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Biomedical subjects

A Ganser

Publications and source records attributed to A Ganser.

At least 109 records · Page 6Linked to original sources
PubMed1998

Safety and toxicity of amphotericin B in glucose 5% or intralipid 20% in neutropenic patients with pneumonia or fever of unknown origin: randomised study.

OBJECTIVE: To compare the feasibility of treatment, safety, and toxicity of intravenous amphotericin B deoxycholate prepared in either glucose or intralipid for empirical antimycotic treatment of neutropenic cancer patients. DESIGN: Single centre stratified, randomised non-blinded phase II study. SETTING: University hospital providing tertiary clinical care. SUBJECTS: 51 neutropenic patients (leukaemia (35), lymphoma (11), solid tumours (5)) with refractory fever of unknown origin (24) or pneumonia (27). INTERVENTIONS: Amphotericin B 0.75 mg/kg/day in 250 ml glucose 5% solution or mixed with 250 ml intralipid 20%, given on eight consecutive days then alternate days, as a 1-4 hour infusion. MAIN OUTCOME MEASURES: Feasibility of treatment, subjective tolerance (questionnaire), and objective toxicity (common toxicity criteria of the National Cancer Institute). RESULTS: Study arms were balanced for age, sex, underlying malignancy, renal and liver function, and pre- and concomitant treatment with antibiotics and nephrotoxic agents. No statistically significant or clinically relevant differences were found between the treatment groups for: daily or cumulative dose and duration of treatment with amphotericin B; incidence and time of dose modifications or infusion duration changes related to toxicity; dose or duration of symptomatic support with opiates, antipyretics, or antihistamines; renal function; subjective tolerance; most common toxicity scores; course of infection; and incidence of treatment failures. Patients treated with amphotericin B in intralipid were given fewer diuretics (P<0.05) and therefore had more peripheral oedema (P<0.01) and needed less potassium supplementation (P<0.05) than patients given amphotericin in glucose. Acute respiratory events were more common in the intralipid arm (P<0.05). CONCLUSIONS: Amphotericin B 0.75 mg/kg/day in intralipid given on eight consecutive days then alternate days provides no benefit and is associated with potential pulmonary side effects possibly because of fat overload or an incompatibility of the two drugs.

Adolescent↗
PubMed1998

Correction of respiratory burst activity in X-linked chronic granulomatous cells to therapeutically relevant levels after gene transfer into bone marrow CD34+ cells.

Chronic granulomatous disease (CGD) is a disorder of the lymphohematopoietic system, whereby phagocytes of affected patients are unable to kill microorganisms. CGD is caused by a functional defect in the phagocytic nicotinamide adenine dinucleotide phosphatase (NADPH) oxidase (phox) enzyme complex, leading to a lack of microbicidal metabolites. As a therapeutic approach toward the predominant X-linked form of CGD, we have developed a bicistronic retroviral vector containing the coding sequences of gp91-phox and a cytoplasmically truncated version of the human low-affinity receptor for nerve growth factor (deltaLNGFR). Full reconstitution of superoxide-generating activity was achieved with this vector in a gp91-phox-deficient cell line. Using an optimized gene transfer protocol, up to 85% of the CD34+ cells obtained from the bone marrow of X-CGD patients were transduced. CD15+ cells differentiated in vitro from transduced X-CGD CD34+ cells showed correction of NADPH oxidase activity to 45-52% of normal levels whereas deltaLNGFR expression was found in 40-67% of the CD15+ cells. Moreover, immunoblots prepared from extracts of transduced CD15+ cells revealed gp91-phox protein levels similar to those found in neutrophils derived from normal CD34+ cells. Taking into consideration that superoxide production in only 5 to 10% of wild-type neutrophils is sufficient to protect X-CGD heterozygotes from serious infections, the results achieved in this study shows that for X-CGD patients a curative approach based on the genetic modification of hematopoietic stem/progenitor cells is feasible.

