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C Dumontet

Publications and source records attributed to C Dumontet.

At least 73 records · Page 4Linked to original sources
PubMed1997

Intensive therapy with peripheral stem cell transplantation in 16 patients with mantle cell lymphoma.

BACKGROUND: Despite improved detection of mantle cell lymphoma (MCL), results of its treatment with conventional therapies remain disappointing and the survival rate poor. The role of high-dose chemotherapy has recently been investigated but no potential benefit has been clearly established. We report here our experience with MCL patients treated with intensive chemotherapy and autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: Of the 16 MCL patients who received high-dose chemotherapy and ASCT beginning in 1989, six were treated in first-line and 10 in sensitive relapse. Twelve of 16 patients received regimens which included total body irradiation. All patients received peripheral blood stem cells (PBSC) with the exception of one, who underwent bone marrow transplantation. RESULTS: Three patients died of toxic effects of treatment, Three months after transplant, seven achieved complete response, (CR) and two partial responses (PR), two were stable and two had progressed. With a median follow-up after transplant of 22 months, five of the six surviving patients were without progression, and three were in CR. The median times for event-free survival (EFS) and overall survival (OS) were, respectively, 249 and 317 days. The expected three-year EFS and OS were 24%. The median survival after diagnosis was only 29 months. None of the criteria appeared to be significantly associated with a better outcome, but first-line intensification and a short delay after initial diagnosis may be favorable. CONCLUSION: In this study we were not able to confirm the hypothetical benefit of high-dose chemotherapy and PBSC transplantation in mantle cell lymphoma, even though this approach may be promising in a subgroup of patient.

Antineoplastic Agents, Alkylating↗
PubMed1997

Tumor necrosis factor ligand-receptor system can predict treatment outcome in lymphoma patients.

PURPOSE: A prospective study was performed to assess plasma measurement of tumor necrosis factor (TNF), lymphotoxin alpha (LTalpha), and their soluble receptors (p55 and p75) for prognostic risk assignment in patients with malignant lymphomas. PATIENTS AND METHODS: One hundred forty-two patients, 124 with non-Hodgkin's lymphoma (NHL) and 18 with Hodgkin's disease (HD), were analyzed. Plasma samples were tested by enzyme-linked immunoabsorbent assay (ELISA). RESULTS: Elevated plasma levels of TNF, p55,and p75 were associated with an Eastern Cooperative Oncology Group (ECOG) status > or = 2, Ann Arbor stage III/IV, elevated serum lactate dehydrogenase (LDH) and beta2-microglobulin levels, > or = two involved extranodal sites, B symptoms, anemia, and low serum albumin level. Elevated levels of p55 and p75 were associated with older age and higher values of C-reactive protein. TNF, p55, and p75, but not LTalpha, plasma levels higher than median predicted shorter freedom from progression (FFP) survival and overall survival. Three distinct risk groups for patient outcome were identified: patients with low risk (TNF, p55, and p75 below median values), intermediate risk (one or two parameters higher than median), and high risk (all three parameters higher than median). At a median follow-up duration of 25 months, the actuarial 2-year FFP survival rates were 79%, 60%, and 37%, respectively (P < .0001), and overall survival rates were 91%, 82%, and 51% (P < .0001). The addition of the TNF ligand-receptor-based model to the International Prognostic Index (IPI) yielded a significant improvement of the predictive value of IPI. CONCLUSION: TNF and its soluble receptors' plasma measurements represent valuable prognostic markers in lymphoma patients.

Antigens, CD↗
PubMed1997

Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients.

