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Biomedical subjects

D Bron

Publications and source records attributed to D Bron.

At least 19 recordsLinked to original sources
PubMed1995

Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma.

BACKGROUND: High-dose chemotherapy followed by autologous bone marrow transplantation is a therapeutic option for patients with chemotherapy-sensitive non-Hodgkin's lymphoma who have relapses. In this report we describe a prospective randomized study of such treatment. METHOD: A total of 215 patients with relapses of non-Hodgkin's lymphoma were treated between July 1987 and June 1994. All patients received two courses of conventional chemotherapy. The 109 patients who had a response to chemotherapy were randomly assigned to receive four courses of chemotherapy plus radiotherapy (54 patients) or radiotherapy plus intensive chemotherapy and autologous bone marrow transplantation (55 patients). RESULTS: The overall rate of response to conventional chemotherapy was 58 percent; among patients with relapses after chemotherapy, the response rate was 64 percent, and among those with relapses during chemotherapy, the response rate was 21 percent. There were three deaths from toxic effects among the patients in the transplantation group, and none among those in the group receiving chemotherapy without transplantation. The two groups did not differ in terms of prognostic factors. The median follow-up time was 63 months. The response rate was 84 percent after bone marrow transplantation and 44 percent after chemotherapy without transplantation. At five years, the rate of event-free survival was 46 percent in the transplantation group and 12 percent in the group receiving chemotherapy without transplantation (P = 0.001), and the rate of overall survival was 53 and 32 percent, respectively (P = 0.038). CONCLUSIONS: As compared with conventional chemotherapy, treatment with high-dose chemotherapy and autologous bone marrow transplantation increases event-free and overall survival in patients with chemotherapy-sensitive non-Hodgkin's lymphoma in relapse.

Adolescent↗
PubMed1995

Comparison of the coexpression of CD38, CD33 and HLA-DR antigens on CD34+ purified cells from human cord blood and bone marrow.

Human umbilical cord blood (UCB) cells are currently considered as a potential source of stem cells for transplantation. However, it remains unclear whether a single collection of UCB contains enough progenitors to allow a successful engraftment in adult patients. We were interested in the comparison of the frequency of primitive progenitors in UCB and in human bone marrow (BM). UCB and BM CD34+ cells were purified and compared for their coexpression of CD38, CD33 and HLA-DR. UCB and BM mononuclear fractions were enriched in CD34+ cells using the CEPRATE LC system (CellPro, Bothell, WA). Double-labeling analysis with a flow cytometer showed that 67.9 +/- 7.2% of UCB CD34+ cells are CD38-, while in BM only 10.9 +/- 4.9% of CD34+ are CD38- (p < 0.001). Moreover, our study indicated that a significantly higher percentage of UCB CD34+ is CD33- (97.1 +/- 1.2%) compared to BM (61.8 +/- 8.6%) (p = 0.013). The coexpression of CD34 with HLA-DR was not significantly different in UCB and in BM (respectively, 86.3 +/- 2.7% and 92.7 +/- 5.1%). On the other hand, in vitro assays showed that the number of multipotent (colony-forming units granulocyte-erythroid-macrophage-megakaryocyte [CFU-GEMM]), myeloid (colony-forming units granulocyte-macrophage [CFU-GM]) and erythroid (burst-forming units-erythroid [BFU-E]) progenitors is lower in the CD34+ population from UCB than from BM. In conclusion, in UCB, we have found a significantly higher percentage of CD34+ cells which lacked the expression of CD38 and CD33 antigens suggesting that UCB contains higher proportions of immature progenitor cells (CD34+CD38- and CD34+CD33-) than BM. It seems thus likely that fewer UCB CD34+ cells than BM CD34+ cells would be required for sustained engraftment following transplantation.

Antigens, CD↗
PubMed1995

Comparative analysis of cytokines released by bone marrow stromal cells from normal donors and B-cell chronic lymphocytic leukemic patients.

