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Biomedical subjects

R Haas

Publications and source records attributed to R Haas.

At least 253 records · Page 14Linked to original sources
PubMed1993

Sustained remission of idiopathic hypereosinophilic syndrome following alpha-interferon therapy.

Two patients with idiopathic hypereosinophilic syndrome (HES) refractory to treatment with corticosteroids and hydroxyurea received alpha-interferon (alpha-IFN) for 3 and 1 years, respectively. Eosinophil counts dropped below 1.5 x 10(9)/l at weekly doses of 2-7 x 3 million units alpha-IFN. More than a year after discontinuation of alpha-IFN, 1 patient remains in a stable remission. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plasma levels were found to be normal in this patient, although GM-CSF is known to stimulate eosinophil proliferation in vitro. Based on the favorable clinical results of alpha-IFN, further studies are necessary to define its role in the treatment of HES.

Adult↗
PubMed1993

Autografting with peripheral blood stem cells mobilized by sequential interleukin-3/granulocyte-macrophage colony-stimulating factor following high-dose chemotherapy in non-Hodgkin's lymphoma.

This report summarizes our results of sequential treatment with IL-3 and GM-CSF following high-dose chemotherapy with respect to the yield and composition of peripheral blood stem cells (PBSC). Eight patients with high-grade non-Hodgkin's lymphoma were included in the study. Starting 24 h after high-dose cytosine arabinoside (Ara C)/mitoxantrone, IL-3 was given for 6 days, followed by GM-CSF. The increase of circulating hematopoietic progenitor cells during leukocyte recovery varied substantially from patient to patient. Up to a 22-fold interindividual difference was observed for the peak levels of CD34+ cells. A special focus of our study was the antigenic profile of the CD34+ PBSC. On analysis of the antigenic profile of the CD34+ cells, the proportion of CD34+/HLA-DR- and CD34+/CD38- cells representing non-committed hematopoietic stem cells was consistently < 5%. The vast majority of CD34+ cells was found to coexpress CD33 (86.3 +/- 2.1%, mean +/- SEM), reflecting myeloid lineage commitment. CD71 antigen was present on 47.4 +/- 3.0% CD34+ cells with two populations (CD71dim/bright), while the percentage of early B lymphoid (CD34+/CD19+) progenitor cells was extremely low (0.38 +/- 0.13%). We therefore conclude that the cytokines currently available such as G-CSF, GM-CSF or IL-3 facilitate an ontogenetic phenomenon supporting the redistribution of hematopoietic progenitor cells after cytotoxic treatment. Six patients were autografted with the IL-3/GM-CSF-exposed blood stem cells following high-dose conditioning therapy. It is worth noting that no additional BM or hematopoietic growth factors were given post-transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Increased serum levels of granulocyte colony-stimulating factor after autologous bone marrow or blood stem cell transplantation.

The objective of our study was to evaluate the biologic role of granulocyte colony-stimulating factor (G-CSF) for hematologic reconstitution following autologous bone marrow transplantation (ABSCT). Using a commercially available enzyme-linked immunosorbent assay, serum levels of G-CSF were measured in samples from 48 patients (30 male/18 female) who underwent ABMT or ABSCT. Their median age was 34.5 years (range 16 to 51). Autografting was performed (40 ABMT, 8 ABSCT) in 23 AML, 8 ALL and 17 malignant lymphoma patients. Patients transplanted with blood stem cells had a faster leukocyte and neutrophil recovery compared with the ABMT patients (p < 0.025 and p < 0.05, respectively). During marrow aplasia G-CSF serum levels were elevated in all patients, with a median peak value of 2199 pg/mL (range 453 to 8676 pg/mL). A strong reverse correlation (R = -0.76, p < 0.01) could be demonstrated between G-CSF serum level and white blood count (WBC). An additional increase of G-CSF serum levels on days of fever (> or = 38.5 degrees C) or documented infectious disease was observed. During the early phase of marrow aplasia, the endogenously produced amounts of G-CSF reached concentrations which are used for in vitro stimulation of colony-forming unit granulocyte (CFU-G). The relationship between G-CSF serum level and WBC supports the central role of this circulating hemopoietin following myeloablative treatment and autotransplantation. During periods of higher demand such as fever and infectious complications, endogenous G-CSF production is enhanced.

Adolescent↗
PubMed1993

Successful autografting following myeloablative conditioning therapy with blood stem cells mobilized by chemotherapy plus rhG-CSF.

