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C Reuter

Publications and source records attributed to C Reuter.

At least 19 recordsLinked to original sources
PubMed2006

[Oxygen-enhanced MRI of the lung: optimized calculation of difference images].

BACKGROUND: In oxygen-enhanced lung MRI, difference maps of acquisitions during inhalation of room air and pure oxygen are calculated to assess lung function. The purpose of this study was to analyze how the calculation of these difference maps depends on the delayed signal change after switching the gas supply. METHODS: Ten healthy volunteers were examined with an ECG and respiratory-triggered T1-weighting inversion recovery HASTE sequence with parallel imaging. Four blocks with 20 repetitions of up to 6 coronal slices were continuously acquired; in blocks 1 and 3 room air was supplied, in blocks 2 and 4 oxygen. Data were postprocessed, discarding between 0 and 19 repetitions after each change of gas supply before calculating the relative signal difference. RESULTS: The averaged relative signal difference increases from 9.4 to 17.4% when the number of discarded acquisitions increases; the ratio of signal difference and spatial standard deviation reaches a maximum at 5-8 discarded acquisitions. CONCLUSIONS: An optimized ratio of signal difference and statistical error is found if about 5-8 of 20 respiratory-triggered repetitions are discarded after each change of gas supply for the calculation of difference maps.

Adult↗
PubMed2001

A self-threaded "molecular 8".

A new type of [1]rotaxanes containing two aliphatic bridges between axle and wheel is obtained in 39% yield in a one-step synthesis starting from a [2]rotaxane which contained one sulfonamide group each in both the wheel and the axle. Temperature controlled chemoselective substitution reactions first at these sulfonamide nitrogens and then subsequently at the various other carboxamide nitrogens in the wheel and axle give rise to the formation of an isomeric mixture of three double-bridged [1]rotaxanes which could be separated by HPLC. Structure determination of the main product 3a was possible by NMR experiments supported by molecular modeling calculations. Using different reaction conditions, a double-substituted but not yet bridged [2]rotaxane 4 could be isolated as an intermediate giving further evidence for the assigned structure of 3a and the way of its formation. The shape of this double-bridged [1]rotaxane 3a reminds of a self-intertwining chiral "molecular 8", in which any possible racemization due to deslipping is hindered by the two stoppers originating from the former rotaxane axle. Hence, to the best of our knowledge this is the first example of a molecule in which both concepts, cycloenantiomerism and helical chirality, are realised in one structure. Enantiomer separation of the main product was possible by further HPLC using chiral stationary phases. The Cotton effects of the circular dichrograms are different to those of the already synthesized [1]rotaxanes bearing just one aliphatic bridge between axle and wheel.

Journal Article↗
PubMed2000

[1]rotaxanes and pretzelanes: synthesis, chirality, and absolute configuration [In Process Citation]

The synthesis of aliphatically bridged [1](n)rotaxanes and (n)pretzelanes in preparative yields and the dependency of their chiroptical properties on the length (n) of their bridge are reported. A cycloenantiomeric bis(sulphonamide)[2]rotaxane with a sulphonamide group in its axle and its wheel was intramolecularly dialkylated by homologous bifunctional oligomethylene reagents to form chiral [1](n)rotaxanes bearing bridges of different lengths (n) between the axle and the wheel. Intramolecular dialkylation by 1,omega-dibromoalkanes of a topologically chiral bis(sulphonamide)[2]catenane with a sulphonamide group in both of the macrolactam rings leads to pretzel shaped molecules ((n)pretzelanes) with homologous bridges between the two macrocycles. Their yields decrease with decreasing length of the bridge. The shortest bridge isolated so far in reasonable amounts consists of six methylene groups ((6)pretzelane). Remarkably, a covalent connection of axle and wheel in a [2]rotaxane was successful even with much shorter bridges-down to only three methylene groups ([1](3)rotaxane). The structural changes of the [1](n)rotaxanes with decreasing bridge length is expressed by an increasing high-field shift in the 1H NMR spectra. Enantiomeric resolution of the racemates of both series was achieved in seven cases for the [1](n)rotaxanes and two for the (n)pretzelanes by use of chiral HPLC columns. The circular dichrograms of both compound families show a strong dependency on the length of the bridge. However, the shortest bridges displayed some additional unexpected deviations. A new specification of the absolute configuration of supramolecules, such as [n]catenanes, [n]rotaxanes and (n)pretzelanes is introduced together with some nomenclature additions.

