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Biomedical subjects

A Tobler

Publications and source records attributed to A Tobler.

At least 91 records · Page 5Linked to original sources
PubMed1994

[Prognostic value of bone marrow examinations on day 8 and day 17 of the first induction therapy cycle in acute myeloid leukemia].

Bone marrow examination yields valuable diagnostic information for evaluation of treatment efficacy in acute myelogenous leukemia (AML) patients. However, the ideal timing of this procedure remains to be defined. Usually the first follow-up examination is performed on day 17 of the induction course. Since an earlier analysis might be helpful in deciding on the subsequent treatment strategy, we explored whether an examination on day 8 might be equivalent, in particular in terms of quality of the specimen, as compared with that on day 17. In 10 AML patients undergoing the same induction treatment, bone marrow aspirates were examined prospectively at diagnosis (day 0), immediately after termination (day 8) and on day 17 of the first treatment course. We found that the number of cells not classifiable due to artifacts, as well as the otherwise non-evaluable cells, did not differ significantly in aspirates obtained on day 8 as compared with those on day 17. The number of leukemic cells decreased significantly from day 0 to day 8, whereas no change was noted between days 8 and 17. We conclude that a marrow examination on day 8 is not more prone to misinterpretation due to artifacts than our standard examination on day 17. Thus, an early marrow analysis immediately after completion of the first induction cycle might be a helpful tool in evaluating course of AML.

Adult↗
PubMed1994

[Treatment of severe idiopathic cold-agglutinin diseases using interferon-alpha 2b].

Cold agglutinin disease is an immunohemolytic anemia in which the autoantibody directly agglutinates human red blood cells below body temperature, maximally at 0 to 5 degrees C. The disease is considered to occur in primary (idiopathic) or secondary forms. The secondary form is noticed in the setting of infections (e.g. Mycoplasma pneumoniae, infectious mononucleosis), or patients with lymphoproliferative disorders. Affected patients show varying clinical presentation ranging from mild to serious hemolytic anemia, episodic hemoglobinuria, acrocyanosis, or other peripheral vaso-occlusive events which are all occasioned by cold exposure. In mild chronic cold agglutinin disease preventing cold exposure usually suffices to avoid disease exacerbation. However, treatment of severe disease is difficult. Splenectomy or glucocorticoids are generally disappointing, but exceptions have been reported. Treatment with alkylating agents, as for example chlorambucil or cyclophosphamide, may be effective in some patients. However, late effects, and in particular their carcinogenic potential when used as long-term treatment, must be born in mind. We report on a 59-year-old woman with severe cold agglutinin disease who was at first treated successfully with chlorambucil and prednisone. Based on in vitro evidence, primary cold agglutinin disease can be considered as a low grade malignant lymphoproliferative disorder in which interferon-alpha has been shown to be an effective therapeutic agent, at least in forms such as hairy cell leukemia. We therefore switched therapy to interferon-alpha 2b (three million units/m2 body surface area subcutaneously three times weekly). 18 months after treatment initiation there was no remission, but improvement of clinical and laboratory signs of the disease was noted.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Hemolytic, Autoimmune↗
PubMed1994

Hematologic, clinical, and cytogenetic analysis in 109 patients with primary myelodysplastic syndrome. Prognostic significance of morphology and chromosome findings.

