PubMed Health⌕ Search

Biomedical subjects

H M Lokhorst

Publications and source records attributed to H M Lokhorst.

At least 19 recordsLinked to original sources
PubMed1998

[Multiple myeloma; treatment in the year 1998].

There are a number of studies dealing with intensive chemotherapy and stem cell transplantation in multiple myeloma. As to autologous transplantation best results have been obtained with younger patients (below 60 years) who had responsive disease and received their transplant within one year after start of treatment. Unfavourable prognostic factors were a high beta 2-microglobulin level and abnormal cytogenetics including any translocation or chromosome 11/13 abnormalities. Only one phase III study has been published, indicating a favourable effect of autologous transplantation. Despite the existence of a so-called 'graft-versus-myeloma effect' the overall outcome of patients after allogeneic transplantation is not better than after autologous transplantation, probably due to the inclusion in the published studies of heavily pretreated and refractory patients responsible for a high treatment related mortality. The ultimate value of intensive treatment of multiple myeloma will become clear in the coming years when more data become available from current phase III studies including the Dutch HOVON multicentre trial in which conventional treatment is compared with intensified therapy including bone marrow ablation and autologous stem cell transplantation.

Adult↗
PubMed1998

Lung-resistance-related protein expression is a negative predictive factor for response to conventional low but not to intensified dose alkylating chemotherapy in multiple myeloma.

This study was undertaken to assess the significance of lung-resistance related protein (LRP) expression in plasma cells from untreated multiple myeloma (MM) patients and to determine whether LRP was associated with a poor response and survival in patients treated with different dose regimens of melphalan. Seventy untreated patients received conventional oral dose melphalan (0.25 mg/kg, day 1 to 4) combined with prednisone (MP) or intravenous intermediate-IDM; 70 mg/m2) or high- (140 mg/m2) dose Melphalan (HDM). LRP expression was assessed with immunocytochemistry using the LRP-56 monoclonal antibody. LRP expression was found in 47% of patients. In the MP treated patients, LRP expression was a significant prognostic factor regarding response induction (P < .05), event free survival (P < .003), and overall survival (P < .001). In the intensified dose melphalan treated patients LRP did not have a prognostic value. The response rates of LRP-positive patients to MP and IDM/HDM were 18% versus 81%, respectively (P < .0001). We conclude that LRP is frequently expressed in untreated MM patients and is an independent predictor for response and survival in patients treated with MP. Pretreatment assessment of LRP identifies a subpopulation of patients with a poor probability of response to conventional dose melphalan. Dose intensification of melphalan is likely to overcome LRP-mediated resistance.

Adult↗
PubMed1998

[Clinical judgment and decision making in medical practice. A retiree with fatigue and foot drop].

A 64-year-old former civil servant consulted his general practitioner because of severe fatigue. Later he began to lose weight and gradually developed chronic sensorimotor polyneuropathy characterized by sensory nerve loss which started in his legs. After a year he needed a wheel chair and developed cachexia. IgG paraprotein was detected. Morbid-anatomical examination of enlarged supraclavicular lymph nodes revealed plasma cell angiofollicular hyperplasia, characteristic of Castleman's disease. Treatment with corticosteroids led to marked improvement of the patient's condition. He was able to walk again, using an ankle orthosis on both legs.

Anti-Inflammatory Agents↗
PubMed1998

Putative myeloma precursor cells expressing 2,6 sialic acid-modified antigens actually belong to the erythroid lineage.

The Golgi enzyme alpha2,6-sialyltransferase modifies glycoconjugates by adding sialic acid. In lymphocytes, different epitopes that result from this modification have been identified by the B cell-related CDw75, CDw76, HB4 or HB6 Ab. We previously described positive staining with these Ab of a highly transferrin receptor-positive (CD71) cell type in the bone marrow of multiple myeloma patients. These cells were distinct from plasma cells, but did contain Ig of the same isotype and idiotype as seen in the plasma cells. We postulated a precursor role for this cell type in myeloma. Here, we report that this CD71+ (HB4/HB6/CDw75/CDw76)+ cell is an erythroid precursor cell instead. RT-PCR did not detect Ig mRNA, and from immuno electron microscopy Ig appeared to be endocytosed rather than synthesized by these cells. At their cell surface the erythroid/megakaryocytic markers CD36 and CD41, and the erythroid-specific glycophorin A can be detected, while haemoglobin can be detected antigenically in the cytoplasm. Finally, purified cells proliferate in vitro upon addition of erythropoietin. Uptake of Ig could be explained by the presence of Fc gammaRIII(CD16), which has also been found on other haematopoietic precursor cells.