Journal Article↗
PubMed2000

Rotaxanes via Michael addition

[reaction: see text] The application of a template effect to the classical Michael addition of heteronucleophiles to various Michael acceptor systems leads in good yields to a new trapping synthesis of [2]rotaxanes with conjugated functional groups in their axles.

Journal Article↗
PubMed2000

Unequal nondisjunction frequencies of trivalent chromosomes in male mice heterozygous for two Robertsonian translocations.

Robertsonian (Rb) translocation heterozygosity may cause pairing problems during prophase and segregation irregularities at anaphase of meiosis I. These stages of meiosis I were studied in male mice doubly heterozygous for the two Rb chromosomes Rb(9.19)163H and Rb(16.17)8Lub. At pachytene both Rb chromosomes similarly showed pairing irregularities like unpaired segments. However, highly different nondisjunction frequencies of chromosomes forming the respective trivalents were found. The nondisjunction frequency of the Rb8Lub trivalent chromosomes was about 40%, whereas a very low frequency of nondisjunction was found in combination with the Rb163H trivalent. Since both trivalents were together in the same cell, differences in kinetochore function are assumed to be responsible for the diverse frequency of nondisjunction.

Animals↗
PubMed1998

Identification of group VS116 strains among Borrelia burgdorferi sensu lato grown from the hard tick, Ixodes ricinus (Linnaeus, 1758) by off-coupled restriction fragment length polymorphism analysis.

A total of 67 spirochetal isolates grown from the hard tick, Ixodes ricinus were analysed by PCR amplification of the spacer region between two conserved structures, the 3' end of the 5S rRNA and the 5' end of the 23S rRNA genes of Borrelia burgdorferi sensu lato. A 246-255 bp amplicon was generated from 13 reference strains of B. burgdorferi sensu lato representing the three major genospecies, B. burgdorferi sensu stricto, B. garinii, and B. afzelii, and from all 67 spirochetal isolates from ticks but not from B. hermsii. As could be confirmed by DNA sequence analysis, restriction fragment length polymorphism (RFLP) analysis of the PCR product after cleavage with DraI and MseI distinguished between the three major genospecies: out of the 67 B. burgdorferi sensu lato isolates from ticks, 27 (40.3%) were typed as B. burgdorferi sensu stricto including five isolates with a unique DraI or MseI pattern. 26 isolates (38.8%) were typed as B. garinii and 6 (9.0%) as B. afzelii, respectively. A group of eight isolates (11.9%) displayed a unique MseI pattern identical to that described for a putative new European genospecies of Borrelia burgdorferi sensu lato designated VS116. DNA sequences of the PCR product of seven of these isolates tested were by less than 88.5% identical with the established European major genospecies but shared 98% to 100% homology with that of database-derived sequences of strain VS116 from Switzerland and strain UK from England which are both representatives of the European genomic group VS116.

Animals↗
PubMed1997

Activity of thymidine kinase and of polymerase alpha as well as activity and gene expression of deoxycytidine deaminase in leukemic blasts are correlated with clinical response in the setting of granulocyte-macrophage colony-stimulating factor-based priming before and during TAD-9 induction therapy in acute myeloid leukemia.

