PubMed Health⌕ Search

Biomedical subjects

M J Rapp

Publications and source records attributed to M J Rapp.

At least 37 records · Page 2Linked to original sources
PubMed1998

High-dose therapy with stem cell transplantation for mantle cell lymphoma: results and prognostic factors, a single center experience.

From 1991 to 1997 18 consecutive patients with well-defined mantle cell lymphoma (MCL) underwent high-dose therapy with unpurged autologous (17 patients) or allogeneic (one patient) stem cell transplantation. Tissue sections were reviewed for morphology, immunophenotype, cyclin D1 and P53 expression as well as proliferation index (PI). Median age of patients was 47 years (range 40-60). Sixteen had stage IV disease with bone marrow involvement in 12 and performance status was > or =1 in 12 patients. At the time of high-dose therapy 10 patients were in first partial response (PR), one was in second complete remission (CR), four were in second PR and three were refractory to conventional anthracycline-containing chemotherapy. The conditioning regimen consisted of TBI plus chemotherapy in 13 patients and chemotherapy only (BEAM) in five patients. No treatment-related deaths were observed. With a median follow-up of 36 months (range 13-80) after transplant, disease-free survival (DFS) and overall survival (OS) are estimated to be 48 and 80% at 4 years, respectively. Significantly better results are achieved for patients transplanted after a TBI containing regimen with a 4 year OS and DFS estimated at 89 and 71%, respectively compared to 60 and 0% respectively for patients who were conditioned without TBI (P = 0.07 for OS and P < 0.0001 for DFS). There is a trend towards better DFS when the transplant is performed in PR1 (4 year DFS: 80% with eight patients out of 10 in continuous CR 13 to 80 months, median 36 months after transplant) compared to more advanced stages (4 year DFS: 18% with only three patients out of eight in continuous CR 16, 17 and 58 months after transplant). Blastic histology and P53 overexpression are also associated with a trend towards a worst prognosis.

Adult↗
PubMed1998

The absence of CD56 (NCAM) on malignant plasma cells is a hallmark of plasma cell leukemia and of a special subset of multiple myeloma.

In this study, we show that malignant plasma cells from patients with either primary (n=12) or secondary (n=15) plasma cell leukemia (PCL) do not express CD56 at all, neither in the bone marrow nor the peripheral blood in 81% of cases. On the other hand, multiple myeloma (MM) at diagnosis overexpress it in 63 of 94 (67%) cases (P=0.0001). In three secondary PCL evaluated serially, CD56 was also lacking at diagnosis showing that CD56 is not downregulated at the end stage of the disease but rather not upregulated in this subset of patients. This last concept is strengthened by the observation that 29% of MM patients lacking CD56 or weakly expressing it at diagnosis present a detectable leukemic phase vs 11% only in CD561 MM (P=0.06). Forty percent of all the CD56(-/weak) malignant plasma cell disorders present or develop a leukemic phase vs only 15% of CD56+ cases (P < 0.008). CD56(-/weak) MM subset is also associated with a significantly less aggressive osteolytic potential (P=0.012). We conclude that the lack or weak expression of CD56 is a characteristic feature of PCL but also delineates a special subset of MM at diagnosis mainly characterized by a lower osteolytic potential and a trend for malignant plasma cells to circulate in the peripheral blood more overtly.

Bone Marrow↗
PubMed1998

Early intensive therapy with autologous stem cell transplantation in high-risk Hodgkin's disease: long-term follow-up in 35 cases.

Thirty-five adult patients with high-risk HD (HD) defined by (1) Ann Arbor stage IV or bulky nodal disease (tumor/thorax ratio > 0.45) and (2) no or partial response (PR) (< 75%) to the initial 3 courses of ABVD, received an early intensive therapy with autologous stem cell transplantation (ASCT). Thirty patients were considered as partial responders and 5 as refractory to initial chemotherapy. Conditioning regimen consisted of chemotherapy alone (CBV in 11 patients before 1993, BEAM in 13 patients since 1993) followed by adjuvant radiotherapy: 40 Gy) on the initial sites of bulky disease, or 12 Gy total body irradiation plus 120 mg/kg cyclophosphamide in 11 patients with disseminated extra-nodal disease. All 30 patients in PR at the time of ASCT experienced prolonged complete remission (CR). One patient died in CR from an acute myocardial infarction 48 months after ASCT. Four out of the 5 patients with refractory disease at the time of ASCT experienced rapid progression of HD leading to death in 3 cases. After 6 years of CR post-ASCT, the last refractory patient died of myelodysplastic syndrome diagnosed 2 years after intensive therapy. With a median follow-up for surviving patients of 51 months (range: 11-111), the cumulative probability of 8-year overall survival is 75.6% for the entire group of patients, 94.1% for the chemosensitive ones, and 0% for the primary refractory (P < .0001). The cumulative probability of 8-year event-free survival is 79.9% for the entire group of patients, 94.1% for the chemosensitive ones, and 0% for the primary refractory (P < .0001). We conclude that early intensive therapy with ASCT is feasible in patients with high-risk HD and induces a high cure rate in chemosensitive patients. In primary refractory patients, new therapeutic approaches are warranted.