Antigens, CD34↗
PubMed1998

Effect of stimulation by interferon gamma and tumor necrosis factor alpha on CD54 expression and homotypic aggregation of blasts of acute lymphoblastic leukemias.

CD54 (intercellular adhesion molecule-1, ICAM-1) surface expression on the blasts in ten cases of acute lymphoblastic leukemia (ALL) and its up-regulation by human recombinant interferon-gamma (IFNgamma) and/or tumor necrosis factor-alpha (TNFalpha) were studied in a serum-free culture system. In addition, the function of CD54 was assessed by a cellular aggregation assay. Prior to in vitro culture, only 3/10 ALL cases had more than 20% CD54-positive blasts. A 24-h incubation in serum-free medium alone induced CD54 positivity in another two cases. In these two ALLs, stimulation with IFNgamma and/or TNFalpha further enhanced CD54 positivity. In addition, TNFalpha induced CD54 expression in one further case. In the remaining four cases no CD54 expression was induced by either cytokine. Of the six cases with constitutive or inducible CD54 expression, only five displayed CD54-dependent cellular aggregation. Taken together, the ALLs studied were heterogeneous with respect to their constitutive and cytokine-driven CD54 expression, while TNFalpha seemed to be more effective than IFNgamma. In most cases, the CD54 molecule was functionally active, in that CD54 expression was paralleled by CD54-dependent homotypic aggregation of the blasts.

Adolescent↗
PubMed1998

Elevated pretreatment serum levels of soluble vascular cell adhesion molecule 1 and lactate dehydrogenase as predictors of survival in cutaneous metastatic malignant melanoma.

Very rapid progression of disease with a median survival of 6-9 months is a common feature of metastatic cutaneous malignant melanoma. Nevertheless, substantial variability of survival suggests that metastatic cutaneous malignant melanoma can be divided into several biological subgroups. Pretreatment serum levels of soluble adhesion molecules and various clinical parameters in cutaneous metastatic malignant melanoma were evaluated to determine their prognostic value. In this study pretreatment serum levels of soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular cell adhesion molecule 1 (sICAM-1), soluble endothelial leukocyte adhesion molecule 1 (sE-selectin) and multiple clinical factors were assessed in relation to overall survival of 97 consecutive patients with metastatic cutaneous malignant melanoma seen at our institution between May 1990 and April 1996. For statistical analysis, both univariate and multivariate Cox proportional-hazards models were used. Elevated pretreatment serum levels of sVCAM-1 (P < 0.005) and of lactate dehydrogenase (P < 0.002) were rendered statistically independent and were significantly associated with unfavourable outcome. Patients were assigned to one of three risk categories (low, intermediate and high) according to a cumulative risk score defined as the function of the sum of these two variables. There were significant differences in overall survival (P < 0.0001) between low- (n = 53, 5-year survival probability of 23.3%), intermediate- (n = 29, 5-year survival probability of 9.9%) and high-risk (n = 15) patients. Elevated pretreatment serum levels of sVCAM-1 and of lactate dehydrogenase correlate with poor outcome in metastatic cutaneous malignant melanoma. These data support risk stratification for future therapeutic trials and identify factors that need to be validated in prospective studies and may potentially influence decision-making in palliative management of patients with disseminated cutaneous malignant melanoma.

Adult↗
PubMed1998

Risk and outcome in metastatic malignant melanoma patients receiving DTIC, cisplatin, BCNU and tamoxifen followed by immunotherapy with interleukin 2 and interferon alpha2a.

