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PubMed1992

[Activation of protooncogenes by point mutations in hematological malignancies].

The activation of protooncogenes (ras, fms and myc genes) by point mutations in hematological malignancies are described in this review. Ras mutations are found in a variety of human malignancies at codon 12, 13, and 61. Generally, N-ras mutations are frequent in hematological malignancies. Fms mutation at codon 301 and 969, which are seen in 10 to 20% cases of AML and MDS, increase tyrosine kinase activity of the fms products. Ras and fms mutations are postulated to influence leukemogenesis at rather early stages. Burkitt lymphomas are characterized by specific chromosomal translocations between c-myc gene and one of the immunoglobulin genes. Furthermore, mutations in the 3' border of the exon 1 of c-myc are frequent, and may play an additional role in pathogenesis of Burkitt lymphoma.

Animals↗

PubMed2004

Hematopoietic stem cell transplantation in hematologic malignancy.

Hematopoietic stem cell transplantation has become increasingly important in the treatment of hematologic malignancies over the past 20 years. While it is associated with significant morbidity, it offers the only chance of cure in many circumstances. Autologous and allogeneic transplantation have been used successfully to treat a variety of hematologic malignancies. These 2 approaches offer different risks and benefits which are discussed in this review. Timing of transplantation and selection of patients are also discussed. New innovations in stem cell transplantation including umbilical cord blood and non-myeloablative transplantation are reviewed.

Hematologic Neoplasms↗

PubMed2002

Hematopoietic system-specific antigens as targets for cellular immunotherapy of hematological malignancies.

Allogeneic stem cell transplantation (SCT) is the treatment of choice for many hematological malignancies. Its curative graft-versus-leukemia (GvL) effect is mainly mediated by donor-derived alloreactive T cells. However, if the donor T cells are not selected for their reactivity against leukemic cells, the GvL effect is often associated with graft-versus-host disease (GvHD), a major complication of SCT. Here we summarize our current knowledge on leukemia-associated antigens and discuss strategies to apply minor and major histocompatibility antigens for cellular immunotherapy of hematological malignancies with a low risk of GvHD.

Antigens, Neoplasm↗

PubMed2004

Dose-ranging pharmacodynamic study of tipifarnib (R115777) in patients with relapsed and refractory hematologic malignancies.

PURPOSE: Tipifarnib, an orally bioavailable inhibitor of farnesyl transferase, has activity in hematologic malignancies, but the dose required to achieve the proposed biologic end point, inhibition of farnesylation, is unknown. PATIENTS AND METHODS: The impact on post-translational farnesylation was assessed in 42 patients with refractory hematologic malignancies and bone marrow involvement. Tipifarnib was taken orally for 21 days of a 28-day cycle. For cycle 1, patients were randomly assigned to one of four dose levels: 100 mg bid, 200 mg bid, 300 mg bid, and 600 mg bid. In cycle 1, peripheral blood and bone marrow mononuclear cells were analyzed for inhibition of HDJ2 prenylation by Western blot analysis at baseline and on day 21. RESULTS: Twenty-three patients were assessable for analysis of HDJ2 prenylation before and after therapy. Inhibition of farnesylation was noted at all dose levels, although the highest level of inhibition was noted at the 300-mg-bid dose. The inhibition of farnesylation in the peripheral blood correlated with the inhibition in the bone marrow (r = 0.62). Of the 26 patients assessable for clinical activity after cycle 1, three patients had a significant decrease in total blasts count (acute myeloid leukemia in two patients, and chronic myelogenous leukemia in one patient). The inhibition of farnesylation was greater in the three responders than the nonresponders (P = .03). CONCLUSION: Farnesylation as measured by HDJ2 analysis was inhibited at all dose levels administered. Clinical activity may correlate with the degree of farnesylation inhibition, rather than dose of tipifarnib, and escalation beyond 300 mg bid might not result in additional clinical activity.

Administration, Oral↗

PubMed1998

Genetic alterations in the retinoblastoma protein-related p107 gene in human hematologic malignancies.

Genetic alterations in the p107 gene, a close relative of the retinoblastoma tumor suppressor gene, have never been identified in human malignancies. When we searched for such alterations in human hematologic malignancies by Southern blot analysis, 2 of 21 cell lines and 1 of 88 primary disorders had genomic alterations within the gene. Particularly, an altered p107 gene in a diffuse-large B-cell lymphoma cell line, KAL-1, harbored an intragenic deletion of about 15 kbp leading to the expression of an altered p107 mRNA devoid of 819 nucleotides of the coding sequences, which predicts to encode an approximately 87-kDa protein. This cell line was found to express solely a p107 derivative of 84 kDa by immunoblotting analysis. These results suggest that alterations in the p107 gene are probably related to a limited subset of human hematologic malignancies.