Adolescent↗
PubMed1998

CD28, a marker associated with tumoral expansion in multiple myeloma.

CD28 expression was thoroughly investigated on plasma cells of monoclonal gammopathy of undetermined significance, multiple myeloma (MM), and human myeloma cell lines. CD28+ plasma cells were detected in 19% of 31 monoclonal gammopathy of undetermined significance, 41% of 116 MM, and 100% of 13 human myeloma cell lines. CD28+ myeloma cells were detected in 21 of 79 (26%) MM cases at diagnosis, 13 of 22 (59%) at medullary relapse (P < 0.009), and 14 of 15 (93%) at extramedullary relapse (P = 0.05), including 10 of 10 (100%) secondary plasma cell leukemias (P = 0.05). Serial studies in individual patients confirmed the emergence of CD28+ myeloma cells with tumoral expansion and treatment failure. This was significantly correlated with the expression of CD28 ligand, i.e., CD86 (but not CD80), and with an increase in the proliferative activity (labeling index) of myeloma cells in bone marrow. Whereas the expression of CD56 defines a particular subset of myeloma patients, CD28 is the only antigen for which expression correlates with tumor progression. Our data show that an aggressive compartment of CD28+ and CD86+ myeloma cells emerges during the course of MM in vivo, indicating that CD28 could be aberrantly expressed on highly malignant (possibly mutated) myeloma cells. Conversely, a subset of proliferative plasmablasts coexpressing CD28 and CD86 could be the normal counterpart of the clonogenic myeloma stem cell because a subset of CD28+ plasma cells was observed in 6 of 6 cases of reactive plasmocytosis.

Antigens, CD↗
PubMed1997

Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells.

Multiple myeloma is a very devastating cancer with a high capacity to destroy bone matrix. Matrix metalloproteinases (MMPs) play a critical role in bone remodeling and tumor invasion. In this study, we have investigated the involvement of interstitial collagenase (MMP-1) and gelatinases (MMP-2 and MMP-9) in the biology of multiple myeloma. We show (1) that myeloma cells express MMP-9 and (2) that this expression is not subjected to regulation either by interleukin-6 (IL-6), the major myeloma cell growth factor, or by other cytokines involved in the multiple myeloma cytokine network. In the tumoral environment, we show that bone marrow stromal cells express MMP-1 and MMP-2. Whereas MMP-1 is positively regulated by IL-1beta, tumor necrosis factor-alpha, and Oncostatin M, MMP-2 is not modulated by any of these cytokines. To evaluate whether myeloma cells can modify the bone marrow stromal environment, we have examined these MMP activities in coculture. Interestingly, we have observed an upregulation of MMP-1 and a partial conversion of the proMMP-2 into its activated form. We conclude that the increase of MMP activity produced or induced by myeloma cells in these cocultures could favor bone resorption and tumor invasion. Inhibition of such activities could represent a new therapeutical approach in multiple myeloma.

Antineoplastic Agents↗
PubMed1996

G-CSF alone mobilizes sufficient peripheral blood CD34+ cells for positive selection in newly diagnosed patients with myeloma.

We have evaluated CD34+ cell positive selection from granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPC) in 26 patients with either multiple myeloma (MM, n = 18) or follicular non-Hodgkin's lymphoma (NHL, n = 8). 26 PBPC were collected with two leukaphereses: 16 contained sufficient numbers of CD34+ cells and were elected. The absolute number of CD34+ cells in the leukapheresis products was found to be significantly related to the duration of underlying disease and exposure to prior treatment. CD34+ cell positive selection allowed recovery of a median of 35% of CD34+ cells, the selected fraction containing a median number of 1.43 x 10(6)/kg CD34+ cells/kg (range 0.48-41.5). 10 patients were transplanted and received a median dose of 1.51 x 10(6) CD34+ cells (range 0.48-4.2). The median time to granulocyte ( > 0.5 x 10(9)/l) and platelet ( > 20 x 10(9)/l) engraftment was 12 and 13 d respectively (ranges 10-13 and 0-95). Lymphoma cells were found by a sensitive polymerase chain reaction technique in four out of five CD34+ cell fractions tested.

