Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to develop a flow cytometric test to quantitate low levels of circulating myeloma plasma cells, and to determine the relationship of these cells with disease stage. Cells were characterized using five-parameter flow cytometric analysis with a panel of antibodies, and results were evaluated by comparison with fluorescent consensus-primer IgH-PCR. Bone marrow myeloma plasma cells, defined by high CD38 and Syndecan-1 expression, did not express CD10, 23, 30, 34 or 45RO, and demonstrated weak expression of CD37 and CD45. 65% of patients had CD19- 56+ plasma cells, 30% CD19- 56(low), and 5% CD19+ 56+, and these two antigens discriminated myeloma from normal plasma cells, which were all CD19+ 56(low). Peripheral blood myeloma plasma cells had the same composite phenotype, but expressed significantly lower levels of CD56 and Syndecan-1, and were detected in 75% (38/51) of patients at presentation, 92% (11/12) of patients in relapse, and 40% (4/10) of stem cell harvests. Circulating plasma cells were not detectable in patients in CR (n = 9) or normals (n = 10), at a sensitivity of up to 1 in 10,000 cells. There was good correlation between the flow cytometric test and IgH-PCR results: myeloma plasma cells were detectable by flow cytometry in all PCR positive samples, and samples with no detectable myeloma plasma cells were PCR negative. Absolute numbers decreased in patients responding to treatment, remained elevated in patients with refractory disease, and increased in patients undergoing relapse. We conclude that flow cytometry can provide an effective aternative to IgH-PCR that will allow quantitative assessment of low levels of residual disease.
 ...
PMID:Circulating plasma cells in multiple myeloma: characterization and correlation with disease stage. 1093 Oct 11

While plasmacytosis is a common occurrence in early post-bone marrow transplantation biopsy specimens, the significance of plasma cells in such specimens from patients with multiple myeloma (MM) is unknown. We attempted to retrospectively determine, by morphologic assessment of plasma cell percentage, immunohistologic assessment of plasma cell light chain ratio (LCR), and correlation with clinical outcome, the prevalence and significance of plasmacytosis in the posttransplantation bone marrow biopsy specimens of 25 patients with MM who underwent autologous peripheral blood stem cell transplantation (PBSCT). No pre-PBSCT morphologic or immunologic characteristics were significantly associated with the post-PBSCT outcome in this group of patients. While 9% of all biopsy specimens and 25% of hypocellular biopsy specimens obtained during the first 60 days after the PBSCT contained more than 10% plasma cells, 34% of all biopsy specimens obtained during this period had elevated LCRs. The dominant light chain in all cases with high LCRs was the same as that of the original tumors, implying that these plasma cells represent a portion of the patients' original tumors. However, the presence of tumoral plasma cells during the early post-PBSCT period was not associated with outcome (P>.5 at 30 days and 60 days after transplantation). Histologic features of recurrent MM and elevated LCR occurring at day 90 or later are correlated with progression of disease (P=.02 and P=.0001, respectively). We conclude that the presence of tumoral plasma cells in the early post-PBSCT period likely represents residual tumor and should not be regarded as indicating imminent relapse, while the presence of tumor as assessed by histologic or immunohistochemical evaluation during the late post-PBSCT period should raise the concern of relapse and disease progression.
 ...
PMID:The significance of light chain-restricted bone marrow plasma cells after peripheral blood stem cell transplantation for multiple myeloma. 916 60

Treatment with combination chemotherapy has not resulted in long-term remissions in multiple myeloma (MM) despite advances in drug discovery and protocol improvement over the last 25 years. Increasingly, peripheral blood (PB) stem cell transplants (PBSCT) are being used along with chemotherapy and total body irradiation as treatment for multiple myeloma. Although the majority of tumor cells are found within the bone marrow (BM), tumor cells circulate in the PB in patients with MM. Therefore, one potential problem with PBSCT is contamination of the stem cell harvests with tumor cells. Although substantial reduction in BM tumor load is achieved after chemotherapy and autologous transplantation, most patients still relapse. In an attempt to identify and quantitate the residual tumor within sequential BM and PB samples of patients with MM following autologous PB stem cell transplants we have used a tumor-specific detection assay, allele-specific oligonucleotide-PCR (ASO-PCR). We found that while the BM tumor burden may fluctuate in some patients by as much as 4-logs after transplant, the PB tumor remains quite stable, and does not reflect the tumor burden in the BM. Moreover, analysis of PB involvement over time was not predictive of marrow involvement or of potential relapse. These results suggest that the PB is frequently involved in MM and further indicate that it represents a compartment that is only minimally altered by intensive therapy.
 ...
PMID:Sequential analysis of bone marrow and peripheral blood after stem cell transplant for myeloma shows disparate tumor involvement. 930 13