The present study was undertaken to assess the predictive value of pretherapeutic determinants of ara-C metabolism and proliferative activity of leukemic blasts for early response to antileukemic therapy in the setting of granulocyte-macrophage colony-stimulating factor (GM-CSF)-based priming before and during TAD-9 induction in 36 consecutive patients with de novo acute myeloid leukemia (AML). Ara-C metabolism was assessed by the activities of deoxycytidine kinase (DCK), deoxycytidine deaminase (DCD), DNA polymerase alpha (Poly alpha), and overall polymerase (overall Poly). The fraction of cells in S phase (%S phase) and thymidine kinase (TK) activity were determined as a measure of proliferative activity. Early response to therapy was defined by the percentage of leukemic blasts in the bone marrow 5 to 7 days after completion of TAD-9 with less than 5% signaling an adequate response and greater than 5% indicating an inadequate early reduction, respectively. While neither %S phase, DCK, nor overall Poly activity were predictive for early response, TK and Poly alpha activities were significantly higher for cases with adequate blast cell clearance. The respective median values were for TK 3.8 versus 1.85 pmol/min/mg protein (P = .012), and for Poly alpha 1.9 versus 0.69 pmol/min/mg protein (P = .014). An inverse relation was detected for DCD activity which was significantly lower in responding patients with a median of 0.33 nmol/min/mg protein (range, 0.0 to 29.5) as compared to a median of 5.1 nmol/min/mg protein (range, 0.11 to 8.45) in early nonresponders, (P = .009). Taking the respective median values as arbitrary cut-points for high or low enzyme activities, responders and nonresponders could be discriminated prospectively. Hence, 14 of 16 cases (88%) with DCD activities below the median of 1.56 nmol/min/mg protein responded as compared to only 3 of 14 (22%) patients with higher DCD activities (P = .0004). From the 15 patients with TK activity above the overall median of 3.2 pmol/min/mg protein, 11 cases (73%) achieved an adequate blast cell clearance while only 6 of 17 cases (35%) with lower values responded (P = .035). Similarly, 12 of 15 patients (80%) with high Poly alpha levels (>1.22 pmol/min/mg protein) responded to induction therapy as compared to only 5 of 14 patients (36%) with lower enzyme activities (P = .02). By logistic regression analysis of enzyme activities, DCD activity was found to be the most sensitive parameter to predict an adequate blast cell clearance (P = .032). Activities of DCD and TK were not only associated with initial response but were also found predictive for remission duration. Hence, from 11 patients with low TK levels 8 (73%) relapsed within 1 year, whereas only 2 of 11 (18%) patients with high TK activity experienced a recurrence of their disease (P = .015). Six of 9 (66%) patients with higher than median DCD levels relapsed within 1 year, whereas 10 of 14 patients (71%) with lower DCD levels had a longer remission duration (P = .085). Analysis of DCD gene expression at the mRNA level by a semi-quantitative reverse transcriptase-polymerase chain reaction method showed that a high transcription rate of the DCD gene was associated with high enzyme activities and vice versa. Hence, the observed intraindividual differences in DCD activity are a reflection of differences in gene activity and transcription rate rather than of variants in translation. Although further analyses are needed to elucidate the molecular mechanisms that determine the variation of enzyme activities in individual patients, the present study strongly suggests that pretherapeutic determination of TK and Poly alpha as well as of DCD allows to predict response to TAD-9 + GM-CSF induction therapy and may provide the means for the development of a risk adapted treatment strategy.

Acute Disease↗
PubMed1997

Preoperative risk assessment of hepatic resection for malignant disease.

Clinical, laboratory, functional, and volumetric data of 340 consecutive patients undergoing hepatic resection for malignant disease between November 1990 and June 1995 were analyzed. The operative mortality was 3.3% (8/244 patients). Among 178 patients with liver metastases and 66 with primary hepatobiliary tumors the hospital mortality was 4.1% (10/244 patients) and morbidity 22.0% (54/244 patients). Survival after hepatectomy was strongly influenced by the extent of resection quantified by the parenchymal hepatic resection rate. The prediction of fatal postoperative complications can be improved for patients with hepatic metastases by calculating the liver resection index (sensitivity 75%, specificity 83%).

Adult↗
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↗
PubMed1996

Addition of anticholinergic solution prolongs bronchodilator effect of beta 2 agonists in patients with chronic obstructive pulmonary disease.