Gene Deletion↗

PubMed2001

Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells.

Glucocorticoids play an important role in the treatment of a number of hematological malignancies, such as multiple myeloma. The effects of glucocorticoids are mediated through the glucocorticoid receptor alpha, the abundance of which can be modulated by alternative splicing of the glucocorticoid receptor mRNA. Two splice variants of the glucocorticoid receptor mRNA have been described: glucocorticoid receptor beta, which reportedly has a dominant negative effect on the actions of the glucocorticoid receptor alpha, and glucocorticoid receptor P, of which the effects are unknown. In this study, we have investigated the expression levels of these two splice variants at the mRNA level in multiple myeloma cells and in a number of other hematological tumors. Although the glucocorticoid receptor beta mRNA was, if at all, expressed at very low levels, considerable amounts (up to 50% of the total glucocorticoid receptor mRNA) glucocorticoid receptor P mRNA was present in most hematological malignancies. In transient transfection studies in several cell types and in multiple myeloma cell lines, the glucocorticoid receptor P increased the activity of the glucocorticoid receptor alpha. These results suggest that the relative levels of the glucocorticoid receptor alpha and the glucocorticoid receptor P may play a role in the occurrence of glucocorticoid resistance in tumor cells during the treatment of hematological malignancies with glucocorticoids.

Alternative Splicing↗

PubMed2006

[Research advance on SDF-1/CXCR4 axis associated with hematological malignancies: review].

The stromal cell-derived factor 1 (SDF-1) interacts with its receptor CXCR4 to transduction signals, playing important roles in most physiological and pathological processes. It is reported that CXCR4 is highly expressed in many kinds of hematological malignancies and closely related to the prognosis, drug resistance and relapse of diseases. The growth of tumor cells can be inhibited by the anti-SDF-1 antibody or anti- CXCR4 antibody, supporting a new way for the therapy against hematological malignancies. Their expression in relation with prognosis and drug resistance of hematological malignancies are summarized in this review.

Chemokine CXCL12↗

PubMed1996

Hematologic malignancies developing in Syrian golden hamsters during induction of pancreatic carcinoma.

We report 30 hematologic malignancies arising in 25 of 236 Syrian golden hamsters (SGH) that received combinations of N-nitrobis(2-oxopropyl)amine (BOP) and Streptozotocin (STZ). Lesions developed with morphological similarity to human small lymphocytic (n = 7), diffuse mixed (n = 2), diffuse large cell lymphoma (n = 13), follicular lymphoma (n = 2), anaplastic large cell lymphoma (n = 3), hairy cell leukemia (n = 2), malignant histiocytosis (n = 1) and discordant lymphomas (n = 5). The types and distribution of these lesions are different from epizootic lymphomas in SGH. We also report a higher percentage (12 versus 4.6%) and the earlier appearance (< or = 40 versus 80-112 weeks) compared with aging-associated spontaneous SGH lymphoma. The features of these hematologic malignancies have not been previously reported in epizootic or aging-associated spontaneous lymphomas and therefore suggest a new class of hematologic lesions in SGH. Benign and atypical hyperplasia correlated with STZ administration (r = 0.97, P = 0.03). The malignant lesions correlated with areas of lymphoid hyperplasia (r = 0.78, P= 0.004). Only one of the 21 untreated SGH spontaneously developed a low grade lymphoma. The unusual types, distribution and occurrence of these lesions may suggest a role for these carcinogens in their induction.

Aging↗

PubMed2003

Outcome and early prognostic indicators in patients with a hematologic malignancy admitted to the intensive care unit for a life-threatening complication.