One hundred and nine patients with primary myelodysplastic syndrome (MDS) were classified according to the French-American-British (FAB) criteria: 27 refractory anemia (RA, 25%), 26 RA with ringed sideroblasts (RARS, 24%), 16 RA with excess of blasts (RAEB, 15%), 10 RAEB in transformation (RAEB-t, 9%), 25 chronic myelomonocytic leukemia (CMMoL, 23%), and five unclassifiable MDS (4%). Forty-three were women and 66 were men (sex ratio 2:3). Age ranged from 30-92 years (mean 69 years) with nine patients aged less than 50 years (8%). A cytogenetic result was obtained in all cases. At initial study, a chromosome defect was observed in 56% of patients. Rates of abnormality depended on FAB subtype: 52% in RA, 100% in RA 5q-, 50% in RARS, 56% in RAEB, 70% in RAEB-t and 44% in CMMoL. The most frequent single defects were del(5q), -7/del(7q), del(20q), Y loss, and +8. Except for the 5q- syndrome entity, specific chromosome defects were not associated with particular FAB subtypes. Bone marrow (BM) insufficiency (22%) and leukemic transformation (21%) were the most important causes of death. The rate of leukemic transformation increased with the number of dysplastic BM cell lineages and was also associated with karyotype complexity and the proportion of abnormal/normal metaphases. The longest median survivals were observed in RARS (142 months) and RA/RA5q- (91 months) types. Median survivals decreased with increasing Bournemouth score values. Patients with three abnormal cell lineages had a median survival shorter than those with one or two abnormal lineages. Similarly, patients with complex defects had shorter survival than those with single or double defects or a normal karyotype. There was no statistically significant difference between survival of NN (normal), AN (abnormal/normal), and AA patients or between survival of patients with del(5q), -7/del(7q), +8 or del(20q).

Adult↗
PubMed1994

Evaluation of the Fresenius cell separator AS 104 for harvesting peripheral blood stem cells in pediatric patients.

In a single institution trial we carried out 35 peripheral blood stem cell harvesting procedures in 12 children with advanced malignancies to evaluate the procedure's safety and the collection efficiency of the Fresenius blood cell separator AS 104 in a pediatric population. Despite a significant mean decrease of 21% (+/-8%) in systolic blood pressure after starting the procedure, all children tolerated leukapheresis without any adverse reaction. After termination of leukapheresis there was a significant decrease of all determined hematological parameters, as compared with pre-harvest values. The mean mononuclear cell recovery was 64% (+/-26%), and in 25/35 (71%) harvesting procedures the minimum progenitor number required for safe autografting could be obtained by one single leukapheresis. We conclude that the Fresenius AS 104 blood cell separator provides a high cell yield and is a safe device for leukapheresis in pediatric patients.

Adolescent↗
PubMed1994

High incidence of infections after 2-chlorodeoxyadenosine (2-CDA) therapy in patients with malignant lymphomas and chronic and acute leukaemias.

BACKGROUND: 2-chlorodeoxyadenosine (2-CDA) is a new purine analogue which has been shown to be highly active in lymphoproliferative disorders. In this clinical trial we assessed 2-CDA toxicity and response rate in patients with various haematological malignancies who were heavily pre-treated and mostly refractory to standard treatment regimens. PATIENTS AND METHODS: Twenty-two refractory patients, 51 relapsing after standard chemotherapy and seven non-pre-treated patients were treated in a non-randomized prospective phase II multicentric study. Their median age was 54 years (range 18-84) and 56 of them were male. Thirty-one had non-Hodgkin's lymphoma (NHL), 11 chronic lymphocytic leukaemia (CLL), 1 prolymphocytic leukaemia (PLL), 13 hairy-cell leukaemia (HCL), 2 mycosis fungoides (MF), 3 multiple myeloma, 7 acute myeloblastic leukaemia (AML), 2 acute lymphoblastic leukaemia (ALL), 6 chronic myeloid leukaemia (CML) in blast crisis, 2 Hodgkin's disease, 1 Waldenström's macroglobulinemia and 1 Langerhans histiocytosis. 2-CDA 0.1 mg/kg/day was given as a continuous intravenous infusion for 7 days and recycled every 4 weeks. RESULTS: One hundred thirty-two courses of 2-CDA were administered to 80 patients, 76 of whom were evaluable for response. A) Toxicity: Myelosuppression: Neutropenia to over 50% of initial value occurred in 46% of patients, thrombocytopenia in 8%, and lymphopenia < 0.5 x 10(9)/l was seen in 41%. Infections occurred in 34/80 patients (43%). The risk of severe infections (WHO grades 3-4) correlated with increasing number of years after first diagnosis (p = 0.01) and low lymphocyte counts on days 1 and/or 14 (p = 0.04); 21 infections were opportunistic. B) Response: 70% patients with lymphoproliferative disorders of low malignancy attained complete or partial response (low-grade NHL 12/16, CLL + PLL 9/12, HCL 13/13, MF 2/2, myeloma 0/3); in patients with AML, ALL, CML in myeloid (n = 4) or lymphoid (n = 2) blast crisis and high-grade lymphoma responses were seen in only 11%. Response was inversely related to the number of pretreatments (p = 0.045). In responding NHL patients the mean lymphocyte count on day 14 of cycle 1 was significantly lower (median 0.6 x 10(9)/l) than that of non-responders (1.2 x 10(9)/l, p = 0.04). CONCLUSION: 2-CDA had a high activity even in heavily pretreated and refractory patients with low-grade lymphoproliferative disorders. In contrast to previously published studies, infections, mainly opportunistic, were a serious side effect in our study. In patients with severe lymphopenia at therapy initiation, the value of prophylactic anti-infective treatment should be studied.

