PubMed Health⌕ Search

Biomedical subjects

R Schots

Publications and source records attributed to R Schots.

At least 19 recordsLinked to original sources
PubMed2005

A defined donor activating natural killer cell receptor genotype protects against leukemic relapse after related HLA-identical hematopoietic stem cell transplantation.

Killer cell immunoglobulin-like receptors (KIRs) recognize different groups of Human Leukocyte Antigen (HLA) class I alleles and are expressed by natural killer (NK) cells and some T lymphocytes. NK cell cytotoxicity is triggered by failure to recognize the appropriate HLA class I ligand on target cells. Recently, it has been shown that HLA class I ligand incompatibility in the graft-versus-host (GvH) direction is associated with a better outcome in haploidentical hematopoietic stem cell transplantation (HSCT). Since KIR genotypes are very diverse in the population, we explored whether or not the donor KIR genotype could affect the graft-versus-leukemia (GvL) effect in the related HLA-identical HSCT setting. We determined the KIR and HLA genotypes of 65 HLA-identical patient-donor siblings. We found that the presence of two activating KIRs, 2DS1 and 2DS2, in the donor was significantly associated with a decreased leukemic relapse rate (P=0.03; OR=0.18; 95% CI: 0.037-0.88). Moreover, the probability of relapse at 5 years was significantly lower for patients who received a graft from a donor with the 2DS1(+)2DS2(+) genotype than for those who received a transplant from other donors (17 vs 63%, respectively; P=0.018). In conclusion, this study suggests that a joint effect of these two selected activating KIRs in the donor might confer some protection against leukemic relapse.

Adolescent↗
PubMed2004

Novel universal approach for preimplantation genetic diagnosis of beta-thalassaemia in combination with HLA matching of embryos.

BACKGROUND: Beta-Thalassaemia results from co-inheritance of two mutant beta-globin alleles. Allogeneic cord blood cell transplantation (CBT) from an HLA-identical sibling donor is an excellent treatment option for beta-thalassaemia. In families with an affected child and willing to have another child, IVF followed by preimplantation genetic diagnosis (PGD) can be applied to exclude affected embryos. Furthermore, healthy embryos could be HLA matched with the affected child so that cord blood from the future newborn can be used to transplant the affected sibling. METHODS: We developed an indirect single-cell HLA typing technique based on the use of a bank of seven microsatellite markers within the HLA locus from which four informative and evenly distributed markers were selected. RESULTS: The methodology was validated in three beta-thalassaemia families having six ovarian stimulation cycles in view of IVF and PGD. Six PGD cycles were performed in two families. On 58 embryos tested, the combined PCR was successful in 54 (93%). Two transfers were done and one clinical pregnancy was obtained. Using confirmatory analysis on 50 embryos, the accuracy for HLA typing was 100%. CONCLUSION: This strategy offers a new therapeutic option for patients with beta-thalassaemia and other monogenic diseases that can be cured with CBT.

Embryo Transfer↗
PubMed2003

Proinflammatory cytokines and their role in the development of major transplant-related complications in the early phase after allogeneic bone marrow transplantation.

Serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF)-alpha were frequently measured during the first 30 days after allogeneic bone marrow transplantation (BMT) in 84 consecutive adult patients. Major transplant-related complications (MTCs) occurred in 33% of cases and included veno-occlusive liver disease, idiopathic pneumonia syndrome, severe endothelial leakage syndrome and >grade II acute graft-versus-host disease. Compared with patients having minor complications, those with MTCs developed higher levels at times of maximal clinical signs (all cytokines, P<0.001), between days 0-5 post-BMT (IL-6 and IL-8, P<0.05) and days 6-10 (L-6, P<0.001; IL-8 and TNF, P<0.01) post-BMT. We could not discriminate patterns of cytokine release that were specific for any subtype of MTC. Higher levels of IL-8 during days 0-5 were associated (P=0.044) with early (<40 days) death. Multivariate analysis including patient and transplant characteristics as well as post-BMT levels of C-reactive protein showed that high average levels of one or more of the cytokines within the first 10 days post-BMT were independently associated with MTC (Odd's ratio: 2.3 [1.2-4.5], P=0.011). This study shows that systemic release of proinflammatory cytokines contributes to the development of MTC and provides a rationale for pre-emptive anti-inflammatory treatment in selected patients.

