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PubMed1999

Cytogenetic polyclonality in hematologic malignancies.

The present study was undertaken to ascertain the frequency of cytogenetic polyclonality in various hematologic malignancies and to investigate whether morphologic subgroup, age, gender, or previous genotoxic exposure influences the incidence. Among 2,243 cytogenetically investigated hematologic malignancies, 10 acute myeloid leukemias (AML), 5 myelodysplastic syndromes (MDS), 2 acute lymphoblastic leukemias (ALL), 1 acute undifferentiated leukemia (AUL), 1 atypical Philadelphia chromosome-negative (Ph-) chronic myeloid leukemia (CML), 1 chronic myeloproliferative disorder (CMD), and 1 chronic lymphoproliferative disorder (CLD) with karyotypically unrelated clones were identified, constituting 2.6% of AML, 1.6% of MDS, 0.8% of ALL, 13% of AUL, 9.1% of Ph- CML, 1.5% of CMD, and 2.8% of CLD with chromosomal abnormalities. In contrast to the cytogenetic features, the X-inactivation pattern was monoclonal in the two informative female patients that could be investigated. Among 17,733 karyotypically aberrant published cases surveyed, significant frequency differences (P < 0.001) were discerned: 1.7% of 6,526 AML, 3.4% of 2,391 MDS, 0.4% of 1,920 Ph+ CML, 2.9% of 856 CMD, 0.9% of 4,226 ALL, and 5.8% of 1,814 CLD displayed unrelated clones. The incidence of cytogenetic polyclonality did not differ significantly among the MDS, CMD, or ALL subgroups, between males and females, between children (< 16 years) and adults, or between B- and T-cell ALL, whereas the frequencies varied among the AML FAB types (P < 0.05), among the different CLD entities (P < 0.001), and between B- and T-cell CLD (P < 0.001). Furthermore, the incidence was higher in therapy-related AML and MDS than in de novo AML and MDS (P < 0.001 and P < 0.01, respectively).

Adolescent↗

PubMed1996

Phase I trial of an antisense oligonucleotide OL(1)p53 in hematologic malignancies.

PURPOSE: The phosphoprotein p53 is involved in transcriptional regulation and is detected in hematologic malignancies. In vitro incubation of acute myelogenous leukemia with OL(1)p53, a 20-mer phosphorothioate oligonucleotide complementary to p53 mRNA, results in leukemic cell death. A phase I dose-escalating trial was conducted to determine the toxicity of OL(1)p53 following systemic administration to patients with hematologic malignancies. PATIENTS AND METHODS: Sixteen patients with either refractory acute myelogenous leukemia (n = 6) or advanced myelodysplastic syndrome (n = 10) participated in the trial. Patients were given OL(1)p53 at doses of 0.05 to 0.25 mg/kg/h for 10 days by continuous intravenous infusion. RESULTS: No specific toxicity was directly related to the administration of OL(1)p53. One patient developed transient nonoliguric renal failure. One patient died of anthracycline-induced cardiac failure. Approximately 36% of the administered dose of OL(1)p53 was recovered intact in the urine. Plasma concentrations and area under the plasma concentration curves were linearly correlated with dose. Leukemic cell growth in vitro was inhibited as compared with pretreatment samples. There were no clinical complete responses. CONCLUSION: A phosphorothioate oligonucleotide, OL(1)p53, can be administered systemically without complications. This type of modified oligonucleotide can be administered without complete degradation, as it was recovered from the urine intact. This oligonucleotide may be useful in combination with currently available chemotherapy agents for the treatment of malignancies.

Adult↗

PubMed2002

Anemia of hematologic malignancies: what are the treatment options?

