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Biomedical subjects

M Symann

Publications and source records attributed to M Symann.

At least 19 recordsLinked to original sources
PubMed2000

Meropenem versus ceftazidime as empirical monotherapy for febrile neutropenic cancer patients.

A total of 101 cancer patients with 121 febrile neutropenia episodes were randomised to receive empirical treatment with i.v. meropenem (1g/8 h) or ceftazidime (2 g/8 h). After 3 days, 89% of patients were on unmodified therapy in the meropenem group, compared with 83% in the ceftazidime group. Of the evaluable episodes (n = 106), the success rate with unmodified empirical therapy until the end of the treatment course was slightly higher with meropenem than with ceftazidime (48% vs 38%, P=0.39). Furthermore, initial success with further infections was observed in 22% of episodes treated with meropenem and in 13% of episodes treated with ceftazidime. Glycopeptides were used as first modification in 28% and 39% of meropenem and ceftazidime recipients, respectively. Both treatments were well tolerated and there were no reports of drug-related nausea/vomiting or seizures. No significant differences in response rate or in tolerability were observed when analysing only the first febrile episodes. In conclusion, meropenem seems to be as efficacious and well tolerated as ceftazidime and may be associated with a lesser requirement for the addition of glycopeptides.

Adolescent↗
PubMed2000

Pitfalls in the detection of disseminated non-hematological tumor cells.

There is not yet a consensus on the reliability of the methods that should be used for the detection of rare disseminated tumor cells from non-hematological malignancies. In this review, we will discuss the advantage and drawbacks of the classical approach of immunocytochemistry and the molecular detection by reverse transcriptase polymerase chain reaction (RT-PCR). The interpretation of the biological significance of circulating tumor cells and the pitfalls of the detection techniques are the main causes of discrepancy between the conclusions of different tumor-cell detection (TCD) studies.

DNA, Neoplasm↗
PubMed2000

Highly purified CD34+ cells isolated using magnetically activated cell selection provide rapid engraftment following high-dose chemotherapy in breast cancer patients.

The primary objective of this study was to evaluate the safety of infusion of CD34+ cells, selected using a clinical scale magnetically activated cell sorting device, assessed by time to hematological engraftment and incidence of adverse events. Secondary objectives included evaluation of device performance in terms of purity and recovery of the CD34+ cell product. Breast cancer patients suitable for transplantation received cyclophosphamide and filgrastim for mobilisation, followed by three leukaphereses. The products of the first two leukaphereses underwent CD34+ cell selection. The product of the third leukapheresis was cryopreserved unmanipulated. Following high-dose cyclophosphamide, thiotepa and carboplatin, selected CD34+ cells were infused. In 54 patients who received selected cells only, the median time to platelet recovery and neutrophil recovery was 11 days (range 5-51) and 9 days (range 5-51), respectively. There were no adverse events associated with infusion of selected cells. A total of 126 leukapheresis samples was available before and after selection for central CD34+ analysis. The median purity was 96.1% (27.4-99.4) and the median recovery was 52. 3% (15.2-146.3). These data show that cells selected using magnetically activated cell selection provide safe and rapid engraftment after high-dose therapy. Bone Marrow Transplantation (2000) 25, 243-249.

Adolescent↗
PubMed1999

Retrovirus-mediated gene transfer of the human multidrug resistance-associated protein into hematopoietic cells protects mice from chemotherapy-induced leukopenia.