PURPOSE: To assess the incidence of lymphoma transformation in the natural history of follicular lymphoma (FL) patients and the factors that are predictive of this event. PATIENTS AND METHODS: Two hundred twenty patients with FL treated in our institution between 1975 and 1990, with a median follow-up duration of 9 years, were included in this retrospective analysis. RESULTS: Transformation was proven by histology in 34 patients or by cytology in 13 patients and was considered as highly probable on clinical arguments in five patients for an overall incidence of 24%. The probability of transformation was 22% at 5 years and 31% at 10 years and tended to plateau after 6 years. Predictive factors for transformation were nonachievement of complete remission (CR) after initial therapy (P < 10(-4), low serum albumin level (< 35 g/L) (P = .001), and beta 2-microglobulin level greater than 3 mg/L (P = .02) at diagnosis. In a multiparametric analysis, only beta 2-microglobulin level retained prognostic significance for freedom-from-transformation (FFT) survival (P = .04). Transformation accounted for 44% of deaths and was associated with a poor outcome, with a median survival time of 7 months. CONCLUSION: Transformation is an early event in the course of the disease and is mainly observed in patients with known adverse prognostic factors or those who do not achieve CR after initial treatment. These findings may be useful to select follicular lymphoma patients for intensive therapeutic approaches.

Adult↗
PubMed1997

Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients.

PURPOSE: Characteristics and outcome of 108 patients with mucosa-associated lymphoid tissue (MALT) lymphoma were analyzed according to initial location of the lymphoma, within or outside of the gastrointestinal (GI) tract. PATIENTS AND METHODS: One hundred eight patients with MALT lymphoma were studied. Fifty-five patients (51%) had GI involvement and 53 patients (49%) had another involved extranodal site: 13 orbit; 11 lung; 10 skin; seven parotid; six thyroid; three Waldeyer's ring; two breast; and one pancreas involvement. At diagnosis, 47 patients (44%) had stage IE, 26 (24%) had stage IIE, and 35 (32%) had disseminated disease. No significant difference in the clinical or biologic characteristics was observed between GI and non-GI patients. RESULTS: Complete response after the first treatment was reached in 76% of the patients, with no difference between the two subgroups. With a median follow-up of 52 months, median survival was not reached and was identical in the two subgroups, but GI MALT patients had a longer time to progression (8.9 years compared with 4.9 years in non-GI patients; P = .01). The different non-GI locations seemed to have a similar outcome. CONCLUSION: MALT lymphoma is an indolent disease that usually presents as localized extranodal tumor without accompanying adverse prognostic factor, and these patients have a good outcome. However, non-GI patients seem to progress more often than GI patients.

Adult↗
PubMed1997

Elderly patients with aggressive non-Hodgkin's lymphoma: disease presentation, response to treatment, and survival--a Groupe d'Etude des Lymphomes de l'Adulte study on 453 patients older than 69 years.

PURPOSE: To clarify disease characteristics and optimal treatment for elderly patients with non-Hodgkin's lymphoma (NHL), we performed a randomized trial in 453 patients older than 69 years with aggressive lymphoma. PATIENTS AND METHODS: Two hundred twenty patients received cyclophosphamide 750 mg/m2, teniposide (VM-26) 75 mg/m2, and prednisone 40 mg/m2/d for 5 days (CVP) and 233 patients received CVP plus pirarubicin (THP-doxorubicin) 50 mg/m2 (CTVP), each for six courses every 3 weeks. RESULTS: The median age was 75 years. Most patients had clinically aggressive disease; 30% had one and 53% two or three adverse prognostic parameters as defined by the International Prognostic Index. More patients on the CTVP arm had an elevated lactic dehydrogenase (LDH) level, but the two groups were otherwise well balanced. CTVP treatment was more frequently associated with leukopenia, thrombocytopenia, and infectious complications. Death during chemotherapy occurred in 16% and 21% of patients on the CVP and CTVP arms, respectively (not significant). Forty percent of patients achieved a complete response (CR): 47% on CTVP and 32% on CVP (chi2 = 20.98, P = .0001). The median time to treatment failure (TTF) was 7 months for CTVP versus 5 months for CVP (log-rank test, P < .05). The median survival time was 13 months in both groups; however, the 5-year survival rate was 26% with CTVP versus 19% with CVP (chi2 = 4.68, P < .05). Lymphoma progression was the primary cause of death. CONCLUSION: Elderly patients with aggressive lymphoma have an aggressive disease with adverse prognostic parameters at the time of diagnosis. Slightly longer survival was observed for patients treated with an anthracycline-containing regimen.

Aged↗
PubMed1996

Resistance mechanisms in human sarcoma mutants derived by single-step exposure to paclitaxel (Taxol).

