Biomedical subjects

Jean-François Rossi

Publications and source records attributed to Jean-François Rossi.

13 recordsLinked to original sources

PubMed2006

Functional regulatory T cells are collected in stem cell autografts by mobilization with high-dose cyclophosphamide and granulocyte colony-stimulating factor.

High-dose cyclophosphamide (Cy) and G-CSF are widely used to mobilize hemopoietic stem cells for treating patients with high-dose chemotherapy and autologous stem cell transplantation (ASCT). Because lymphocyte count in the graft collected after Cy-G-CSF treatment is an independent survival factor after ASCT for patients with multiple myeloma, our purpose was to study how Cy-G-CSF treatment affects the phenotype and function of T cells in patients with multiple myeloma. Cy induced a 3-fold decrease of T cell counts with a slow and partial T cell recovery of one-third at the time of hemopoietic stem cell collection. Cy-G-CSF treatment did not affect the relative ratios of central memory, effector memory, and late effector CD4+ or CD8+ T cells, but a decrease in the percentage of naive CD4+ cells was observed. The percentages of CD25+ cells increased 2- to 3-fold in CD4+ and CD8+ T cells, the former including both activated CD25low and CD25high cells. CD4+CD25high cells were regulatory T cells (Treg) that expressed high levels of FOXP3, CTLA-4, and GITR and displayed in vitro suppressive properties. The recovery of Treg absolute counts after Cy-G-CSF treatment was higher than the recovery of other lymphocyte subpopulations. In conclusion, Cy-G-CSF treatment induces a severe T cell count decrease without deleting Treg, which are potent inhibitors of antitumor response. The present data encourage novel therapeutic strategies to improve T cell recovery following ASCT while limiting Treg expansion.

CD4-Positive T-Lymphocytes↗

PubMed2006

Microarray-based understanding of normal and malignant plasma cells.

Plasma cells (PCs) develop from B lymphocytes following stimulation by antigen and express a genetic program aimed at the synthesis of immunoglobulins. This program includes the induction of genes coding for transcription factors such as PRDM1, X-box-binding protein 1 and BHLHB3, cell-surface molecules such as CD138/syndecan-1, and for the unfolded protein response. We review how the microarray technology has recently contributed to the understanding of the biology of this rare but essential cell population and its transformation into premalignant and malignant PCs.

B-Lymphocytes↗

PubMed2006

Thalidomide versus placebo in myeloid metaplasia with myelofibrosis: a prospective, randomized, double-blind, multicenter study.

BACKGROUND AND OBJECTIVES: In non-randomized studies, thalidomide appeared to be effective in myeloid metaplasia with myelofibrosis (MMM). We compared thalidomide to placebo for treatment of anemia in MMM. DESIGN AND METHODS: A prospective phase II B, randomized double-blind multicenter trial comparing thalidomide 400 mg/d with placebo for 180 days was conducted in 52 anemic patients (hemoglobin pounds Sterling 9 g/dL or transfused). The main outcome measure was a 2 g/L increase in hemoglobin or 20% reduction in transfusions. RESULTS: In the thalidomide group only 10 patients completed 6 months of treatment. At 180 days, in an intention-to-treat analysis, no difference was observed between the thalidomide and placebo groups as regards improvement of hemoglobin levels (one patient in each group) or reduction of red blood cell transfusions (three vs five patients, respectively). The spleen size, determined by ultrasonography, increased significantly less in the thalidomide group than in the placebo group (p < 0.05). Thalidomide had no apparent benefit on the Dupriez score, the severity score, survival, death, or any other clinical or biological parameter. Somnolence, gastro-intestinal signs, weight gain, and edema were significantly more frequent in the thalidomide group. Outpatient discontinuation of thalidomide was significantly correlated with a high severity score > 4 (odds ratio, OR = 16; p < 0.01), and g-glutamyl transferase levels > 40 IU/L (OR = 12; p < 0.05). INTERPRETATION AND CONCLUSIONS: Thalidomide (200-400 mg/d) does not demonstrate substantial efficacy in anemic MMM patients. The natural history of disease in the placebo group revealed spontaneous periods of remission of anemia. Tolerance of thalidomide was significantly correlated wih the severity and liver involvement of the disease.