Combined chemo-/immunotherapy has shown high objective response rates and a significant though small proportion of long-term complete responders in metastatic malignant melanoma. The purpose of this study was to determine response rates, freedom from treatment failure (FFTF) and overall survival in patients with advanced metastatic malignant melanoma treated with combined chemo-/immunotherapy, and to determine the value of a prognostic model for prediction of treatment outcome, FFTF and survival. Sixty-nine patients with metastatic malignant melanoma received combined chemo-/immunotherapy consisting of up to four cycles of DTIC (220 mg m(-2) i.v. days 1-3), cisplatin (35 mg m(-2) i.v. days 1-3), BCNU (150 mg m(-2) i.v. day 1, cycles 1 and 3 only) and tamoxifen (20 mg orally, daily). Two cycles of chemotherapy were followed by 6 weeks of outpatient immunotherapy with combined interleukin 2 (20 x 10(6) IU m(-2) days 3-5, weeks 1 and 4; 5 x 10(6) IU m(-2) days 1, 3, 5, weeks 2, 3, 5, 6) and interferon-alpha (6 x 10(6) IU m(-2) s.c. day 1, weeks 1 and 4; days 1, 3, 5, weeks 2, 3, 5, 6). All patients were evaluated on an intention-to-treat basis. Of 69 patients entered in the study, seven achieved complete remissions and 20 reached partial remissions with an objective response rate of 39% (95% confidence interval 28-52%). Median survival was 11 months, median FFTF was 5 months. Seven patients achieved ongoing long-term remissions, with maximum survival of 58 + months, and maximum FFTF of 58 + months. By Kaplan-Meier survival analysis and two-proportional Cox regression analysis, pretreatment performance status and serum lactic dehydrogenase were statistically significant and independent predictors of survival; risk groups could be defined as (a) the absence of both or (b) the presence of either one or both of these risk factors. Whereas survival and response were significantly influenced by patient risk, no influence could be demonstrated for FFTF. This combined outpatient chemo-/immunotherapy is feasible and results in objective response rates and survival similar to earlier trials. Pretreatment risk, as defined by serum lactate dehydrogenase (LDH) and performance status, has a significant impact on treatment outcome and patient survival.

Adult↗
PubMed1998

Chemotherapy-induced mobilization of karyotypically normal PBSC for autografting in CML.

High-dose chemotherapy with autologous transplantation of in vivo purged PBSC is a new and interesting therapeutic option for CML patients not eligible for allogeneic transplantation. We investigated the feasibility and toxicity of this approach in 57 patients with Ph-positive CML. For mobilization of Ph-negative PBSC, patients were treated either with '5 + 2/7 + 3'- type chemotherapy or with 'mini-ICE/ICE' chemotherapy followed by administration of G-CSF. Fourteen patients were in early chronic phase, 30 patients in late chronic phase and 13 patients in accelerated phase (AP) or blast crisis (BC). Cytogenetic responses in the PBSC harvests were dependent on both disease stage and type of chemotherapy: in late chronic phase and AP/BC, a complete or major cytogenetic response could be obtained in nine out of 13 patients treated with 'mini-ICE/ICE' but only in three out of 23 patients treated with '5 + 2/7 + 3' chemotherapy. However, in early chronic phase a Ph-negative autograft could be obtained in three out of eight patients upon mobilization with '5 + 2' chemotherapy. Thirty-one patients underwent PBSC transplantation and all of them successfully engrafted. Post-transplant cytogenetic analysis was available on 21 cases, of whom seven achieved a complete or major cytogenetic response, with two minor cytogenetic remissions. One patient (1/57) in blast crisis died during mobilization therapy (1.8%). Transplantation related mortality was 0%. This study demonstrates that mobilization of Ph-negative PBSC after myelosuppressive chemotherapy is feasible in CML patients and is associated with acceptable toxicity. Autologous transplantation of in vivo purged PBSC is a safe procedure with rapid and complete hematopietic recovery.

Adult↗
PubMed1998

Effect of topical oral G-CSF on oral mucositis: a randomised placebo-controlled trial.

