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 regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) has demonstrated significant activity in adult lymphocytic leukemia (ALL) and in other hematologic malignancies, including Burkitt's disease, lymphoblastic lymphoma, mantle cell lymphoma, and multiple myeloma. This article presents the rationale for the development of this regimen, describes the program, summarizes the results of the large clinical trials developed at the University of Texas M. D. Anderson Cancer Center, and discusses strategies to improve the results.
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PMID:The hyper-CVAD regimen in adult acute lymphocytic leukemia. 1114 29

Acute leukemia is the most frequent therapy-related malignancy. Together with the increasing use of chemo- and radiotherapy, individual predisposing factors play a key role. Most of secondary leukemias can be divided in two well-defined groups: those secondary to the use of alkylating agents and those associated to topoisomerase inhibitors. Leukemias induced by alkylating agents usually follow a long period of latency from the primary tumour and present as myelodysplasia with unbalanced chromosomal aberrations. These frequently include deletions of chromosome 13 and loss of the entire or of part of chomosomes 5 or 7. The loss of the coding regions for tumor suppressor genes from hematopoietic progenitor cells is a particularly unfavourable event, since the remaining allele becomes susceptible to inactivating mutations leading to the leukemic transformation. The tumorigenic action of topoisomerase inhibitors is on the other hand due to the formation of multiple DNA strand breaks, resolved by chromosomal translocations. Among these, chromosome 11, band q23, where the myeloid-lymphoid leukemia (MLL) gene is located, is often involved. Frequent partners are chromosomes 9, 19 and 4 in the t(9;11), t(19;11) and t(4;11) translocations. Younger age, a mean period of latency of 2 years and monocytic subtypes are characteristic features of this type of leukemia. Among patients at risk for secondary leukemia, those with Hodgkin's disease are the most extensively studied, with the major impact of alkylating agents included in the chemotherapy schedule. The same is true for non-Hodgkin's lymphoma, while in multiple myeloma and acute lymphoblastic leukemia determinants are the dose of melphalan and of epypodophyllotoxin, respectively. Patients with breast, ovarian and testicular neoplasms are also at risk, in particular if trated with the association of alkylating agents and topoisomerase II inhibitors. According to the EBMT registry, in patients with lymphoma treated with high-dose therapy and autologous stem cell transplantation the cumulative risk of inducing leukemia at 5 years is 2.6%. Among treatment options, supportive therapy is indicated in older patients, while allogeneic stem cell transplantation, related or matched-unrelated, is feasible in younger patients. These data indicate the need for the identification of predisposing factors for secondary leukemia. In particular, frequent follow-up of patients at high-risk should be performed and any peripheral blood cytopenia should be considered suspicious. Whenever possible, the exclusion of drugs known to be leukemogenic from the treatment schedules should be considered, especially in young patients.
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PMID:Therapy related leukemias: susceptibility, prevention and treatment. 1137 39

In this prospective study we analyzed pre-emptive donor leukocyte infusions (DLI) in 82 consecutive patients transplanted with partially T cell-depleted grafts for acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, refractory anemia with excess of blasts, refractory anemia with excess of blasts in transformation and multiple myeloma. Donors were HLA-identical siblings. Patients without significant acute (>grade 1) and/or chronic GVHD were scheduled to be treated with DLI (35 patients) and 31 actually received DLI. Patients who developed acute GVHD >grade 1 and/or chronic GVHD were not scheduled to receive DLI and served as a comparison group (47 patients). The median interval between BMT and DLI was 22 weeks. The first six patients received 0.7 x 10(8) CD3+ cells/kg body weight (b.w.). Five out of these six patients developed acute GVHD (grade 1: n = 2, grade 3: n = 2 and grade 4: n= 1) which was more frequent and more severe than we had anticipated. In the next 25 patients the number of T lymphocytes was diminished to 0.1 x 10(8) CD3+ cells/kg b.w. which resulted in less frequent and less severe GVHD. Eight patients in this group developed acute GVHD (grade 1: n = 4, grade 2: n = 4) and three patients had limited chronic GVHD. Patients in the DLI group needed more time to establish complete donor chimerism confirmed by a higher number of mixed chimeras at 6 months after BMT. The projected 3-year probability of disease-free survival was 77% for the 35 patients intended to treat with DLI and 45% for the patients of the comparison group (P = 0.024). Relapse rate at 36 months after transplantation was 18% in the patients who were intended to treat with DLI and 44% in the comparison group (P = 0.026). We conclude that pre-emptive DLI is feasible and generates favorable relapse rates in patients who are at high risk for relapse. Furthermore, the incidence and severity of GVHD disease after DLI is dependent on the number of CD3+ cells infused.
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PMID:Induction of graft-versus-leukemia to prevent relapse after partially lymphocyte-depleted allogeneic bone marrow transplantation by pre-emptive donor leukocyte infusions. 1151 94

