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PubMed2005

Predicting the effect of transcription therapy in hematologic malignancies.

Molecular lesions of genes encoding for transcriptional regulatory proteins are common oncogenic events in hematologic malignancies. Transcriptional activation and repression both occur by virtue of the choreographed recruitment of multisubunit cofactor complexes to target gene loci. As a consequence, the three-dimensional structure of the target gene is altered and its potential to support transcription is increased or decreased. The complexity of the transcriptional process offers a rich substrate for designing therapeutic agents. The objective of such 'transcription therapy' is to regain control over cohorts of target genes and restore the normal genetic and epigenetic programming of the cancer cell. The success of all-trans retinoic acid in the treatment of acute promyelocytic leukemia indicates that transcription therapy can be highly effective and safe. A classification scheme of these therapeutic strategies is proposed herein, which allows predictions to be made regarding specificity, efficacy, disease spectrum and side effects. This framework could help facilitate discussion of the mechanisms of action of transcription therapy drugs as well as the design of preclinical and clinical trials in the future.

Antineoplastic Agents↗

PubMed2006

Home care management of patients affected by hematologic malignancies: a review.

Home care (HC) has an increasingly expanding role in the global management of patients affected by hematologic malignancies. Integrated strategies, including causal-targeted and supportive treatments according to hematologic expertise and a holistic approach inspired by the philosophy and practice of palliative medicine, may allow suitable management and the possibility for most patients to stay at home. Physical, social and psychological needs of patients are likely to vary according to the course of their disease and the treatments they are receiving. Therefore, consideration should be given to different models of care and how to tackle patients' diverse needs, as outlined by reported experiences which claimed that HC can provide appropriate solutions not only for terminally and chronically ill patients but also for those in other phases of disease. According to these studies and to our own experience, when appropriate measures and structured operating models are adopted, HC results in a safe, effective and economically realistic alternative to traditional in-hospital treatment. Therefore, all efforts should be made to overcome budget and administrative barriers and to ensure a more widespread use of this model of care.

Disease Management↗

PubMed2002

Evidence-based assessment of primary antifungal prophylaxis in patients with hematologic malignancies.

Invasive fungal infection is an increasing source of morbidity and mortality in patients with hematologic malignancies, particularly those with prolonged and severe neutropenia (absolute white blood cell count < 100/microL). Early diagnosis of invasive fungal infection is difficult, suggesting that antifungal prophylaxis could be the best approach for neutropenic patients undergoing intensive myelosuppressive chemotherapy. Consequently, antifungal prophylaxis has been extensively studied for more than 20 years. Nonabsorbable polyenes reduce superficial mycoses but are not effective in preventing or treating invasive fungal infections. Intravenous amphotericin B and the newer azoles were used in numerous clinical trials, but the value of antifungal prophylaxis in defined risk groups with cancer is still open to discussion. Recipients of allogeneic stem cell transplants and patients with a relapsed leukemia are high-risk patient populations. In addition, certain risk factors are well defined, for example, neutropenia more than 10 days, corticosteroid therapy, sustained immunosuppression, and graft-versus-host disease. In contrast to study efforts, evidence-based recommendations on the clinical use of antifungal prophylaxis according to risk groups are rare. The objective of this review of 50 studies accumulating more than 9000 patients is to assess evidence-based criteria with regard to the efficacy of antifungal prophylaxis in neutropenic cancer patients.

Adrenal Cortex Hormones↗

PubMed2002

Outcome and prognostic features of intensive care unit treatment in patients with hematological malignancies.

OBJECTIVE: To assess the outcome of intensive care unit (ICU) treatment in patients with hematological malignancies. DESIGN AND SETTING: Retrospective cohort study in the medical ICU of a university hospital. PATIENTS: 104 critically ill patients after receiving conventional chemotherapy or autologous hematopoietic stem cell transplantation. INTERVENTIONS: We analyzed demographic data, underlying disease, intensity of antineoplastic regimen, cause of admission, need for mechanical ventilation, and hemofiltration, ICU survival, and survival after discharge, furthermore neutrophil count, C-reactive protein ( 150 mg/l), antithrombin III, prothrombin time, and SAPS II ( 50) at ICU admission. All recorded variables were evaluated for prognostic relevance by univariate and multivariate analyses. MEASUREMENTS AND RESULTS: Overall ICU mortality was 44%, with significantly higher mortality in ventilated patients (74% vs. 12% in nonventilated patients, p<0.001). Overall survival for the entire group 6 months and 1 year after ICU admission was 33% and 29%, respectively. Multivariate analysis revealed mechanical ventilation and SAPS II as independent prognostic factors of both ICU mortality and long-term survival, while C-reactive protein predicted only ICU mortality. CONCLUSIONS: The outcome of patients not requiring ventilatory support in this study was encouraging, while invasive ventilation was again confirmed as predicting a dismal prognosis in this population. Efforts should be directed to avoiding this procedure by reducing the pulmonary toxicity of antineoplastic treatment and to making ventilatory support more tolerable.