A randomized, double-blind placebo-controlled clinical trial was designed to assess the safety, efficacy, and duration of the bronchodilation resulting from the addition of 500 micrograms of ipratropium bromide (Atrovent; Boehringer Ingelheim, CT) inhalation solution to standard small volume nebulizer treatments with 2.5 mg albuterol inhalation solution. A total of 195 patients (63% men, average age 64 years) with > 10 pack-year smoking histories and stable, moderate-to- severe chronic obstructive pulmonary disease (COPD; forced expiratory volume in 1 second [FEV1] 1.02 liter, 38.8% predicted) from eight university-affiliated chest clinics in seven U.S. cities were enrolled into the study. Asthma, rhinitis, and eosinophilia were exclusions, as was daily use of > 10 mg of prednisone (or 20 mg on alternate days). There was a 2-week stabilization period during which the patients were instructed in the use of the small volume nebulizers, which they used three times daily with albuterol alone. They were asked to keep daily logs of peak flow rates, pulmonary symptoms, and additional medication usage. On their test day 1 the subjects came to the pulmonary function laboratory having been off theophylline for 24 hours and beta 2-agonists for 12 hours and performed a baseline spirometry. They then received their morning small volume nebulizer treatment of albuterol to which was added either 500 micrograms if ipratropium bromide or a saline placebo. Spirometry was repeated at 15, 30, and 60 minutes, and then hourly for 8 hours. Subjects then took home a 2-week supply of albuterol and test drug for thrice daily use in their small volume nebulizer. They were evaluated for pulmonary symptoms and adverse effects every 14 days. The 8-hour spirometry was repeated on test day 43 and finally on test day 85. Primary data evaluated were the peak increase in FEV1 and the area between the FEV1 baseline value and the 8-hour FEV1 curve. Similar calculations were made for forced vital capacity (FVC) and 25-75% forced expiratory flow (FEF25-75%). On test day 1 the peak increase in FEV1 for the ipratropium bromide + albuterol subjects was 26% greater than those on placebo + albuterol (p < 0.003). The area under the 8-hour FEV1 curve was 64% greater in those given ipratropium bromide on test day 1 (p < 0.0002). Similar increases were seen in FVC and FEF25-75%. The peak improvements in FEV1 and FVC with the addition of ipratropium bromide to albuterol were maintained on test days 43 and 85. Considering the safety and efficacy profiles of this combination, the data would suggest that ipratropium bromide inhalation solution should be considered first-line therapy for those patients with COPD requiring small volume nebulizer treatments.

Administration, Intranasal↗
PubMed1996

Primary culture of Borrelia burgdorferi from Ixodes ricinus ticks.

A total of 971 Ixodes (I.) ricinus ticks field-collected in May and June 1993 and 1994 in two different geographic regions (Middle Hesse and Lower Saxony) were examined for the presence of Lyme borreliosis spirochetes (Borrelia burgdorferi sensu lato) by primary culture using nonselective and selective BSK II medium. Modifications of BSK II medium with varying concentrations of bovine serum albumin and with rabbit serum being replaced by horse serum were examined for their ability to support growth of borreliae from ticks. Spirochetes were isolated from 17.8% each of female and male I. ricinus from Lower Saxony. Isolation rates from female and male I. ricinus originating from Middle Hesse were 13.5% and 19.6%, respectively. In comparison to nonselective BSK II medium the isolation rate of borreliae from the tick midgut was increased significantly (35%) by additional culture in selective BSK II medium. Most spirochetal isolates (85%) were detected within three weeks of incubation. Compared to isolation in standard BSK II medium, reduction of bovine serum albumin by 50% did not diminish the isolation rate of borreliae from ticks. Spirochetal isolates were identified as Borrelia burgdorferi sensu lato by PCR using a primer set based on ribosomal DNA sequences to amplify the variable spacer region between two conserved structures, the 3'end of the 5S rRNA and the 5'end of the 23S rRNA.

Animals↗
PubMed1995

A comparison of different techniques for liver resection: blunt dissection, ultrasonic aspirator and jet-cutter.

In a prospective study 116 patients underwent liver resection. Three different resection techniques, blunt dissection (n = 61), ultrasonic aspirator (CUSA) (n = 27) and jet-cutter (n = 28) were compared. Speed of resection, blood loss, transfusion rate, liver hilus clamping time and tissue damage were evaluated on the basis of area of transected liver surface. Liver resection with the jet-cutter was significantly faster with a resection time of 0.33 min/cm2 in comparison to blunt dissection (0.57 min/cm2) and CUSA (0.50 min/cm2) (P < 0.01) and associated with lower blood loss of 17.7 ml/cm2 (P < 0.01) than the other techniques (blunt dissection 32.5 ml/cm2, CUSA 24.3 ml/cm2). Tissue damage with respect to transaminases SGOT and SGPT was comparable to the other techniques. The jet-cutter is a promising new instrument in liver surgery.

Adult↗
PubMed1995

Blast cell proliferative activity and sensitivity to GM-CSF in vitro are associated with early response to TAD-9 induction therapy in acute myeloid leukemia.