Oral mucositis is a dose-limiting toxicity of intensive chemotherapy. It is caused directly by the cytotoxic effect of chemotherapeutic agents and indirectly by sustained neutropenia. Severe oral mucositis is an important predisposing factor for life-threatening septic complications during aplasia. It also reduces quality of life. At present, no effective causal prophylaxis or treatment against oral mucositis is established. We performed a prospective randomised placebo-controlled trial using topical oral r-metHuG-CSF (filgrastim) in high-grade lymphoma patients treated according to the B-NHL protocol, which contains high-dose methotrexate and causes severe oral mucositis (WHO grades I-IV) in >50% of patients. Between August 1996 and July 1997, a total of 32 chemotherapy cycles were documented in eight patients (four male, four female). Mucosal erythema and ulceration were recorded. All patients assessed their oral pain and impact on swallowing daily, using a subjective scale from no to maximal discomfort (1-10). In addition, oral mucositis was assessed according to the WHO score. Filgrastim was administered in 16 cycles as a viscous mouthrinse (carboxymethylcellulose 2%, oleum citrii) 4 x 120 microg/day from days 10 to 16. Sixteen cycles were given to control patients, of these 14 with placebo, and another two cycles with no treatment. Severe mucositis (WHO grade III/IV) was documented in 21 of 32 cycles (65.5%). A difference of borderline significance was observed for the reduction of maximum severity of oral mucositis between G-CSF vs placebo (P = 0.058), with a reduction of WHO grade IV of 50% (four G-CSF vs eight control). The number of days in hospital was reduced significantly in the G-CSF group (P = 0.02). In conclusion, topical oral G-CSF mouthrinses may be beneficial to reduce oral mucositis.

Administration, Topical↗
PubMed1998

Effective reversal of a transformed phenotype by retrovirus-mediated transfer of a ribozyme directed against mutant N-ras.

A hammerhead ribozyme directed against oncogenic N-ras (N13-ras) was introduced into a retroviral vector and its activity evaluated in vitro and in cell lines. The catalytic efficiency of the ribozyme embedded within a 2618 nucleotides in vitro-generated transcript was not significantly affected by the length of non-base pairing flanking sequences. A sensitive assay based on N-ras/luciferase fusion transcripts as a reporter system was used to assess ribozyme activity in mammalian cells. More than 95% reduction in luciferase activity was observed in cells transduced with a retrovirus containing the active form of the ribozyme, whereas no significant reduction was observed with the inactive form of the same ribozyme. In order to assay the activity of the retrovirally encoded ribozyme in a biological setting, the IL-3-dependent cell line TF-1 was transformed with N13-ras. Expression of N13-ras in these cells induced factor-independent colony growth and a dose-dependent proliferative response to erythropoietin (Epo). Retrovirus-mediated expression of the active form of the ribozyme in these cells restored factor-dependent colony growth and abolished the proliferative response to Epo. The reversion of the transformed phenotype correlated with a reduction in the amount of N13-ras mRNA.

Animals↗
PubMed1998

Pharmacokinetics of recombinant human interleukin-2 in advanced renal cell carcinoma patients following subcutaneous application.

AIMS: The aim of the study was to investigate the pharmacokinetics of recombinant human interleukin-2 (rhIL-2) in patients with metastatic renal cell carcinoma following different subcutaneous (s.c.) administration regimens. METHODS: RhIL-2 was administered subcutaneously to 10 patients according to two different dosing regimens: group A received 20 x 10(6) IU m(-2) once daily and group B 10 x 10(6) IU m(-2) twice daily (every 12 h). Additionally, in all patients the influence of soluble interleukin-2 receptor (sIL-2R) on the pharmacokinetics of rhIL-2 was investigated. RESULTS: The mean area under the serum concentration-time curve to 24 h (AUC(0,24 h)) was 627 IU ml(-1) h in treatment group A and 1130 IU ml(-1) h (P=0.029) in treatment group B. In both study groups Cmax and AUC(0,12 h) were not significantly different. Seventy-two hours after the beginning of s.c. rhIL-2 therapy the sIL-2R increased significantly (P=0.016), and sIL-2R levels over 1200 pmol l(-1) seemed to reduce the AUC. CONCLUSIONS: In patients with metastatic renal cell cancer administration of 20 x 10(6) IU m(-2) of rhIL-2 s.c. in two daily doses (10 x 10(6) IU m(-2) every 12 h) provides better bioavailability and is preferable to the single dose administration.

