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Biomedical subjects

A Ganser

Publications and source records attributed to A Ganser.

At least 127 records · Page 7Linked to original sources

[Possibilities and limits of ambulatory supportive measures in oncology exemplified by antibiotic therapy of febrile neutropenia].

Neutropenia is common after intensive chemotherapy. Hospitalization and intravenous broad-spectrum antibiotics are the standard of care for febrile neutropenic patients because of the risk of serious complications and associated mortality. Short neutropenic periods (< 7 days) are considered to be at a low-risk in cases when fever occurs in clinically stable patients. Recent work suggests that such a low-risk population of febrile neutropenic patients might benefit from alternatives to inpatient care. The agents that best qualify for outpatient treatment include quinolones i.v./p.o., glycopeptides, ceftriaxone and aminoglycosides, particularly if the latter are given once daily. Response rates to antimicrobial therapy range from 80 to 95% in low-risk febrile neutropenia episodes. Treating these patients in an outpatient setting avoids hospitalization in 75 to 95%. There is no doubt that outpatient therapy may have several advantages, including lower costs and an improved quality of live. Outpatient antibiotic therapy for febrile low-risk neutropenia should be considered as an acceptable alternative to inpatient treatment.

Administration, Oral↗

A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group.

The safety and efficacy of filgrastim as an adjunct to acute myeloid leukemia (AML) induction and consolidation therapy was assessed in this prospective double-blind, randomized, placebo-controlled, multicenter trial. A total of 521 consecutive de novo AML patients aged 16 or more years were randomized to receive filgrastim (5 microg/kg/d subcutaneously) or placebo after standard induction as well as consolidation chemotherapy. Blinded study drug was given from 24 hours after chemotherapy until the absolute neutrophil count was >/=1.0 x 10(9)/L for 3 consecutive days. The overall complete remission rate was 68%. After a median follow-up of 24 months (range 5 to 40) the median disease-free survival was 10 months (95% confidence interval [CI], 8.7 to 10.8) and the median overall survival was 13 months (95%CI, 12.2 to 14.6). These did not differ between treatment groups. Patients receiving filgrastim experienced neutrophil recovery 5 days earlier after induction 1 than those receiving placebo (P < .0001). This was accompanied by reductions in the duration of fever (7 v 8.5 days; P = .009), parenteral antibiotic use (15 v 18.5 days; P = .0001), and hospitalization (20 v 25 days; P = .0001). Similar reductions were seen after induction 2 and the consolidation courses. There was a significant reduction in the number of patients requiring systemic antifungal therapy in the filgrastim group during induction treatment (34% v 43%; P = .04). In conclusion, filgrastim is safe in that it had no negative impact on the prognosis of the AML patients. In addition, it effectively reduced the duration of neutropenia, leading to significant clinical benefits by reducing the duration of fever; requirement for parenteral anti-infectives, specifically amphotericin B; and the duration of hospitalization.

Adolescent↗

The human C3a receptor is expressed on neutrophils and monocytes, but not on B or T lymphocytes.

The pathophysiological relevance of the complement split product C3a as a proinflammatory mediator is still ill defined. The expression pattern of the human C3a receptor (C3aR) can provide important clues for the role of this anaphylatoxin in inflammation. There is strong evidence for C3aR expression on basophils, and eosinophils, but additionally, only on tumor cell lines of leukemic or hepatic origin. It is unclear whether neutrophils also express the C3aR, but need a costimulus provided by eosinophils for certain biological responses, or whether neutrophils lack the C3aR and respond to C3a via a secondary stimulus generated by eosinophils, i.e., by an indirect mode. In the present study, polyclonal antiserum raised against the second extracellular loop of the C3aR was used to characterize C3aR expression on peripheral blood leukocytes. For high degree purification of neutrophils, a negative selection method was established that decreased the contamination with CD9(bright+) eosinophils down to <0.2%. Flow cytometric analyses, functional assays, and binding assays on highly purified neutrophils confirmed C3aR expression and coupling. Monocytes were identified as an additional C3aR-positive cell population of the peripheral blood. The expression of the C3aR on eosinophils could be confirmed. In contrast, the receptor could not be detected on unchallenged B or T lymphocytes (or lymphocyte-derived Raji cells).