Utilization of chemotherapy for the treatment of tumors is mainly limited by its hematological toxicity. Because of the low-level expression of drug resistance genes, transduction of hematopoietic progenitors with multidrug resistance 1 (MDR1) or multidrug resistance-associated protein (MRP) genes should provide protection from chemotherapeutic agent toxicity. Successful transfer of drug resistance genes into hematopoietic cells may allow the administration of higher doses of chemotherapy and, thus, increase regression of chemosensitive tumors. The interest in the use of MRP as an alternative to MDR1 for bone marrow protection lies in its different modulation. This would allow, in the same patient, the use of MDR1 reversal agents to decrease MDR1 tumor resistance without reversing bone marrow (BM) protection of the MRP-transduced hematopoietic cells, since MRP expression is not reversed by these agents. We have constructed MRP-containing retroviral vectors using the phosphoglycerate kinase promoter and generated ecotropic producer cells. Lethally irradiated mice were engrafted with BM cells transduced by coculture with MRP producer cells. Evidence of long-term (9 months) gene transfer was provided by PCR of peripheral blood from MRP-transduced mice. Southern blot analysis confirmed the integrity of the provirus in the MRP-transduced mice. Long-term MRP expression (>5 months) was detected by RT-PCR and fluorescence-activated cell sorting of blood from living mice. High-level expression of MRP in murine hematopoietic cells reduces doxorubicin-induced leukopenia and mortality. Furthermore, we show in vivo selection of MRP-transduced cells following doxorubicin administration, with better and more significant chemoprotection after the second chemotherapy cycle. These data indicate that MRP retroviral gene transfer may be useful for chemoprotection and selection.

ATP-Binding Cassette Transporters↗
PubMed1999

Clinical activity and benefit of irinotecan (CPT-11) in patients with colorectal cancer truly resistant to 5-fluorouracil (5-FU).

The aim of this prospective study was to assess the efficacy, clinical benefit and safety of CPT-11 (irinotecan) in patients with stringently-defined 5-fluorouracil-resistant metastatic colorectal cancer (CRC). 107 patients with documented progression of metastatic CRC during 5-FU were treated with CPT-11 350 mg/m2 once every 3 weeks in a multicentre phase II study. Tumour response and toxicity were assessed using WHO criteria. Changes in performance status (PS), weight and pain were also measured. The WHO response rate was 13/95 (13.7%, 95% CI 7.5% to 22.3%) eligible patients with a median duration of response of 8.5 months (37 weeks, range: 18-53+). There was also a high rate of disease stabilisation (44.2%) with a median duration of 4.8 months. The probability of being free of progression at 4 months was 50%. Median survival from first administration of CPT-11 was 10.4 months or 45 weeks (range: 3-66+ weeks). There was weight stabilisation or gain in 81% (73/90) of patients, a favourable outcome in PS in 91% (82/90) (improvement of WHO PS 2 or stabilisation of PS 0-1), and pain relief in 54% (26/48). There were no toxic deaths. Neutropenia was short-lasting and non-cumulative. Diarrhoea grade > or = 3 occurred in 7% of cycles and 28/107 (26%) of patients. CPT-11 350 mg/m2 once every 3 weeks has an encouraging degree of activity in progressive metastatic CRC truly resistant to 5-FU with a relatively high rate of tumour growth control translated into clinical benefit. The toxicity profile of CPT-11 is becoming better understood and has been considerably improved.

Adult↗
PubMed1999

Clearance kinetics of CD34+ cells from peripheral blood: an independent predictor of hematologic recovery after high-dose chemotherapy and hematopoietic stem cell transplantation.

We measured the concentration of CD34+ cells in peripheral blood (PB) (1/2) h prior to and (1/2), 1, 3, 6, and 12 h following hematopoietic stem cell (HSC) infusion in 34 breast cancer patients treated with high-dose chemotherapy (HDC). The decrease in these concentrations over time enabled us to determine the clearance kinetics of CD34+ cells from PB. The absolute number of CD34+ cells in PB generally peaked at (1/2) h after infusion, then rapidly declined from 1 to 3 h post infusion and continued to fall until 12 h post transplant, but more slowly. In univariate analysis, CD34+cells/kg infused, CFU-GM/kg infused, the CD34+ count at (1/2) h, and the 12-h clearance of CD34+ cells from PB were predictors of hematologic recovery, as were each of the two phases of clearance when the slope was divided into rapid and slow phases (from (1/2) to 3 and from 3 to 12 h post transplant, respectively). We then stratified our population by the number of CD34+ cells/kg infused. In group 1, patients received </=7.5 x 10(6) CD34+ cells/kg; in group 2, >7.5 x 10(6) CD34+ cells/kg. After adjusting for CD34+ cells injected, age, and purged or unpurged graft in multivariate analysis, the 12 h clearance remained a predictor of hematologic recovery in group 1. In addition, the second phase of clearance (from 3 to 12 h after infusion) was an even better predictor than the 12 h clearance. In group 2, however, no statistically significant correlation was observed, even with the number of HSC injected. Results suggest that rapidity of clearance of CD34+cells from PB is an independent indicator of hematologic recovery in patients receiving lower doses of CD34+ cells. When the cell dose injected is over a threshold, PB clearance correlations with hematologic recovery are masked.