Aged↗
PubMed1998

Sustained decrease of peripheral lymphocytes after allogeneic blood stem cell aphereses.

48 healthy donors underwent peripheral blood stem cell (PBSC) apheresis for allogeneic transplantation beginning on day 4 of G-CSF (2 x 5 microg/kg) mobilization. In one to four (median two) large-volume mononuclear cell aphereses, a median of 55.9 x 10(9) of lymphocytes (range 21.0-109.2 x 10[9]) were collected, an amount comparable to lymphocyte numbers removed by therapeutic lymphaphereses in autoimmune diseases. Mean peripheral lymphocyte counts decreased from premobilization values of 2.31 x 10(9)/l to 1.31 x 10(9)/l at a median of 34 d (1 month) and 1.53 x 10(9)/l at a median of 327 d (11 months). The decrease in peripheral lymphocyte counts was significantly correlated with the number of lymphocytes removed and the number of aphereses. Neutrophil and platelet counts returned to normal values after 1 month whereas monocyte counts and haemoglobin concentrations were significantly decreased at 1 month but not at 11 months.

Female↗
PubMed1998

Detection of karyotypic aberrations in acute myeloblastic leukaemia: a prospective comparison between PCR/FISH and standard cytogenetics in 140 patients with de novo AML.

In 140 patients with de novo acute myeloid leukaemia (AML) standard cytogenetics were compared with RT-PCR for the detection of t(8;21), t(15;17) and inv(16) and fluorescence in situ hybridization (FISH) for numerical aberrations of chromosomes 7, 8, X and Y. RT-PCR detected 18 cases with t(8;21), 12 with t(15;17) and seven with inv(16). In two cases with t(8;21), two with t(15;17) and four with inv(16) these aberrations had not been detected by standard cytogenetics. There were no false negative PCR results. In 12 patients with these chromosomal changes, standard cytogenetics revealed additional chromosomal aberrations. In 16 patients sole numerical aberrations of the chromosomes 7, 8, X or Y were found by FISH. In these patients the sensitivity of FISH and standard cytogenetics was comparable. In 87 patients no aberrations could be found by PCR and FISH whereas in 24 of these patients standard cytogenetics revealed an abnormal karyotype. These data recommend the combination of standard cytogenetics and molecular techniques to improve the sensitivity for the detection of genetic lesions in AML. Once chromosomal markers have been identified by combined analysis these markers could be used to monitor residual disease during/after chemotherapy, by RT-PCR and/or FISH.

Adult↗
PubMed1998

Elevated plasma levels of interleukin-1 receptor antagonist are associated with decreased cellular BCL-2 oncoprotein expression in B-chronic lymphocytic leukemia.

Plasma IL-1Ra levels and cellular BCL-2 oncoprotein expression were measured in a total of forty blood samples obtained from twenty-eight B-CLL patients and four healthy subjects. High IL-1Ra plasma levels (as defined by mean + three times standard deviation of normal controls) were observed in eleven samples (ten patients) which showed a significantly decreased cellular expression of BCL-2 protein (14.7 +/- 16.3% of cells as determined by immunofluorescence) when compared to B-CLL samples with no elevated IL-1Ra (BCL-2, 31.0 +/- 18.6%; p < or = 0.0115). Albeit correlational only, our results may encourage further experiments to elucidate potential regulatory effects of IL-1Ra for cellular BCL-2 oncoprotein expression.

Adult↗
PubMed1998

Experience with PACS in an ATM/Ethernet switched network environment.