Adult↗
PubMed1996

A pilot study of 220 mg/m2 melphalan followed by autologous stem cell transplantation in patients with advanced haematological malignancies: pharmacokinetics and toxicity.

We studied the pharmacokinetics and toxicity of 220 mg/m2 melphalan (HDM 220) followed by autologous stem cell transplantation in 16 patients with advanced haematological malignancies. Pharmacokinetic parameters (mean values of steady-state volume of distribution 14.6 l/m2, total body clearance 313 ml/min/m2, elimination half-life 46 min) were the same as those of 140 or 200 mg/m2 melphalan in previous reports. HDM 220 was feasible. Extramedullary toxicity was mainly W.H.O. grade 4 mucositis (13/16 patients). The median duration of 41 d (10, not reached) of thrombocytopenia < 25 x 10(9)/l was long. In multiple myeloma the response rate was 89% in heavily pretreated patients, suggesting that HDM 220 could be considered earlier in the course of the disease as an alternative consolidation therapy.

Adolescent↗
PubMed1996

Successful allogeneic bone marrow transplantation for early relapse after autologous bone marrow transplantation in two cases of aggressive high-grade non-Hodgkin's lymphoma.

Two patients with high-grade disseminated non-Hodgkin's lymphoma relapsed 3 and 7 months respectively after high-dose chemotherapy and autologous BMT performed in first complete remission. Both patients had an HLA-identical sibling and received an allogeneic BMT 5 and 10 months after autologous BMT, after conditioning with fractionated 12 Gy total body irradiation plus cyclophosphamide. They both are alive and well, with a Karnofsky score of 100%, 15 and 27 months after allogeneic BMT. For selected patients with HLA-identical siblings and good performance status who relapse after autologous transplantation for high-grade non-Hodgkin's lymphoma, allogeneic BMT may be an option.

Adolescent↗
PubMed1996

13q14 deletions are not primary events in B-cell chronic lymphocytic leukemia: a study of 100 patients using fluorescence in situ hybridization.

Fluorescence in situ hybridization with a chromosome 12-specific alpha-centromeric probe and a 13q14 yeast artificial chromosome probe was performed on interphase cells from 100 patients with B-cell chronic lymphocytic leukemia. Thirty-one patients exhibited a 13q14 deletion. No correlation was found between 13q14 deletions and clinical stage, sex, or morphology. Sixteen patients had trisomy 12, including 6 (of 12) with an atypical morphology. Trisomy 12 and 13q14 abnormalities were detected concomitantly in three patients only. The analysis of patients with deletions clearly showed that in five cases a significant number of cells retained two signals with the yeast artificial chromosome probe, indicating a genetic heterogeneity among the leukemic population. Our data confirm that the 13q14 deletion is a frequent event, indicate that the concomitant occurrence of 13q14 deletion and trisomy 12 is rare but possible, and show that both abnormalities are secondary events in B-cell chronic lymphocytic leukemia.

Chromosome Deletion↗
PubMed1995

Adhesion molecules on human myeloma cells: significant changes in expression related to malignancy, tumor spreading, and immortalization.

In order to evaluate putative changes of major adhesion molecule expression on plasma cells (PCs) associated with malignant transformation, tumor spreading, and immortalization, we have quantified and compared the expression of CD56, CD44, CD11a, CD49e, and CD45 RO/RA on normal PCs, malignant PCs from multiple myeloma patients in chronic phase, in accelerated phase with or without extramedullary progression, and from human myeloma cell lines. Plasma cell phenotype was defined with the use of two-color immunofluorescence in combination with B-B4 or anti-CD38 antibodies. We found that all the adhesion antigens were expressed on normal PCs. Malignancy was characterized by an overexpression of CD56, whereas extramedullary spreading was associated with a dramatic down expression of CD56. Although CD44 remained unchanged, the subpopulation of PCs expressing CD11a, CD49e, and CD45RA/RO were significantly reduced during malignancy, and each of these negative subpopulations increased during disease acceleration. We demonstrated that CD11a and CD49e expression were correlated and defined the same subpopulation of PCs. The phenotype of HMCLs was similar to the expression profile of patients in accelerated phase with extramedullary spreading. In conclusion, we show that significant changes of PC phenotype were associated with malignancy, were correlated with the disease evolution, and could be of diagnostic and prognostic value in individuals with monoclonal gammopathy and patients with multiple myeloma.