In response to antigen stimulation, B cells undergo a germinal center(GC) reaction such as somatic hypermutations of the immunoglobulin variable region genes, which results in the production and selection of antigen-specific antibodies with increased affinity. Therefore, somatic hypermutations are considered to be a hallmark of GC B cells and their descendants. Pre-GC B cells(precursor B cells, immature B cells, naive B cells and CD5+ B cells) carry no somatic hypermutations, whereas GC B cells and post-GC B cells(memory B cells and plasma cells) express somatic hypermutations. This phenomenon is useful in identifying the cellular origin of various B-cell neoplasms. Precursor B-lymphoblastic leukemia/lymphoma, mantle cell lymphoma, and most B-CLL originate from pre-GC B cells, and follicular lymphoma, Burkitt's lymphoma, marginal zone B-cell lymphoma, diffuse large B-cell lymphoma and myeloma from GC B cells or post-GC B cells. Nodular lymphocyte-predominant Hodgkin's disease and most classical types of Hodgkin's disease are derived from GC B cells. Most human-B cell neoplasms including Hodgkin's disease are derived from GC B cells or their descendants. Molecular processes that modify the DNA of GC B cells, such as somatic hypermutation, class switching and receptor editing occur in the environment of the GCs, and increase the risk of malignant transformation.
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PMID:[Cellular origin of human B-cell neoplasms and Hodgkin's disease based on analysis of somatic hypermutations in the immunoglobulin variable region genes]. 1157 86

Solid tumor growth consists of an avascular and a subsequent vascular phase. Several studies have now shown that, as in solid tumors, angiogenesis also plays a critical role in the progression of hematological malignancies. Monoclonal gammopathy of undetermined significance (MGUS) and non-active to active multiple myeloma (MM) progress when plasma cells induce angiogenesis and this in turn promotes progression. The increased bone marrow neovascularization, increased angiogenic and proteolytic potential of plasma cells may explain the frequent occurrence of extramedullary localization in MM. As observed in active MM, enhanced bone marrow neovascularization is apparent in acute untreated lymphoblastic leukemia. In B-cell non-Hodgkin's lymphomas, angiogenesis is significantly enhanced in relation to progression. Angiostatic molecules, such as thalidomide, could also be considered for the clinical management of hematological tumors.
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PMID:Angiogenesis, angiogenic factor expression and hematological malignancies. 1190 88