Legacy local area network (LAN) technologies based on shared media concepts are not adequate for the growth of a large-scale picture archiving and communication system (PACS) in a client-server architecture. First, an asymmetric network load, due to the requests of a large number of PACS clients for only a few main servers, should be compensated by communication links to the servers with a higher bandwidth compared to the clients. Secondly, as the number of PACS nodes increases, the network throughout should not measurably cut production. These requirements can easily be fulfilled using switching technologies. Here asynchronous transfer mode (ATM) is clearly one of the hottest topics in networking because the ATM architecture provides integrated support for a variety of communication services, and it supports virtual networking. On the other hand, most of the imaging modalities are not yet ready for integration into a native ATM network. For a lot of nodes already joining an Ethernet, a cost-effective and pragmatic way to benefit from the switching concept would be a combined ATM/Ethernet switching environment. This incorporates an incremental migration strategy with the immediate benefits of high-speed, high-capacity ATM (for servers and high-sophisticated display workstations), while preserving elements of the existing network technologies. In addition, Ethernet switching instead of shared media Ethernet improves the performance considerably. The LAN emulation (LANE) specification by the ATM forum defines mechanisms that allow ATM networks to coexist with legacy systems using any data networking protocol. This paper points out the suitability of this network architecture in accordance with an appropriate system design.

Local Area Networks↗
PubMed1998

Fluorescence in situ hybridization and surface markers of fine needle aspiration specimen confirm extramedullary myeloblastoma in a patient with chronic myeloid leukemia.

We report on a patient with chronic myeloid leukemia (CML) with a rapidly growing left cervical tumor 5 months after the initial diagnosis of CML. This tumor was diagnosed as a very early manifestation of extramedullary myeloblastoma by a minimally invasive method. A fine needle aspirate (26-gauge needle) was obtained from the tumor. Morphological and cytochemical analysis of the aspirate revealed 19% undifferentiated blasts. The immunophenotype was suggestive of a myeloid differentiation of the blasts (CD33+). The CML origin of the blasts was confirmed by the detection of the bcr-abl gene rearrangement in the blasts by two-color fluorescence in situ hybridization (FISH). We conclude that fine needle aspiration in combination with immunophenotyping and FISH analysis of the aspirate is a minimally invasive and rapid diagnostic tool to confirm extramedullary manifestation in CML. To our knowledge, this is the first case of extramedullary myeloblastoma confirmed by this combined technique.

Adult↗
PubMed1998

A patient-oriented approach to treatment of myelodysplastic syndromes.

BACKGROUND AND OBJECTIVE: There are several therapeutic options for patients with myeiodysplastic syndrome (MDS) but most of them are poorly effective and the potentially curative ones are available only for a minority of individuals. The aim of this article is to define a rational basis for a patient-oriented approach to treatment of MDS. EVIDENCE AND INFORMATION SOURCES: All four authors have done clinical studies of treatment of MDS, including stem cell transplantation, intensive and low-dose chemotherapy, and use of hematopoietic growth factors. They also participated in the Fourth international Symposium on MDS (Barcelona, 24-27 April 1997). In addition, the present review critically examines relevant articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF THE ART AND PERSPECTIVES: At present, the only two treatments that can prolong survival are allogeneic stem cell transplantation (SCT) and intensive chemotherapy, but only a minority of MDS patients can really benefit from them. The heterogeneity of MDS patients, the wide variety of patient inclusion criteria and transplant procedures used, and relatively small numbers of patients in the individual reports of allogeneic SCT make it difficult to draw many definitive conclusions. However, approximately 40% of patients with MDS who are eligible for allogeneic SCT are likely to be cured by this treatment. Intensive chemotherapy with a combination of cytosine arabinoside and an anthracycline should be offered to all patients with an increase in bone marrow blasts who are not eligible for allogeneic SCT, especially those patients up to 65 years of age. Complete remission rates are similar to those obtained in patients with acute myelogenous leukemia, but probability of long-term survival is low. The remaining treatments validated in clinical trials (erythropoietin and/or granulocyte colony-stimulating factor, low-dose cytosine arabinoside) can improve the efficiency of hematopoiesis in subsets of patients. Responsive individuals might experience an improvement in quality of life but very few studies have addressed this question so far. The majority of MDS patients still rely upon supportive therapy. A clinical decision path based on findings of clinical trials and the patient's expectations can help physicians in decision making. Because of the inadequacies of all current treatment modalities, participation in clinical trials should always be encouraged.

Antineoplastic Combined Chemotherapy Protocols↗