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R Schots

Publications and source records attributed to R Schots.

At least 37 records · Page 2Linked to original sources
PubMed1999

The belgian experience in unrelated donor bone marrow transplantation: identification of center experience as an important prognostic factor.

BACKGROUND AND OBJECTIVE: We reviewed all unrelated donor bone marrow transplants (UDBMT) performed in Belgium up to December 1995 to identify prognostic factors for relapse, transplant-related mortality and survival. DESIGN AND METHODS: A total of 163 UDBMT were performed in 92 males and 71 females aged 1-55 (median 26) years. Patients were transplanted for ALL (n=35), AML (n=34), CML (n=51), other myeloid malignancies (n=14), SAA (n=21) or miscellaneous other diseases (n=8). Most patients had advanced disease; a few patients were in CR1 (n=10) or early chronic phase (CP) of CML (n=5). RESULTS: Overall survival at 5 yrs was 17% (95% confidence interval: 8-32%), but survival was significantly better for patients with non-malignant disorders (55% at 4 yrs). The relapse rate +/-SE was projected to be 40 (28-54)% at 5 yrs, 36 (20-56)% for standard-risk and 68 (43-85)% for high-risk malignancies (p=0.0029). There was no relapse in CML patients transplanted in 1st CP compared to 68% at 4 yrs with more advanced CML (p=0.0033). Grade II-IV acute graft-versus-host disease (aGVHD) occurred in 55% by day 100 and was strongly modulated by age, ranging from 41% in <20-yr-old to 80% in >40-yr-old patients (p=0. 0021). Transplant-related mortality (TRM) was projected to be 72 (52-87)% at 5 yrs including 2 very late deaths from lung fibrosis and secondary cancer. Main causes of death were original disease in 27, secondary malignancy in 2, GVHD in 28, interstitial pneumonia in 21, other infections in 19, and miscellaneous toxic causes in 21 patients. In multivariate analysis, the relapse rate was strongly dependent on the disease status (p=0.0029), TRM being significantly worse with older age (p=0.0049), and overall survival being significantly worse in more advanced disease (p=0.0006), after a second transplant (p=0.0166), in centers of smaller size (p=0.0316) and in older patients (NS). INTERPRETATION AND CONCLUSIONS: Although results have improved somewhat in recent years, UDBMT remains a procedure with a high TRM. UDBMT should be performed in patients with less advanced diseases and in centers with more experience, particularly in the treatment of adult patients.

Adolescent↗
PubMed1998

Monitoring of C-reactive protein after allogeneic bone marrow transplantation identifies patients at risk of severe transplant-related complications and mortality.

Patterns of C-reactive protein (CRP) release were derived from frequent CRP measurements in a cohort of 66 consecutive patients receiving allogeneic bone marrow transplants (BMT) in our unit. Based on a retrospective study of clinical events occurring within the first 40 days after BMT, patients with major transplant-related complications (MTC+ group, n = 22) could be separated from those with fever or mild complications only (MTC- group, n = 44). Treatment-related mortality in the MTC+ group was significantly higher: 32 vs 0% (P < 0.001). Major complications included veno-occlusive liver disease (VOD), severe endothelial leakage syndrome (ELS), pneumonitis and acute GVHD >II. The severity of complications was reflected by the patterns of CRP release with continuously high levels preceding the maximal signs and symptoms of MTC. Univariate analysis showed that, among other variables (sex, age, disease status at transplant, +/- TBI in the conditioning regimen, +/- use of myeloid growth factors after BMT, time to reach PN >200/mm3), three factors were significantly associated with MTC: maximal levels of CRP during the post-transplant episode (CRPmax) (296.6 +/- 91.8 vs 88.9 +/- 55.8 mg/100 ml, P < 0.001), the use of unmanipulated graft (no T depletion) (46.9 vs 12.5%, P < 0.009) and the CRP level on the day of BMT (CRPo) (42.7 +/- 55.4 vs 18.2 +/- 19.5, P = 0.045). In multivariate analysis, using a stepwise logistic regression model including the same variables, CRPmax appeared to be the strongest independent variable (P < 0.001) and a reliable (94% accuracy) parameter to assess the risk of MTC. Based on this model, CRP levels of 200 and 300 mg/100 ml are associated with a risk of 48 and 94% of developing MTC, respectively. We conclude that CRP monitoring after BMT identifies patients at risk of severe transplant-related complications and mortality.