Acute Disease↗
PubMed1994

Constitutive mRNA and protein production of macrophage colony-stimulating factor but not of other cytokines by synovial fibroblasts from rheumatoid arthritis and osteoarthritis patients.

This study analyses the mRNA and protein production and their regulation of macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8 and IL-6 by synovial fibroblasts obtained from patients with RA and OA. M-CSF was found to be produced constitutively as opposed to other cytokines. Stimulation of the cells with IL-1 beta caused a marked increase of GM-CSF, IL-8, IL-6 and as well as of M-CSF mRNA levels. In parallel, a time-dependent increase of M-CSF, GM-CSF, IL-8 and IL-6 protein production was observed. Among the cytokine mRNAs examined only that of M-CSF exhibited a pronounced stability in unstimulated synovial fibroblasts, whereas the other cytokines displayed short mRNA half-lives of 1-2 h. Induction by IL-1 beta markedly prolonged IL-8, IL-6 and GM-CSF mRNA half-lives to > 8 h which indicates increased mRNA stability. These findings suggest that among the cytokines that are produced in the inflamed synovium M-CSF may be particularly important for sustaining long-term influx, activation and survival of mononuclear phagocytes. GM-CSF, IL-8 and IL-6, by contrast, may be more involved in more acute cellular responses.

Arthritis, Rheumatoid↗
PubMed1994

Randomized study of recombinant human granulocyte colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation for high-risk lymphoid malignancies.

PURPOSE: The aim of this prospective randomized trial was to examine the efficacy and safety of filgrastim after high-dose chemotherapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Patients with poor-risk non-Hodgkin's lymphoma or relapsed Hodgkin's disease were treated in a randomized, open-label trial to study the use of filgrastim as an adjunct to high-dose chemotherapy and ABMT. Of 43 assessable patients, 19 were randomized to receive filgrastim by continuous subcutaneous infusion at a dose of 10 micrograms/kg/d, 10 to filgrastim 20 micrograms/kg/d, and 14 to a parallel control group that received no filgrastim after ABMT. RESULTS: For all filgrastim-treated patients analyzed together, the median time to neutrophil recovery > or = 0.5 x 10(9)/L after the day of ABMT was significantly accelerated to 10 days compared with 18 days in control patients (P = .0001). The median number of platelet transfusions was identical in both groups. Clinical parameters, including the median number of days with fever (1 v 4, P = .0418) and neutropenic fever (5 v 13.5, P = .0001) were significantly shorter in the filgrastim than in the control group. The number of days on intravenous antibiotics and duration of hospitalization were also shorter in the treated groups; however, the differences did not reach statistical significance. For patients treated with the two different dose levels of filgrastim, the neutrophil recovery and clinical results were similar. Filgrastim-associated toxicity appeared to be minimal, with five adverse events considered at least possibly related to filgrastim: two in the higher-dose group and three in the lower-dose group. All of these were rated moderate, except one case of severe bone pain that did not preclude continued filgrastim treatment at a lower dose. Survival and relapse-free survival were similar for control and filgrastim-treated patients. CONCLUSION: Taken together, the results of this first randomized study support the role of filgrastim given as an adjunct to ABMT in accelerating neutrophil recovery, as well as in reducing treatment-related morbidity and overall duration of the treatment procedure.