The current study was undertaken to determine the relevance of leukemic blast cell proliferative activity, cellular parameters of Ara-C metabolism and the in vitro sensitivity to GM-CSF in association with the clinical response to TAD-9 induction therapy in 66 patients with de novo acute myeloid leukemia (AML). Proliferative activity was assessed by 3H-thymidine (3H-TdR) incorporation and thymidine kinase (TK) activity, parameters of Ara-C metabolism comprised the activities of deoxycytidine kinase (DCK) and DNA polymerase alpha (poly alpha) as well as Ara-CTP concentrations and 3H-Ara-C uptake into DNA. GM-CSF sensitivity was determined by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4 h concurrent exposure to GM-CSF and 3H-TdR (0.5 microCi/ml). The following results were obtained as expressed by median values and ranges: 3H-TdR incorporation: 1.07 pmol/10(5) cells (0.0-10.1), TK: 7.3 pmol/min/mg protein (1.3-56.0), DCK: 9.3 pmol/min/mg protein (0.77-47.1), poly alpha: 1.7 pmol/min/mg protein (0.00-28.9), Ara-CTP: 53.3 ng/10(7) cells (13.3-211.0), 3H-Ara-C uptake: 0.06 pmol/10(5) cells (0.0-0.57). 3H-Ara-C uptake was correlated with 3H-TdR incorporation (r = 0.74) and with the (S-phase dependent) activities of TK (r = 0.73) and poly alpha (r = 0.71, but not with DCK activity or intracellular Ara-CTP content. Blast cells of 37 from 55 analyzed patients were found to be sensitive to GM-CSF stimulation as defined by an increase in 3H-TdR incorporation > or = 1.5-fold over control values after the 48 h GM-CSF exposure. In vitro data were related with clinical response to TAD-9 induction therapy in 43 patients with newly diagnosed AML, taking the blast cell reduction at day 10 or 16 to < 5% or > or = 5% residual blasts as early parameter for adequate or inadequate response, respectively. While neither 3H-Ara-C uptake, nor intracellular Ara-CTP concentration, TK nor DCK activity were predictive for response, a high 3H-TdR incorporation and a high poly alpha activity were associated with adequate blast cell reduction. Median values of 3H-TdR incorporation were 2.26 pmol/10(5) cells for patients with adequate blast cell clearance and 0.80 pmol/10(5) cells for patients with inadequate blast cell clearance (P = 0.11), the respective values for poly alpha were 3.22 pmol/min/mg protein for responders and 1.1 pmol/min/mg protein for non-responders (P = 0.0085).(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

New perspectives in the treatment of acute myeloid leukemia by hematopoietic growth factors.

The application of hematopoietic growth factors in the treatment on acute myeloid leukemia (AML) may principally aim at shortening the period of treatment associated neutropenia and reducing the rate of infectious complications by their post-therapeutic administration but may also be used to increase the sensitivity of leukemic blasts to antileukemic therapy by pretherapeutic growth stimulation. Both aspects were addressed in subsequent clinical phase II studies and preclinical investigations. In a first clinical trial, 36 patients with high-risk AML received granulocyte-macrophage colony-stimulating factor (GM-CSF) after successful cytoreductive chemotherapy and experienced a shortening of the period of post-therapeutic neutropenia by 6 to 9 days, leading to a significant reduction of treatment-associated deaths from 39% to 14%. In preclinical studies an enhancement of the cytotoxicity of cytosine arabinoside (AraC) on leukemic blasts could be shown by pretreatment with GM-CSF or IL-3. Investigations on the impact of hematopoietic growth factors on the intracellular metabolism of AraC indicated that this effect was primarily mediated by an increase in the activity of DNA-polymerase-alpha. The evaluation of different doses of AraC showed the most marked increase after the combination of GM-CSF with conventional rather than high doses of AraC. Based on these preclinical experiments, a prospective randomized trial was subsequently initiated investigating the effect of GM-CSF before and during induction, consolidation, and the first two cycles of maintenance chemotherapy in newly diagnosed AML. This ongoing trial has enrolled 67 patients at the current time. An early interim analysis showed no differences in remission rates but a tendency toward a longer remission duration in patients receiving GM-CSF. These data indicate that hematopoietic growth factors like GM-CSF in particular may provide a new perspective in the treatment of acute myeloid leukemia with the possibility of reducing treatment associated mortality and perhaps of increasing the efficacy of antileukemic treatment.