Acute Disease↗
PubMed1998

Circulating CD34+ cells in cord blood and mobilized blood have a different profile of adhesion molecules than bone marrow CD34+ cells.

The expression of adhesion molecules was studied on CD34+ hematopoietic precursors in cord blood, bone marrow and mobilized blood. The samples were labeled in a double immunofluorescence procedure with a CD34 monoclonal antibody and with antibodies against maturation and differentiation antigens and adhesion molecules. Myeloid precursors formed the majority of the CD34+ cells in all samples. In bone marrow a separate cluster of B-cell precursors with low forward scatter was present. Nearly all CD34+ cells in normal bone marrow expressed VLA-4 and VLA-5, PECAM-1, LFA-3 and HCAM. The majority of the CD34+ cells also had LFA -1 and L-selectin on the surface membrane. A small subset was VLA-2, VLA-3, ICAM-1 or Mac-1 positive. CD34+ cells expressing the vitronectin receptor or the CD11c antigen were rare. Cord blood and mobilized blood CD34+ cells had a lower expression of VLA-2, VLA-3 and VLA-5 and a higher expression of LFA-1, ICAM-1 and L-selectin than bone marrow CD34+ cells. Except for LFA-1, this was not due to the presence of more myeloid precursors in these samples. Low beta1 integrin expression may lead to less adhesion to the extracellular matrix. High expression of L-selectin may facilitate interaction with endothelial cells. Therefore, this phenotype may favour mobilization.

Adult↗
PubMed1997

Establishment and characterization of a human stroma-dependent myeloma cell line (MM5.1) and its stroma-independent variant (MM5.2).

Although IL-6 has been identified as a major growth factor in multiple myeloma (MM), it is believed that maintenance of tumor growth in vivo depends on one or more additional stroma-derived factors. We describe a new human myeloma cell line (MM5.1) that can be maintained in the presence of bone marrow-derived stromal cell layers, and not only when cultured with exogeneous IL-6. This cell line expresses the same immunoglobulin kappa light chain RNA sequence as the patient's original tumor cells, has a plasma cell morphology and expresses plasma cell antigens (cytoplasmic kappa light chain, CD38, BB4). Without the presence of stromal factors, MM5.1 cells become apoptotic. A low proliferative effect was observed in the presence of oncostatin M (OSM) but other cytokines (IL-10, IL-11, stem cell factor (SCF) and leukemia inhibitory factor (LIF)) had no effect at all. We observed that MM5.1 cells also grow when physically separated from stromal cell layers by a 0.45 microm microporous membrane or when cultured in conditioned medium from stromal marrow cells. Unexpectedly, the growth in stromal supernatants was markedly inhibited by an anti-IL-6 antiserum and an anti-IL-6 receptor transducer chain (gp130) mAb in a dose-dependent manner. This implies that MM5.1 cells are IL-6 responsive only when exposed to one or more additional soluble factor(s) derived from bone marrow stroma. Coculturing MM5.1 cells with IL-6 and cytokines that were described to increase the IL-6 responsiveness of myeloma cells (G-CSF, GM-CSF and IL-3) had no effect on the growth or survival. A strong proliferative effect was observed when MM5.1 cells were cultured with IL-6 and soluble IL-6 receptor (sgp80). However no sgp80 could be detected in stromal supernatants using a sensitive immunoassay. This indicates that sustained proliferation of the MM5.1 cell line depends on a combination of IL6 and at least one, thus far unidentified, stroma-derived factor. After more than 1 year in continuous culture, we could obtain a variant of the line (MM5.2) that shows an improved growth rate and grows stroma independently. Molecular analysis revealed clonal identity with the early passage form and Epstein-Barr virus antigen expression was negative. The two variants of this cell line offer a useful model to identify molecular mechanisms involved in clonal evolution towards stroma-independent growth of myeloma cells.

Adipose Tissue↗
PubMed1997

Persistence of residual tumour cells after cytokine-mediated ex vivo expansion of mobilized CD34+ blood cells in multiple myeloma.