OBJECTIVES: To assess the outcome and to identify early prognostic indicators in a global population of patients with hematologic malignancy admitted to the intensive care unit for a life-threatening complication. DESIGN: Retrospective observational study. SETTING: Medical intensive care unit at a tertiary university hospital. PATIENTS: A total of 124 consecutive critically ill patients with a hematologic malignancy admitted to the intensive care unit during a 3.5-yr period. MEASUREMENTS We collected variables at admission and during admission and identified predictors of in-hospital mortality by stepwise logistic regression analysis. MAIN RESULTS: Mean Acute Physiology and Chronic Health Evaluation II score was 26 +/- 7.7. Sixty-one percent had a high-grade malignancy, and 27% had active disease. Thirty-five percent were leukopenic (leukocyte count, <1.0 x 10(9)/L) at admission. Respiratory failure (48%), sepsis (18.5%), and neurologic impairment (17%) were the major reasons for admission at the intensive care unit. Seventy-one percent of the patients required ventilatory support for a median duration of 6 (3-17) days, 46% received vasopressors at admission, and 26.6% needed renal replacement therapy during their intensive care unit stay. A recent bacteremia precipitating intensive care unit admission was found in 21.8% of the patients. Crude intensive care unit, in-hospital, and 6-month mortality rates were 42%, 54%, and 66%, respectively. Four variables were independently associated with outcome in a multivariate logistic regression analysis: leukopenia (odds ratio, 2.9; 95% confidence interval, 1.1-7.7), vasopressors (odds ratio, 3.74; 95% confidence interval, 1.4-9.8), and urea of >0.75 g/L (>12 mmol/L) (odds ratio, 9.4; 95% confidence interval, 4.2-26) at admission were associated with poor outcome, whereas recent bacteremia (odds ratio, 0.17; 95% confidence interval, 0.05-0.58) was associated with better prognosis. Using these variables, we arbitrarily categorized our population into three groups for survival analysis: a low-risk group (low urea with or without either leukopenia or vasopressors, n = 60), an intermediate-risk group (high urea or a combination of leukopenia and vasopressors, n = 34), and a high-risk group (high urea in combination with leukopenia or vasopressors, n = 27). Patients with a bacteremia prompting intensive care unit admission were allocated to a one-step-lower risk group. Survival probabilities at 30 days and 6 months were 75% and 55% in the first group, 35% and 21% in the second group, and 4% and 0%, respectively, in the third group ( <.001). CONCLUSION: The general reluctance to admit patients with a hematologic malignancy to the intensive care unit, even with severe critical illness, is unjustified. However, we identified four early predictors of outcome that may be of value in deciding in which patients advanced or prolonged support should not be continued.

Adult↗

PubMed2006

[A new method for 5, 10-methylenetetrahydrofolate reductase single nucleotide polymorphisms genotyping used to study susceptibility of hematological malignancy].

The aim of this study was to set up a new method for 5, 10-Methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms (SNP) genotyping, and to investigate the hereditary susceptibility of hematological malignancy. Prepared an aimed gene microarray based on cDNA microarray theory, dual-color fluorescence hybridization was used to detect SNP loci, and DNA sequencing was performed to confirm the results. The MTHFR C677T SNP loci of 157 controls and 127 patients with hematological malignancies (30 multiple myeloma, 28 non-Hodgkin's lymphoma, 22 acute lymphoblastic leukemia, 40 acute myeloid leukemia, 7 chronic myeloid leukemia) from Jiangsu province were detected. The results showed that after overlapping, homozygous wild type, heterozygote type and homozygous mutant type yielded green, yellow and red fluorescence, respectively. DNA sequencing validated these results. The allele frequency of 677C and 677T in patients and controls were 58.7% and 66.9%, 41.3% and 33.1% respectively, showing statistically significant difference (chi2 = 4.077, P = 0.043). 677TT genotype showed a significantly higher risk of MM (OR = 4.21; 95% CI = 1.50 - 11.83; P = 0.006). It is concluded that this microarray-based method is accurate, high-throughput and inexpensive, suitable for SNP genotyping in a large number of individuals. C677T polymorphisms influence the risk of hematological malignancies. 677TT genotype is susceptive to MM.

Adult↗

PubMed2000

Gene therapy of hematologic malignancies.

Gene therapy offers many new and exciting treatment strategies for patients with hematologic malignancies. Through the transfer of genes into hematopoietic stem cells, one can reduce the sensitivity of myeloid cells to chemotherapy. Donor T cells can be modified to become sensitive to otherwise nontoxic prodrugs, allowing for their safer use as effectors in graft-versus-leukemia immune reactions following allogeneic transplantation. Neoplastic cells also may be modified to enhance their sensitivity to various drugs. Finally, neoplastic cells can be modified to enhance their immunogenicity using genes that encode immune stimulatory cytokines or cell surface proteins. Recent studies, for example, indicate that the stealth-like phenotype of leukemia cells can be reversed through transfer of genes such as the one encoding CD154, the ligand for CD40. A phase I clinical trial using autologous CD154-transduced leukemia cells as a cellular vaccine has provided encouraging results. Indeed, we may soon enter an era of effective gene therapy for hematologic malignancies.