Anemia is a common complication in patients with hematologic malignancies, with incidence rates ranging up to 63%. In myelodysplastic syndromes, anemia is an essential feature of the disease. The decrease in hemoglobin may lead to several symptoms such as fatigue, exhaustion, and impaired quality of life, and it may worsen prognosis. Before the introduction of recombinant human erythropoietin (rHuEPO, epoetin alfa), red blood cell transfusions were the traditional treatment for improvement of Hb levels. Transfusions, however, are associated with several adverse events and risks, have only transient effects, and have a limited capacity to ameliorate the symptoms of anemia. Epoetin alfa represents a physiologic treatment option, especially in the long-term treatment of cancer- and cancer treatment-associated anemia, and is well tolerated, with response rates as high as 80%. Epoetin alfa is less effective in the treatment of the anemia of myelodysplastic syndrome, but appears to be synergistic with granulocyte-colony stimulating factor. However, not every patient responds to epoetin alfa; to avoid unnecessary interventions and costs, predictors of response have been proposed. This article outlines the advantages and disadvantages of the two major treatment forms of anemia: transfusions and epoetin alfa. Representative studies on the efficacy of epoetin alfa in anemic patients with hematologic malignancies as well as models to predict response to epoetin alfa treatment are summarized.

Anemia↗

PubMed2005

Bacteremia in patients with hematological malignancies.

BACKGROUND: An appropriate regimen in the empirical therapy of neutropenic fever episodes must be individualized at each institution. Hospitals have different patterns of microbial isolates and antibiotic resistance that must be taken into account. The aim of this study was to investigate isolates of bacteremia and their antibiotic susceptibility in patients with hematological malignancies. METHODS: All positive blood cultures at a medical center in Taiwan between 1999 and 2002 from patients with hematological malignancies were evaluated. Eleven kinds of antibiotics were tested for antimicrobial activities. The risk factors for mortality were evaluated. RESULTS: Three hundred seventy-one episodes of bacteremia in 266 patients with hematological malignancies were recorded. Gram-negative bacilli (GNB) were still predominant and accounted for 78.2% of isolates, followed by gram-positive cocci for 20.8% of isolates, and anaerobes for 1% of isolates. Escherichia coli was the most common isolated organism accounting for 27.5% of GNB isolates. Other isolates included Klebsiella pneumoniae (19.3%), Pseudomonas aeruginosa (11%), and Enterobacter cloacae (10.1%). The most isolated microorganisms were susceptible to cefoperazone/sulbactam, piperacillin/tazobactam, cefepime or imipenem. Age, GNB microorganism and inadequate empirical antibiotics were risk factors. CONCLUSIONS: We suggest that cefoperazone/sulbactam, piperacillin/tazobactam, cefepime or imipenem is an ideal empirical therapy.

Adolescent↗

PubMed1996

[Effective clinical use of cyclophosphamide in hematological malignancies].

Cyclophosphamide (CPA) is the most widely used alkylating agent in the treatment of hematological malignancies. We review current clinical potential of high-dose CPA administration in this field. The efficacy of dose intensification of CPA in CHOP regimen for patients with aggressive lymphoma is being investigated in some clinical trials. High-dose CPA administration and G-CSF infusion effectively mobilize high levels of peripheral blood stem cell suitable for autografting. High-dose regimens of CPA alone or in combination with other agents also have been used to treat various hematological malignancies in conjunction with stem cell transplantation (SCT). A variety of adverse effects have been observed with the high-dose CPA used in preparative regimens for SCT. Hemorrhagic cystitis and cardiac toxicity are common and dose-limiting toxic effect of high-dose CPA administration.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Interleukin-2 after autologous stem cell transplantation for hematologic malignancy: a phase I/II study.