A fluctuation analysis experiment was performed by exposing 15 expanded populations of MES-SA sarcoma cells to paclitaxel (Taxol) at a concentration of 10 nM for 7 days. The mutation rate was approximately 8 multiplied by 10(-7)/cell generation. ANOVA supports a stochastic cell survival mechanism of spontaneous mutation rather than induction of an adaptive response under these selection conditions. Surviving colonies were found in 12 populations, 9 of which had clones that remained resistant to paclitaxel after a 2-month period of propagation. Analysis of mdr1 gene expression by reverse transcription PCR demonstrated positive clones in 4 of the 9 populations with stable resistance. Accumulation of [(3)H]paclitaxel was decreased in these clones but not in the mdr1-negative clones compared with parental cells. A high degree of resistance to paclitaxel (36- to 93-fold) was selected by this single drug exposure in all 9 stably resistant mutants. Those with mdr1 activation demonstrated a broad cross-resistance to vinblastine, doxorubicin, and etoposide, whereas the other 6 mutants were cross-resistant only to the Vinca alkaloids. Because tubulins are the target molecules for paclitaxel cytotoxicity, we evaluated total tubulin content by immunoblotting and performed semiquantitative reverse transcription PCR analysis for expression of the alpha-tubulin isotypes B alpha 1, K alpha 1 and H alpha 44, the beta-tubulin isotypes M40, beta9, 5beta, beta2 and beta4, and gamma-tubulin. Total tubulin content was decreased significantly in one of the single-step mutants. All surviving clones, both resistant and sensitive to paclitaxel, displayed reduced expression of the 5beta and beta 4 beta-tubulin isotype transcripts in comparison with the parental cell line. These data suggest that stringent exposure to paclitaxel selected clones with reduced transcript levels of 5beta and beta4 beta-tubulin isotypes, but that these reduced levels were not directly involved in the resistance of the clones to paclitaxel. The results suggest an important role for non-multidrug-resistant mechanisms of resistance to paclitaxel. These mechanisms do not involve reduced drug accumulation and provide cross-resistance among both paclitaxel and tubulin depolymerizing agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Differential expression of tubulin isotypes during the cell cycle.

Microtubules play an essential role in cell division. Little is known about possible variations of total tubulin and tubulin isotype expression during the cell cycle. We analyzed the total tubulin content, tubulin polymerization status and tubulin isotype content in resting and dividing human K562 leukemic cells and human MES-SA sarcoma cells. Although the total cellular tubulin content increases as the cells progress toward mitosis, the total tubulin/total protein ratio is stable during the cell cycle. Reverse transcriptase-polymerase chain reaction was applied to analyze the levels of expression of alpha, beta, and gamma-tubulin isotypes. Whereas alpha-tubulin isotype and gamma-tubulin transcripts were found to be expressed at constant levels throughout the cell cycle, some of the beta-tubulin isotype transcripts were found to be more highly expressed in dividing then in resting cells. Both of the class IV beta-tubulin isotype transcripts (human 5 beta and beta 2, Class IVa and IVb, respectively) were expressed in dividing K562 and MES-SA cells at twice the levels found in resting cells. Increased expression of the class IV isotype proteins in dividing cells was confirmed by immunoblotting, both in K562 and in MES-SA cells. A larger fraction of total cell tubulin was found to be polymerized in dividing cells (36-40%) than in resting cells (27-30%). The degree of polymerization of class IV tubulin in dividing and resting cells was similar to that of total tubulin. These results show that total tubulin is expressed as constant levels throughout the cell cycle but that the degree of polymerization is increased as cells are committed to division. The relative overexpression of the two class IV beta-tubulin isotypes in dividing cells suggests functional specificity for these isotypes and a regulatory role of these isotypes on the microtubule network during mitosis.

Cell Cycle↗
PubMed1996

Early diagnosis of ventilator-associated pneumonia. Is it possible to define a cutoff value of infected cells in BAL fluid?