Apoptosis↗

PubMed2002

Elevation of serum KL-6 levels in patients with hematological malignancies associated with cytomegalovirus or Pneumocystis carinii pneumonia.

The level of serum KL-6 antigen has been reported to be a sensitive indicator of various interstitial pneumonitis, but in patients with hematological malignancies who were accompanied by infective interstitial pneumonitis like Pneumocystis carinii or cytomegalovirus (CMV) pneumonia, it is still unknown whether serum KL-6 level is useful as a good marker for the diagnosis or disease activity. In this study, the serum levels of KL-6 and soluble intercellular adhesion molecule 1 (sICAM-1) were evaluated in five patients with malignant lymphoma or adult T-cell leukemia. Serum KL-6 and sICAM-1 levels at the time of diagnosis of P. carinii or CMV pneumonia were 1220+/-323 U/ml (mean+/-SD) and 1246+/-485 ng/ml, respectively. These levels were apparently high, when compared with standard value of serum KL-6 (<520 U/ml) and that of sICAM-1 (115-306 ng/ml). In patients without P. carinii or CMV pneumonia, who had hematological malignancies or AIDS, serum level of KL-6 was not high (299+/-122 U/ml), but sICAM-1 was high (651+/-495 ng/ml) because of the elevation of sICAM-1 in four of five cases. These findings suggest that, in patients with hematological malignancies, serum level of KL-6 antigen rather than sICAM-1 may be useful in the evaluation of CMV or P. carinii pneumonia.

Aged↗

PubMed2003

Epoetin alfa corrects anemia and improves quality of life in patients with hematologic malignancies receiving non-platinum chemotherapy.

Anemia, a commonly occurring morbidity in patients with cancer, often leads to diminished quality of life (QOL). Numerous clinical trials have shown that epoetin alfa treatment improves hematologic and QOL variables in cancer patients. The clinical trial analysis reported here was performed to assess response to epoetin alfa in patients with hematologic malignancies. Cancer patients with anemia undergoing non-platinum-based chemotherapy who were enrolled in a multinational, randomized (2:1), double-blind, placebo-controlled trial were prospectively stratified by tumor type (hematologic, solid). Efficacy endpoints included proportion of patients transfused after day 28; change in hemoglobin (Hb) level from baseline to last assessment; proportion of treatment responders (increase in Hb > or =2 g/dl unrelated to transfusion) and correctors (patients whose Hb levels reached > or =12 g/dl during the study); and QOL. The protocol was amended before unblinding to prospectively collect and assess survival data 12 months after the last patient completed the study, and survival for the full study cohort was estimated using Kaplan-Meier techniques. Efficacy analyses of hematologic and QOL variables, as well as Kaplan-Meier estimates of survival, were performed post hoc for the hematologic tumor stratum. Among patients with hematologic malignancies, the mean increase in Hb levels was greater with epoetin alfa than with placebo treatment (2.2 vs. 0.3 g/dl). Transfusion requirements were lower in patients who received epoetin alfa versus placebo (25.2 vs. 43.1%), and the proportion of responders and correctors was higher with epoetin alfa than with placebo (75.2 vs. 16.7% and 72.6 vs. 14.8%, respectively). Patients who received epoetin alfa had improved QOL while patients who received placebo had decreased QOL. These results are similar to those seen in the full study cohort, where differences between epoetin alfa and placebo were significant (P<0.05) for all five primary cancer- and anemia-specific QOL domains evaluated. Although the study was not powered for survival, Kaplan-Meier estimates showed a trend in overall survival favoring epoetin alfa in both the full study cohort and the hematologic subgroup. Epoetin alfa treatment was well tolerated. Epoetin alfa therapy increased Hb levels, reduced transfusion requirements, and improved QOL in patients with anemia undergoing non-platinum chemotherapy for hematologic malignancies.

Adult↗

PubMedDate not supplied

[Chronic reactive inflammations in the etiopathogenesis of malignant hematologic proliferations].

The malignant proliferations are induced by a multitude of etiological factors and possible pathogenic mechanisms. Three new clinical cases and other four previously reported cases of haematological malignant proliferations occurring during the evolution of some chronic reactive inflammatory processes due to various forms of immune deficit are discussed. A review of the literature and of the opinions regarding the pathogenic mechanism responsible for the occurrence and growth of malignant proliferations, especially in the cases with inborn or acquired immunodeficiency, are also included. The authors' pathogenic hypothesis for the cases with various acquired immune deficits and with secondary infectious or allergic reactions is that altered immune responses made possible a lasting antigenic stimulation of certain cell clones of the reactive inflammatory process. By this excessive demand, and instability of the genes has occurred and during their rearrangement a mutation with the depression of an oncogene, responsible for malignant growth, has resulted.