Adult↗
PubMed1999

Unreliability of carcinoembryonic antigen (CEA) reverse transcriptase-polymerase chain reaction (RT-PCR) in detecting contaminating breast cancer cells in peripheral blood stem cells due to induction of CEA by growth factors.

RT-PCR is increasingly used for the detection of minimal residual disease in solid tumors. Carcinoembryonic antigen (CEA) RT-PCR seemed to be highly specific for detection of tumor cells when tested on PBMC. A very high frequency of RT-PCR amplification product for CEA in PBSC from breast cancer patients mobilized with G-CSF was found. However, this result contrasted with tumor cell detection by immunocytochemistry (ICC) which showed no correlation with RT-PCR results. In addition, CEA mRNA was amplified in most G-CSF-mobilized PBSC samples derived from patients with hematological malignancies and from healthy donors of allogeneic stem cells, although no circulating epithelial cells could be demonstrated by ICC. CEA RT-PCR expression was observed in PBMC from healthy individuals incubated in vitro with G-CSF. These data suggest that CEA transcription can be induced by G-CSF, resulting in a loss of specificity of CEA RT-PCR for tumor cell detection in PBMC. We conclude, CEA RT-PCR may not be recommended to detect tumor cell contamination in peripheral blood from patients treated with G-CSF. This may have implications on tumor cell detection by RT-PCR in tissues where endogenous or exogenous growth factors may induce the transcription of CEA or other genes.

Breast Neoplasms↗
PubMed1999

The administration of 10 microg/kg granulocyte colony-stimulating factor (G-CSF) alone results in a successful peripheral blood stem cell collection when previous mobilization with chemotherapy and hematopoietic growth factor failed.

Some heavily pretreated cancer patients fail to mobilize enough peripheral blood stem cells (PBSC) after stimulation with chemotherapy and hematopoietic growth factors. For these patients the best way to obtain an adequate PBSC collection is unknown. Here we report 6 heavily pretreated cancer patients who failed to mobilize sufficient PBSC after stimulation with chemotherapy and G-CSF 5 microg/kg/day. In these cases, we used G-CSF 10 microg/kg/day alone for six days at least 3 weeks after the last chemotherapy. After three consecutive leukaphereses starting on day 5, five patients had adequate PBSC collections. With 6 days of G-CSF 10 microg/kg/day alone, 2.8 x 10(6) (+/- 1) CD34+ cells/kg were collected. This was significantly higher than the number of CD34+ cells/kg collected after chemotherapy and G-CSF 5 microg/kg 0.3 x 10(6) (+/- 0.1) [P = 0.05]. Four patients received high-dose chemotherapy with PBSC support. Hematologic recovery observed in these patients was as expected. In conclusion, G-CSF 10 microg/kg alone can mobilize progenitor cells into peripheral blood when previous mobilization with chemotherapy and G-CSF 5 microg/kg fails.

Adult↗
PubMed1998

Augmentation of the number of nucleolar organizer regions in human megakaryocyte cell lines after induction of polyploidization by a microtubule inhibitor.