Angiogenesis Inhibitors↗

PubMed2005

Early allogeneic stem-cell transplantation for young adults with acute myeloblastic leukemia in first complete remission: an intent-to-treat long-term analysis of the BGMT experience.

PURPOSE: We analyzed the impact of allogeneic stem-cell transplantation (alloSCT) as an early consolidation for young patients with acute myeloblastic leukemia in first complete remission (CR1) through four successive protocols. PATIENTS AND METHODS: Of the 472 patients who achieved CR1, 182 (38%) had an HLA-identical sibling (donor group), and alloSCT was performed in 171 patients (94%). Of the 290 patients without donor (no-donor group), 62% received an autologous SCT. RESULTS: In an intent-to-treat analysis based on donor availability, the overall 10-year survival probability was 51% v 43% (P = .11) for the donor and no-donor groups, respectively. A Cox analysis determined that four factors had independent prognostic significance for survival (initial WBC count, French-American-British subtypes, cytogenetic risk, and number of induction courses). This permitted constitution of a simple index that reclassified 21% of the patients compared with usual cytogenetic classification and identified three subpopulations with different outcome and different impact of alloSCT. CONCLUSION: AlloSCT was associated with a survival advantage for an intermediate-risk group. In other groups, numbers are limited for definitive conclusion. However, early performed alloSCT does not seem to be the optimal treatment of high-risk patients or offer any advantage over intensive chemotherapy in low-risk patients.

Acute Disease↗

PubMed2005

Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy.

Dexamethasone alone increases life expectancy in patients with relapsed multiple myeloma (MM); however, no large randomized study has compared dexamethasone and dexamethasone-based regimens with standard melphalan-prednisone in newly diagnosed MM patients ineligible for high-dose therapy. In the Intergroupe Francophone du Myélome (IFM) 95-01 trial, 488 patients aged 65 to 75 years were randomized between 4 regimens of treatment: melphalan-prednisone, dexamethasone alone, melphalan-dexamethasone, and dexamethasone-interferon alpha. Response rates at 6 months (except for complete response) were significantly higher among patients receiving melphalan-dexamethasone, and progression-free survival was significantly better among patients receiving melphalan (P < .001, for both comparisons), but there was no difference in overall survival between the 4 treatment groups. Moreover, the morbidity associated with dexamethasone-based regimens was significantly higher than with melphalan-prednisone, especially for severe pyogenic infections in the melphalan-dexamethasone arm and hemorrhage, severe diabetes, and gastrointestinal and psychiatric complications in the dexamethasone arms. Overall, these results indicated that dexamethasone should not be routinely recommended as first-line treatment in elderly patients with MM. In the context of the IFM 95-01 trial, the standard melphalan-prednisone remained the best treatment choice when efficacy and patient comfort were both considered. These results might be useful in the context of future combinations with innovative drugs.

Aged↗

PubMed2003

Comparison of murine leukemia virus, human immunodeficiency virus, and adeno-associated virus vectors for gene transfer in multiple myeloma: lentiviral vectors demonstrate a striking capacity to transduce low-proliferating primary tumor cells.