Adult↗
PubMed2002

An early increase in serum levels of C-reactive protein is an independent risk factor for the occurrence of major complications and 100-day transplant-related mortality after allogeneic bone marrow transplantation.

We monitored levels of C-reactive protein (CRP) in 96 consecutive adult allogeneic BMT patients (age 15-50 years) transplanted in our unit. Major transplant-related complications (MTC) occurred in 32% of cases and included: hepatic veno-occlusive disease, pneumonitis, severe endothelial leakage syndrome and >II acute GVHD. Transplant-related mortality (TRM) before day 100 post-BMT was 13.5%. Variables included in a stepwise logistic regression model were: gender, age, disease category, donor type, T cell depletion, TBI, use of growth factors, bacteremia, mean CRP-levels >50 mg/l between days 0 and 5 (CRP day 0-5) and >100 mg/l between days 6 and 10 (CRP day 6-10) post-BMT. Only high CRP-levels (for MTC and TRM) (P < 0.001) and donor-type (for TRM) (P= 0.02) were independent risk factors. The estimated probability for MTC was 73% (CRP day 6-10 >100 mg/l) vs 17% (CRP day 6-10 <100 mg/l). Using the same cut-off levels, the probabilities for TRM were 36.5% vs 1% in the identical sibling donor situation and 88% vs 12.5% in other donor-type transplants. We conclude that the degree of systemic inflammation, as reflected by CRP-levels, during the first 5-10 days after BMT identifies patients at risk of MTC and TRM. Our data may be useful in selecting patients for clinical trials involving pre-emptive anti-inflammatory treatment.

Adolescent↗
PubMed2002

Extramedullary plasmacytoma of the cavernous sinus.

We present the case of an 80-year-old male with an history of multiple myeloma (MM) stage I with extramedullary plasmacytoma of the neck, diagnosed 18 months before and in complete remission after radiation therapy and melphalan-prednisone therapy. He was admitted with signs and symptoms characteristic for cavernous sinus syndrome, including diplopia, exophthalmia, ptosis and orbital pain. Magnetic resonance imaging showed a mass lesion in the cavernous sinus, consistent with relapsing extramedullary plasmacytoma. The patient received palliative radiation therapy and high dose dexamethasone, but treatment failed and the patient died. This case represents one of the few reports of extramedullary plasmacytoma of the cavernous sinus. The development of a clinical presentation of cavernous sinus syndrome in a patient with a history of MM or extramedullary plasmacytoma should raise the suspicion of a plasmacytic involvement of the cavernous sinus.

Aged↗
PubMed2002

Ethical considerations on preimplantation genetic diagnosis for HLA typing to match a future child as a donor of haematopoietic stem cells to a sibling.

Recently, several requests were made by couples with an affected child who wanted preimplantation genetic diagnosis (PGD) to select embryos in the hope of conceiving an HLA identical donor sibling. This article considers the ethical arguments for and against the application of PGD for this goal. Only embryos HLA matched with an existing sibling in need of a compatible donor of haematopoietic stem cells would be transferred. The main arguments are the instrumentalization of the child, the best-interests standard, the postnatal test for acceptability and the experience of the donor child. It is argued that conceiving a child to save a child is a morally defensible decision on the condition that the operation that will be performed on the future child is acceptable to perform on an existing child. The instrumentalization of the donor child does not demonstrate disrespect for its autonomy or its intrinsic worth.

Ethics, Medical↗
PubMed2001

Growth factor receptor profile of CD34+ cells in AML and B-lineage ALL and in their normal bone marrow counterparts.

Leukaemic cells show a low clonogenic activity and a heterogeneous proliferative response to growth factors. We investigated whether this could be due to an altered expression of growth factor receptors on the leukaemic precursors. Receptors for G-CSF, stem cell factor (SCF), IL-3, IL-6 and IL-7 were detected on CD34+ cells in AML and B-lineage ALL with monoclonal antibodies and flow cytometry. The expression was compared with that on myeloid and B-lymphoid CD34+ cells in normal bone marrow. Leukaemic CD34+ cells expressed the same receptors as their normal counterparts. AML and B-lineage ALL could be distinguished by the growth factor receptor profile of their CD34+ cells. SCFR, G-CSFR and IL-6Ralpha were found in AML, IL-7R in B-lineage ALL and IL-3Ralpha in both. IL-3Ralpha was upregulated in AML and B-lineage ALL CD34+ cells, while samples with low or high expression were present for the other receptors. This variable expression could correlate with the heterogeneous response of leukaemic cells to growth factors. Functional studies on isolated CD34+ cells are needed to investigate this further.