Adolescent↗
PubMed1994

Polyclonal and monoclonal thyroid nodules coexist within human multinodular goiters.

Although somatic mutations have been identified in a subset of thyroid nodules, the pathogenesis of nodules in multinodular goiters remains unclear. Clonal analysis indicates whether a nodule arises from the polyclonal proliferation of a group of cells or forms a clone from a genetically altered cell. Individual thyroid nodules have been shown to be of polyclonal or monoclonal origin. In this study we examined the clonality of several different nodules in patients with multinodular goiters. Clonality was established using the X-chromosomal probe M27 beta, which detects a multiallelic polymorphism at the locus DXS255 in 90% of females. Twenty-five nodules from 9 multinodular goiters were analyzed; 9 nodules were polyclonal, and 16 were monoclonal. Three goiters contained only polyclonal nodules, whereas 3 contained only monoclonal nodules. Polyclonal and monoclonal nodules coexisted in 3 goiters. In 2 goiters, the monoclonal nodules were shown to derive from different progenitor cells. We conclude that polyclonal and monoclonal nodules may coexist in multinodular goiters and that monoclonal nodules can originate from different cells. The coexistence of polyclonal and monoclonal nodules suggests that different pathogenic mechanisms occur simultaneously or that monoclonal nodules emerge secondarily from a polyclonal population due to a growth advantage from a genetically altered cell.

Adult↗
PubMed1994

[Stem cell apheresis--experiences in children].

Stem cell apheresis, as a means to support patients during aplasia, has become an important support in the management of patients with various malignant diseases in need for heavy therapeutic regimens. Progress in this field is due, among other reasons, to better knowledge of pathophysiology in haematopoiesis and of the functioning of cytokines. Furthermore, the technical feasibility of apheresis has been improved to such an extent as to allow for collection of a stem cell-containing fraction almost in pure form. Our experience with stem cell apheresis is relatively short but includes also children between the ages of 1 and 21 years (median: 5 1/2 years). Whereas the clinical results have been published elsewhere, we here report our experience in terms of safety, using the Fresenius AS 104 machine.

Adolescent↗
PubMed1993

Constitutive expression of interleukin-8 and its receptor in human myeloid and lymphoid leukemia.

Interleukin-8 (IL-8), a member of the family of small inducible cytokines, is mainly known for its striking neutrophil-activating properties. Constitutive IL-8 production is negligible in normal leukocytes. We examined expression of IL-8 and its receptor in purified leukemic cells from patients with untreated acute myeloblastic leukemia (AML) and lymphoid leukemias. In the majority of cases (18 of 26 AML, 8 of 15 lymphoid leukemias), the cells constitutively expressed IL-8 mRNA transcripts. In all but 3 of these cases, IL-8 mRNA-expressing cells secreted biologically active IL-8 protein. Immunocytochemical analysis showed intracellular IL-8 (5% to 90% of total cells), demonstrating that the leukemic cells themselves rather than contaminants (monocytes or lymphocytes) were the source of IL-8. Ten of 25 AML samples expressed IL-8 receptor mRNA and, with 1 exception, the IL-8 receptor expressing cells also produced its ligand. In contrast, all lymphoid leukemias were negative. Furthermore, frequent coexpression of IL-8 and IL-1 beta transcripts was seen in both AML and lymphoid leukemia samples, whereas fewer cases coexpressed IL-8 and either macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. In leukemic cells expressing the IL-8 receptor, IL-8 induced cytosolic free calcium changes, indicating activation of the classical signaling pathway. These results suggest that IL-8 may have biologic activities in hematopoiesis.