Genetic modification of primary tumor cells by gene transfer is of major interest to study the role of specific genes in the biology of a given malignancy and to modify tumor cells for therapeutic use. Multiple myeloma (MM) is a low-proliferating cancer, with often less than 1% of the cells in the S phase of the cell cycle. As primary myeloma cells are notoriously difficult to transduce, we conducted a comparison of various viral vectors, known to integrate the transgene of interest into the target genome, for their ability to stably promote the expression of an enhanced green fluorescent protein (EGFP) transgene. We compared three murine leukemia virus-based vectors, differing only in their viral envelope, a human immunodeficiency virus (HIV)-based vector pseudotyped with the vesicular stomatitis virus glycoprotein (VSV-G), and an adeno-associated virus type 2 vector. Transduction characteristics of these vectors were evaluated in human myeloma cell lines and in primary myeloma cells. Unequivocally, we observed that the VSV-G/HIV vector was the most efficient vector for transducing the cell lines and the only one able to transduce primary myeloma cells reproducibly. The mean percentage of transduced primary myeloma cells was 43.6% (range, 16.3-77.6%), with one round of infection at a low multiplicity of infection, including MM cell samples with less than 1% of cells in the S phase. A quantitative polymerase chain reaction assay demonstrated that this more efficient EGFP expression was associated with a higher GFP copy number in the targeted cell. We propose that lentiviral vectors should be used for transduction of nonproliferating primary tumor cells such as myeloma cells.

Adenoviridae↗

PubMed2003

BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone.

Identification of growth factors in neoplasias may be a target for future therapies by blocking either growth factor receptor interaction or the induced pathway. Using gene expression profiling, we identified overexpression of 2 receptors for a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) in malignant plasma cells compared with normal plasma cells. APRIL and BAFF are involved in a variety of tumor and autoimmune diseases, including B-cell malignancies. We confirmed the expression of BAFF and APRIL receptors (B-cell maturation antigen [BCMA], transmembrane activator and calcium modulator and cyclophilin ligand interactor [TACI], and BAFF-R) in a majority of 13 myeloma cell lines and in the purified primary myeloma cells of 11 patients. APRIL and BAFF were potent survival factors for exogenous cytokine-dependent myeloma cell lines and were autocrine growth factors for the RPMI8226 and L363 autonomously growing cell lines. These factors activated nuclear factor (NF)-kappaB, phosphatidylinositol-3 (PI-3) kinase/AKT, and mitogen-activated protein kinase (MAPK) kinase pathways and induced a strong up-regulation of the Mcl-1 and Bcl-2 antiapoptotic proteins in myeloma cells. BAFF or APRIL was also involved in the survival of primary myeloma cells cultured with their bone-marrow environment, and protected them from dexamethasone (DEX)-induced apoptosis. Finally, the serum levels of BAFF and APRIL were increased about 5-fold in patients with multiple myeloma (MM) as compared with healthy donors. Altogether, these data suggest that APRIL/BAFF inhibitors may be of clinical value in MM.

Apoptosis↗

PubMed2003

An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti-IL-6 antibody-induced apoptosis.

We previously found that some myeloma cell lines express the heparin-binding epidermal growth factor-like growth factor (HB-EGF) gene. As the proteoglycan syndecan-1 is an HB-EGF coreceptor as well as a hallmark of plasma cell differentiation and a marker of myeloma cells, we studied the role of HB-EGF on myeloma cell growth. The HB-EGF gene was expressed by bone marrow mononuclear cells in 8 of 8 patients with myeloma, particularly by monocytes and stromal cells, but not by purified primary myeloma cells. Six of 9 myeloma cell lines and 9 of 9 purified primary myeloma cells expressed ErbB1 or ErbB4 genes coding for HB-EGF receptor. In the presence of a low interleukin-6 (IL-6) concentration, HB-EGF stimulated the proliferation of the 6 ErbB1+ or ErbB4+ cell lines, through the phosphatidylinositol 3-kinase/AKT (PI-3K/AKT) pathway. A pan-ErbB inhibitor blocked the myeloma cell growth factor activity and the signaling induced by HB-EGF. This inhibitor induced apoptosis of patients'myeloma cells cultured with their tumor environment. It also increased patients' myeloma cell apoptosis induced by an anti-IL-6 antibody or dexamethasone. The ErbB inhibitor had no effect on the interaction between multiple myeloma cells and stromal cells. It was not toxic for nonmyeloma cells present in patients' bone marrow cultures or for the growth of hematopoietic progenitors. Altogether, these data identify ErbB receptors as putative therapeutic targets in multiple myeloma.

Antineoplastic Agents, Hormonal↗

PubMed2003

Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence.