BACKGROUND: Megakaryocyte polyploidization is an advantageous and regulated mechanism that leads to an increase in platelet production. In megakaryocytic cell lines, polyploidization can be obtained by using colchicine, an inhibitor of the tubulin spindle. The nucleolar organizer regions (AgNORs) are parts of nucleolar DNA transcribed into ribosomal RNA and are detected by the silver-staining technique. Their number is proportional to protein synthesis. RESULTS: To estimate protein synthesis in polyploid megakaryocytes, AgNORs are measured in three cell lines with megakaryocyte properties (DAMI, HEL and K562) after a 4-day culture in the presence or absence of colchicine. The mean number of AgNORs per cell was 16+/-4 (mean+/-SEM), 24+/-3 and 14+/-3 for DAMI, HEL and K-562 cell lines respectively. The addition of colchicine (10 ng mL[-1]) significantly increased the number of AgNORs per cell (DAMI 556%, HEL 338% and K-562 300% of controls, P < 0.05 using the t-test). Moreover, the number of nucleoles per cell after the addition of colchicine was augmented significantly (DAMI 246%; HEL 237% and K-562 148% of controls, P < 0.05 using the t-test). The total protein content estimated by Bradford's method increased significantly to 226%, 215% and 304% of controls in DAMI, HEL and K562 respectively (P < 005 using the t-test). After treatment with colchicine, the endomitotic index (EI) [mean of (log2 DNA content expressed in N)-1] measured by flow cytometry (and reflecting ploidy) increased to 234%, 255% and 301%, respectively, in DAMI, HEL and K-562 cell lines (P < 0.05 using the t-test). Concomitantly, the number of AgNORs per unit of DNA increased in the DAMI and HEL cell lines (P < 0.05 using the t-test) from 48+/-8 and 39+/-5, respectively, to 79+/-11 and 61+/-10. In contrast, the number of nucleoles and the total protein content per endomitotic index were not affected by colchicine (P > 0.05 using the t-test), but the number of nucleoles per endomitotic index of DAMI cells was affected. CONCLUSION: The increase in the number of the NORs induced by an agent known to stimulate polyploidization of megakaryocytic cell lines suggests that polyploidization occurs by a proportional increase in protein synthesis per DNA unit.

Cell Count↗
PubMed1998

Induction and enhancement of normal human megakaryocyte polyploidization are concomitant with perturbation in the actin metabolism.

BACKGROUND: Megakaryocyte polyploidization results from the lack of cytoplasmic separation while the nucleus keeps dividing. METHODS: To investigate the role of actin in the megakaryocyte polyploidization, three human cell lines with megakaryocytic properties (DAMI, HEL and K562) were incubated in the presence of cytochalasin B, an inhibitor of actin polymerization. These data were then compared with normal megakaryocytes. RESULTS: Compared with control conditions, cells cultured in the presence of cytochalasin B revealed an augmentation of cell size and ploidy and an arrest of cell proliferation. The expression of platelet membrane glycoproteins Ib, IIb/IIIa, IIIa and thrombospondin and transferrin receptors was augmented after treatment with cytochalasin B. Physiologically, the role of actin in inducing polyploidization could be related to an imbalance between G- and F-actins. To test this hypothesis, we measured G-, F- and total actin in cytochalasin B-treated cells. Actin was found to be increased significantly in cytochalasin B-treated DAMI and HEL cell lines. In contrast, the G/F-actin ratio was not affected by cytochalasin B. To confirm these actin changes in physiological megakaryocytopoiesis, G- and F-actin contents were then estimated in normal megakaryocytes. The G- and F-actin contents of megakaryocytes from eight normal patients exponentially decreased from 2 to 128n, whereas the total actin content per cell kept increasing. The G/F ratio was unaffected. CONCLUSION: Polyploidization of human megakaryocytes results from either a diminution of actin synthesis or an increased actin turnover, which in turn possibly abrogates the formation of the actin cleavage furrow in telophasis.

Actins↗
PubMed1998

Analysis of megakaryocytes by flow cytometry.