We studied the production of cytokines (G-CSF, GM-CSF, IL-6, LIF and IL-10) by bone marrow stromal cells of five untreated patients with B-CLL, in Rai stage 0, I and II, and of 8 healthy subjects. The production of G-CSF, GM-CSF, LIF and IL-10 did not differ significantly between controls and B-CLL patients. However, the ability of stromal cells to release IL-6 in response to LPS was decreased in all patients: 36 +/- 5 ng/ml versus 123 +/- 47 ng/ml for normal controls (p < 0.004). Moreover, a soluble activity that inhibited hematopoietic colony formation was detected in B-CLL stromal cell conditioned media. Some potential inhibitors were envisaged and the results indicated an increased production of TGF-beta by B-CLL stromal cells compared to normal stromal cells (respectively 53 +/- 10 versus 15 +/- 4 ng/ml, p < 0.03). The reduced capacity of B-CLL stromal cells to produce IL-6 was associated with this excessive release of TGF-beta; indeed, addition of anti-TGF-beta neutralizing antibody to B-CLL stromal cells, before LPS stimulation, totally normalized the production of IL-6. TGF-beta and IL-6 were also measured in serum samples from normal subjects and B-CLL patients. No significant difference was seen in the production of total TGF-beta (bioactive and latent forms) between normal and B-CLL sera but the mean level of bioactive protein in B-CLL sera was increased in comparison with normal sera (1.74 +/- 0.44 versus 0.67 +/- 0.2 ng/ml, p < 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Immunological definition of acute minimally differentiated myeloid leukemia (MO) and acute undifferentiated leukemia (AUL).

Immunophenotyping has become an important tool in the diagnosis of acute leukemia for several reasons. Indeed the use of a standardized panel of monoclonal antibodies (MoAb) to B and T cells, and myeloid cells, as well as non lineage restricted antigens, permits allocation of more than 98% of acute leukemia to their respective lineage. In ALL, immunophenotyping has established a basis for precise and biologically oriented classification of the disease which may be of prognostic importance. In AML immunological markers are particularly important for identification of acute leukemia with minimal myeloid, erythroblastic or megakaryoblastic differentiation. Immunological markers also allow the identification of acute leukemias with minimal or aberrant marker expression, acute biphenotypic leukemia in which single cells coexpress different lineage associated markers and acute bilineage leukemia where there are two separate blast cell populations (usually lymphoid and myeloid). There is sometimes confusion in the literature about the definition of acute unclassifiable and acute undifferentiated leukemia. This is mainly due to misinterpretation of phenotypic data or to the lack of relevant lineage specific markers in these studies, especially for the detection of cytoplasmic antigens. Indeed, it is important to stress that in hematopoietic precursors, antigens detected by monoclonal antibodies first appear in the cytoplasm during early differentiation and are only expressed on the membrane later. This has been demonstrated not only for the T lineage (Cy CD3), the B lineage (CyCD22) but also for the myeloid lineage (CyCD13).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Modulation of human cord blood progenitor cell growth by recombinant human interleukin 3 (IL-3), IL-6, granulocyte-macrophage colony stimulating factor (GM-CSF) and stem cell factor (SCF) in serum-supplemented and serum-free medium.

UNLABELLED: We evaluated the growth of cord blood myeloid progenitors or colony forming units granulocyte-macrophage (CFU-GM) and their response to various recombinant growth factors or colony stimulating factors (CSFs): interleukin 3 (IL-3), IL-6, granulocyte-macrophage CSF (GM-CSF) and stem cell factor (SCF). Using classical stimulant (human placenta conditioned medium or HPCM), we observed a significantly higher day-14/day-7 CFU-GM ratio in CB than in bone marrow (BM). The association of IL-3, IL-6, GM-CSF and SCF induced significantly more CB day-14 CFU-GM than HPCM. This effect is significantly greater in CB than in bone marrow. Since fetal calf serum (FCS) is known to contain inhibitors, we have compared the ability of CSFs to induce CFU-GM formation in FCS-supplemented and FCS-free culture. In CB, using HPCM, we obtained significantly more CFU-GM in FCS-free medium than in FCS-supplemented medium. This difference was corrected by the addition of anti-transforming growth factor-beta (TGF-beta) neutralizing antibody. However, with the association of the four CSFs, no significant difference between FCS and FCS-free culture was observed. IN CONCLUSION: a) day-14/day-7 CFU-GM ratio was higher in CB than in BM indicating that CB CFU-GM are more primitive than BM CFU-GM; b) FCS can be successfully replaced by serum-free medium; c) FCS contains inhibitors of day-14 CFU-GM and among them TGF-beta; and d) the association IL-3, SCF, GM-CSF and IL-6 seems able to totally overcome the inhibitory effect of FCS.

Bone Marrow↗
PubMed1994

EORTC study of non-Hodgkin's lymphoma: phase III study comparing CHVmP-VB and ProMACE-MOPP in patients with stage II, III, and IV intermediate- and high-grade lymphoma.