Mobilized CD34+ blood cells were immunomagnetically enriched from leukapheresis products in five multiple myeloma (MM) patients. Thawed samples of selected CD34+ cells were cultured for up to 21 d in a liquid and stroma-free culture system with different combinations of recombinant cytokines. The most successful cell expansion was obtained when a combination of rh-IL-1beta, rh-IL-3, rh-IL-6, rh-SCF, rh-G-CSF and rh-GM-CSF was used. After 14 d this mixture gave a 120-187-fold overall increase of total nuclear cells and a 4-8-fold overall increase of early CFU-GM numbers. In four patients a very sensitive patient-specific PCR analysis showed the presence of monoclonal cells in the initial leukapheresis products. After immunomagnetic separation a tumour cell depletion of 2-4 logs was observed, although all samples still contained malignant cells. Cell suspensions that were cultured with the most potent cytokine combination showed tumour contamination in two-thirds of evaluable cases at the moment of maximal CFU-GM output. Serial cDNA dilution experiments indicated that the positive PCR results at day 14 reflected the persistence of pre-culture tumour cells rather than in vitro expansion of tumour cells in two cases. This study demonstrates that ex vivo expansion of myeloid precursor cells from mobilized CD34+ cells in MM patients does not always result in an effective purging of residual tumour cells. On the other hand, our culture conditions do not seem to favour in vitro expansion of malignant cells, despite the use of a cytokine cocktail that includes potential myeloma growth factors.

Adult↗
PubMed1997

Long-term survival in an adult metastatic renal peripheral primitive neuroectodermal tumor (PPNET) with multimodality treatment including high-dose chemotherapy.

We describe a 42-year-old male patient with a primitive peripheral neuroectodermal tumor (PPNET) arising from the kidney. The patient was treated sequentially with surgery, radiotherapy, experimental cytokine treatment (rhIL-6), combination chemotherapy and consolidated in complete remission with high-dose chemotherapy, supported by autologous stem cells (AST) and hematopoietic growth factors. The patient remains in complete remission at 34+ months after AST and is surviving disease-free for five years after initial presentation. The case presented here is unusual because of the renal origin and the long remission duration and survival when compared with the usual outcome of adult metastatic PPNET. High-dose chemotherapy may have favorably influenced the outcome in this patient. The case is discussed in the context of the general treatment of metastatic PPNET.

Adult↗
PubMed1997

Different expression of adhesion molecules on myeloid and B-lymphoid CD34+ progenitors in normal bone marrow.

The expression of adhesion molecules was studied on B lymphoid and myeloid CD34+ precursors in normal bone marrow. Bone marrow aspirates were labelled in a double fluorescence procedure with the CD34 monoclonal antibody 43A1 and with antibodies directed against maturation and differentiation antigens and adhesion molecules. Three clusters of CD34+ cells could be distinguished by their light scatter characteristics in flow cytometry. The population with the lowest forward scatter contained B-lymphoid precursors while the two others showed phenotypic characteristics of, respectively, early and late myeloid precursors. Nearly all CD34+ cells in the 3 subpopulations expressed VLA-4, VLA-5, LFA-3 and H-CAM. B-lymphoid progenitors showed a higher density of VLA-4 and VLA-5 than the myeloid progenitors. Myeloid precursors, and particularly the late subset, expressed more HCAM than the B-lymphoid progenitors. The majority of the CD34+ cells also expressed LFA-1 and L-selectin. Higher numbers of positive cells were found in the myeloid subset. The early myeloid subset showed the highest positivity for L-selectin. We conclude that B lymphoid and early and late myeloid CD34+ precursors in normal bone marrow show a different profile of adhesion molecules. These profiles could reflect a higher tendency of the myeloid CD34+ precursors to circulate.

Adult↗
PubMed1996

Adhesive interactions between tumour cells and bone marrow stromal elements in human multiple myeloma.