Antigens, CD↗
PubMed1995

High incidence of deletions but infrequent inactivation of the retinoblastoma gene in human myeloma cells.

We have studied the retinoblastoma (RB-1) susceptibility gene status and pRB expression in 22 human myeloma cell lines (HMCL) and in 10 patients with advanced multiple myeloma (MM). Deletions of the RB-1 gene were observed in 81% (17/21) of the informative HMCL, regardless of their paracrine or autocrine interleukin-6 (IL-6) status. Among the deleted HMCL, only one (U266) had a biallelic deletion and lacked pRB expression. Monoallelic deletions had no consequence on the RB-1 gene activation and pRB expression. One patient of 10 presented the same biallclic deletion as U266 and six of 10 had monoallelic deletions. We conclude that monoallelic deletions of the RB-1 gene are frequent in HMCL and MM patients but have no consequence on gene activation and pRB expression.

Blotting, Southern↗
PubMed1995

An interleukin 1 receptor antagonist blocks the IL-1-induced IL-6 paracrine production through a prostaglandin E2-related mechanism in multiple myeloma.

By analogy with the model of pristane-induced mouse plasmacytomas, we have wondered about the putative role of prostaglandin E2 (PGE2) in the human multiple myeloma (MM) cytokine network, involving interleukin 6 (IL-6) and interleukin 1 (IL-1) as essential myeloma cell growth factors and inducing cofactors respectively. We show that PGE2 is produced in short-term cultures of bone marrow cells of patients with MM, concomitantly with both IL-6 and IL-1. Indomethacin, a potent inhibitor of cyclo-oxygenase and of PGE2 synthesis, significantly inhibits IL-6 production (but not IL-1 production) by 35% to 90% depending on the different MM patients studied and concurrently to that of PGE2. Exogenous PGE2 reverses this inhibition or even stimulates IL-6 production. An IL-1 receptor antagonist (IL-1RA) also significantly inhibits PGE2, IL-6 production and myeloma cell growth. The inhibition of IL-6 production is reversed by adding exogenous PGE2. These results show that induction of IL-6 by IL-1 is related to PGE2 in the bone marrow of patients with MM. Inhibition of PGE2 synthesis (as obtained with indomethacin and the IL-1RA) might be helpful to inhibit myeloma cell proliferation by reducing IL-1-induced endogenous IL-6 production not only in vitro (as demonstrated here) but also in vivo.

Animals↗
PubMed1994

Expression of CD28 and CD40 in human myeloma cells: a comparative study with normal plasma cells.

CD28 and CD40 are important activation pathways for T and B lymphocytes, respectively. The aim of this study was to determine the phenotype of plasma cells (PCs) and the expression of these two molecules, CD28 and CD40. Therefore, we have compared their expression on normal PCs from bone marrows and tonsils with that of freshly explanted malignant PCs from 31 patients with multiple myeloma (MM) and those from 12 human myeloma cell lines. For this purpose, we first described a new approach to identify plasma cells in bone marrow using two-color immunofluorescence analysis with anti-CD38 and B-B4 antibodies. B-B4 specifically recognizes all PC; all B-B4 cells are located within the CD38 bright fraction and vice versa. CD19 and CD56 expression, which was previously shown to discriminate normal from malignant PCs, was also evaluated. In the current report, we show that normal PCs express CD19, CD40, and CD56 (weakly as a subset) and lack CD28. Regardless of whether they express CD19, CD56 is clearly upregulated during the medullary chronic and accelerated phases of MM, but is absent in patients with extramedullary involvement. Although the level of CD40 expression is variable, only patients in accelerated phases expressed high CD40 levels. Finally, whereas CD28 was negative in chronic phase (as in normal PCs), it was expressed in 63% of the patients in accelerated phases and 100% of cell lines. Our data strongly suggest that both disease activity and medullary homing (or not) are correlated with the expression of CD19, CD40, CD28, and CD56 on human myeloma cells.

Antibodies, Monoclonal↗
PubMed1994

Total body irradiation and high-dose cyclophosphamide, BCNU and VP-16 (CBV) as a new preparatory regimen for allogeneic bone marrow transplantation in patients with advanced hematologic malignancies.