Antigens, CD↗
PubMed1998

Multidrug-resistant acute leukemia cells are responsive to prolonged exposure of daunorubicin: implications for liposome-encapsulated daunorubicin.

We examined the cytotoxic effects of free daunorubicin (DNR) and liposome-encapsulated DNR on multidrug-resistant (MDR1) leukemia cells of patients with acute leukemias who had failed primary induction treatment that included DNR. This was analyzed ex-vivo with DNR concentrations and exposure times that normally can be achieved in-vivo for both drugs with induction treatment. The leukemic blasts of patients both with drug-resistant AML and drug-resistant ALL were, ex-vivo, very sensitive to DNR concentrations and exposure times that can be achieved in-vivo by liposome-encapsulated DNR. However, under identical conditions, free DNR and liposome-encapsulated DNR had a similar cytotoxic profile, arguing against a unique mechanism of cytotoxicity by the liposomal constructure. These data suggest that liposome-encapsulated DNR may be preferable to free DNR for the treatment of acute leukemias.

Adult↗
PubMed1998

CD44 isoforms distinguish between bone marrow plasma cells from normal individuals and patients with multiple myeloma at different stages of disease.

CD44 variant isoforms (CD44v) have been shown to be important factors in adverse prognosis in hematological malignancies. To investigate whether CD44 expression is associated with malignant transformation in multiple myeloma, RNA and protein expression of CD44 standard (CD44s) and CD44v4, v6, v9, v10 containing isoforms was compared on bone marrow plasma cells from normal individuals and myeloma patients at different stages of disease. CD44s protein expression is strongly decreased on myeloma plasma cells and non-malignant B cells in affected bone marrow of myeloma patients, while no differences in CD44s expression were found between blood B cells from normal individuals and myeloma patients. CD44v isoforms were expressed on plasma cells in the majority of normal and myeloma samples analyzed. CD44v9 and v10 containing isoforms were differentially expressed on bone marrow plasma cells from normal individuals (predominantly CD44v9+v10+) and myeloma patients with stable (predominantly CD44v9-v10+) or progressive (predominantly CD44v9+v10- disease. Normal and myeloma plasma cells contained CD44 mRNA transcripts consisting of multiple CD44v exons. In addition, CD44v9 positive myeloma cells carried large CD44 transcripts. These results imply that detection of CD44v isoforms may be a valuable diagnostic tool for monitoring myeloma disease progression and response to treatment.

Bone Marrow Cells↗
PubMed1998

Long-term bone marrow cultured stromal cells regulate myeloma tumour growth in vitro: studies with primary tumour cells and LTBMC-dependent cell lines.

Long-term bone marrow cultured stromal cells (LTBMC) produce IL-6 after contact with tumour cells from multiple myeloma patients. We found that LTBMC could substitute for exogenous IL-6 in the stimulation of bone marrow plasma cells from myeloma patients with active disease in short-term cultures. In addition, tumour cells of some patients with inactive disease, which were unresponsive to exogenous IL-6, were induced to IL-6-dependent growth after LTBMC co-culture. To study the role of LTBMC in myeloma tumour growth in vitro, plasma cell lines UM-2 and UM-3 were selected. UM-2 and UM-3 grew in contact with LTBMC and proliferation was blocked by antibodies against IL-6, IL-6 receptor (IL-6R, gp80, CD126) or the common signal transducing unit, gp130 (CD130). Culture with IL-6 alone or combined with GM-CSF resulted in cell death via apoptosis. The combination of IL-6 with soluble gp80, however, maintained in vitro proliferation of UM-2 and UM-3 cells. These data imply that LTBMC regulate myeloma growth in vitro via production of IL-6, possibly via induction of a functional IL-6 receptor on the tumour cells.

Base Sequence↗
PubMed1998

Chimaeric anti-interleukin 6 monoclonal antibodies in the treatment of advanced multiple myeloma: a phase I dose-escalating study.