High-dose conditioning therapy followed by autografting with blood stem cells rather than bone marrow has become an increasingly used transplantation modality for patients with chemosensitive malignancies. We treated 10 patients with malignant lymphoma in sensitive relapse with recombinant human granulocyte colony-stimulating factor (rhG-CSF) following salvage therapy. rhG-CSF was given subcutaneously (5 micrograms/kg/day) starting 24 hours after chemotherapy and stem cell collection was performed by repeated leukaphereses during leukocyte recovery. The yield of myeloid progenitors varied between 0.79 and 38.36 x 10(4) CFU-GM/kg body weight (median 4.1 x 10(4). A strong correlation was found between the number of granulocyte-macrophage colony-forming cells (CFU-GM) plus blast-forming erythroid cells (BFU-E) and CD34-positive (CD34+) cells (R = 0.80; p < 0.001). The majority of CD34+ cells (> 95%) strongly coexpressed human lymphocyte antigen-DR (HLA-DR) and CD38, whereas CD33 varied between 20% and 94%. Costaining of CD34+ cells for CD19 above the control level could not be detected, suggesting that early B lymphoid progenitors are not expanded or released into the circulation by rhG-CSF. Following total body irradiation (TBI)/cyclophosphamide or the CBV regimen (cyclophosphamide, BCNU, VP-16), all patients achieved complete engraftment with a median of 14 days for 1.0 x 10(9)/L white blood cells (WBC), 15 days for 0.5 x 10(9)/L polymorphonuclear cells (PMN) and 22 days for 20 x 10(9)/L platelets. The quantity of CFU-GM/kg transplanted was predictive for neutrophil and platelet recovery. The strongest correlation, however, was found between the number of CD34+ cells/kg autografted and platelet recovery (R = -0.86; p < 0.001). The patients transplanted with more than 5 x 10(6)/kg CD34+ cells reached an unsubstituted platelet count > 20 x 10(9)/L within 8 to 12 days. Our data demonstrate that rapid and complete engraftment can be achieved following myeloablative conditioning therapy with rhG-CSF-exposed blood stem cells without the need for additional bone marrow support or growth factor administration posttransplantation.

Adult↗
PubMed1993

Autologous blood progenitor cell transplantation in relapsed Hodgkin's disease--the role of haematopoietic growth factors.

Thirty-seven patients with Hodgkin's disease in sensitive relapse were autografted using blood-derived haematopoietic progenitor cells. At the time of transplantation 22 patients were in complete remission and 15 patients in partial remission. Twenty-six patients were male and 11 female, with a median age of 31 years (range 21-52). The pre-transplant conditioning therapy consisted of cyclophosphamide, BCNU and etoposide (CBV). Five patients died of transplant-related complications and 11 patients relapsed after a median time of four months following autografting. For the remaining 21 patients the probability of event-free survival (EFS) was 45% at 68 months. Blood progenitor cell collection can be integrated into salvage therapy by administering haematopoietic growth factors (HGFs) to enhance the chemotherapy-induced progenitor cell rebound during leucocyte recovery. In a subgroup of 14 patients, seven received recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (250 micrograms/m2/day) by continuous intravenous infusion following dexamethasone, BCNU, etoposide and melphalan (Dexa-BEAM) as salvage therapy, while seven patients were treated without haematopoietic growth factor (HGF) post-chemotherapy. The yield of total nucleated cells (TNC) and granulocyte-macrophage colonies (CFU-GM) collected per leukapheresis was 2.2- and 2.4-fold higher respectively in the rhGM-CSF-treated patients. Following high-dose conditioning therapy, the seven patients autografted with rhGM-CSF-mobilised stem cells showed a faster leucocyte recovery compared with the control group. Neutrophil recovery (> 1.0 x 10(9)/L) and platelet recovery (> 20 x 10(9)/L) were also accelerated in the rhGM-CSF-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Idarubicin/cytosine arabinoside and mitoxantrone/etoposide for the treatment of de novo acute myelogenous leukemia.