Acute Disease↗
PubMed2001

Clinical findings and magnetic resonance imaging in severe cyclosporine-related neurotoxicity after allogeneic bone marrow transplantation.

OBJECTIVES: Severe neurotoxicity is a recognized complication of cyclosporin A (cyclosporine, CSA). Neuroimaging studies typically show reversible brain lesions, predominantly confined to the white matter. Our aim was to delineate clinical characteristics and to specify results of magnetic resonance imaging (MRI) and computerised tomography (CT) scan findings. METHODS: Cases of severe cyclosporine-related neurotoxicity (SNCT) were identified among a series of 129 consecutive allogeneic transplant recipients. Clinical features were analysed, including CSA levels, electrolytes, cholesterolemia and magnesemia. MRI and/or CT scans were obtained within 24 h to 4 d after the onset of neurotoxicity. RESULTS: Six patients (4.6%) developed a prodromal phase (headache and/or hypertension), followed by SCNT, including generalized seizures (n = 5), occipital blindness (n = 1) and hemiparesis (n = 1). There was no correlation between the laboratory findings and the onset of SNCT. All patients were on corticosteroid treatment. MRI studies showed hyperintensity lesions, predominantly in the posterior cerebrum, with both subcortical and cortical involvement in 4 out of 5 patients. Cerebellar involvement (n = 4) was also a frequent finding. The signal abnormalities, corresponding to the anastomotic border zones between major cerebral and cerebellar arteries, were limited to the respective cortical areas. CONCLUSION: Association of corticosteroids is a trigger in the development of SCNT. MRI is recommended for the early identification of the transient brain lesions in patients with a prodromal phase. The more specific distribution of the lesions in the anastomotic border zones suggests vascular injury as a contributing factor in the pathology of SNCT.

Adolescent↗
PubMed2001

The impact of partial T cell depletion on overall transplant-related toxicity, graft function and survival after HLA-identical allogeneic bone marrow transplantation in standard risk adult patients with leukemia.

In this single-center study, a consecutive cohort of 59 adult patients transplanted with HLA-identical bone marrow and receiving graft-versus-host disease (GVHD) prophylaxis with either standard cyclosporine/methotrexate (n = 33) or partial T cell depletion (E-rosetting) (TCD, n = 26 were analyzed). Only patients with chronic myeloid leukemia in first chronic phase or acute leukemia/myelodysplasia in first or second remission were included. Except for age (median 28 vs 42 years), both groups were comparable in terms of diagnosis, conditioning regimen and growth factor support. TCD significantly reduced >grade II acute GVHD (0 vs 24%, P = 0.02), chronic GVHD (8.5 vs 45%, P = 0.007) and other major bone marrow transplant (BMT)-related complications (4 vs 36%, P = 0.005). TCD decreased overall transplant-related mortality (11.5 vs 36%, P = 0.04). In the TCD group faster neutrophil (13 vs 22 days, P = 0.02) and platelet recoveries (18 vs 26 days, P < 0.001) were noted. The relapse risk was higher after TCD (57.5 vs 21.5%, P = 0.04). Overall survival probability at 10 years was identical in both groups (54 vs 53.5%, P = 0.33). We found a relationship between the number of T cells in the graft and the occurrence of major complications (P < 0.001) and relapse (P = 0.03). This comparative analysis shows that graft-derived T cells have a major role in overall BMT-related toxicity and that partial TCD is an acceptable approach in terms of survival for patients between 40 and 50 years of age.

Adolescent↗
PubMed2000

The clinical impact of early gram-positive bacteremia and the use of vancomycin after allogeneic bone marrow transplantation.