Long-term bone marrow cultures (LTBMC) were established from marrow samples obtained from 6 myeloma patients and 5 healthy donors and were examined by in situ immunogold-silver staining. During the culture period, the established stroma in myeloma LTBMC revealed a lower level of confluency compared to the normal LTBMC. In addition, an increasing proportion of macrophages and osteoclasts was observed in the myeloma stroma throughout the culture period. Moreover, plasma cells were detectable by wk 8, mostly organized in small clusters. They strongly expressed VLA-4 (6/6), H-CAM (6/6), ICAM-1 (6/6) and N-CAM (3/6). In most cases, a weak expression of the other members of beta 1-integrins was observed. The expression of beta 2-integrins was always absent. Stromal fibroblasts were found to be weakly positive for VLA-2, VLA-3 and VLA-5 and showed strong expression of VCAM-1, H-CAM and ICAM-1. N-CAM expression could not be detected. By comparing the adhesion molecule profile of the stromal cells in myeloma cultures with normal bone marrow (BM) cultures, no particular defects could be observed. The stroma displayed most of the potential ligands which could interact with adhesion molecules detected on the myeloma cells. Among these ligands we could find fibronectin and VCAM-1 for VLA-4, collagen I for VLA-2 and VLA-3 and laminin for VLA-2, 3 and 6. Four myeloma cell lines, i.e. OPM-1, U266, RPMI 8226 and JJN3, with a representative phenotype, were used to study the adhesive interactions of myeloma cells with the BM microenvironment. All the myeloma cell lines bound strongly to the marrow cell layers and also showed a high binding to purified fibronectin (FN). However, the adhesion of the cell lines to intact stroma could not be significantly inhibited by anti-FN receptors antibodies. Nor could it be prevented when the latter were combined with anti-H-CAM, V-CAM and ICAM-1 antibodies, as tested in the JJN3 cell line. This implies that other unknown mechanisms contribute to the myeloma cell binding.

Bone Marrow↗
PubMed1996

The absolute number of circulating CD34+ cells predicts the number of hematopoietic stem cells that can be collected by apheresis.

We report our single institution's effort to standardize the method of collecting peripheral blood progenitor cells (PBPC) used for autologous transplantation. PBPC were mobilized by different types of chemotherapy followed by G-CSF (24 patients) or G-CSF alone (six patients) in 30 patients with various underlying neoplastic diseases. A median of three aphereses (range: 2-7), using the CS3000 cell separator was performed and a blood volume of 101 was processed. We studied the relationship between the absolute numbers of circulating leukocytes, mononuclear cells and CD34+ cells and the amount of PBPC collected during a single apheresis procedure. CD34+ cells were quantified by leukocyte subset analysis based on flow cytometry. Both CFU-GM and CD34+ cell contents of the apheresis products (69 procedures analyzed) correlated strongly: rho = 0.936, P = 0.0001). Regression analysis showed that the total number of CD34+ cells or CFU-GM content of the apheresis products could be predicted (r = 0.915, P = 0.0001) from the absolute number of CD34+ cells in the blood. A number of 10 circulating CD34+ cells per mm3 blood ensured a minimum of 0.5 x 10(6) CD34+ cells per kg, collected on the same day. Of the 30 patients, 17 received an autologous graft that contained only PBPC in 13. Long-term and complete hematological reconstitution was observed in all patients who had a minimum of 2 x 10(6) CD34+ cells per kg reinfused.

Adult↗
PubMed1993

Experience with high dose chemotherapy and autologous bone marrow transplantation in testicular cancer.

Carboplatin based HDCT followed by ABMT produces reasonable response rates (40-60%) and some durable remissions in patients with advanced and cisplatin resistant testicular cancer. Patients eligible for such an approach are those with primary refractory or recurrent disease and low probability for salvage by conventional dose regimens. The use of recombinant human growth factors and peripheral stem cell transplantation will probably reduce the toxicity and mortality of HDCT.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Chemotherapy-induced acral erythema and acute graft-versus-host disease after allogeneic bone marrow transplantation.

Chemotherapy-induced acral erythema is a rare disorder characterized by a painful and intense erythema of the palms and the soles. In allogeneic bone marrow transplant patients, the differential diagnosis of acute graft-versus-host disease (AGVHD) may be difficult. We describe a case of concurrent acral erythema and AGVHD. The clinical features of both conditions as well as the histological findings on serial skin biopsy specimens are discussed.

Acute Disease↗
PubMed1991

Southern blot analysis in a case of Richter's syndrome. Evidence for a postrearrangement heavy chain gene deletion associated with the altered phenotype.