STUDY OBJECTIVE: To assess the usefulness of quantification of infected cells (ICs) in BAL fluid for the diagnosis of ventilator-associated pneumonia (VAP). DESIGN: A prospective study. SETTING: A medico-surgical ICU in a tertiary health-care institution. PATIENTS: One hundred thirty-two patients (mean age, 52 +/- 19 years). The suspicion of nosocomial pneumonia was strong in these patients: all had fever (> or = 38.5 degrees C), purulent tracheal aspirates, leukocytosis (> or = 10,000 cells per cubic millimeter), and new or persistent radiographic lung infiltrates. INTERVENTIONS: One hundred sixty-three samples (BAL and protected specimen brushes [PSB]) were obtained. RESULTS: VAP was present in 56 cases. The diagnosis was excluded in the remaining 107 cases. The IC count was performed on 100 cells in BAL fluid. The percentage of IC was significantly higher (12.6 +/- 12.4 vs 1.14 +/- 3.39; p < 0.0001) in patients with pneumonia: the area under the receiver operating characteristic (ROC) curve was 0.888 and a threshold of 2% of IC corresponded to a sensitivity of 84%, a specificity of 80%, a positive predictive value of 69%, and a negative predictive value of 90%. CONCLUSIONS: It is possible to define a threshold of IC in BAL fluid with a good reliability by using an ROC curve. This technique is useful for the early diagnosis (< 2 h) of nosocomial bacterial pneumonia in mechanically ventilated patients and allows a rapid and appropriate treatment of most of the patients with suspected VAP.

Bronchoalveolar Lavage Fluid↗
PubMed1996

Methionine dependence of tumor cells: programmed cell survival?

A majority of tumor cell lines are considered to be "methionine-dependent" because of their inability to grow in culture when methionine is replaced by its precursor, homocysteine. We have previously shown that this phenotype is not due to the incapacity to synthesize methionine from homocysteine but rather to a deficiency in the "methionine salvage pathway", including 4-methylthio-2-oxobutanoic acid (MTOB), which is transaminated into methionine. At low concentrations MTOB can restore normal growth of methionine-dependent cell lines in the absence of methionine. However, when MTOB concentrations are increased the cells undergo apoptosis. Methional, a metabolite of MTOB produced by the branched-chain oxo acid dehydrogenase complex, is a potent inducer of apoptosis in a murine lymphoid cell line. We suggest that the methionine-dependent phenotype is associated with a reduced content of methional, which behaves as a proapoptotic agent. For this reason, methionine-dependent cells have a relative survival advantage.

Animals↗
PubMed1995

Decreased mutation rate for cellular resistance to doxorubicin and suppression of mdr1 gene activation by the cyclosporin PSC 833.

BACKGROUND: Various mechanisms can contribute to cellular resistance to doxorubicin. These include expression of the multidrug transporter P-glycoprotein (product of the mdr1 gene [also known as PGY1], Mrp (multidrug resistance-associated protein), the p110 major vault protein, altered glutathione metabolism, and altered levels or activity of topoisomerase II (Topo II). We reported recently that single-step treatment of human MES-SA sarcoma cells with 40 nM doxorubicin resulted in selection of spontaneous mutants at a rate of 1.8 x 10(-6) per cell generation. All individually selected mutants manifested the multidrug-resistant phenotype, related to activation of the mdr1 gene. PURPOSE: Luria and Delbrück fluctuation analysis was performed with MES-SA cells to determine the mutation rate and the nature and mechanisms of resistance after single-step selection with doxorubicin in the presence of the cyclosporin PSC 833, a potent modulator of multidrug resistance. METHODS: Ten flasks were seeded with 2000 cells/flask and grown to confluent populations of approximately 8 x 10(6) cells. After reseeding in 96-well plates, the populations were treated with 40 nM doxorubicin and 2 microM PSC 833 for 3 weeks. Surviving colonies were scored, individually harvested, and propagated. The drug-resistant phenotype was assessed by the tetrazolium dye (MTT) cytotoxicity assay and by monitoring cellular glutathione content and radiolabeled drug accumulation. Coupled reverse transcription-polymerase chain reaction (RT-PCR) was used to evaluate mdr1, MRP, Topo II alpha, and Topo II beta gene expression. Topo II, P-glycoprotein, and p110 levels were examined by immunoblotting or immunocytochemistry. Topo II activity was assessed by decatenation of kinetoplast DNA, and etoposide-induced cleavable complex formation was studied by the potassium-sodium dodecyl sulfate precipitation assay. RESULTS: Mutations were detected at a rate of 2.5 x 10(-7) per cell generation. Analysis of variance indicates that spontaneous mutations, rather than changes in cellular function, conferred resistance to doxorubicin and PSC 833. None of the isolated clones expressed mdr1 messenger RNA or P-glycoprotein, and none exhibited an increase in MRP expression. No alterations were found in cellular glutathione content, intracellular accumulations of daunorubicin and etoposide, levels of p110 protein, or levels of Topo II beta transcripts. However, a significant decrease in Topo II alpha messenger RNA and protein was found in all examined clones, as well as decreased Topo II catalytic activity and reduced cleavable complex formation in the presence of etoposide. CONCLUSIONS: PSC 833 co-selection reduced the mutation rate for doxorubicin-selected resistance by 10-fold and suppressed the emergence of mdr1 mutants. Survival of cells exposed to doxorubicin and PSC 833 occurs by selection of spontaneously arising mutants that exhibit altered Topo II alpha expression. IMPLICATIONS: Our results suggest that treatment with multidrug resistance modulators such as PSC 833 together with multidrug resistance-related cytotoxins may suppress the activation of mdr1 and prevent the emergence of resistant cancer cell clones with the multidrug-resistant phenotype.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Methional derived from 4-methylthio-2-oxobutanoate is a cellular mediator of apoptosis in BAF3 lymphoid cells.