Since January 1989, 56 patients (31 females and 25 males) with de novo acute myelogenous leukemia have been included in the study. Their median age was 43 years (range, 15 to 60 years) with a distribution according to French-American-British morphologic subtypes as follows: six M1, 14 M2, four M3, 19 M4, nine M5, two M6, and two M7. The induction regimen (IDAC) consisted of idarubicin (12 mg/m2/d intravenously [IV] days 1 to 3) in combination with cytarabine (100 mg/m2/d continuous IV days 1 to 7). Patients achieving complete remission (CR) or partial remission received another cycle of IDAC followed by NOVE (mitoxantrone 10 mg/m2/d IV days 1 to 5 and etoposide 100 mg/m2/d IV days 1 to 5). Fifty-four patients are evaluable for response: after two cycles of IDAC, 42 patients had attained CR (78%), while 76% of these had already reached CR after the first cycle. Of the initial 11 nonresponders to IDAC, four obtained CR after NOVE. Thus, 46 of 54 patients (85%) achieved CR after sequential treatment with IDAC and NOVE. In the last 17 patients who entered CR or partial remission after the first cycle of IDAC, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; 3 micrograms/kg/d) was administered for 6 days starting 3 days prior to the second cycle of IDAC. For consolidation with NOVE, rhGM-CSF was given according to the same dosage schedule. After 72 hours of rhGM-CSF treatment, the white blood cell count showed a median 3.9-fold increase, without appearance of myeloblasts in the peripheral blood. During sequential chemotherapy, no significant complications (in particular, no major cardiac toxicity) were observed. Postremission, patients were either given bone marrow transplants, received late consolidation with high-dose cytarabine/mitoxantrone, or were followed up without any further treatment. Of the 46 patients evaluable for disease-free survival, 21 patients (45%) remain in CR with a 34% probability of disease-free survival at 37 months. The response-adapted treatment with IDAC/NOVE is effective and very well tolerated. To define the therapeutic impact of rhGM-CSF, a randomized trial will be required.

Acute Disease↗
PubMed1992

Treatment of relapsed or refractory adult acute lymphocytic leukemia.

Sixty-six adult patients were treated for relapsing or refractory acute lymphocytic leukemia (ALL). The induction treatment consisted in a (1) first phase with vindesine 3 mg/m2 intravenously (IV) on days 1, 8, and 15; daunorubicin 45 mg/m2 IV on days 1, 8, and 15; erwinia-asparaginase 10,000 U/m2 IV on days 7, 8, 14, and 15; and prednisone 60 mg/m2 orally on days 1 to 21 and a (2) second phase with cytarabine 3000 mg/m2 as a 3-hour infusion two times a day on days 1 to 4 (in patients greater than 50 years of age we used 1000 mg/m2), and etoposide 100 mg/m2 IV on days 1 to 5. Side effects of induction Phase I were predominantly hematologic with subsequent infections. In Phase II, some patients additionally had gastrointestinal, cutaneous, ocular, and hepatic toxicity. Five patients died during Phase I and another died during Phase II. Five of these patients had T-cell ALL. Thirty-four (64%) of 54 patients in their first relapse had a complete remission (CR) with a median disease-free survival (DFS) of 2.9 months. The median overall survival (OAS) was 6.6 months. Seven of 12 patients with primary refractory disease, a second relapse, or relapse after bone marrow transplantation (BMT) had a CR. The CR rate and survival after first relapse was significantly better in patients with a preceding CR of more than 18 months compared with those with a shorter preceding remission. The leukocyte count was a second significant but not independent risk factor. There was a negative correlation between the leukocyte count and the duration of the preceding CR. The duration of the preceding CR was the major prognostic factor for survival in multivariate analysis. Twenty-two patients received BMT. None of nine patients with autologous BMT is alive and disease-free; 5 of 13 who underwent allogeneic BMT are. It was concluded that this treatment efficiently induced remission with tolerable toxicity. The remission duration should be improved by optimized consolidation treatment.

Adult↗
PubMed1992

Cloning and genetic characterization of a Helicobacter pylori flagellin gene.

Helicobacter pylori produces polar sheathed flagella, which are believed to be essential for the bacterial colonization of the human gastric mucosa. Here we report on the cloning and genetic characterization of a H. pylori gene encoding the subunit of the flagellar filament, the flagellin. Screening of a genomic library of H. pylori with an oligonucleotide probe derived from the N-terminal amino acid sequence of purified flagellin resulted in a recombinant plasmid clone carrying the flagellin-encoding gene flaA on a 9.3 kb Bg/II fragment. The nucleotide sequence of flaA revealed an open reading frame of 1530 nucleotides, encoding a protein with a predicted molecular mass of 53.2 kDa, which is similar in size with the purified flagellin protein in SDS-polyacrylamide gel electrophoresis. Sequence alignment of H. pylori flagellin (FlaA) with other bacterial flagellins demonstrates a high degree of similarity in the amino-terminal and carboxy-terminal regions, including those of the closely related genus Campylobacter (56% overall identity with Campylobacter coli flaA), but little homology in the central domain. Southern hybridizations of chromosomal DNA with flaA-specific probes did not reveal the presence of additional homologous flagellin genes in H. pylori. Sequence analysis of the flaA flanking regions and mapping of the flaA mRNA start site by a primer extension experiment indicated that transcription of the gene is under the control of a sigma 28-specific promoter sequence in H. pylori. The region upstream of the flaA promoter is subject to local DNA modification, resulting in the masking of two out of three closely linked HindIII restriction sites in the chromosome of strain 898-1. Escherichia coli strains harbouring the recombinant plasmid did not produce full-length flagellin and data obtained with FlaA fusion proteins using an E. coli plasmid expression system suggest that a distinct nucleotide sequence in the gene interferes with productive translation of this protein in E. coli.