In the EORTC lymphoma cooperative group, a randomized phase III study was done for patients with stage II, III, IV intermediate- and high-grade lymphoma. Eight courses of CHVmP-VB were compared to eight courses of ProMACE-MOPP. Response was evaluated after 8 courses. Of 430 patients entered, 346 were eligible for this first analysis. Additional radiotherapy was given at initial large masses or residual disease after three courses. Response rate was higher in the CHVmP-VB arm in comparison to the ProMACE-MOPP arm, 82% vs. 65% (p < 0.0005). In the ProMACE-MOPP arm, treatment had to be interrupted because of patient refusal in 7% of the patients. So far there has been no significant difference in freedom from progression at 5 years (49% vs. 47%), relapse-free survival (59% vs. 59%), or overall survival (55% vs. 49%). Patients with early response at 4 courses showed no better RFS in comparison with late responders between 4 and 8 courses. The International Index, based on age, stage, SLDH, performance status, and number of extranodal localizations showed a good prognostic significance in this series of patients.

Adult↗
PubMed1994

Graft-versus-host disease.

Combinations of drugs such as methotrexate, cyclosporin A, and prednisone have reduced the incidence of graft-versus-host disease (GVHD) to 20% to 30%. However, GVDH remains a major complication (up to 90%) following allogeneic bone marrow transplantation from unrelated or mismatched donors. GVHD is now understood as a two-step phenomenon: first, the activation of specific cytotoxic T cells and second, the release of several cytokines. Recent treatment modalities, including new immunosuppressors, T-cell depletion, and anticytokine monoclonal antibodies are discussed.

Acute Disease↗
PubMed1994

Decreased production of cytokines after cytomegalovirus infection of marrow-derived stromal cells.

Cytomegalovirus (CMV) infection is frequently associated with graft failure in bone marrow transplant patients; the pathogenesis of this myelosuppression in not clearly understood. We have previously documented that CMV-induced myelosuppression is related to an alteration of the marrow microenvironment. To further investigate the effect of CMV on stromal cell function, conditioned media (CM) from CMV-infected or uninfected stromal cells were tested for their capacity to promote the growth of granulocyte/macrophage colony-forming cells (CFU-GM) and for their concentration in colony-stimulating factors (CSFs) such as interleukin-3 (IL-3), IL-6, granulocyte-macrophage and granulocyte colony-stimulating factors (GM-CSF and G-CSF). CM from CMV-infected stromal cells failed to sustain granulocyte-macrophage colony-forming unit (CFU-GM) growth. The production of IL-6, GM-CSF, and G-CSF, measured by enzyme-linked immunosorbent assay (ELISA), was 21,150 +/- 3392, 57 +/- 15, and 2340 +/- 717 pg/mL, respectively, in CMV-infected stromal cells stimulated by lipopolysaccharide (LPS) and was significantly decreased (p < 0.01) from the control values (177,138 +/- 98,692, 113 +/- 20, and 5533 +/- 1306 pg/mL). These results suggest that the myelosuppressive effect of CMV is primarily due to a lack of CSF production. To further document this hypothesis, primitive marrow progenitor cells (blast colony-forming cells [Bl-CFC]) cultured on CMV-infected stromal layer have been grown in the presence of IL-3 (20 ng/mL), IL-6 (20 ng/mL), GM-CSF (40 ng/mL), and G-CSF (50 ng/mL). Used alone, all these CSFs partially reverse the CMV-induced inhibition of Bl-CFC growth; the combination of these CSFs completely restores normal Bl-CFC values. These data strongly suggest that CMV-induced myelosuppression is related to the lack of CSF production by the cells of the marrow microenvironment.

Adolescent↗
PubMed1993

Excessive production of transforming growth factor-beta by bone marrow stromal cells in B-cell chronic lymphocytic leukemia inhibits growth of hematopoietic precursors and interleukin-6 production.

