, it still seems justified to watch the natural course of the disease and to start therapy not before the occurrence of B-symptoms, hematopoietic insufficiency or progression of lymphoma. Intensification of initial cytoreductive chemotherapy does not result in a prolonged survival or a higher remission rate. However, maintenance therapy with interferon alpha following successful initial cytoreductive chemotherapy appears to have a favorable impact on disease-free and possibly also overall survival. New perspectives result from the introduction of new cytostatic compounds and the purine analogues in particular as well as the development of effective immunotoxins and antibody-conjugated radio-isotoes. Furthermore, myeloablative radiochemotherapy followed by autologous bone marrow or peripheral stem cell transplantation provides a promising approach with curative potential even in advanced stages of the disease.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

In vivo 31P NMR spectroscopy of human musculoskeletal tumors as a measure of response to chemotherapy.

The value of in vivo 31P NMR spectroscopy to provide indicators of response to cytostatic chemotherapy was studied in patients with malignant musculoskeletal tumors. Characteristics of untreated cancers were strong signals of PME and PDE, moderately increased Pi and low PCr. The intracellular pH was slightly alkaline. The intracellular concentration of free magnesium was 70% of that in muscle. Spectroscopic findings at different times of therapy were compared with the percentage of tumor necrosis after surgical resection in 28 patients. In follow-up studies, energy-rich phosphates declined in nonresponders, while PME, Pi and frequently PDE increased. Treatment response appeared to involve the reversal of these trends. In five responders, a biphasic pattern was observed, i.e. initially the spectrum changed into that of severely ischemic cell injury followed by a successive phase of apparent 'tumor activation'. Pretreatment levels of (PCr+Pi)/total phosphate > or = 0.35 and PCr/ alpha-NTP > or = 1.5, an accelerated increase in total low-energy phosphates/total high-energy phosphates (> or = 3.0%/day) after the initial drug application, and a long-term decrease (< or = -0.4%/day) during later therapy were highly indicative of tumor response to chemotherapy. Such spectroscopic predictors for treatment response proved to be superior to currently used indices such as tumor size.

Adolescent↗

PubMed1996

A cell-surface epitope associated with liver-preferential metastasis detected by the new monoclonal antibody 3H4 in the murine tumor model ER 15-P.

In the tumor model ER 15-P, a chemically induced pleomorphic myofibrosarcoma of the C57/Bl6J mouse, cell lines with liver-preferential metastatic tumor spread were selected in vivo. In order to describe cell-surface molecules relevant for hepatic metastasis, monoclonal antibodies were raised against the liver-preferential variants. In a syngeneic immunization with viable tumor cells cyclophosphamide was used for augmentation of the humoral antitumor immunity. The monoclonal antibody mAb 3H4, an IgG2b isotype, reacted with a cell-surface epitope exclusively detected on the liver-preferential metastatic phenotype (Me) of the tumor model ER 15-P; no reactivity with the non-organ-specific metastatic phenotype (P) was observed. Regarding the morphological heterogeneity of different Me and P tumor cell populations, mAb 3H4 antigen expression was consistently associated with liver-preferential metastasis, not with different morphological stages of differentiation. It showed no cross-reaction with other tumor cell lines tested except MethA murine fibrosarcoma. The antibody was unreactive with normal tissue cells in C57/Bl6J mice. mAb 3H4 antigen expression was not dependent on the cell cycle. In an experimental assay of hematogenous metastasis, preincubation with mAb 3H4 significantly reduced the number of liver metastases of the liver-preferential tumor cells. Although no crossreaction of the primary ER 15-P with mAb 3H4 was observed, the antibody also significantly reduced the number of renal metastases of the P tumor cell population. The syngeneic IgG2b monoclonal antibody mAb 3H4 identified a new tumor-associated cell-surface antigen correlating with liver-preferential metastasis. mAb 3H4 antigen expression was a stable property of the liver-preferential tumor cells regardless of morphological diversity or functional cell status. In an in vivo blocking assay mAb 3H4 reduced liver colonization in vivo.

Animals↗

PubMed1996

Paraneoplastic hypokalemia in acute myeloid leukemia: a case of renin activity in AML blast cells.

Hypokalemia due to renal potassium loss has frequently been observed in patients with acute myeloid leukemia (AML). The pathogenic mechanism for this hyperkaluresis is unclear. In this report we describe a patient with AML FAB M4, in whom the clinical course, the electrolyte disturbances, the serum aldosterone levels, and the diffuse hyperplasia of the adrenal cortex documented a typical case of marked secondary hyperaldosteronism. On analysis of the leukemic cells of this patient compared with normal bone marrow cells, a significant increase of renin-like activity in the cytosol of the blast cells was noted. Activation of the renin-angiotensin-aldosterone system by paraneoplastic production of renin-like activity in AML blast cells might contribute to the hypokalemia often observed in patients with acute myeloid leukemia.

Acute Disease↗

PubMed1996

De novo AML with dysplastic hematopoiesis: cytogenetic and prognostic significance.

Dysplastic hematopoiesis is the morphological hallmark of myelodysplastic syndromes. Dysplastic features in one or more lineages are also found frequently in bone marrow aspirates from patients with de novo AML and have been associated with an unfavorable prognosis. We asked whether dyshematopoiesis is an independent prognostic factor or an indicator of unrecognized secondary leukemia, identified by characteristic chromosomal abnormalities. Bone marrow aspirates from 102 patients with newly diagnosed AML were analyzed. Morphological analysis was obtained in all patients, flow cytometric analysis in 96 and successful cytogenetic analysis in 65 bone marrow aspirates. Dysgranulopoiesis (DysG) was found in 55, dysmegakaryopoiesis (DysM) in 32 and dyserythropoiesis (DysE) in 23 patients. Decreased side scatter signals of neutrophils in the flow cytometric analysis (DysS) were detected in 32 patients. DysG and DysS showed a highly significant correlation (P = 0.0005). DysG was an adverse negative prognostic factor for remission rate and event-free survival (P = 0.04, P = 0.02). An unfavorable karyotype was associated with a significantly lower chance for event-free survival (P = 0.002). The incidence of an unfavorable karyotype was significantly higher in patients with DysG (P = 0.01), DysM (P = 0.02) and DysS (P = 0.01). In patients with an unfavorable karyotype, dysplasia had no additional prognostic influence, however, in patients with a normal, favorable or prognostically uncertain karyotype DysG remained a predictor of lower remission rate (P = 0.03). We conclude that dysgranulopoiesis, dysmegakaryopoiesis and decreased side scatter signals of neutrophils are indicators of secondary leukemias in bone marrow aspirates from patients with de novo AML.

Bone Marrow↗