In multiple myeloma (MM), allogeneic bone marrow transplantation may produce complete and durable responses, but is accompanied by significant transplant-related mortality (TRM). To assess feasibility and possible advantages offered by the use of allogeneic, growth factor-primed PBSC instead of marrow, we analyzed the data of 10 patients with MM (IgG = 6, IgA = 1, BJ = 2, non-secreting = 1; stage II = 1, stage III = 8, plasma-cell leukemia = 1) who received an allogeneic transplant with PBSC. Their age ranged between 35 and 53 years (median 45). All were HLA-identical to their sibling donors. Prior to allograft, six patients received standard-dose chemotherapy (DAV or CY-Dexa) and four a sequential intensified scheme with autologous PBSC support. At the time of transplantation, three patients were in CR, three in PR, three had refractory disease, one progressive disease. Patients were conditioned with busulfan-melphalan (n = 9) or busulfan-cyclophosphamide (n = 1), and were allografted with unmanipulated PBSC obtained by apheresis after treatment with G-CSF alone (n = 6) or GM-CSF followed by G-CSF (n = 4). All patients engrafted, with 0.5 x 10(9)/l PMN and 50 x 10(9)/l platelets on (median) day 13. Four patients had > or =grade II acute GVHD (grade II in 3, grade III in 1). Following allograft, CR was achieved in 71% patients. Eight are currently alive, with six in CR at a median of 18.5 months (range 7-28) from the transplant. Two patients died, 1 and 4 months from the allograft, respectively, and one is alive with progression. A PCR analysis of IgH rearrangement showed that residual disease was no more molecularly detectable in four out of seven evaluated patients following allograft. The results suggest that PBSC may improve the therapeutic efficacy of allogeneic transplant in MM, not only by a reduction of TRM but also by an improvement of rate and quality of response.
 ...
PMID:Allogeneic transplantation of unmanipulated peripheral blood stem cells in patients with multiple myeloma. 973 68

Myeloablative chemotherapy improved the results of multiple myeloma treatment but the disease remains incurable. Residual disease eradication is one of the main clues for further improvement of the prognosis of myeloma patients. Interferon alpha maintenance therapy has controversial results. New methods, such as consolidation therapy, antibodies, gene therapy, interleukins, immunotoxins, dendritic cells, vaccines and induction of graft-versus-tumor effect, are tested in the phase I/II clinical trials. This article briefly reviews the new treatment modalities of immunotherapy. Progress in adoptive cellular immunotherapy and progress in induction of graft versus myeloma effect are very promising. We are still not able to transfer very good preclinical results of immunotherapy into clinical results in vivo measured by event free and long-term survivals. Combination of myeloablative therapy followed a new type of immunotherapy focusing on residual disease eradication evaluated in the setting of sensitive disease may be optimal. Such approach could improve the current controversial status of immunotherapy in MM.
 ...
PMID:Current role of immunotherapy in multiple myeloma. 981 99

A variety of approaches to antitumor therapy are currently being explored that use both antigen-encoding DNA and noncoding nucleotides as a component of gene vaccination. Among the specific strategies reviewed are a construct that fuses a single-chain variable fragment (scFv) that incorporates both the variable-region genes necessary to encode the idiotypic determinants with fragment C (FrC) of tetanus toxin; a novel vector system using herpes simplex virus 1 (HSV-1) for in vivo gene delivery; the possibility of eliciting hyperacute xenograft response to treat human cancer; and the use of gene gun-mediated granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA-based tumor cell vaccines. The protection provided by DNA vaccination against viral diseases such as influenza suggested a role for such vaccines against cancer. However, unlike vaccines against infectious diseases, cancer vaccines are therapeutic, rather than prophylactic. With multiple myeloma, for example, it is possible that the optimal timing of administration of such a vaccine is during a remission that has been induced by traditional therapies, to eliminate residual disease. DNA cancer vaccines are designed to activate immune responses to tumor antigens to which the immune system has already been exposed. To do so, the vaccines must first overcome immune tolerance that may have already developed to the tumor. There is increasing evidence that tumor antigens, unlike viral or bacterial antigens, do not consistently activate an immune response. One major factor in determining whether a reaction occurs appears to be whether antigen presentation is accompanied by danger signals. With viral or bacterial infection, the accompanying tissue destruction and inflammation produce costimulatory signals that promote T-cell activation. However, inflammatory and tissue-destructive processes are absent during initial tumor transformation. The typical outcome may be immunologic tolerance.
 ...
PMID:DNA vaccination against multiple myeloma. 998 89