A flow cytofluorometric measurement of megakaryocyte ploidy has been adapted from Tomer's method. Briefly, bone marrow is aspirated through a medium containing theophyllin, prostaglandin-E1 and other antiaggregant agents. Megakaryocytes-enriched buffy coats are recovered. Megakaryocytes are then stained for GP IIIa coupled with FITC and for DNA (propidium iodide). A Becton Dickinson FACScan flow cytometer is used for measuring the ploidy distribution of GP IIIa positive cells. The method we developed presents several advantages. Firstly, the time required is greatly decreased in comparison with other studies. Secondly, the washing steps are limited in number allowing a diminution of the cell loss. Thirdly, the method ensures a better megakaryocyte preservation. Finally, selection of megakaryocytes by ploidy and expression of GP IIIa can be made easily because of the simultaneity of the two stainings as well as by the use of a precise gating on the flow cytometer. Based on these results, we conclude that the present method provides a better means for the isolation and analysis of human normal megakaryocytes. This technique has been applied to the analysis of megakaryocyte populations from patients with abnormal platelet counts. In chronic myeloid leukemia patients, analysis of ploidy distribution shows a shift toward the low ploidy while in patients with immune thrombocytopenic purpura, polycythemia vera and essential thrombocythemia the ploidy distributions are shifted toward the high ploidy.

Adolescent↗
PubMed1997

Primary anaplastic large-cell lymphoma in adults: clinical presentation, immunophenotype, and outcome.

Anaplastic, CD30+, large-cell lymphoma is now a well-recognized pathologic entity that accounts for 2% to 8% of all lymphomas. Recent progress has been made in the understanding of certain biologic features found in anaplastic large-cell lymphoma, but information about its clinical behavior, in comparison to other large-cell lymphomas, is limited. The pathologic review of a large multicenter study of the treatment of aggressive lymphoma identified 146 cases of anaplastic large-cell lymphoma (ALCL) on the basis of morphology and CD30 expression. We compared initial presentation, immunophenotype, and clinical outcome of these cases with those of the 1,695 nonanaplastic diffuse large-cell lymphomas (non-ALCL) included in the same trial. Patients with ALCL were more likely to be male (P = .018) and were younger (P < .0001) than those with non-ALCL. B symptoms were more frequent in ALCL (P = .006). Skin (P < .0001) and lung (P < .05) involvement was also more frequent in ALCL, but frequency of bone marrow involvement was identical (P = . 5). Tumor cell phenotype was B in 56 cases (38%), T in 49 cases (34%), and null in 33 cases (22%). Response to chemotherapy (P = . 001), event-free survival (P = .006), and overall survival (P = . 0004) were better for ALCL than for non-ALCL. Multivariate analyses identified anaplastic character as an independent factor that predicted a longer survival. Tumor cell phenotype did not influence event-free survival (P = .72) or overall survival (P = .83). ALCL in adults is a clinicopathologic entity which, independent of its phenotypic characteristics, has a better outcome than other diffuse large-cell lymphomas.

Adult↗
PubMed1997

Quantification of CD34+ cells mobilized into the peripheral blood predicts the yield of the leukapheresis product and can replace progenitor assays.

We reviewed 333 concomitant blood and cytapheresis samples from 101 patients with solid malignancies of various histological cell types. All samples were analyzed for CFU-GM, BFU-E and CD34+ determination. We found a good correlation between progenitor assays CFU-GM and CD34+ determination in the blood and cytapheresis (r = 0.77, p < 0.0001 and r = 0.79, p < 0.0001 respectively). The number of CD34+ cells in the peripheral blood was predictive of the CD34+ yield in the cytapheresis (r = 0.86, p < 0.0001), and we determined that a threshold of 26 CD34+/microliter of blood was sufficient to harvest 10(6) CD34+/kg in a single apheresis. Thirty breast cancer patients received injections of peripheral blood stem cells after the same high-dose chemotherapy. For these patients, we found a significant correlation between the quantity of CD34+ cells or CFU-GM collected and both granulocyte and platelet recovery. In conclusion, there is a very good correlation between CFU-GM assays and CD34+ determination and a good correlation between circulating CD34+ cells and the yield obtained by the cytapheresis. The number of CD34+ cells collected is also significantly correlated with hematological recovery. Because CD34+ quantification is an accurate, fast and inexpensive technique, this can lead to the progressive forsaking of progenitor assays in a clinical setting.

Adolescent↗