BACKGROUND: Gram-positive bacteremia (GPB) is an increasing infection after allogeneic bone marrow transplantation (BMT). Our purpose was to identify risk factors for GPB, to evaluate its impact on early mortality and morbidity, and to compare prophylactic with empirical intravenous vancomycin. METHODS AND RESULTS: We studied 89 consecutive BMTs in adult patients. Early GPB occurred in 29% of posttransplantation episodes. T-cell depletion (odds ratio [OR]: 0.18) and vancomycin-prophylaxis (OR: 0.28) reduced the risk of GPB. Mortality at 6 weeks was not significantly different in patients with GPB (15% vs. 9.5%, P = 0.669). GPB was associated with the development of major complications, the use of amphotericin B, and prolonged neutropenia. Vancomycin prophylaxis led to an increased risk of early renal dysfunction (OR: 18.7). CONCLUSION: GPB contributes to overall morbidity during the early post-BMT episode but has no impact on mortality. Vancomycin prophylaxis is effective to reduce GPB but has a negative effect on renal function.

Adolescent↗
PubMed2000

Clonally related IgA- and IgE-secreting plasma cells in a myeloma patient.

OBJECTIVES: The purpose of this work was to study the clonal relationship between the cells that secrete monoclonal proteins in an IgA/ IgE double multiple myeloma patient. Double monoclonal gammopathy is a rare condition in which two types of monoclonal proteins can be found in the serum and/or urine of patients with multiple myeloma or gammopathy of undetermined significance. The study of the relationship between the cells expressing the different monoclonal proteins may provide insight in the pathogenesis of these disorders. METHODS: The clonal relationship of the two tumoral plasma cell populations was examined by immunophenotyping and sequence analysis of the variable regions of the immunoglobulin heavy chain genes. Both immunoglobulin sequences were isolated from the bone marrow using a polymerase chain reaction (PCR)-based cloning strategy. Rare isotype-switch variants were detected by a myeloma-specific PCR in combination with different isotype-specific primers. An in vitro culture system, based on the activation of the CD40 molecule on the B cell, was used in order to isolate and expand myeloma-related B cells from peripheral blood that could possibly be regarded as myeloma precursor cells. RESULTS: The variable parts of the immunoglobulin heavy chains linked to either Calpha or Cepsilon were exactly the same, including the same somatic mutations. From the in vitro CD40 cultures B cells could be isolated that either expressed IgA or IgE with exactly the same variable immunoglobulin part as the myeloma clone. No pre-switched IgM myeloma-related B cells could be found. CONCLUSION: Both cell populations in this IgA/IgE myeloma patient shared a common clonal origin. No evidence for a pre-switched IgM precursor myeloma cell was found in this patient.

Aged↗
PubMed2000

Late and localized extramedullary relapse of a light chain kappa myeloma after syngeneic bone marrow transplantation.

We report the case of a 54-year-old female patient with stage IIIA kappa light chain myeloma (MM) who relapsed 7 years after syngeneic bone marrow transplantation (BMT). The relapse occurred as a voluminous soft tissue plasmacytoma in the leg, developing after local trauma. The patient was successfully treated with local radiotherapy and has remained progression-free for more than 2 years. This case represents one of the longest survivors, in complete remission, after syngeneic transplantation for MM. The presentation of recurrent disease as localized plasmacytoma with extramedullary growth is unusual in the post-transplant setting. Bone Marrow Transplantation (2000) 25, 115-117.

Bone Marrow Transplantation↗
PubMed1999

Stem cell factor in combination with filgrastim after chemotherapy improves peripheral blood progenitor cell yield and reduces apheresis requirements in multiple myeloma patients: a randomized, controlled trial.

Stem cell factor (SCF) has been shown to synergize with filgrastim to mobilize CD34(+) cells into the peripheral blood. To determine if addition of SCF to chemotherapy and filgrastim reduces the number of leukaphereses required to achieve a target yield of 5 x 10(6) CD34(+) cells/kg, 102 patients with multiple myeloma were randomized to receive mobilization chemotherapy with cyclophosphamide (4 g/m(2)) and either SCF (20 micrograms/kg/d) combined with filgrastim (5 micrograms/kg/d) or filgrastim alone (5 micrograms/kg/d), administered daily until leukaphereses were completed. After collection, patients were treated with myeloablative therapy supported by autologous peripheral blood progenitor cell (PBPC) infusion and filgrastim (5 micrograms/kg/d). There was a significant difference between the treatment groups in the number of leukaphereses required to collect 5 x 10(6) CD34(+) cells/kg (median of 1 v 2 for SCF + filgrastim and filgrastim alone, respectively, P =.008). Patients receiving the combination of SCF plus filgrastim had a 3-fold greater chance of reaching 5 x 10(6) CD34(+) cells/kg in a single leukapheresis compared with patients mobilized with filgrastim alone. The median CD34(+) cell yield was significantly increased for the SCF group in the first leukapheresis (11.3 v 4.0 x 10(6)/kg, P =.003) and all leukaphereses (12.4 v 8.2 x 10(6)/kg, P =.007). Total colony-forming unit-granulocyte-macrophage (CFU-GM) and mononuclear cell counts were also significantly higher in the SCF group in the first leukapheresis and in all leukaphereses. As expected for patients mobilized to an optimal CD34(+) cell yield, the time to engraftment was similar between the 2 treatment groups. Cells mobilized with the combination of SCF plus filgrastim were thus considered effective and safe for achieving rapid engraftment. Treatment with SCF plus filgrastim was well tolerated, with mild to moderate injection site reactions being the most frequently reported adverse events. There were no serious allergic-like reactions to SCF. The addition of SCF to filgrastim after cyclophosphamide for PBPC mobilization resulted in a significant increase in CD34(+) cell yield and a concomitant reduction in the number of leukaphereses required to collect an optimal harvest of 5 x 10(6) CD34(+) cells/kg.