The success of autologous stem cell transplantation (ASCT) for hematologic malignancy is limited largely by a high relapse rate. It is postulated that IL-2 administered after ASCT may eliminate minimal residual disease and thereby reduce relapses. A phase I/II study was performed to identify a regimen of IL-2 (Chiron) that could be given early after ASCT in phase III trials. In the phase I study, beginning a median of 46 days after ASCT for hematologic malignancy, cohorts of three to four patients received escalating doses of 'induction' IL-2 of 9, 10, or 12 x 10(6) IU/m2/day for 4 or 5 days by continuous i.v. infusion (CIV), followed by a 4-day rest period, and then 1.6 x 10(6) IU/m2/day of maintenance IL-2 by CIV for 10 days. The maximum tolerated dose (MTD) of induction IL-2 was 9 x 10(6) IU/m2/day x 4. In the phase II study, 52 patients received the MTD. Eighty percent of patients completed induction IL-2. Most patients exhibited some degree of capillary leak. One patient died of CMV pneumonia and one died of ARDS. Maintenance IL-2 was well tolerated. In the phase I/II study, 16 of 31 patients with non-Hodgkin lymphoma (NHL), 3/8 with Hodgkin disease (HD), 4/17 with AML, and 4/5 with ALL remain in CR. Two of six multiple myeloma (MM) patients remain in PR. Although the regimen of IL-2 identified had significant side-effects in some patients, it was well tolerated in the majority of patients. Phase III prospectively randomized clinical trials are in progress to determine if this IL-2 regimen will decrease the relapse rate after ASCT for AML and NHL.

Adjuvants, Immunologic↗

PubMed2006

Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center.

Community respiratory viruses (CRVs) have been recognized as a potential cause of pneumonia and death among hematopoietic stem cell transplantation (HSCT) recipients and patients with hematologic malignancies. We reviewed the Microbiology Laboratory records dated from July 1, 2000, to June 30, 2002, to identify patients who had respiratory specimens positive for influenza, parainfluenza, respiratory syncytial virus, or picornavirus. We identified 343 infections among patients with underlying hematologic malignancies and HSCT. We collected data on type of disease, age, sex, type of infection, neutrophil and lymphocyte counts, therapy, and outcome. Influenza, parainfluenza, and respiratory syncytial virus accounted for most cases and were approximately equal in frequency. Most infections occurred predominantly among recipients of allogeneic transplants. Infection progressed to pneumonia in 119 patients (35%) and occurred with similar frequency for the 3 viruses. Patients at greatest risk for developing pneumonia included those with leukemia, those aged more than 65 years, and those with severe neutropenia or lymphopenia. Lack of respiratory syncytial virus-directed antiviral therapy (p=0.025) and age (p=0.042) were associated with development of respiratory syncytial virus pneumonia, and an absolute lymphocyte count<or=200 cells/mL (p=0.049) was associated with development of influenza pneumonia. The overall mortality rate for CRV pneumonia was 15%. The only independent predictor of fatal outcome was an absolute lymphocyte count<or=200 cells/mL (p=0.03) in patients with influenza pneumonia.HSCT recipients and patients with hematologic malignancies who develop upper respiratory infection due to CRVs should be considered for antiviral therapy of proven efficacy to reduce the risk of pneumonia and death.

Adolescent↗

PubMed2006

A prospective study on chemotherapy-induced hepatitis B virus reactivation in chronic HBs Ag carriers with hematologic malignancies and pre-emptive therapy with nucleoside analogues.

Chemotherapy-induced hepatitis B virus (HBV) reactivation is a serious problem in chronic HBV carriers with hematologic malignancies. In 12 patients with hematologic malignancies, we performed a prospective study to determine the effectiveness of nucleoside analogues in the pre-emptive therapy of chemotherapy-induced HBV reactivation. HBV reactivation occurred in seven patients (58.3%) whereas five of the seven patients (71%) responded to nucleoside analogue therapy. HBV reactivation-related acute liver failure and death was not observed in the present study. All five patients with chronic lymphocytic leukemia (CLL) experienced chemotherapy-induced HBV reactivation regardless of the chemotherapy regimen. Therefore, we suggest that CLL carries a significant risk of chemotherapy-induced HBV reactivation. The pre-emptive therapy of chemotherapy-induced HBV reactivation appears to be safe, based on the results of this pilot study. Pre-emptive therapy enables the definition of high-risk patients who cannot be identified by primary prophylaxis.