To explore the pathogenesis of marrow failure in B-cell type chronic lymphocytic leukemia (B-CLL), we have examined the production of interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage CSF (GM-CSF) by the adherent cell population of bone marrow (BM) derived from B-CLL patients and their capacity to support hematopoietic cell proliferation. Lipopolysaccharide-stimulated B-CLL stromal cells produced G-CSF and GM-CSF in amounts similar to normal stromal layers, whereas IL-6 production was significantly decreased. Using the blast-colony forming cell assay (BI-CFC) and the classical colony-forming unit granulocyte macrophage (CFU-GM) assay, we found that: (1) marrow stromal cells of B-CLL were able to support only 25% of the BI-CFC growth supported by normal marrow stromal cells; (2) this anomaly was partially corrected by the addition of exogenous IL-6; (3) the colony-stimulating activity (CSA) of the conditioned medium (CM) of B-CLL stromal cells was lower than that of normal CM; (4) that this was the result of the presence of an inhibitor rather that of a growth factor defect; (5) this inhibition could be abrogated by addition of anti-transforming growth factor-beta (TGF-beta) neutralizing antibody; (6) this antibody corrected the deficient colony supportive activity of the B-CLL stromal cells; (7) TGF-beta production by marrow stromal cells was significantly increased in CLL compared with normal; and (8) that this was not caused by the effect of the B-CLL lymphocytes on the stromal cells. It is concluded that this increased TGF-beta production in B-CLL is probably responsible for the decreased IL-6 production by stromal cells and for the inhibiting activity on hematopoietic precursors as well. We hypothesize that TGF-beta generated at a high level by B-CLL marrow stromal cells could play a major role in the pathophysiology of the BM failure seen in advanced stages of B-CLL.

Aged↗
PubMed1993

Modulation of the growth of hematopoietic human stem cells by growth factors: comparison of umbilical cord blood with bone marrow.

The growth of cord blood and bone marrow myeloid mononuclear cells in response to single and multiple growth factors has been examined. Single factors such as IL-3, IL-6, GM-CSF, and stem cell factor did not optimally stimulate growth of cord blood CFU-GM. However a synergistic stimulation was observed when the factors were combined. This effect was seen in both the presence and absence of added fetal calf serum.

Antigens, CD↗
PubMed1992

Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression.

B chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of slow-dividing and long-lived monoclonal B cells arrested at the intermediate stage of their differentiation. We previously showed that interleukin 4 (IL-4) not only inhibits but also prevents the proliferation of B-CLL cells. We report here that IL-4 protects the B-CLL cells from death by apoptosis (programmed cell death [PCD]). IL-4 inhibits spontaneous and hydrocortisone (HC)-induced PCD of highly purified B cells from 12 unselected CLL patients, as shown by sustained cell viability and lack of DNA fragmentation. IL-1, -2, -3, -5, -6, -7, tumor necrosis factor alpha, and transforming growth factor beta have no protective effect. The in vitro rescue from apoptosis by IL-4 is reflected by an increased expression of Bcl-2 protein, a proto-oncogene directly involved in the prolongation of cell survival in vivo and in vitro. Hence, IL-4-treated B-CLL cells express significantly more Bcl-2 than unstimulated, HC-treated, or fresh B-CLL cells. Furthermore, subcutaneous injection of IL-4 into one CLL patient enhances Bcl-2 protein expression in the leukemic B cells. These data may suggest that IL-4 prevents apoptosis of B-CLL cells using a Bcl-2-dependent pathway. Given our recent observations that fresh T cells from B-CLL patients express IL-4 mRNA, we propose that IL-4 has an essential role in the pathogenesis of CLL disease, by preventing both the death and the proliferation of the malignant B cells.

Adult↗
PubMed1992

Screening for psychiatric disorders in a lymphoma out-patient population.

The Hospital Anxiety and Depression Scale (HADS), a four-point, 14-item self-assessment questionnaire, was tested as a screening method for psychiatric disorders in a sample of 117 Hodgkin's lymphoma and non-Hodgkin lymphoma consecutive out-patients. A receiver operating characteristic (ROC) analysis was performed, giving the relationship between the true positive rate (sensitivity) and the false positive rate (1--specificity). This makes it possible to choose an optimal cut-off score that takes into account the costs and benefits of treatment of psychiatric disorders (mainly adjustment, depressive and anxiety disorders) in a lymphoma out-patient population. A cut-off point of 10 gave 84% sensitivity and 66% specificity. HADS appears in this study to be a well accepted, simple, sensitive and specific tool.

Adjustment Disorders↗
PubMed1992

[Bone marrow autograft in malignant hemopathies. The Team of the Sterile Unit].

Only in the last decade have autologous grafts begun to be studied extensively. Their most attractive feature is the avoidance of GVHD. However, GVHD has antitumoral effect on residual leukemic cells called "graft versus leukemia" effect and better understanding of this phenomenon explains the higher relapse rate after autologous bone marrow transplantation. New approaches such as cyclosporin--induced GVHD and IL-2 administration after autograft bring great expectations in this field. Colony stimulating factors and harvesting of peripheral stem cells help to reduce the duration of neutropenia. Finally, various techniques for marrow purging and hematopoietic cell isolation should make it possible to eliminate minimal residual disease. Recent results of autologous bone marrow transplantation in various malignancies are discussed.