Interleukin 6 plays a key role in the pathogenesis of multiple myeloma (MM). Therefore we conducted a phase I dose-escalating study with chimaeric monoclonal anti-IL6 antibodies (cMab) in MM patients resistant to second-line chemotherapy. The cMab (CLB IL6/8; Kd 6.25 x 10(-12)M) was given in two cycles of 14 daily infusions, starting on day 1 and day 28, repectively, with a daily dose of 5 mg in patients 1-3, 10 mg in patients 4-6, 20 mg in patients 7-9 and 40mg in patients 10-12 (total dose 140 mg, 280mg, 560 mg and 1120 mg of anti-IL6, respectively). 11/12 patients had elevated pretreatment IL6 levels. Except for transient thrombocytopenia in two patients there was no toxicity. There were no changes in haemoglobin levels, granulocyte count, liver enzymes or renal function. No human anti-chimaeric antibodies were induced. This was also reflected in a long half-life time of the cMab (median 17.8 d), resulting in accumulation of the anti-IL6 cMab and high levels of circulating IL6. However, this was in the form of biologically inactive IL6/cMab complexes and did not result in acceleration of the disease. Although C-reactive protein (CRP) levels were decreased to below detection level in 11/12 patients, indicating effective IL6 blocking, none of the patients achieved a response according to the standard criteria. We conclude that this chimaeric anti-IL6 Mab has a low toxicity, low immunogenicity and a long T1/2. A dose of 40 mg/d for 14 d can safely be used in future phase II studies.

Aged↗
PubMed1997

Allogeneic versus autologous bone marrow transplantation for refractory and recurrent low-grade non-Hodgkin's lymphoma.

Patients with recurrent or refractory low-grade non-Hodgkin's lymphoma (NHL) are increasingly treated with myeloablative therapy and autologous stem cell transplantation. However, allogeneic bone marrow transplantation (BMT) is only sporadically performed in such patients. Therefore, we wish to compare treatment results of patients with recurrent or refractory low-grade NHL who underwent allogeneic BMT with those who underwent autologous BMT in our center. Twenty-eight patients were studied. The patients had received 2 to 5 lines of conventional chemotherapy before the BMT procedure. Eighteen patients, all with chemotherapy-sensitive disease at the time of transplantation, underwent autologous BMT and 10 patients, of whom 7 with chemotherapy-resistant disease at the time of transplantation, underwent allogeneic BMT. Furthermore, all allogeneic BMT patients had overt lymphoma infiltration of the BM at the time of transplantation. The conditioning regimen consisted of cyclophosphamide plus total body irradiation in all 28 patients. All allogeneic BMT patients achieved complete remission, 3 patients had a treatment-related death, and 7 patients are alive and disease-free with a median follow-up of 41 months. In contrast, none of the autologous BMT patients died of transplant-related complications. However, despite the fact that all autologous BMT patients had chemotherapy-sensitive disease and partial remission was converted to complete remission by the BMT procedure in 67% of them, only 3 of 18 patients are alive and disease-free. The probability of relapse or disease-progression among allogeneic BMT patients was 0% compared with 83% for autologous BMT patients (P = .002). Progression-free survival rates 2 years after BMT were 68% for allogeneic BMT patients and 22% for autologous BMT patients (P = .049). Although the numbers of patients are small, this study suggests that allogeneic BMT offers a better chance for cure than autologous BMT for patients with poor-prognosis low-grade lymphoma, and the difference in relapse or disease progression is strongly suggestive for the existence of a graft-versus-low-grade lymphoma effect.

Adult↗
PubMed1997

Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation.

Donor leukocyte infusions (DLI) can induce sustained remissions in patients with acute and chronic myeloid leukemia who relapse after allogeneic bone marrow transplantation (allo-BMT). Also, in multiple myeloma (MM), incidental reports have indicated the existence of a graft-versus-myeloma effect (GVM) induced by allo-reactive T cells. We performed a retrospective study in a larger group of MM patients to characterize better the effect, prognostic factors, and toxicity of this new treatment modality. Thirteen patients with relapsed MM after allo-BMT were studied. Patients received a total of 29 DLI with T-cell doses ranging from 1 x 10(6)/kg to 33 x 10(7)/kg. Repetitive courses, sometimes with escalated cell doses, were undertaken in case of no response to or relapse after DLI. Eight of 13 patients responded: 4 patients achieved a partial remission and 4 patients achieved a complete remission. Dose escalation was effective in 3 patients. The time to response was median 6 weeks (range, 4 to 10 weeks). Major toxicities were secondary to acute and chronic graft-versus-host disease (GVHD), which occurred in 66% and 56% of all patients and in 87% and 85% of the responders, respectively. Two responding patients developed fatal BM aplasia. The only prognostic factors for response were a T-cell dose greater than 1 x 10(8)/kg and the occurrence of GVHD. Seven of nine patients developing acute GVHD responded, as compared with only 1 response in the 4 patients without GVHD and 6 of 7 patients with chronic GVHD responded, whereas no response was observed in the 5 patients without chronic GVHD. DLI are effective in a high percentage of patients with relapsed MM after allo-BMT, although it is associated with a high treatment-related toxicity. The dose of T cells used may be important in determining the GVM effect, with the highest probability of response after infusion of more than 1 x 10(8) T cells. Because the optimal individual dose may vary, patient-adapted therapy consisting of repeated infusions with escalating dose of donor leukocytes until maximum response is achieved may therefore be preferable.