Adult↗

PubMed2003

[Effect of prophylaxis against myocosis in patients with hematological malignancy disease: efficacy of dosage of itraconazole].

Prophylactic effect of itraconazole (ITCZ) in mycosis associated with hematological malignancy was studied. In a total of 12 patients of hematological malignancy admitted to Hokkaido University Hospital from April, 2001 to March, 2002, six patients received 100 mg per day of ITCZ and the other six received 200 mg per day of ITCZ. ITCZ was administrated from the starting of chemotherapy, and from the time point capable of oral administration in bone marrow transplantation patients. ITCZ administration was finished based on docter's judgement. As the results of this study, three cases with 100 mg per day of ITCZ had mycosis, but none with 200 mg per day of this drug had it. Mild itching associated with ITCZ was found only one case. In conclusion, we suggest that ITCZ is effective and safe drug in terms of prophylaxis of mycosis.

Administration, Oral↗

PubMed1978

Effect of human serum thymic factor on immature T lymphocytes in acute leukemia and other hematologic malignancies.

In 37 patients with acute leukemia and in 13 patients with other hematologic malignancies, E-rosette formation of peripheral blood mononuclear cells, before and after incubation with human serum thymic factor, was studied. This assay showed that incubation with thymic factor caused a clear-cut increase of E-rosette-forming cells in 8 of the 37 acute leukemia patients. Among the 13 patients with other hematologic malignancies, a similar effect was observed in two with pediatric Hodgkin's disease and in one adult with Waldenström's macroglobulinemia. These results support the contention that a significant percentage of the so-called "null" cells circulating in the blood of the above-mentioned patients were, in fact, immature T cells (T0 lymphocytes) that were shifted to a more mature stage (T1) by thymic factor.

Child↗

PubMed2006

Hematological malignancy and pregnancy: a single-institution experience of 21 cases.

The incidence of hematological malignancies during pregnancy is low, and treatment in this setting is problematic. This study observed 21 pregnancies in 18 patients with hematological malignancies. Patients' ages were between 19 and 43 (median 25) years. Two pregnancies ended with spontaneous abortion, one pregnancy ended with in utero death, three therapeutic abortions were carried out, and 15 infants were born alive but three of them died later. The median birth weight was 2.47 kg. Twelve babies survived to a median age of 36 (range 4-117) months. Eight babies were exposed to chemotherapy during the in utero period. One baby was exposed to chemotherapy during all the trimesters and was born prematurely and later died because of intracranial bleeding. Four babies were exposed to chemotherapy during the first trimester, one of them had low birth weight and floating thumb malformation, two of them had only low birth weight, and one was born healthy, but died at 3 months of age as a result of severe gastroenteritis. Two babies were exposed to chemotherapy during the second and third trimesters; one of them had low birth weight, and the other pregnancy ended in in utero death. One infant was exposed to chemotherapy during the third trimester and was born at term, but died because of pulmonary hemorrhage. We concluded that chemotherapy during all trimesters of pregnancy carries a significant risk for an unfavorable outcome.

Abortion, Spontaneous↗

PubMed2004

Impact of surveillance for vancomycin-resistant enterococci on controlling a bloodstream outbreak among patients with hematologic malignancy.

OBJECTIVE: To determine the impact of stool surveillance cultures of critically ill patients on controlling vancomycin-resistant enterococci (VRE) outbreak bacteremia. DESIGN: Stool surveillance cultures were performed on patients who had hematologic malignancy or were critically ill at the time of hospital admission to identify those colonized with VRE. Hence, contact isolation was initiated. SETTING: A tertiary-care cancer center with a high prevalence of VRE. PARTICIPANTS: All patients with hematologic malignancy who were admitted to the hospital as well as all of those admitted to the intensive care unit were eligible. RESULTS: Active stool surveillance cultures performed between 1997 and 2001 decreased the incidence density of VRE bacteremias eightfold while vancomycin use remained constant. In fiscal year (FY) 1997 and FY 1998, there were five and three VRE outbreak bacteremias, respectively. The outbreak clones were responsible for infection in 69% of those patients with VRE bacteremia. However, the stool surveillance program resulted in the complete control of VRE bacteremia by FY 1999 until the end of the study. CONCLUSION: Despite the steady use of vancomycin, the active surveillance program among high-risk patients with hematologic malignancy and those who were critically ill resulted in the complete control of VRE outbreak bacteremia at our institution.

Bacteremia↗