Interleukin (IL)-6, a pleiotropic cytokine with varied systemic functions, plays a major role in inflammatory processes. It modulates the transcription of several liver-specific genes during acute inflammatory states, particularly C-reactive protein, and controls the survival of normal plasmablastic cells. In addition, IL-6 has been implicated in hematopoiesis as a cofactor in stem cell amplification and differentiation. This article is the first review of clinical studies in the 1990s with anti-IL-6 monoclonal antibodies (mAbs) in the treatment of patients with cancer and related lymphoproliferative disorders. In six clinical studies of mAbs to IL-6 with BE-8 or CNTO 328 in patients with multiple myeloma, renal cell carcinoma, and B-lymphoproliferative disorders, anti-IL-6 mAb treatment decreased C-reactive protein levels in all patients. In most patients, levels decreased below detectable limits. The antibodies were well tolerated, and no serious adverse effects were observed in the vast majority of studies. The fact that anti-IL-6 mAb therapy decreased the incidence of cancer-related anorexia and cachexia may also be useful in the treatment of cancer patients.

Antibodies, Monoclonal↗

PubMed2002

Comparison of gene expression profiling between malignant and normal plasma cells with oligonucleotide arrays.

The DNA microarray technology enables the identification of the large number of genes involved in the complex deregulation of cell homeostasis taking place in cancer. Using Affymetrix microarrays, we have compared the gene expression profiles of highly purified malignant plasma cells from nine patients with multiple myeloma (MM) and eight myeloma cell lines to those of highly purified nonmalignant plasma cells (eight samples) obtained by in vitro differentiation of peripheral blood B cells. Two unsupervised clustering algorithms classified these 25 samples into two distinct clusters: a malignant plasma cell cluster and a normal plasma cell cluster. Two hundred and fifty genes were significantly up-regulated and 159 down-regulated in malignant plasma samples compared to normal plasma samples. For some of these genes, an overexpression or downregulation of the encoded protein was confirmed (cyclin D1, c-myc, BMI-1, cystatin c, SPARC, RB). Two genes overexpressed in myeloma cells (ABL and cystathionine beta synthase) code for enzymes that could be a therapeutic target with specific drugs. These data provide a new insight into the understanding of myeloma disease and prefigure that the development of DNA microarray could help to develop an 'à la carte' treatment in cancer disease.

Adult↗

PubMed2002

Generation of polyclonal plasmablasts from peripheral blood B cells: a normal counterpart of malignant plasmablasts.

A new way to identify tumor-specific genes is to compare gene expression profiles between malignant cells and their autologous normal counterparts. In patients with multiple myeloma, a major plasma cell disorder, normal plasma cells are not easily attainable in vivo. We report here that in vitro differentiation of peripheral blood B lymphocytes, purified from healthy donors and from patients with multiple myeloma, makes it possible to obtain a homogeneous population of normal plasmablastic cells. These cells were identified by their morphology, phenotype, production of polyclonal immunoglobulins, and expression of major transcription factors involved in B-cell differentiation. Oligonucleotide microarray analysis shows that these polyclonal plasmablastic cells have a gene expression pattern close to that of normal bone marrow-derived plasma cells. Detailed analysis of genes statistically differentially expressed between normal and tumor plasma cells allows the identification of myeloma-specific genes, including oncogenes and genes coding for tumor antigens. These data should help to disclose the molecular mechanisms of myeloma pathogenesis and to define new therapeutic targets in this still fatal malignancy. In addition, the comparison of gene expression between plasmablastic cells and B cells provides a new and powerful tool to identify genes specifically involved in normal plasma cell differentiation.

ADP-ribosyl Cyclase↗

PubMed2002

Cooperation between heparin-binding EGF-like growth factor and interleukin-6 in promoting the growth of human myeloma cells.