Animals↗

Specific hammerhead ribozyme-mediated cleavage of mutant N-ras mRNA in vitro and ex vivo. Oligoribonucleotides as therapeutic agents.

Two hammerhead ribozymes targeted to point mutations in codon 13 of the N-ras oncogene were synthesized and their catalytic activity and substrate specificity evaluated in vitro and ex vivo. In vitro studies showed that these ribozymes were specific for the oncogenic form of N-ras, since cleavage was observed only in a 849-nucleotide-long transcript containing mutant but not wild-type N-ras sequences. For the ex vivo studies, the ribozymes were 2'-modified to protect them against degradation by nucleases. 2'-Fluoro-2'-deoxyuridine/cytidine-substituted ribozymes were nearly as active as their unmodified counterparts, but had a prolonged stability in cell culture supernatant containing fetal calf serum. The stability of the modified ribozymes increased by introduction of terminal phosphorothioates groups without significant influence in their catalytic efficiency. A sensitive assay based on the use of N-ras/luciferase fusion genes as a reporter system was established to detect ribozyme-mediated cleavage in HeLa cells. A reduction of nearly 60% in luciferase activity was observed in cells expressing mutant but not wild-type N-ras/luciferase fusion transcripts. Moreover, cleavage of N-ras transcripts in HeLa cells was directly confirmed by a semi-quantitative RT-PCR assay.

Genes, ras↗

IL-3 in the clinic.

Since the cloning of human interleukin 3 (IL-3) in 1986 [1] and the demonstration of its proliferative effects on multiple hematopoietic progenitor cells, IL-3 has been widely studied to treat different states of bone marrow failure or hematologic malignancies, to mobilize or expand hematopoietic progenitor cells for transplantation, and to support engraftment after bone marrow transplantation. However, no condition for the clinical use of IL-3 has been established so far despite its theoretical advantages as an early-acting cytokine and in contrast to erythropoietin (EPO), G-CSF, or GM-CSF all of which have already been approved for several clinical modalities. Here we shortly review our current knowledge about the effects of IL-3 on the molecular and cellular level, summarize recent clinical studies with IL-3, and discuss further perspectives for the use of this cytokine.

Cells, Cultured↗

Acute abdomen due to endometriosis as a diagnostic and therapeutic challenge in the treatment of acute myelocytic leukemia.

Acute abdominal pain is a frequent diagnostic and therapeutic challenge in hematologic patients. We report on the very rare case of organ endometriosis with acute abdominal symptoms in a 43-year-old female patient with AML-M5, starting 4 days after induction chemotherapy with idarubicin, ara-C, and etoposide. The patient presented with an acute abdomen with clinical findings of acute cholecystitis, subileus, and local pain in the right upper abdomen accompanied by severe diarrhea. Probably due to impaired intestinal resorption, menstrual bleeding occurred despite regular administration of lynestrenol. Ultrasound examination of the abdomen disclosed a tumor with poor echoes in the pouch of Douglas, a subcapsular splenic hemorrhage, and a thickened gallbladder wall with surrounding edema. A cystic adnex tumor was confirmed by endovaginal ultrasound. Based on history and the findings on ultrasound, an endometriosis was diagnosed, and the LHRH agonist (nafarelin) was administered nasally in combination with lynestrenol. Following this medication the abdominal pain ceased, supporting the diagnosis of endometriosis. Nasal administration of an LHRH agonist in the following cycles of chemotherapy was effective in preventing further abdominal discomfort and vaginal bleeding. LHRH agonists should be given to patients with known endometriosis before starting myeloablative chemotherapy to prevent painful hemorrhage from endometriosis.

Abdomen, Acute↗

G-CSF and cyclosporin induce an increase of normal cells in hypoplastic paroxysmal nocturnal hemoglobinuria.