Tumor responses after daily oral administration of low-dose etoposide have been demonstrated in both hematological and solid tumors. The aim of the present phase II trial was to determine tumor response, and toxicity and to delineate the pharmacokinetics of oral low-dose etoposide in patients with hematological malignancies in a palliative treatment setting. Thirty-two patients with non-Hodgkin's lymphoma (NHL), acute myeloblastic (AML) and lymphoblastic leukemia, multiple myeloma, and myelodysplastic syndrome (MDS) were included. Patients were given oral etoposide, 100 mg once daily for 14 d in a 21-d cycle. Serum etoposide concentrations were determined on d 1, 7, and 14 of every cycle before etoposide administration and, in addition, 1, 2, 3, 4, and 24 h after drug intake on d 1. The median age of patients was 68 yr (range: 50-89 yr). The median time from diagnosis to inclusion in the study was 21 mo (range: 0.5-144 mo) and most patients had advanced disease and were heavily pretreated. Eleven patients completed three or more cycles. Eight of 11 patients with acute leukemia and 1 of 2 with MDS received only 1 course because of toxicity (n = 5) or progression (n = 4). One patient with AML, a Jehovah's Witness, was treated up-front and achieved a complete remission and two patients with low-grade NHL gained a complete and a partial remission, respectively. Twenty-one of 32 patients were evaluable for toxicity during the first cycle. In 67%, the white blood cell count nadir was < 2.0 x 109/L and in 38% < 1.0 x 10(9)/L. Platelet count nadir was less than 25 x 10(9)/L in 24% of evaluable patients. During all cycles (n = 79), eight patients developed febrile neutropenia, four of whom with a fatal outcome. The correlation between the area under the curve (AUC) of the free fraction of etoposide and leukopenia was statistically significant at a log analysis (n = 12; p < 0.05). There was also a statistically significant correlation between the AUC and the 24-h concentration (n = 15; p < 0.005) and between the concentrations at 24 h and d 7 (n = 11; p < 0.005) of the free fractions of etoposide. In conclusion, etoposide had a moderate clinical effect in this group of heavily pretreated patients. Moreover, toxicity was substantial, in particular leukopenia, which correlated to the free-etoposide AUC.
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PMID:Oral etoposide in patients with hematological malignancies: a clinical and pharmacokinetic study. 1191 53

We investigated mismatch repair (MMR) gene expression in 31 lymphoid tissue specimens and bone marrow aspirates with malignant lymphoproliferative disorders of B-cell origin (25 cases of lymphoma and six cases of plasma cell myeloma). A multiplex RT-PCR assay was employed to assess the relative expression of the hMSH2, hMLH1 and hPMS1 genes, as compared to beta-actin, which was used as an internal control of gene expression. MSH2 was further evaluated at the protein level by immunohistochemistry. The findings were compared to those of a control group of lymphoid tissue specimens without evidence of malignancy (n = 6). Changes in MMR gene expression were observed in 10 out of 31 cases of the study group (32%). All three MMR gene transcripts were low in two out of six plasma cell myelomas, which had extensive bone marrow infiltration by neoplastic cells. The hMSH2 transcript was present in all cases of lymphoma, while the expression of hMLH1 and hPMS1 was significantly low in some large B-cell lymphomas (four and five out of 14 cases, respectively) and in mantle cell lymphomas of the blastoid type (two out of two cases). No MMR gene aberrations were found in seven cases of B-cell lymphocytic leukemia and two cases of mantle cell lymphoma of centrocyte-like type. These findings demonstrate that the expression rates of the hMSH2, hMLH1 and hPMS1 genes differ among various types of B-cell lymphoproliferative disorders, and suggest that MMR gene expression may be related to the natural history of these neoplasms. This study identified a higher incidence of MMR gene aberrations in lymphoma types characterized by aggressive biologic behavior, as compared to neoplasms with a more indolent course.
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PMID:Mismatch repair gene expression in malignant lymphoproliferative disorders of B-cell origin. 1199 75