4-Methylthio-2-oxobutanoic acid is the direct precursor of methional, which is a potent inducer of apoptosis in a BAF3 murine lymphoid cell line which is interleukin-3 (IL3)-dependent. Cultures treated for 8 h with methional in the presence of IL3 show extensive DNA double-strand breaks on flow cytometric analysis, increases in DNA fragmentation as measured by the amount of non-sedimentable DNA present in the 30,000 g supernatant of cell lysates and the typical laddering pattern of multiples of 180 bp seen upon agarose gel electrophoresis. No such features of apoptosis were found in cells treated with 4-methylthio 2-oxobutanoic acid or propanal, suggesting that the simultaneous presence of the methylthio group on the propanal moiety is essential for apoptosis to take place. Methional is further metabolized in cells by two reactions: oxidation via aldehyde dehydrogenase to (methylthio)propionic acid or beta-hydroxylation to malondialdehyde. The formation of malondialdehyde from methional in vitro by chemical hydroxylation under the conditions of the Fenton reaction provides a mechanism for the beta-hydroxylation which takes place in vivo. During apoptosis induced by IL3 deprivation, the ratio of 2,4-DNPH MDA to 2,4-DNPH methional is 0.94 in cells in IL3- medium compared with 0.54 in cells in IL3+ medium. These results support a role of cellular methional and malondialdehyde in apoptosis.

Aldehydes↗
PubMed1995

IL-3 increases marrow and peripheral erythroid precursors in chronic pure red cell aplasia presenting in childhood.

In most patients with Diamond-Blackfan anaemia (DBA) the addition of IL-3 to in vitro cultures increases the number of erythroid progenitors. However, a small proportion of patients show an erythroid response to in vivo administration of IL-3. We treated two adult patients with corticosteroid-refractory DBA, who had shown a clear in vitro erythroid response to IL-3, with increasing doses of IL-3 (from 2.5 to 10 micrograms/kg/d) by subcutaneous injections for 7 and 9 weeks. Monitoring of marrow and circulating progenitors showed a sustained elevation of BFU-E and CFU-E as well as an increase of other progenitors and CD34+ cells during therapy. However, this effect did not translate into a clear clinical response, although transfusion requirements decreased transiently in one patient. This report shows that a sustained elevation of erythroid progenitors induced by in vivo IL-3 administration may not translate into an increase of mature red cells production in DBA patients.

Adult↗
PubMed1995

Novel mechanism of resistance to paclitaxel (Taxol) in human K562 leukemia cells by combined selection with PSC 833.