Although a variable proportion of multiple myeloma patients can achieve response with conventional chemotherapy, residual tumor cells, which are refractory, finally reemerge leading to disease progression. The expression of the multidrug resistance protein (MDR1) has been one of the most extensively explored mechanisms of drug resistance and has been related to a poor response to chemotherapy in several human tumors. Nevertheless, a careful analysis of the literature on MDR1 expression in multiple myeloma (MM) shows the existence of disturbing discrepancies as regards both the incidence of MDR1 over-expression and its clinical value. A prerequisite for the assessment of MDR1 in tumor cells should be the identification of the neoplastic cells present in the sample. This is particularly important in MM, where the percentage of tumor cells in bone marrow (BM) is relatively low. In the present study we have analyzed the functional expression of MDR1 in BM plasma cells (PC), from a group of 40 untreated MM patients. For that purpose, the rhodamine 123 efflux assay was used in combination with specific staining for plasma cells (CD38 strong+). The mean fluorescence channel (MFC) of rhodamine 123 in myelomatous PC from MM patients was 311 and 110 after incubating cells with this fluorochrome for 15 and 60 min, respectively. The median percentage of rhodamine 123 elimination by BM PC was of 61% (range: 0.29 to 88%). Upon analyzing the relationship between the ability of myelomatous PC to eliminate rhodamine 123 and other clinical and biological disease characteristics we found that, within the group of patients displaying high MDR1 expression (>61% rhodamine efflux), there was a higher incidence of cases with bone disease (P = 0.014) and advanced clinical stages (P = 0.031), greater calcium (P = 0.007) and creatinine serum levels (P = 0.061), and lower levels of albumin in serum (P = 0.015). All these parameters are usually associated with a poor prognosis. When we analyzed the possible relationship between the ability of BM PC to eliminate rhodamine 123 and the presence of numerical chromosome abnormalities we observed that a low MDR1 expression was related to a higher incidence of trisomies of chromosomes 6 and 17, although these differences did not reach statistical significance (P = 0.06). In spite of these associations, from the prognostic point of view, MDR1 expression did not correlate with other relevant prognostic factors, response to treatment (P = 0.38) or overall survival (P = 0.12).
 ...
PMID:Correlation of rhodamine 123 efflux by neoplastic plasma cells with clinical and biological characteristics of multiple myeloma. 1008 73

The epithet "less is more" is usually applied to the essentials of good design, but it might be equally true of autologous blood or marrow transplantation. Ever since autologous marrow transplantation was first used to reconstitute recipients of high-dose chemotherapy or radiotherapy, there has been much discussion about the relative contribution of residual tumor cells in the graft to the occurrence of subsequent relapse. It was not until the early 1990s that this risk was finally confirmed by the use of gene marking [1]. A retroviral vector was used to mark a proportion of the autologous remission bone marrow from patients with acute myeloid leukemia (AML) before marrow infusion after high-dose therapy. Two recipients relapsed and both had leukemic blasts with the marker, the neomycin-resistance gene. As the safety of autologous hematopoietic stem cell transplantation has increased, the use of high-dose therapy followed by stem cell "rescue" is becoming more widespread. The malignancies treated in this way include leukemia, lymphoma, myeloma, neuroblastoma, breast cancer, and ovarian tumors. In each of these conditions a number of important questions should be addressed: Can we identify and quantitate tumor cells in the grafts and establish their oncogenic potential? If so, how best can we remove them? Can they be removed without compromising the graft, and will such purging produce a clinically significant reduction in relapse risk? Finally, will the procedure be cost-effective?
 ...
PMID:"Less is More": The Role of Purging in Hematopoietic Stem Cell Transplantation. 1038 58