2-Aminopurine↗

PubMed1987

[Progress in the study, treatment and cure of hematologic malignancies in children in North America].

Progress in the study, treatment and cure of hematologic malignancies in children is one of the most gratifying accounts in the entire history of cancer therapy. It is important to note that progress in treatment and cure have been the direct result of formal study of childhood cancers and the development and clinical trial of new treatments designed to improve the response and cure rate. In the experience of the Children's Cancer Study Group (CCSG), approximately half of the children with cancer which are registered have hematologic malignancies. By far the most significant of these is acute lymphoblastic leukemia (ALL), which accounts for 33% of all the cancers registered with the Group. Acute non-lymphoblastic types of leukemia have amounted to 6% of all cancers in our experience, non-Hodgkin's lymphoma for another 6% and Hodgkin's disease for approximately 5%. The cancer death rate in children under the age of fifteen years has declined very significantly in the United States since 1950. In 1955 the National Cancer Institute organized the first national cooperative groups in order to develop and test new treatments for acute lymphoblastic leukemia. The CCSG was the first of these. The success which has been achieved in treating acute leukemia is remarkable, particularly when one recalls that in 1950 the disease was 100% fatal. The death rate due to Hodgkin's disease has also shown a sharp decline, and more recently, deaths due to non-Hodgkin's lymphomas have also declined.

Child↗

PubMed2002

Macroscopic and microscopic findings of livers in malignant hematologic disorders, biopsied under peritoneoscopy.

It is important to detect liver involvement in extranodal lesions in malignant hematologic disorders to make accurate diagnoses and estimate their clinical stage. We report seven cases of malignant lymphoma and a case of histiocytosis X. All patients expressed positive C-reactive protein and a high erythrocyte sedimentation rate, and a high serum value of alkaline phosphatase or lactic dehydrogenase was seen. Image analyses revealed enlarged livers without any space-occupying lesions. Peritoneoscopy with liver biopsy showed a diffuse presence of white maculae or peliosis hepatis on the liver surface among all the patients, and granulomas with or without malignant cells were observed histologically and congestion was seen in the lobules. Thus, peritoneoscopy with liver biopsy appears to be a useful tool not only to detect early liver involvement in malignant hematologic disorders but also to make their accurate diagnosis.

Adult↗

PubMed2001

Lactic acidosis: a metabolic complication of hematologic malignancies: case report and review of the literature.

BACKGROUND: Lactic acidosis (LA) associated with hematologic malignancies is rare, ominous, and generally occurs in adults. Its pathogenesis is poorly understood. METHODS: The authors present one case of childhood lymphoma and two cases of childhood leukemia associated with LA, and they review the available literature. Plasma concentrations of insulin-like growth factors (IGFs), IGF binding proteins (IGFBPs), and tumor necrosis factor (TNF)-alpha were retrospectively measured to elucidate the pathogenesis of LA. RESULTS: Lactic acidosis has been reported to date in 28 cases of lymphoma and 25 cases of leukemia, including the authors' cases. Ongoing rapid cellular proliferation was indicated in all leukemia cases. The liver was involved in 43 of the 53 cases, and hypoglycemia was present in 20. The acidosis improved only if the disease responded to chemotherapy. Remission was achieved in only five of the reported cases. In the authors' three cases, LA was associated with altered concentrations of IGFs, IGFBPs, and TNF-alpha, although causality was not established. CONCLUSIONS: Lactic acidosis in association with hematologic malignancies carries an extremely poor prognosis. Because cancer cells have a high rate of glycolysis and produce a large quantity of lactate, this condition may result from an imbalance between lactate production and hepatic lactate utilization. The authors speculate that the IGF system is involved in the pathophysiology of LA in these patients. Only chemotherapy so far has been effective in correcting the acute acidosis in a few patients; however, it has not necessarily improved ultimate outcome.

Acidosis, Lactic↗

PubMed1997

Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies.