Adolescent↗

PubMed2006

Polymerase chain reaction screening for fungemia and/or invasive fungal infections in patients with hematologic malignancies.

INTRODUCTION: Invasive fungal infections (IFIs) are a life-threatening complication in patients with hematologic malignancies, mainly in acute leukemia patients, following chemotherapy. IFI incidence is increasing, and associated mortality remains high due to unreliable diagnosis. Antifungal drugs are often limited by inadequate antimicrobial spectrum and side effects. Thus, the detection of circulating fungal DNA has been advocated as a rapid, more sensitive diagnostic tool. PATIENTS AND METHODS: Between June 01 and January 03, weekly blood samples (1,311) were screened from 193 patients undergoing intensive myelosuppressive or immunosuppressive therapy. IFI cases were classified according to European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Fungal DNA was extracted from whole blood and amplified using polymerase chain reaction (PCR) published primers that bind to the conserved regions of the fungal 18S rRNA gene sequence. In our study, two or more consecutive positive samples were always associated with fungal disease. RESULTS: PCR screening predicted the development of IFI to be 17 days (median). This test had a specificity of 91.1% and a sensitivity of 75%. IFI incidence was 7.8%. DISCUSSION: Therefore, our results confirm the potential usefulness of PCR serial screening and the clinical applicability in everyday routine. PCR screening offers a noninvasive repeatable aid to the diagnosis of IFI.

Adolescent↗

PubMed1987

A phase II study of (2"R)-4'-0-tetrahydropyranyladriamycin (THP) in hematological malignancies.

A phase II study of new anthracycline, THP, was conducted in 46 patients with hematological malignancies in a cooperative study. THP was given intravenously either at a dose of 13-34 mg/m2 for 3-5 consecutive days or 35-50 mg/m2 at 3-4 week intervals. Of 21 patients with acute leukemia, complete response (CR) was observed in 3 patients and partial response (PR) in 4. Of 22 patients with malignant lymphoma, CR was observed in 2 and PR in 6. The predominant toxicity was myelosuppression. Leukopenia was noted in 73% of patients and thrombocytopenia in 14%. Anorexia, nausea and vomiting were observed in 49%, 26% and 23%, respectively. Alopecia and acute cardiac toxicities were mild and recovered quickly on discontinuation of THP. Thus, THP was found to be effective for acute leukemia and malignant lymphoma.

Acute Disease↗

PubMed1988

Oral infections and septicemia in immunocompromised patients with hematologic malignancies.

To estimate the role of oral infections during septicemic episodes in immunocompromised patients with hematologic malignancies, 78 febrile episodes in 46 patients were monitored with daily clinical and microbiological investigations. The 19 septicemic episodes did not differ from the 59 other febrile episodes in the qualitative composition of the aerobic and facultatively anaerobic oral microflora or in the presence of teeth or acute oral infections on day 1. The oral prevalence rates of members of the family Enterobacteriaceae were higher on days 10, 11, and 12 in the febrile episodes with septicemia when compared with those of febrile episodes without septicemia. The prevalence of a probable oral focus in septicemia was 10.5%, and the prevalence of a probable or possible oral origin in septicemia was 31.6%. The results suggest that prevention and elimination of oral infections may reduce the morbidity and perhaps even the mortality in these patients.

Adult↗

PubMed2003

HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies.

A hematopoietic cell transplantation (HCT) approach was developed for elderly or ill patients with hematologic malignancies that employed nonmyeloablative conditioning to avoid common regimen-related toxicities and relied on graft-versus-tumor effects for control of malignancy. Eighty-nine patients, median age 53 years, were given fludarabine (90 mg/m2) and 2 Gy total body irradiation. Marrow (n = 18) or granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood mononuclear cells (G-PBMCs; n = 71) were transplanted from unrelated donors matched for human leukocyte antigen A (HLA-A), -B, -C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Donor T-cell chimerism was higher for G-PBMCs compared with marrow recipients. Durable engraftment was observed in 85% of G-PBMCs and 56% of marrow recipients. Cumulative probabilities of grade II, III, and IV acute graft-versus-host disease (GVHD) were 42%, 8%, and 2%, respectively. Nonrelapse mortality at day 100 and at 1 year was 11% and 16%, respectively. One-year overall survivals and progression-free survivals were 52% and 38%, respectively. G-PBMC recipients had improved survival (57% vs 33%) and progression-free survival (44% vs 17%) compared with marrow recipients. HLA-matched unrelated donor HCT after nonmyeloablative conditioning is feasible in patients ineligible for conventional HCT. G-PBMCs conferred higher donor T-cell chimerism, greater durable engraftment, and better progression-free and overall survivals compared with marrow.

Adolescent↗

PubMed2005

Infections of febrile neutropenic patients in malignant hematological diseases (second study period).