Four paroxysmal nocturnal hemoglobinuria (PNH) patients with severe thrombocytopenia, hemolytic anemia and neutropenia were treated using a combination of filgrastim (G-CSF) and cyclosporin. In all patients a trilineage response of hematopoiesis was achieved. In addition, the proportion of glycosyl-phosphatidylinositol (GPI)-deficient granulocytes decreased. All patients mobilized CD34+ hematopoietic progenitors into peripheral blood after starting treatment with G-CSF. The majority of early progenitors (CD34+ CD38-) after mobilization into peripheral blood was found to be unaffected by the GPI-anchoring defect. No patient developed leukemia while under therapy. We conclude from these data that the combination of G-CSF and cyclosporin represents an efficient option for the treatment of hypoplastic PNH.

Adult↗

Clinical use of hematopoietic growth factors in patients with myelodysplastic syndromes.

In myelodysplastic syndromes (MDS), pancytopenia and defective function of neutrophils and platelets lead to a high risk of infectious and hemorrhagic complications. The progression to acute myeloid leukemia adds to morbidity and mortality. Supportive care including red blood cell and platelet transfusions are still the cornerstone of therapeutic management. However, the clinical use of the recombinant hematopoietic growth factors has enlarged the range of therapeutic applications in patients with MDS. It is possible to reverse neutropenia in MDS patients by administration of G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte-monocyte colony stimulating factor). Because of the lower incidence of adverse events, G-CSF is preferable. However, neither G-CSF nor GM-CSF have been shown to reduce the rate of severe infection or mortality from infection when given prophylactically. In the case of a severe infection, therapeutic administration of G-CSF together with antibiotics might be justified in otherwise neutropenic MDS patients. Preliminary data suggest it to be possible to identify MDS patients with a higher than 50% chance of reversal of anemia or transfusion dependency by treatment with high-dose erythropoietin (EPO). Since patients with only slight impairment of erythropoiesis and no transfusion dependency have the highest response rates but need EPO the least, pharmacoeconomic analyses are urgently needed. Controlled randomized trials will have to ascertain whether combinations of EPO with G-CSF or GM-CSF are of benefit. Clinical studies with thrombopoietin (megakaryocyte growth and differentiation factor) have to be initiated to find out whether thrombocytopenia in MDS can be reversed.

Aged↗

Elevated serum levels of S100 and survival in metastatic malignant melanoma.

Current reports suggest serum S100 as a prognostic marker for disease progression in advanced malignant melanoma. In this study, we assessed serum levels of S100 and multiple clinical factors in relation to overall survival in 99 patients with metastatic malignant melanoma seen at our institution between May 1990 and April 1996. For statistical analysis, we used both univariate and multivariate Cox proportional-hazards models. Elevated serum levels of S100 correlated with poor outcome in metastatic malignant melanoma (P < 0.0001), univariate analysis). Upon multivariate analysis, however, S100 added no information to known clinical prognostic parameters.

Aged↗

Immune thyroiditis after transplantation of allogeneic CD34+ selected peripheral blood cells.

A 28-year-old female patient underwent allogeneic PBSCT from her HLA-identical sister for AML in first CR. CD34+ cells were positively selected from PBPC using immunoaffinity columns. She received 8.0 x 10(6) CD34+ cells/kg and 1.74 x 10(6) CD3+ cells/kg body weight (BW). The patient developed acute GVHD III and mild limited chronic GVHD. Thirteen months after transplantation severe thyrotoxicosis requiring plasmapheresis occurred. Immune thyroiditis was confirmed cytologically by lymphocytic infiltration in a fine needle aspirate and by elevated thyroid-Ab-titers. The patient's donor had received thyroid hormone substitution for 10 years for hypothyroidism. The most probable cause of immune thyroiditis after allogeneic BMT is the transfer of antithyroid donor lymphocytes. These lymphocytes can also be transferred with a CD34+ selected peripheral stem cell graft. The transplantation of lymphocyte-depleted autologous bone marrow or PBPC grafts after myeloablative treatment is increasingly considered as potential treatment of severe autoimmune diseases. This case demonstrates that even low numbers of lymphocytes are capable of transferring autoimmune disorders.

Adult↗

Detection of melanoma cells in peripheral blood stem cell harvests of patients with progressive metastatic malignant melanoma.