Amino Acid Sequence↗
PubMed1992

Silent pilin genes of Neisseria gonorrhoeae MS11 and the occurrence of related hypervariant sequences among other gonococcal isolates.

Pilin variation in Neisseria gonorrhoeae depends on a family of variant genes that undergo homologous, intragenic recombination. This work focuses on the repertoire of silent variant pilin genes in strain MS11, which contribute to the extensive variation of the expressed gene copy. A total of 17 silent copies were identified, which are, to varying degrees, truncated at their 5' coding region and grouped in seven distinct pil loci. Most silent copies belong to loci pilS1, pilS2 and pilS6, which contain six, two and three silent copies, respectively, tandemly arranged. The pilS5 and pilS7 loci each contain only a single copy. In addition, two silent copies are associated with each of the two pilE loci. By comparison with sequences present in the expressed gene of other variants of the same strain, it is suggested that each silent locus is capable of donating variant sequences into the expression locus and, thus, each silent copy can contribute to the variability of pilin expression. Often, concomitant with changes in the expressed copy, the silent copies of the pilE1 locus undergo recombinations as well. Analyses of unrelated clinical isolates of N. gonorrhoeae reveal homologies of hypervariant pilin sequences with those present in strain MS11, suggesting a limited diversity of such sequences within the gonococcal population and the existence of substantial functional constraints on the variability of pilin and pili. The data further indicate that hypervariant pilin sequences are subject to horizontal exchange and interstrain recombination.

Bacterial Outer Membrane Proteins↗
PubMed1992

Interaction of two variable proteins (PilE and PilC) required for pilus-mediated adherence of Neisseria gonorrhoeae to human epithelial cells.

Pili confer the initial ability of Neisseria gonorrhoeae to bind to epithelial cells. Pilin (PilE), the major pilus subunit, and a minor protein termed PilC, reportedly essential for pilus biogenesis, undergo intra-strain phase and structural variation. We demonstrate here that at least two different adherence properties are associated with the gonococcal pili: one is specific for erythrocytes, which is virtually unaffected by PilE variation, and another is specific for epithelial cells, and is modulated in response to the variation of PilE. Based on this finding, mutants of a recA- strain were selected that had lost the ability to bind to human cornea epithelial cells (A-) but retained the ability to form pili (P+) and to agglutinate human erythrocytes (H+). The adherence-negative mutants failed to produce detectable levels of PilC1 or PilC2 proteins, representing piIC phase variants generated in the absence of RecA. The A- pilC phase variants were indistinguishable from their A+ parents and spontaneous A+ revertants with regard to the amount of PilE produced and its electrophoretic mobility, the degrees of piliation and haemagglutination, and the pilE nucleotide sequence. These data demonstrate a central role for PilC in pilus-mediated adherence of N. gonorrhoeae to human epithelial cells and further indicate that neither PilC1 nor PilC2 is obligatory for the assembly of gonococcal pili.

Amino Acid Sequence↗
PubMed1992

Production of Neisseria gonorrhoeae pili (fimbriae) in Pseudomonas aeruginosa.

Pseudomonas aeruginosa K/2PfS, when transformed with an expression plasmid harboring the pilin gene (pilE1) of Neisseria gonorrhoeae MS11, was able to express and assemble gonococcal pilin monomers into surface-associated pili, as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, immunoblotting, and immunoelectron microscopy. Concomitant with the expression of gonococcal pili in P. aeruginosa was the virtual loss of production of P. aeruginosa K/2PfS pili normally associated with the host cell.

Amino Acid Sequence↗
PubMed1992

Thrombosis of difficult intracranial aneurysms by the endovascular placement of platinum-Dacron microcoils.