Bone Marrow Transplantation↗
PubMed1991

Parma international protocol: pilot study of DHAP followed by involved-field radiotherapy and BEAC with autologous bone marrow transplantation.

Fifty patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) who had relapsed after a complete remission induced by an Adriamycin-containing chemotherapy regimen participated in this prospective pilot study. The patients ranged in age from 16 to 60 years (median 42 years). All patients received dexamethasone, high-dose cytarabine, and cisplatin (DHAP) for two courses at 3- to 4-week intervals. Patients achieving a partial or complete response were scheduled to receive involved-field radiotherapy and high-dose carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC), followed by autologous bone marrow transplantation (ABMT). Among 48 evaluable patients (ie, 1 was lost to follow-up and 1 had no measurable disease) 7 patients obtained a complete response (CR) and another 21 patients achieved partial response (PR), whereas the remaining 20 patients failed. One responder died of treatment-related toxicity, and six others declined ABMT. The patient with no measurable disease did not progress on DHAP and was submitted to ABMT. Twenty-two patients underwent ABMT [20 with BEAC and 2 with cyclophosphamide plus total body irradiation (TBI)] of whom 2 (9%) died of toxicity and 10 relapsed. One patient was a suicide at 28 months post-ABMT in CCR and 9 are alive disease-free 24 months to 32 months (median 30 months) post-ABMT. The actuarial 2-year event-free survival for patients undergoing transplantation is 40%. This prospective multicenter trial documents the ability of DHAP followed by ABMT to produce durable complete remission in a significant proportion of patients with relapsed aggressive NHL. Forty-four percent of all patients with relapsed lymphoma who entered the study actually underwent ABMT and 20% of the total group are projected to be long-term disease-free survivors.

Adolescent↗
PubMed1991

PARMA international protocol: pilot study on 50 patients and preliminary analysis of the ongoing randomized study (62 patients).

Fifty patients with intermediate- or high-grade non-Hodgkin's lymphoma who had relapsed following a complete remission (CR) induced by a doxorubicin-containing chemotherapy regimen participated in the PARMA pilot study. The patients ranged in age from 16 to 60 years (median age, 42). All patients received DHAP (dexamethasone/high-dose cytarabine/cisplatin) for two courses at 3- to 4-week intervals. Patients achieving a partial response (PR) or CR were scheduled to receive involved-field radiotherapy and high-dose BEAC (carmustine/etoposide/cytarabine/cyclophosphamide) followed by autologous bone marrow transplantation (ABMT). Of 48 evaluable DHAP-treated patients (one patient was lost to follow-up and one had no measurable disease), seven achieved CR, 21 PR, and 20 patients had no response or progressive disease. One responder died from treatment-related toxicity, and six others declined ABMT. The patient with no measurable disease did not progress on DHAP and received ABMT. In all, 22 patients underwent ABMT (20 with BEAC and two with cyclophosphamide plus total body irradiation); two patients (9%) died from toxicity and ten (45%) relapsed. One patient in continuous CR committed suicide 28 months post-ABMT, and nine are alive and disease-free 24 to 32 months (median, 30) post-ABMT. The actuarial 2-year event-free survival for patients undergoing transplantation is 40%. This prospective multicenter trial documented the ability of DHAP followed by ABMT to produce durable CR in a significant proportion of patients with relapsed aggressive non-Hodgkin's lymphoma (NHL). Forty-four percent of all study patients with relapsed lymphoma actually underwent ABMT, and 20% of the total group are projected to be long-term disease-free survivors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Blood coagulation abnormalities during adoptive immunotherapy with interleukin-2 (r-Met Hu IL-2 [ala 125]).

Immunotherapy with Interleukin-2 (IL-2) and LAK cells has shown antitumoral activity in metastatic cancer patients. So far, thrombocytopenia is the major side effect reported in hemostasis. We have studied coagulation parameters in 6 patients treated with r-Met Hu IL-2 [ala-125]. In each case, we have observed a significant fall in prothrombin time, fibrinogen, protein C, anti-thrombin III, plasminogen, alpha 2-antiplasmin and all of the clotting factors except factor VIII. There was a significant increase in the activated thromboplastin time. No significant modifications of the D-Dimer test, fibrin-fibrinogen degradation products (FDP) and thrombin time were observed. Our data suggest that r-Met Hu IL-2 [ala-125] could interfere with the hepatic synthesis of the clotting factors and their inhibitors.

Blood Coagulation↗