Acute Disease↗
PubMed1994

Experimental basis for the use of recombinant human granulocyte-macrophage colony-stimulating factor in patients with acute myeloid leukemia.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) not only stimulates hematopoiesis, but also induces the proliferation and differentiation of leukemic myeloid cells. The observation that clonogenic growth of malignant cells can be induced in vitro has led to the development of therapeutic concepts that aim to increase the sensitivity of cells to cytostatic and cytotoxic agents by priming them with GM-CSF. In in vitro experiments, preincubating leukemic cells with recombinant cytokines including GM-CSF led to a consistent, dose-dependent increase in the cytotoxicity of cytosine arabinoside (Ara-C). This effect has since been observed in patients with acute myeloid leukemia (AML) although its mechanism is not yet entirely clear. It seems that GM-CSF increases the relative number of cells in the S phase of the cell cycle and enhances the activity of DNA polymerases, enzymes that are essential to nucleotide incorporation into DNA. Based on these experimental results, numerous clinical trials have investigated the role of GM-CSF in priming leukemic blasts before chemotherapy. These studies will allow us to determine whether our in vitro observations of increased cytotoxicity translate into higher remission rates and durations, and will help us to identify the patient subgroups most likely to benefit from this therapeutic approach.

Acute Disease↗
PubMed1994

[Leiomyosarcoma of the inferior vena cava--diagnosis and therapy].

We report four patients with primary vascular leiomyosarcoma of the inferior vena cava. Even after radical surgery the prognosis is serious because of local tumor recurrence and distant metastases. Although controlled studies are difficult because of the small number of patients, a multimodal therapeutic approach needs to be developed.

Adult↗
PubMed1994

Modulation of intracellular metabolism of cytosine arabinoside in acute myeloid leukemia by granulocyte-macrophage colony-stimulating factor.

The current study investigated the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the intracellular metabolism and cytotoxicity of 1-beta-D-arabinofuranosylcytosine (araC) in leukemic cells of 45 patients with acute myeloid leukemia (AML). AML blasts from bone marrow (BM) (n = 39) and peripheral blood (PB) (n = 17) were incubated for 48 h with or without GM-CSF (100 U/ml) followed by a concurrent treatment with increasing concentrations of araC (0.06-100 microM) for an additional 24 h. After GM-CSF a 1.5-8.4-fold (median 2.3) increase in 3H-araC incorporation into the DNA was observed in ten of 14 peripheral blast specimens and in 23 of 28 bone marrow samples, 18 of whom also showed an enhanced 3H-TdR incorporation (1.5-8.5-fold, median 2.0-fold). Four different types of response were identified when analyzing 3H-araC incorporation into the DNA of bone marrow samples in relation to the applied araC dose: (i) 8/28 cases had increases of the araC incorporation at all araC dose levels applied (0.06-100 microM), (ii) 12/28 at low araC concentrations only (0.06-1.0 microM), (iii) 3/28 at high araC concentrations only (10-100 microM), and (iv) 5/28 showed no increase at any dose level given. Hence, 20 of the 23 responding patients revealed a GM-CSF induced enhancement of araC incorporation at low or conventional doses of araC (0.06-1.0 microM). Fourteen of the 18 cases with concomitant rises of 3H-TdR and 3H-araC incorporation into the DNA after GM-CSF had elevated DNA polymerase alpha activity (16-531%, median 72%) and in ten cases overall DNA polymerase activity was enhanced (10-70%, median 22.5%). In contrast, thymidine kinase (TK) and deoxycytidine kinase (dCK) activity were elevated after GM-CSF in only ten and five patients, respectively. An increase in the fraction of cells in S phase was found in 11/21 bone marrow specimens and in 5/9 peripheral blast samples. However, no correlation was observed between increases in the proportion of cells in S phase and enhancements in enzyme activities. In 13 cases the cytotoxicity of araC with and without GM-CSF was assessed by means of a blast cell colony assay. Preincubation with GM-CSF increased the araC mediated cytotoxicity in ten of 13 patients by a median of 3.2-fold (range 2.2-229-fold). The respective LD50 values for araC were reduced from 0.45 to 0.19 microM on average.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