Inactivation of the cyclin-dependent kinase inhibitors p16INK4A and p15INK4B are frequent alterations in neoplasia, often resulting from homozygous deletion or promoter region hypermethylation. We have analyzed both modes of inactivation of p15INK4B and p16INK4A in the major types of adult and pediatric hematological malignancies. Hypermethylation of p15INK4B, without alteration of p16INK4A, was an almost universal finding in adult acute myelogenous leukemia, and occurred very frequently in adult acute lymphocytic leukemia and pediatric acute myelogenous leukemia and acute lymphocytic leukemia. In contrast, neither p15INK4B nor p16INK4A were inactivated in any stage of chronic myelogenous leukemia. Hypermethylation of p16INK4A, often without alterations of p15INK4B, was found in non-Hodgkin's lymphoma and was much more frequent in cases with high-grade than low-grade histology. Enriched normal bone marrow stem cells had no detectable promoter region methylation of these genes, as analyzed by a newly developed PCR method. Remarkably distinct patterns of inactivation of p15INK4B and p16INK4A characterize different types of hematological malignancy, and alterations in these tumor suppressor genes are one of the most common alterations in hematological malignancies.

Adult↗

PubMed1996

Molecular characterization of 12p abnormalities in hematologic malignancies: deletion of KIP1, rearrangement of TEL, and amplification of CCND2.

Twenty patients with hematologic malignancies with 12p abnormalities were investigated by fluorescence in situ hybridization (FISH) using probes mapped to specific regions in 12p. The initial analysis using the YAC 964c10 (D12S736) revealed that all four cases with cytogenetically identified del(12p) had lost one copy of this YAC and that submicroscopic deletions had occurred in 10 of the 16 neoplasms with other 12p abnormalities, ie, translocations, additions, and insertions. The deletions were partially mapped with cosmids localized to subregions of 12p. One copy of the gene for p27kip1 (KIP1), involved in cell cycle entrance, was found to be lost in all cases in which deletions could be detected by other probes and in one case with a translocation as the only detectable change. This implicates KIP1 as a possible tumor suppressor gene affected by del(12p). Four translocations with no apparent concomitant deletions were detected. All four breakpoints resulted in a split D12S736 signal. In two of these cases, we showed that TEL was disrupted as a result of a t(5;12)(q32-33;p12) and a t(12;22)(p12;q12), respectively. Two lymphoid neoplasm--one non-Hodgkin's lymphoma and one Burkitt's lymphoma--with 12p amplifications were detected. In both cases cyclin D2 (CCND2) was within the amplified region. Thus, cytogenetic abnormalities of 12p in hematologic malignancies result in at least three different molecular changes: deletions of KIP1, amplifications of CCND2, and structural rearrangements of TEL.

Adult↗

PubMed2006

Fungal pneumonia due to molds in patients with hematological malignancies.

Invasive fungal infections are an important cause of morbidity and mortality in patients with hematological malignancies. In particular, patients with neutropenia and those who have undergone allogeneic hematopoietic stem cell transplantation are at highest risk, with fungal pneumonia being the main clinical manifestation in these patients. The most common pathogens associated with fungal pneumonia are Aspergillus spp. and Zygomycetes. However, other pathogens have also been observed in fungal pneumonia, including Cryptococcus spp., Pneumocystis jirovecii, and Candida spp. This comprehensive review will focus on the important practical aspects relevant to the epidemiology, clinical diagnosis, and therapeutic management of pneumonia due to filamentous fungi in patients affected by hematological malignancies.

Amphotericin B↗

PubMed2003

Staphylococcus aureus bacteremia in patients with hematologic malignancies: a retrospective case-control study.