Interleukin-6 (IL-6) is a major survival and proliferation factor of human malignant plasma cells and IL-6 dependent myeloma cell lines can be obtained from patients with terminal disease. We show here that mutated diphtheria toxin, a specific inhibitor of heparin-binding epidermal growth factor-like growth factor (HB-EGF), blocked the IL-6-induced growth of two myeloma cell lines (XG-1 and XG-14) and did not significantly affect that of two other cell lines (XG-6 and XG-13). The IL-6 mediated growth of myeloma cells was also inhibited by antibodies to ErbB1, a receptor for HB-EGF. The XG-1 and XG-14 cell lines that are sensitive to HB-EGF inhibitors overexpressed HB-EGF and EGF receptor (ErbB1) genes. They also overexpressed CD9, a tetraspanin that binds to the heparin-binding domain of HB-EGF and is critical for promoting ErbB1 activation by HB-EGF. The XG-6 and XG-13 myeloma cells that were not significantly sensitive to HB-EGF antagonists, poorly expressed HB-EGF, ErbB1 and CD9 genes or proteins. We demonstrated that recombinant HB-EGF supported the long-term growth of myeloma cells, as did IL-6. The myeloma cell growth factor activity of HB-EGF was completely inhited by antibodies to ErbB1, but also by antibodies to gp130 IL-6 transducer or to IL-6. These data indicate that in the XG-1 and XG-14 IL-6-dependent myeloma cell lines, the CD9/HB-EGF/erbB1 and the IL-6/IL-6R/gp130 pathways cooperate synergistically to trigger myeloma cell growth. They suggest that inhibitors of the EGF receptor or HB-EGF may be useful for inducing myeloma cell apoptosis in patients with multiple myeloma.

Antigens, CD↗

PubMedDate not supplied

Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia.

BACKGROUND: Both gallium nitrate and pamidronate are highly effective for acute control of cancer-related hypercalcemia. However, the proportion of patients who actually achieve normocalcemia has varied in published reports. Therefore, we conducted an exploratory, randomized, double-blind trial that compared the efficacy and safety of gallium nitrate and pamidronate in hospitalized patients with cancer-related hypercalcemia. PATIENTS AND METHODS: Eligible patients with hypercalcemia, defined as albumin-adjusted serum calcium > or = 12.0 mg/dL after intravenous hydration, were stratified on the basis of tumor histology (i.e., epidermoid or nonepidermoid) and by study site. Patients were then randomly assigned to receive intravenous gallium nitrate 200 mg/m2 daily for 5 days or intravenous pamidronate 60 mg (increased during the study to 90 mg for patients with initial serum calcium > or = 13.5 mg/dL) followed by placebo infusions for 4 days. The primary endpoint of the study was comparison of the proportion of patients who achieved normocalcemia. RESULTS: Sixty-four patients were randomized, and all patients were evaluable for efficacy and safety. Normocalcemia was achieved in 22 of 32 (69%) patients treated with gallium nitrate compared with 18 of 32 patients (56%) treated with pamidronate. Patients randomized to pamidronate with initial serum calcium > or = 13.5 mg/dL did not respond better to 90 mg (3 of 6; 50%) than to 60 mg (7 of 13; 54%), or compared with the response to gallium nitrate in this subset (15 of 21; 71%). Response to pamidronate was also lower in patients with epidermoid cancers (33%, vs 68% for gallium nitrate). Duration of normocalcemia was examined using both an intent-to-treat analysis irrespective of response and an analysis that examined only responding patients. By intent-to-treat analysis, the median duration of normocalcemia was 1 day for the pamidronate group and 7 days for the gallium nitrate group. Estimated normocalcemic duration in responders was 10 days for the pamidronate group and 14 days for the gallium nitrate group. Both drugs were well tolerated, and clinically significant nephrotoxicity was not observed in either treatment group. DISCUSSION: Gallium nitrate appears to be at least as effective as pamidronate for acute control of cancer-related hypercalcemia. Results from this trial suggest that gallium nitrate may be particularly useful in patients with epidermoid cancers or severe hypercalcemia at baseline, and in patients who have previously exhibited a poor response to bisphosphonates.

Bone Density Conservation Agents↗