To increase the cure rate of advanced hematologic malignancies following allogeneic bone marrow transplantation we sequentially evaluated two intensified conditioning regimens. Eleven patients with acute myeloblastic leukemia (AML) beyond the first complete remission or chronic myelogenous leukemia (CML) not in first chronic phase received an association of 13.5 Gy of fractionated total body irradiation (TBI) followed by cyclophosphamide (CY) 120 mg/kg. Following this regimen, the probability of relapse was 47% at 3 years and the non-relapse mortality rate was 27%. Given the acceptable tolerance of this regimen, 13.5 Gy fractionated TBI was associated with intensified chemotherapy consisting of a combination of CY 120 mg/kg, carmustine 300 mg/m2 and etoposide 600 mg/m2 (CBV). This regimen was administered to 22 patients with comparable diseases. Of these patients, 7 received a transplant from a matched unrelated donor and 2 other patients received a second transplant from the original genoidentical donor. For 15 patients with a genoidentical donor, including the 2 second transplant, the 3 year probability of survival, disease-free survival and relapse are 40%, 40% and 14%, respectively. No regimen-related toxic deaths were recorded during the first 100 days. Of 7 patients with matched unrelated donors, 3 died before day 100, one death being directly attributable to the regimen. Early non-fatal regimen-related toxicity consisted mainly in grade II mucositis with no grade III or IV toxicity in recipients of genoidentical marrow. The late deaths were mainly due to chronic GVH-related complications. In conclusion, the association of fractionated 13.5 Gy TBI and CBV carries a high antileukemic activity and an acceptable toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Hb Saint Nazaire (beta 103[G5]Phe-->Ile): a new example of polycythemia due to a hemoglobin variant with increased oxygen affinity.

Hb Saint Nazaire [beta 103 (G5) Phe-->Ile] was found in four apparently unrelated French families. The five patients carrying this hemoglobin have been detected because of a moderate erythrocytosis. The structural abnormality of Hb Saint Nazaire concerns the same residue as in Hb Heathrow [beta 103 (G5) Phe-->Leu). A comparative functional study between these two variants showed that the increase in oxygen affinity is much lower in Hb Saint Nazaire than in Hb Heathrow. The replacement of phenylalanine G5, which is localized within the heme pocket, by a leucine abolishes several contacts between the heme and the globin and leads to an environment of the heme having some similarities with that observed in myoglobin. In contrast, the replacement of G5 by an isoleucine is likely to introduce less structural modifications.

Adolescent↗
PubMed1993

Early intensive therapy with autotransplantation for high-risk Hodgkin's disease.

The purpose of this trial was to evaluate the efficacy and the tolerance of high-dose therapy with autologous stem cell transplantation as part of front-line therapy in Hodgkin's disease for patients with both adverse prognostic factors: high tumor burden at presentation and slow response to initial chemotherapy. In a prospective one-center study, 20 consecutive patients with slow response (tumor reduction < 75%) (16 pts) or refractory (4 pts) to 3-4 courses of conventional HD chemotherapy received high-dose therapy followed with autologous bone marrow (14 pts) or peripheral blood stem cell (6 pts) transplantation. They were 13 males, 7 females, median age 26 years (8-45). At the time of initial diagnosis, all but one of the patients had B symptoms, all had high-risk HD defined as Ann Arbor stage IV (7 pts) or large mediastinal involvement (LMI = tumor/thorax > 0.45 at T5-T6) (6 pts) or both stage IV+LMI (7 pts). Median time between diagnosis and autotransplantation was 5 months. Intensive therapy consisted of either CBV (cyclophosphamide 1.5 g/m2 x 4, BCNU 300 mg/m2, etoposide 200 mg/m2 x 3) (12 pts) or cyclophosphamide 120 mg/kg + 12 Gy total body irradiation for 8 patients with diffuse bone or lung involvement. For pts treated with CBV, 40 Gy involved field radio-therapy was performed after hematological recovery. Median duration of neutropenia was 16 days (9-21). Neither veno-occlusive disease, nor interstitial pneumonitis nor toxic death were observed. Seventeen pts are alive with no progression of the disease (16/16 in partial response after initial chemotherapy, 1/4 with refractory disease).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1984

[Therapeutic leukapheresis in tricholeukocytic leukemia].

Therapeutic leukapheresis was performed in a patient with hairy cell leukaemia (100,000 WBC/mm3; 98 p. 100 hairy cells) without signs of hypersplenism. Twenty-five sessions were carried out in 12 weeks. A rapid and significant improvement was observed with the WBC falling to 25,000 WBC/mm3 with 70 p. 100 of hairy cells and the normalisation of the bone marrow biopsy. When these sessions were finished, splenectomy was performed in optimal conditions. This treatment would seem to be valuable in hairy cell leukaemia without severe hypersplenism. Long-term improvement may be hoped because hairy cells have a very short turnover rate.

Adult↗