To better define the incidence and causes of canine pancytopenia, we retrospectively evaluated the results of complete blood counts submitted to the University of Minnesota Veterinary Teaching Hospital during a 1-year period. Pancytopenia was defined as packed cell volume < 36%, total leukocyte count < 6,000/microliter or total segmented neutrophil count < 3,000/microliter, and platelet count < 200,000/microliter. Of 4,560 complete blood counts, 110 (2.4%) samples from 51 dogs met the criteria for pancytopenia. Eleven different disease processes were identified. These included chemotherapy-associated pancytopenia (n=22), parvovirus infection (n=5), malignant histiocytosis (n=5), idiopathic aplastic anemia (n=3), sepsis (n=3), myelodysplastic syndrome (n=3), immune-mediated hematologic disease (n=3), lymphoblastic leukemia (n=2), ehrlichiosis (n=2), estrogen toxicity (n=2), and multiple myeloma (n=1). Malignant histiocytosis and idiopathic aplastic anemia occurred more frequently than was expected. Doxoruicin was the chemotherapeutic agent associated with pancytopenia. Hematologic recovery and patient survival time varied with the cause of pancytopenia; therefore, a specific diagnosis was essential for establishing prognosis. Differentiation among causes of pancytopenia requires a systemic approach that includes elimination of infectious and drug-induced causes, and examination of bone marrow aspiration and core biopsy specimens.
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PMID:A retrospective study of canine pancytopenia. 1207 15

Activation-induced cytidine deaminase (AID) induces somatic hypermutation (SHM), class switch recombination (CSR), and immunoglobulin gene conversion in B-lymphocytes. Here we report for the first time the expression of AID in healthy human B-lymphocytes and in B-cell non-Hodgkin lymphomas (B-NHL). AID mRNA expression in humans is restricted to the CD19(+)CD38(+)IgD(-) germinal center cells, namely the CD19(+)CD38(+)CD44(-) centroblasts. After in vitro stimulation of naive human B cells by CD40-L and IL-4, AID mRNA is strongly induced for only 48 hours. In a survey of human B-NHL AID was found to be constitutively expressed in follicular lymphoma and in diffuse large B-cell lymphoma but to be absent in B-precursor lymphoblastic leukemia, in mantle cell lymphoma, and in plasma cell myeloma. In B-cell chronic lymphatic leukemia, in immunocytoma, and in extranodal marginal zone B-cell lymphoma of MALT, AID mRNA was expressed only in some samples. In follicular lymphoma and diffuse large B-cell lymphoma, the expression of AID mRNA was coincident with the presence of SHM in the variable region exons of the immunoglobulin heavy-chain gene. In human B-NHL, the AID mRNA is spliced into 4 different variants but does not contain point mutations. Thus AID, which is highly regulated during healthy B-cell development, is constitutively expressed in human germinal center B-NHL and in subsets of nongerminal center B-NHL. This constitutive expression of AID may promote illegitimate DNA recombinations and somatic mutations in B-NHL.
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PMID:Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas. 1251 17

In recent years, it has been reported that bisphosphonates inhibited the cell cycle of myeloma cells to inhibit cell proliferation directly, and it was also reported that bisphosphonates induced apoptosis of myeloma cells in vitro. Recently, YM529 was developed as a new third-generation bisphosphonate. In our experiment, we investigated whether YM529 showed an antitumor effect on hematopoietic tumor cell lines other than myeloma, and we compared YM529 with YM175, which had a relatively more potent antitumor effect than that of existing bisphosphonates. We found that YM529 inhibited cell proliferation in various hematopoietic tumor cell lines (acute promyelocytic leukemia cell line HL-60, chronic myeloid leukemia cell line K562, histiocytic lymphoma cell line U937, lymphoblastic leukemia T cell line Jurkat, acute lymphoblastic leukemia T cell line MOLT-4, lymphoblastic leukemia B cell line CCRF-SB) including myeloma (myeloma cell line HS-Sultan) dose-dependently and time-dependently to a degree equivalent or superior to that in myeloma, and induced apoptosis at a lower concentration as compared with YM175. We confirmed many dead cells as well as apoptosis based on the detection of the nuclei with separate globular structure, the activation of caspase-3, and the decrease in mitochondrial transmembrane potential. Therefore, it is concluded that further utilization of YM529 can be expected against hematopoietic tumor cells in the future.
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PMID:Apoptosis-inducing effect of a new bisphosphonate, YM529, on various hematopoietic tumor cell lines. 1252 Jan 82


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