Richter's syndrome (RS) can be defined as the emergence of an aggressive lymphoma in patients suffering from chronic lymphocytic leukemia (CLL). The authors performed immunophenotypic and Southern blot analysis of the peripheral blood and tissue specimen of a patient with RS. Using immunoperoxidase and immunogold-silver staining techniques and a panel of monoclonal antibodies, the authors found that the large cells characteristic of RS showed an altered immunophenotype as compared with the CLL cells and did not express mu heavy chain. Southern blot analysis revealed identical kappa light chain rearrangements in both tumoral cell populations consistent with a common clonal origin. Using the JH probe and several restriction enzymes, the authors also found evidence for a postrearrangement deletion of the heavy chain mu gene. These findings suggest that in this case of RS, a deletion of the heavy chain mu gene resulted in loss of mu expression by the larger cells that were characteristic of RS and was associated with their altered phenotype.

Blotting, Southern↗
PubMed1991

Expression of cytoadhesion molecules (CD56, CD54, CD18 and CD29) by myeloma plasma cells.

Recently we reported the expression of the human natural killer cell associated antigen CD56 (Leu 19/NKH1) in plasma cells of a majority of multiple myeloma (MM) patients. CD56 is known to be an isoform of the human neural adhesion molecule N-CAM which is involved in homotypic adhesive interactions. By immunophenotyping using four CD56 specific monoclonal antibodies and immunoprecipitation analysis we here confirm that the Leu 19 antigen expressed by myeloma plasma cells is identical to N-CAM and corresponds to the 145 kDa isoform. Because of the possible biological role of adhesion molecules on myeloma cells, we compared the expression of N-CAM with the intercellular adhesion molecule 1 (ICAM-1) and the beta 1 and beta 2 integrins. By immunogold-silver staining of cytospin preparations of mononuclear cell suspensions, bone marrow plasma cells of 17 MM patients were analysed. Plasma cells expressed N-CAM (CD56) in 14 patients. ICAM-1 (CD54) in 16 patients, and beta 2 integrins (CD18) in eight patients. beta 1 integrins (CD29) were expressed in all patients. The expression of beta 2 integrins was always very weak while N-CAM, ICAM-1 and the beta 1 integrins showed a moderate to strong positivity. The plasma cells of five haematological normal individuals lacked significant N-CAM expression but were positive for ICAM-1 and both integrin subgroups. One plasma cell leukaemia patient and two out of four end-stage MM patients showed no expression of N-CAM or beta 2 integrins on their circulating plasma cells. Among 11 previously established myeloma cell lines, surface expression of ICAM-1 and the integrins was detected in most cases, while N-CAM was present in only four lines. Most cell lines showed coexpression of the fibronectin receptors (VLA-4 and VLA-5) and the laminin receptor (VLA-6). The collagen receptor (VLA-2) was not expressed. The N-CAM negative cell lines included four cell lines that were derived from plasma cell leukaemia patients. These results indicate that the expression of adhesion molecules is an intrinsic part of the biology of multiple myeloma.

Antigens, CD↗
PubMed1990

Immunomagnetic purging of bone marrow grafts for autologous transplantation in neuroblastoma.

Bone marrow grafts of 5 patients with stage IV neuroblastoma and one patient with stage IV retinoblastoma were harvested during complete remission and in vitro processed for autologous transplantation. Because of the risk to reinfuse metastatic cells, the grafts were immunomagnetically purged. After preparation of the buffy coat fraction, mononuclear cells (mnc) and progenitor cells (CFU-GM) were enriched by density centrifugation and incubated successively with a cocktail of five tumour reacting monoclonal antibodies and magnetic microparticles. Target cells were removed by a set of samarium cobalt magnets. The purged grafts were stored in liquid nitrogen. After the complete procedure, an average of 16% nucleated cells of the initial harvest could be recovered. This corresponds with a mean number of 0.5 X 10(8) mnc and 2.4 X 10(4) CFU-GM per kg body weight being available for grafting. So far, 5 patients received their purged marrow graft and showed a sustained take.

Bone Marrow Cells↗
PubMed1990

Malignant lymphoma of the bone.

Two cases of bone involvement by a malignant lymphoma are described. The first patient suffered from primary, polyostotic non-Hodgkin's lymphoma of lymphoblastic histology, a rare clinical picture according to literature data. The second patient had mediastinal Hodgkin's lymphoma of the nodular sclerosing type with a unique secondary localization in the femoral bone, that led to the final diagnosis. The diagnostic and therapeutical approach of bone lymphoma is discussed.

Adolescent↗