Adult↗
PubMed1997

Anti-adhesive signals are mediated via major histocompatibility complex class II molecules in normal and neoplastic human B cells: correlation with B cell differentiation stage.

We show that major histocompatibility complex (MHC) class II molecules on B cells transit signals which regulate adhesion in a negative manner. Engagement of MHC class II molecules with antibodies results in detachment of B cells previously bound to interferon-gamma-activated human umbilical cord venous endothelial cells. This process depends on metabolic energy, active signaling and protein tyrosine kinase activity. The adhesion pathway influenced by this signaling event is neuraminidase sensitive. The anti-adhesive signaling program is activated in B cell lines with a mature phenotype, e.g. normal B cells from spleen and tonsil. In contrast, cell lines with a pre-B cell phenotype and normal B cells from peripheral blood are refractory to MHC class II-mediated regulation of adhesion. These results extend to neoplastic cells from patients with lymphoproliferative diseases representing different stages of B cell maturation. These results suggest that MHC class II-mediated signals regulate B cell adhesion in a developmentally programmed fashion; this might have implications for clinical behavior of B cell malignancies.

Animals↗
PubMed1997

Modulation of chronic excessive interleukin-6 production in multiple myeloma does not affect thyroid hormone concentrations.

Interleukin-6 (IL6) is believed to be involved in alterations of thyroid hormone metabolism in acute nonthyroidal illness. To evaluate the effects of IL6 on thyroid hormone metabolism in a chronic IL6-mediated disease, we measured thyroid hormone concentrations in multiple myeloma patients treated with intravenous anti-IL6 chimeric monoclonal antibodies ([cMabs] Kd = 6.25 x 10(-12) mol/L). Twelve patients were studied, receiving at least one complete treatment cycle of 14 days (daily dose: 5 mg, n = 3; 10 mg, n = 3; 20 mg, n = 3; and 40 mg, n = 3). Eight of them also completed a second treatment cycle of 14 days. Thyroid hormone concentrations were measured before, during, and after treatment with the anti-IL6 cMab. Even in the group with the lowest dosage, IL6 activity measured by the B9 bioassay was blocked completely. Compared with the reference ranges, 10 of 12 patients had one or more abnormal pretreatment values for thyroid hormone concentrations. Thyroid autoantibodies were negative in all patients. There was no correlation between thyroid hormone concentrations and IL6 levels, although plasma IL6 levels were increased in all but one subject. Moreover, neutralization of free IL6 by the anti-IL6 cMab did not affect thyroid hormone concentrations, although IL6-dependent C-reactive protein (CRP) levels decreased to undetectable levels in 11 of 12 patients. Two patients developed infectious complications resulting in increased free IL6 and CRP levels and in profound alterations of thyroid hormone levels consistent with an acute euthyroid sick syndrome. We conclude that IL6 is not a major determinant of thyroid hormone abnormalities in a chronic disease like multiple myeloma, but IL6 may be involved in thyroid hormone metabolism in acute diseases (probably in combination with other factors).

Aged↗
PubMed1997

Cyclosporin for thrombotic thrombocytopenic purpura after autologous bone marrow transplantation.

Thrombotic thrombocytopenic purpura (TTP) after bone marrow transplantation (BMT) is a serious complication that, in contrast to classic TTP, is generally not responsive to therapeutic plasma exchange. We describe the remission of TTP after autologous BMT by administration of cyclosporin in four patients, either after failure of plasmapheresis (two patients) or as primary treatment modality (two patients). Cyclosporin may be an attractive drug for post autologous BMT-TTP.

Adolescent↗
PubMed1997

Drug resistance in multiple myeloma.

The development of multidrug resistance (MDR) is a major obstacle to improving treatment outcomes in multiple myeloma. Recent studies have indicated that several specific mechanisms of MDR may be involved in clinically refractory multiple myeloma patients, such as expression of P-glycoprotein (P-gp), expression of the lung-resistance protein (LRP) and suppression of apoptosis via expression of Bcl-2. The emergence of these mechanisms of MDR in multiple myeloma is enhanced by exposure to chemotherapeutic agents. Recently, clinical reversal of MDR by noncytotoxic P-gp modulators such as verapamil, cyclosporin A (CsA), and PSC 833 was explored in acute leukemia and multiple myeloma. Preliminary results from clinical phase I/II trials indicate that reversal of MDR via modulation of P-gp is possible and that coadministration of these MDR modulators with chemotherapeutic agents alters the plasma pharmacokinetics of chemotherapeutic agents. Phase II and III clinical trials investigating the efficacy of these and other agents in the reversal of MDR in hematologic malignancies are ongoing.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Different CD44 splicing patterns define prognostic subgroups in multiple myeloma.