Blotting, Southern↗
PubMed1993

[Emergency blood picture].

Assessment of peripheral blood counts and blood film analysis are frequently performed as diagnostic procedures in emergency medicine. Far fewer situations exist, however, in which these analyses are the main clue in establishing an emergency diagnosis. Artifacts can lead to wrong diagnosis, e.g. pseudo-thrombocytopenia, which is defined as a low platelet count resulting from a laboratory artifact. Severe neutropenia (agranulocytosis) and extreme hyperleukocytosis, as well as suspicion of acute leukemia, require a rapid diagnostic work-up. A newly detected anemia should not necessarily be treated by packed red cell transfusions. The decision whether an anemic patient ought to receive transfusions should be based on the speed with which the anemia has developed, as well as on clinical judgement. As a rule a chronic anemia patient with hemoglobin above 70 g/l does not need transfusions. An uncritical transfusion policy can even cause emergencies, e.g. in patients with megaloblastic anemia or in anemic multiple myeloma patients with a hyperviscosity syndrome. An elevated hematocrit requires prompt further investigations. This is of utmost importance if one considers the diagnosis of polycythemia vera rubra, a disease in which patients are particularly prone to thrombotic complications. Fragmented red cells (schistocytes) on peripheral blood smears constitute a cardinal diagnostic clue for the detection of microangiopathic hemolytic anemias (MAHA), in particular for the diagnosis of the life-threatening thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). Malaria is another example for a chief role of blood smears examination in achieving a rapid diagnosis. If one encounters an unexpected severe thrombocytopenia, a marrow examination reveals whether it is due to rapid peripheral destruction, or due to a marrow failure. Furthermore, in any patients with an unanticipated thrombocytopenia, a disseminated intravascular coagulation and a MAHA should be ruled out. Heparin-induced thrombocytopenia is a rare, but possibly fatal complication of therapy with heparins.

Blood Cell Count↗
PubMed1993

cDNA cloning of human N-Oct3, a nervous-system specific POU domain transcription factor binding to the octamer DNA motif.

Octamer transcription factors (Oct or OTF) are a subset of the POU family of transcription factors which regulate transcription of cellular and viral genes by binding to the octamer sequence motif ATGCAAAT. Neurons and astroglial cells harbour, in addition to the ubiquitous Oct 1 factor, at least four specific factors termed N-Oct 2,3,4 and 5. Here we report the cloning of a human brain-derived cDNA that encodes the N-Oct 3 protein (443 aa) which is the human counterpart of the murine brain-2 gene product. Extracts from mammalian cells transfected with an N-Oct 3 expression vector yield three octamer DNA binding complexes in the electrophoretic mobility shift assay (EMSA): N-Oct 3 and two smaller complexes comigrating with the N-Oct 5A and 5B proteins of brain extracts. We present data suggesting that the N-Oct 5A and 5B proteins are generated by alternative translation initiation at internal AUG residues which are located before the POU domain. In contrast to the putative N-Oct 5 proteins, which are transcriptionally inert, the N-Oct 3 protein activates transcription from a reporter gene promoter with an octamer sequence, when transiently expressed in HeLa cells.

Amino Acid Sequence↗
PubMed1993

[The role of cytokines in normal and in leukemic hematopoiesis].

There have been astonishing advances in the field of cytokines in recent years. In the present paper we focus on a few hematopoietic cytokines and discuss some aspects of the biology and pathophysiology of cytokines and their receptors in normal and leukemic hematopoiesis. We also address future developments and in particular the role of negative stem cell regulators.

Animals↗