Patients with symptomatic aneurysms that are not excluded from the cerebral circulation have a poor prognosis. Standard treatment is surgical exploration with direct clipping of the aneurysm. Because of their large size or relationship to the base of the skull, some aneurysms may not be suitable for direct surgical clipping and may require alternative treatment modalities. A prospective clinical and radiological study of seven patients treated with the endovascular placement of platinum-Dacron microcoils to exclude the aneurysm from the cerebral circulation is reported. The seven patients ranged in age from 37 to 63 years; four were women. At completion of the endovascular procedure, total occlusion of the aneurysm with preservation of the parent artery had been achieved in four patients and 90% occlusion of the aneurysm in two. In the seventh patient, occlusion of the internal carotid artery resulted in the patient's death. At the 6-month follow-up review, both patients with an aneurysm less than 20 mm in size had persistent aneurysm thrombosis; however, the two patients with giant aneurysms had partial recanalization. Both required repeat thrombosis of their aneurysm with the placement of additional microcoils, one at 6 weeks and one at 6 months. These two patients have persistent aneurysm thrombosis at 12 months following their second procedure. The patient mortality rate for this study was 14%, while the procedure mortality/morbidity rate was 9%. It is concluded that thrombotic aneurysm therapy of difficult aneurysms is a safe procedure and will have a place in the treatment of selected aneurysms.

Adult↗
PubMed1992

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) subsequent to chemotherapy improves collection of blood stem cells for autografting in patients not eligible for bone marrow harvest.

Fourteen patients with relapsed Hodgkin's disease responded to a salvage therapy with Dexa-BEAM (dexamethasone, BCNU, etoposide, Ara-C and melphalan). In seven patients a continuous i.v. infusion with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was started subsequent to Dexa-BEAM (+rhGM-CSF) while the other seven patients received no hemopoietic growth factor (-rhGM-CSF). It was our objective to study the impact of rhGM-CSF on the collection of blood-derived hemopoietic stem cells in patients with extensive prior chemo- and radiotherapy not eligible for marrow harvest. Compared to baseline, we observed a significant increase of colony-forming units granulocyte-macrophage (CFU-GM) in the peripheral blood of patients receiving rhGM-CSF (p less than 0.05). On average, the yield of total nucleated cells and CFU-GM collected per single leukapheresis was 2.2 and 2.4-fold higher in the rhGM-CSF-treated patients respectively (p less than 0.05). With rhGM-CSF the interval from the start of chemotherapy to the end of blood stem cell collection could be reduced by 6 days (p less than 0.05). Following the CBV pretransplant regimen (cyclophosphamide, BCNU, etoposide), the reinfusion of rhGM-CSF-exposed stem cells resulted in a shorter time of leukocyte recovery (p less than 0.05). The number of CFU-GM/kg body weight transplanted was found to be predictive for the time of neutrophil recovery (p less than 0.05). In patients with bone marrow hypoplasia or fibrosis, rhGM-CSF as part of an effective salvage therapy improves the collection of blood stem cells that are capable of restoring hemopoiesis after high-dose pretransplant therapy.

Adult↗
PubMed1991

Etoposide in acute leukemia. Past experience and future perspectives.

Etoposide as a single agent is active in relapsed and refractory acute myelogenous leukemia (AML), with complete responses (CR) rates of 10% to 25%. The drug has been safely combined with cytarabine, azacytidine, vinca alkaloids, and anthracyclines, inducing remission rates of 20% to 60% in patients with previously treated AML. The experience with etoposide in acute lymphoblastic leukemia is less extensive, but the drug seems to be active in combination with cytarabine or aclacinomycin. In addition, etoposide is combined with cytarabine and anthracyclines for the primary treatment of AML. The response rates thus achieved are comparable with those obtained with standard regimens. A Phase I/II trial was initiated to study the efficacy of the NOVE combination (mitoxantrone [10 mg/m2/d, days 1 to 5] plus etoposide [100 mg/m2/d for 3, 4, or 5 days] in patients with refractory AML. The results showed that extended duration of etoposide administration is associated with higher CR rates. Overall, a CR rate of 43% was achieved in 61 patients. A sequential regimen with IDAC (idarubicin/cytarabine) and NOVE was designed for primary treatment of adult patients with AML. Cycles of IDAC or NOVE are applied depending on response. The results of the pilot study with this strategy were encouraging with 18 of 20 patients achieving CR. Further studies are under way to verify the efficacy of this strategy.

Antineoplastic Combined Chemotherapy Protocols↗