Adult↗
PubMed1999

Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) DNA sequences are absent in leukapheresis products and ex vivo expanded CD34+ cells from multiple myeloma patients.

Recently it was reported that Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) infects bone marrow (BM) dendritic cells (DC) in multiple myeloma (MM) patients and therefore might play a role in MM development. Because of the use of myeloid growth factors like GM-CSF and G-CSF for the mobilization of peripheral blood progenitor cells (PBPC), the subsequent increase of DC precursors might imply a risk for KSHV contamination in PBPC grafts. Therefore, in this study leukapheresis products and ex vivo cultured CD34+ cell suspensions were analysed. KSHV DNA could not be amplified in any of them.

Antigens, CD34↗
PubMed1999

The genetic variability of the VH genes in follicular lymphoma: the impact of the hypermutation mechanism.

Follicular lymphoma (FL) cells have inherited an activated hypermutation mechanism from their origin of germinal centre B cells. Based on today's knowledge of the intrinsic properties related to this mechanism and the VH base composition, reconsideration of previous reports should be made on a broader range of samples. The present study examined the mutation pattern of the VH genes expressed by 55 cases of FL. FL VH genes showed evidence of antigenic selection in 30% of cases with 88% carrying a functional sIg and 78.2% showing intraclonal variation. VH family and gene segment utilization was found to be roughly similar to that of normal B lymphocytes. FL VH genes revealed extensive variations. 17% of the VH exons harboured a total of five deletions, three duplications and two insertions as compared to the most homologous germline counterpart. The VH genes of one tumour displayed three populations with varying CDR3 length at diagnosis. At relapse, emergence of a differently mutated gene, additional mutations reminiscent of ongoing mutations or no variation was prominent. From this study the heterogeneity of FLs is well established and ongoing mutations are seen in the scope of the activated status of the hypermutation mechanism rather than antigen-stimulated tumour growth.

Amino Acid Substitution↗
PubMed1999

Different expression of adhesion molecules on CD34+ cells in AML and B-lineage ALL and their normal bone marrow counterparts.

The expression of adhesion molecules on CD34+ cells in acute myeloid leukemia (AML) and B-lineage acute lymphoblastic leukemia (B-lineage ALL) was compared with that on the myeloid and B-lymphoid CD34+ cells in normal bone marrow. Bone marrow aspirates of 10 patients with AML, 8 patients with B-lineage ALL and of 6 healthy volunteers were examined. The phenotype of the CD34+ cells was determined with a double immunofluorescence method and flow cytometry. CD34+ cells in AML and B-lineage ALL showed a lower expression of VLA-2 and VLA-3 and a higher expression of ICAM-1 and LFA-3 than their normal bone marrow counterparts. AML CD34+ cells had less L-selectin but more VLA-5 on their surface membrane than normal myeloid CD34+ cells. B-lineage ALL CD34+ cells showed an overexpression of LFA-3. In individual patients deficiencies or over-expression of the beta1 integrin chain, VLA-4, PECAM-1 or HCAM also occurred. An abnormal adhesive capacity of the leukemic cells may influence their proliferation, their localisation and apoptosis. An aberrant expression of adhesion molecules may be used for the detection of minimal residual leukemia in these patients.

Acute Disease↗