The detection of melanocyte-specific messenger RNA in patients with malignant melanoma suggests the potential contamination of peripheral blood stem cell (PBSC) harvests by neoplastic cells. In this study, the melanocyte-specific transcripts of tyrosinase and Melan-A/MART-1 were used to detect neoplastic cells in PBSC harvests of nine metastatic malignant melanoma patients. Only one patient's PBSC harvest tested positive for tyrosinase. All harvests were negative for Melan-A/MART-1. Our results suggest that contamination of PBSC harvests with neoplastic cells may not contribute to disease progression following high-dose chemotherapy in advanced malignant melanoma.

Adult↗

Clinical and in vitro response to 13-cis-retinoic acid in interferon-alpha resistant renal cell carcinoma.

Retinoids are known to control many important biological processes, including differentiation, morphogenesis, growth and tissue homeostasis. More recently, clinical and pre-clinical results provide evidence for an antiproliferative effect of 13-cis-retinoic acid (13cRA) in interferon-alpha (IFN-alpha) treated renal cell carcinoma patients. The manner in which 13cRA augments antitumor effects and modulates biologic and clinical responses of renal cell carcinoma to IFN-alpha remains elusive. In the present study, we report induction of apoptosis and objective tumor regression in response to 13cRA in advanced renal cell carcinoma patients refractory to IFN-alpha. Among 21 patients treated there were one complete and four partial remissions (objective response rate, 24%; median response duration 8+ months). Preliminary evidence suggests that 13cRA acid may reverse IFN-alpha resistance in renal cell carcinoma.

Aged↗

Use of hematopoietic growth factors in the treatment of acute myelogenous leukemia.

Several randomized trials evaluating the effect of hematopoietic growth factors, especially granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), in the treatment of patients with acute myeloid leukemia, recently have been completed. The results of these trials generally show a reduction in the duration of neutropenia with variable results as far as severe infections, antibiotic use, and duration of hospitalization are concerned. Combining the data from the studies and especially from those with higher patient numbers, complete remission rates, event-free survival, and overall survival do not appear to be affected by the use of either G-CSF or GM-CSF after induction and consolidation therapy. The use of G-CSF or GM-CSF either before or during induction chemotherapy in an attempt to increase the leukemic cell kill has not resulted in improved response rates or survival. Only a few case reports indicate that G-CSF and GM-CSF might induce terminal differentiation of leukemic blast cells. Recently started trials evaluating the effect of megakaryocyte growth and development factor on platelet recovery indicate that it might not be easy to show a clinical benefit, possibly because of the rather low threshold counts needed for the prevention of overt bleeding. It still remains unclear whether the use of hematopoietic growth factors in these patients is cost-effective.

Acute Disease↗

Clinical use of hematopoietic growth factors in the myelodysplastic syndromes.

Recent advances in the molecular genetics of myelodysplastic syndromes (MDS) have shed new light on the pathogenesis of MDS allowing a better understanding of the defects of differentiation of the transformed clone and suppression of normal hematopoiesis. The clinical hematologist, however, continues to be challenged with the treatment of patients with MDS. Pancytopenia and defective function of neutrophils and platelets lead to a high risk of infectious and hemorrhagic complications. The progression to acute myeloid leukemia adds to morbidity and mortality. Supportive care including red blood cell and platelet transfusions are still the cornerstone of therapeutic management. While prophylactic administration of G-CSF or GM-CSF cannot be recommended, treatment of febrile neutropenia might benefit from administration of G-CSF in addition to antibiotics. Administration of high-dose erythropoietin will improve erythropoiesis in around 20% of the patients, mainly in those with rather preserved erythroid function and no or low transfusion need. Coadministration of erythropoietin with either G-CSF or GM-CSF could increase the response rate. Allogeneic stem cell transplantation still is the only curative treatment and prolongs survival. Intensive chemotherapy for advanced MDS is possible with an acceptably low rate of early death and a complete remission rate between 45% to 60%, while initial results of autologous transplantation are promising.

Antineoplastic Combined Chemotherapy Protocols↗