BACKGROUND AND OBJECTIVES: Staphylococcus aureus bacteremia (SAB) continues to be a major problem related to both community and nosocomially acquired infection. Nevertheless few data are presently available in literature about this infection in patients with hematologic malignancies. DESIGN AND METHODS: The purpose of this retrospective study was to report further data on the clinical characteristics and outcome of patients with SAB. All episodes of SAB occurring between January 1997 and June 2001 were identified and defined by analysis of the patients' clinical records. RESULTS: The nosocomial mortality rate was only 3.5% and no patient developed secondary complications. Comparison between neutropenic hematologic patients with SAB and neutropenic hematologic patients with Gram-negative bacteremia (GNB) revealed an higher mortality in the latter group (p=0.03); furthermore, severe sepsis and septic shock were more frequent in patients with GNB (p<0.001). Comparison between neutropenic patients with hematologic malignancies and non-neutropenic ones with other underlying diseases revealed significantly higher morbidity and mortality rates in the latter group. Non neutropenic patients seemed to be more susceptible to both early complications, such as severe sepsis or septic shock (p=0.002) and to later ones, such as endocarditis and metastatic abscesses (p=0.02). INTERPRETATION AND CONCLUSIONS: Our results seem to suggest that SAB in patients with hematologic malignancies is often a low inoculum infection associated with negligible morbidity and mortality rates, especially when adequate antistaphylococcal therapy is administered promptly.

Adolescent↗

PubMed2000

Alterations of the PPP1R3 gene in hematological malignancies.

PPP1R3 (protein phosphatase 1, regulatory subunit 3) is a candidate tumor suppressor gene at chromosome 7q31, since nonsense and missense mutations of the PPP1R3 gene have been detected in a variety of human cancers. Loss of chromosome 7q is a recurrent abnormality in hematological malignancies, especially of myeloid lineage, and a common region of 7q deletions has been mapped to 7q31. Thus, it has been suggested that 7q31 harbors a tumor suppressor gene whose functional loss contributes to leukemogenesis. To evaluate the possible involvement of the PPP1R3 gene in the development of hematological malignancies, we examined 72 leukemia and lymphoma cell lines for alterations of the PPP1R3 gene by PCR-SSCP and direct sequence analyses. Mutations were detected in 1 (2.8%) of 36 myeloid cell lines, 4 (20.0%) of 20 B-lineage lymphoid cell lines and none of 16 T-lineage lymphoid cell lines. All the mutations were heterozygous, and they consisted of two missense mutations and three silent mutations. The PPP1R3 gene was expressed in cell lines of various cell lineages. These results indicate that PPP1R3 is not a major target of 7q deletions in myeloid leukemia, however, alterations of the PPP1R3 gene may contribute to the development of a subset of hematological malignancies.

Amino Acid Substitution↗

PubMed2005

Secondary hematological malignancies after breast cancer chemotherapy.

According to several reports, the 10 year incidence of secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after systemic chemotherapy is approximately 1.5%. The cumulative risk increases by 0.25--1% for the first 8 years after treatment. We have reported only 6 cases of hematological malignancies (0.3%) after breast cancer chemotherapy in our institute. We detected 2 cases of secondary AML and 1 case of MDS, 19, 52 and 12 months, respectively, after systemic chemotherapy for breast cancer. Published data on the occurrence of secondary hematological malignancies other than AML or MDS in this setting are scarce. We encountered diffuse large B-cell lymphoma, angioimmunoblastic lymphoma and mantle cell lymphoma as secondary hematological malignancies after systemic chemotherapy for breast cancer.

Breast Neoplasms↗

PubMed2005

Disseminated Ochroconis gallopavum infection in a chronic lymphocytic leukemia: a case report and review of the literature on hematological malignancies.

Disseminated fungal infection is an important cause of morbidity and mortality among patients with hematological malignancies. Ochroconis gallopavum is a dematiaceous and thermotolerant fungus that causes opportunistic infections in immunocompromised hosts. About only 30 cases of this organism infection have been reported worldwide. We report a disseminated Ochroconis gallopavum infection in a B-cell chronic lymphocytic leukemia patient. In spite of intensive anti-fungal treatment, no improvement in the clinical condition was observed and the patient died 4 months after diagnosis of the infection. Ochroconis gallopavum infection is a potentially fatal disease in hematological malignancies.

Aged↗