Myeloablative chemotherapy or radiation therapy supported by autologous stem cell transplantation (SCT) for the treatment of hematologic malignancies such as acute leukemia, lymphoma, and myeloma is associated with high rates of relapse. The reasons for this are 1) autologous transplantation lacks the in vivo graft-vs.-tumor (GVT) effect associated with allogeneic SCT, which is effective in controlling or eliminating residual malignant cells remaining in the body after high-dose therapy, and 2) contaminating malignant cells in the autologous graft are reinfused into the body. Some researchers have attempted to administer immunomodulatory cytokines to simulate a GVT effect, and although this has shown some efficacy, it has several disadvantages. These include high toxicity associated with systemic administration, a short in vivo half-life, and insufficient levels reaching the site of residual disease. As an alternative, we investigated whether delivery of the cytokine interleukin (IL)-2 to the bone marrow can exert an antileukemic effect while avoiding the problems associated with systemic administration. We describe the delivery of IL-2 to the bone marrow by transplantation of syngeneic bone marrow, retrovirally transduced with the gene for IL-2, into lethally irradiated mice. We were able to efficiently transduce murine bone marrow with the IL-2 gene without adversely affecting clonogenic output from hematopoietic progenitors, and we were able to achieve expression of the transgene in transplanted animals. However, IL-2 transduction inhibited hematopoietic reconstitution in lethally irradiated mice. Marrow transduced with high-titer, high-expressing IL-2 retrovirus failed to engraft, and a low-titer, low-expressing IL-2 retrovirus also demonstrated reduced engraftment, although engraftment was sufficient to support survival of transplanted mice. Long-term, low-level expression of the IL-2 transgene was detectable in these mice and was effective in exerting an antileukemic effect. Mice transplanted with control marrow and challenged with leukemic cells suffered 100% mortality within 70 days, whereas mice transplanted with IL-2-transduced marrow exhibited 50% survival over the 175-day duration of this study. The work shows that delivery of immunomodulatory cytokines to the bone marrow can be achieved by transplantation of genetically modified hematopoietic cells. Furthermore, low-level IL-2 expression can exert an antileukemic effect. These data suggest that this may be an effective immunotherapeutic strategy to reduce relapse after autologous transplantation, but the selection and expression of the cytokine must be carefully considered to minimize adverse effects on hematopoiesis.
 ...
PMID:Antileukemic effect of interleukin-2-transduced murine bone marrow after autologous transplantation. 1046 3

Myeloablative chemotherapy or radiation therapy supported by autologous stem cell transplantation (SCT) for the treatment of hematologic malignancies such as acute leukemia, lymphoma, and myeloma is associated with high rates of relapse. The reasons for this are 1) autologous transplantation lacks the in vivo graft-vs.-tumor (GVT) effect associated with allogeneic SCT, which is effective in controlling or eliminating residual malignant cells remaining in the body after high-dose therapy, and 2) contaminating malignant cells in the autologous graft are reinfused into the body. Some researchers have attempted to administer immunomodulatory cytokines to simulate a GVT effect, and although this has shown some efficacy, it has several disadvantages. These include high toxicity associated with systemic administration, a short in vivo half-life, and insufficient levels reaching the site of residual disease. As an alternative, we investigated whether delivery of the cytokine interleukin (IL)-2 to the bone marrow can exert an antileukemic effect while avoiding the problems associated with systemic administration. We describe the delivery of IL-2 to the bone marrow by transplantation of syngeneic bone marrow, retrovirally transduced with the gene for IL-2, into lethally irradiated mice. We were able to efficiently transduce murine bone marrow with the IL-2 gene without adversely affecting clonogenic output from hematopoietic progenitors, and we were able to achieve expression of the transgene in transplanted animals. However, IL-2 transduction inhibited hematopoietic reconstitution in lethally irradiated mice. Marrow transduced with high-titer, high-expressing IL-2 retrovirus failed to engraft, and a low-titer, low-expressing IL-2 retrovirus also demonstrated reduced engraftment, although engraftment was sufficient to support survival of transplanted mice. Long-term, low-level expression of the IL-2 transgene was detectable in these mice and was effective in exerting an antileukemic effect. Mice transplanted with control marrow and challenged with leukemic cells suffered 100% mortality within 70 days, whereas mice transplanted with IL-2-transduced marrow exhibited 50% survival over the 175-day duration of this study. The work shows that delivery of immunomodulatory cytokines to the bone marrow can be achieved by transplantation of genetically modified hematopoietic cells. Furthermore, low-level IL-2 expression can exert an antileukemic effect. These data suggest that this may be an effective immunotherapeutic strategy to reduce relapse after autologous transplantation, but the selection and expression of the cytokine must be carefully considered to minimize adverse effects on hematopoiesis.
 ...
PMID:Antileukemic effect of interleukin-2-transduced murine bone marrow after autologous transplantation. 1039 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>