A paclitaxel-resistant cell line, KPTA5, was established by co-selecting the parental erythroleukemic cell line K562 with stepwise increased concentrations of paclitaxel (Taxol) in the presence of the cyclosporin D analogue PSC 833 (2 microM), a potent modulator of the multidrug resistance phenotype. KPTA5 cells are 9-fold resistant to paclitaxel and taxotere, but do not exhibit significant resistance to Vinca alkaloids, etoposide, anthracyclines, antimetabolites, or alkylating agents. Doubling time and morphology were similar to the parental K562 cells. Reverse transcriptase-polymerase chain reaction (rt-PCR) analysis revealed no alterations in the expression of the mdr1 and MRP genes. Cellular paclitaxel accumulation was unchanged. Cell cycle analyses showed that at 20 nM there was a significantly higher proportion of K562 cells blocked in G2/M, in comparison with KPTA5 cells. In both cases, disruption of the mitotic spindles and the presence of multiple mitotic asters were comparable but occurred at lower paclitaxel concentrations in K562 cells than in KPTA5 cells. There was no difference in total tubulin content between K562 and KPTA5 cells as analyzed by immunoblotting with an anti-beta-tubulin monoclonal antibody. However, we found that KPTA5 cells presented a 2-fold increase both in 5 beta-tubulin mRNA expression and in the corresponding tubulin protein Class IV isotype content, as evaluated by rt-PCR and immunostaining. In conclusion, the KPTA5 cell line displays a novel mechanism of resistance to paclitaxel which does not involve altered cellular drug accumulation. The data presented suggest that alterations in expression of the 5 beta-tubulin gene may be involved in paclitaxel resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Inhibition of immune cell proliferation and cytokine production by lipoprotein-bound gangliosides.

We have analyzed the immunomodulatory effect of human melanoma gangliosides bound to serum lipoprotein fractions on normal human immune-competent cells in vitro. Total melanoma gangliosides in micelles inhibited proliferation of peripheral blood mononuclear cells stimulated by various mitogens, modulated lymphocyte surface molecules CD2, CD3, CD4, CD5 and CD8 and inhibited the production of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha) and IL-6 by stimulated adherent cells. Most of these effects were abrogated in the presence of serum. Purified serum lipoprotein fractions were tested for their ability to allow or inhibit the immunomodulatory effects of gangliosides. Melanoma gangliosides bound to very-low-density lipoproteins (VLDL) were shown to be as potent modulators of the immune response in vitro as when they were presented to cells in the form of micelles. Gangliosides bound to low-density lipoproteins were less active and gangliosides bound to high-density lipoproteins or the lipoprotein-free fraction had no immunomodulatory effects. Given the fact that gangliosides are predominantly bound to lipoproteins in serum, we conclude that lipoproteins are important determinants of the immunomodulating potential of tumor gangliosides, and that the immunomodulatory effects of melanoma gangliosides observed in vitro may also occur in vivo.

Antigens, CD↗
PubMed1994

Heterogeneity of acute lymphoblastic leukemia in HIV-seropositive patients.

BACKGROUND: As opposed to large-cell or Burkitt's-type non-Hodgkin's lymphoma, acute lymphoblastic leukemia (ALL) is rarely observed in HIV-seropositive patients and is not a criteria of AIDS in the 1986 classification established by the C.D.C. Furthermore, the few cases of ALL reported so far were B-cell ALL, Burkitt's-type. DESIGN: We recently observed, with unexpected frequency, ALL cases in this setting: over a 5-year period, 5 of 25 HIV-positive patients referred to our center for hematological malignancies, had ALL. Three patients, who had previously been asymptomatic with regard to HIV infection, had typical Burkitt's-type ALL. Complete remission was achieved in all cases with high-dose lymphoma-type chemotherapy regimens, but 2 patients relapsed 3 and 27 months after diagnosis. Their clinical characteristics and outcome are discussed with reference to the cases reported thus far in the literature. One patient had common early pre-B ALL with the Philadelphia chromosome, and one had a T-cell ALL with an unusual CD7+, CD4-, CD8- phenotype. Prognosis was very poor in both cases. CONCLUSION: The exact incidence and the therapeutic management of B-cell ALL in HIV-positive patients warrants further evaluation. In addition, we show that there may be a heterogeneity among ALL cases in this setting, with the first description of 2 non-Burkitt's ALL with atypical features in HIV-positive patients.

Adult↗