CD44 variant isoforms (CD44v) are generated by alternative splicing of the nuclear RNA resulting in the expression of additional protein domains in the extracellular region of the CD44 standard molecule (CD44s). In multiple myeloma (MM), CD44 mediates binding of tumor cells to stroma and regulates interleukin-6 production. To evaluate the role of CD44v isoforms in MM, CD44v expression was analyzed by immunohistochemical staining of 64 bone marrow biopsies from 38 MM patients. Expression of variant isoforms containing the 9v domain was observed in 36% of cases and was associated with an advanced stage (P < .02; n = 61), a progressive disease (P < .001; n = 61), and a shorter overall survival (P < .02; n = 36). In contrast, 3v, 4v, 6v, or 10v isoforms were detected only in a small percentage of the patients. To analyze the exon composition in RNA-transcripts, reverse transcriptase polymerase chain reaction analyses followed by Southern hybridization with exon-specific probes were performed in fluorescence-activated cell sorted myeloma plasma cells. Tumors expressing the 9v domain showed complex, 9v-containing transcripts in combinations with the 3v, 7v, 8v, and 10v exons. Identical transcripts were detected in several myeloma cell lines and in a Ki-1 B-immunoblastic lymphoma. Similar to high-grade non-Hodgkin's lymphoma and gastric and renal cell carcinoma, overexpression of 9v-containing isoforms in MM is related to an unfavorable clinical presentation and represents a new prognostic parameter.

Adult↗
PubMed1996

Endogenous interleukin 6 production in multiple myeloma patients treated with chimeric monoclonal anti-IL6 antibodies indicates the existence of a positive feed-back loop.

In vitro as well as in vivo observations have shown that IL6 plays a key role in the pathogenesis of multiple myeloma. Therefore we started a phase I/II dose escalating study with chimeric monoclonal anti-IL6 antibodies (cMab) in multiple myeloma (MM) patients resistant to second-line chemotherapy. Here we describe the pharmacological data as well as a new method for calculating the endogenous IL6 production. The cMab (CLB IL6/8; Kd: 6.25 x 10(-12) M) was given in two cycles of 14 daily infusions, starting on day 1 and day 28. Daily dose: 5 mg in patients 1-3, 10 mg in patients 4-6, and 20 mg in patients 7-9 (total dose 140, 280, and 560 mg of anti-IL6, respectively). Using the pharmacokinetic data of free IL6 and the binding characteristics of the cMab, the endogenous IL6 production could be calculated from day to day using a one-compartment open model. The median half-life time of this antibody was 17.6 d. No human antichimeric antibodies were induced. Pre-treatment median endogenous IL6 production in the MM patients was 60 micrograms/d (range 13.8-230; normal controls < 7 micrograms/d). During treatment with anti-IL6 cMabs, the endogenous IL6 production immediately decreased in all patients to below 3 micrograms/d and never reached the pre-treatment value during the treatment period, except in two patients who developed an active infection, resulting in an IL6 production of 128 and 1,208 micrograms/d, respectively. We concluded that in MM patients endogenous IL6 production is 2-30 times higher than in healthy individuals. The anti-IL6 cMab strongly suppress this endogenous IL6 production, probably by blocking a positive feed-back loop, but this cMab does not prevent infection-induced IL6 production. The chimeric anti-IL6 Mabs have a long half-life time, a low immunogenicity, and are able to block IL6-dependent processes in vivo.

Aged↗
PubMed1996

Graft-versus-myeloma effect in two cases.

BACKGROUND: Allogeneic bone-marrow transplantation (BMT) is associated with the graft-versus-leukaemia effect because of the antileukaemic action of donor lymphocytes. We describe a graft-versus-myeloma effect after BMT in multiple myeloma. METHODS: Two patients with recurrent multiple myeloma after allogeneic BMT (T cells partly depleted, 10(5) T cells infused per kg) received leucocyte infusions obtained by leukapheresis from their original marrow donors. The patients were a 48-year-old woman and a 49-year-old man. FINDINGS: Both patients developed graft-versus-host disease and achieved complete remission of myeloma. Chimerism was complete in both patients in that all peripheral blood cells were of donor origin. INTERPRETATION: We see our results as evidence for a graft-versus-myeloma effect. Using this form of adoptive immunotherapy, we could administer 1000-3000 times more T cells than with the earlier BMT.

Bone Marrow Transplantation↗