Sixty-one febrile episodes among 27 neutropenic patients with malignant hematological diseases were studied during a study period between 1998 and 2001. The results were compared with the previous 3-year period. The main differences in treatment were that we did not use ciprofloxacin prophylaxis routinely and we added granulocyte-macrophage colony-stimulating factor to the antimicrobial treatment regimen. The clinical and microbiological spectra of diseases shifted toward Gram-positive bacteremia and lower respiratory infections. The number and rate of infections and the mortality rate did not change significantly.

Antibiotic Prophylaxis↗

PubMed1996

Hematological malignancies in the Republic of Belarus after the Chernobyl accident.

The data on post Chernobyl hematological malignancies incidence rates in Belarus are plotted. No statistically significant increase of incidence rates in childhood is observed in contrast to adults. However, no direct association of the incidence rates with a radiation factor is discovered 10 years following Chernobyl. Some indirect correlations are found like chemical pollutions and a possible synergistic effect of the latter with ionising radiation exposure may appear as risk factors for these diseases. Adults demonstrate a significant increase of morbidity due to these malignancies after the Chernobyl disaster.

Adolescent↗

PubMed2001

[Study on hypermethylation of the calcitonin gene in malignant hematological disorders].

OBJECTIVE: To investigate the clinical significance of hypermethylation of the calcitonin (CT) gene in malignant hematological disorders (MHD). METHODS: Polymerase chain reaction (PCR) in combination with digestion of DNA with Hpa II was used to examine the methylation patterns of the CT gene in 73 patients with MHD, 6 healthy people and 24 patients with nonmalignant hematological disorders (NON-MHD). RESULTS: Hypermethylation of the CT gene occurred in 12 of 14 (85.7%) patients with acute lymphoblastic leukemia (ALL), 9 of 15 (60%) acute nonlymphocytic leukemia (ANLL), 8 of 10 (80%) chronic myelogenous leukemia (CML), 5 of 15 (33.3%) malignant lymphoma (ML), 2 of 5 patients with myelodysplastic syndrome (MDS), 1 of 2 malignant histiocytosis (MH), 1 of 3 chronic lymphocytic leukemia (CLL) and 1 of 9 multiple myeloma (MM). However, it did not occur in normal controls and NON-MHD. CONCLUSION: Hypermethylation of CT gene may serve as an important molecular maker for tumorous cell clone and may be useful in diagnosing MHD, monitoring minimal residual disease and predicting prognosis.

Calcitonin↗

PubMed2002

Administration of a phorbol ester to patients with hematological malignancies: preliminary results from a phase I clinical trial of 12-O-tetradecanoylphorbol-13-acetate.

PURPOSE: Phorbol esters are capable of inducing a broad range of cellular effects,including the maturation/differentiation of hematopoietic cell lines (E. Huberman and M. F. Callaham, Proc. Natl. Acad. Sci. USA, 76: 1293-1297, 1979; J. Lotem and L. Sachs, Proc. Natl. Acad. Sci. USA, 76: 5158-5162, 1979; G. Rovera et al., Proc. Natl. Acad. Sci. USA, 76: 2779-2783, 1979; H. P. Koeffler, J. Clin. Investig., 66: 1101-1108, 1980). The ability to induce this differentiation at very low concentrations stimulated investigators to administer a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), to patients with myeloid leukemias in the People's Republic of China (Z. T. Han et al., Proc. Natl. Acad. Sci. USA, 95: 5357-5361, 1998). The tolerability of this therapy in China prompted Phase I studies of TPA in the United States. The purpose of this report is to demonstrate the tolerance of TPA at doses that result in detectable biological activity in blood and malignant cells. EXPERIMENTAL DESIGN: TPA was administered to patients with relapsed/refractory hematological malignancies. RESULTS: Phenotypic effects were detected in malignant cells and TPA-associated biological activity was present in blood for up to several hours after the infusion. CONCLUSIONS: These studies confirm the feasibility of TPA administration to humans and establish the foundation for the development of phorbol esters as therapy for patients with a variety of malignant and nonmalignant disorders.

Adult↗

PubMed1998

Pooled analysis of p53 mutations in hematological malignancies.

A computerized database is described that contains information about 507 mutations in the p53 gene of hematologic tumors and corresponding cell lines. Analysis of these mutations indicated the following findings: First, mutational spectrum analysis in these tumors was found to be similar to the pattern found for other solid tumors. However, when the patterns of base substitutions were examined separately according to the types of hematologic malignancies, followed by subgroup analysis, notable differences (in some cases of statistical significance) emerged. Second, mutational pattern analysis indicates that about 48% of base substitutions in hematologic tumors are suspected to be associated with carcinogen exposure. Third, deletions and insertions are localized mainly to exons 5-8 and repeated DNA sequences. However, the unusual profile of variations in frequency within each type of tumor suggests that, in addition to endogenous damage to template DNA, there is the factor of exposure to environmental physical and chemical carcinogens/mutagens. Fourth, p53 protein alterations analysis indicate that most of the changes in the amino acids are "semiconservative," presumably in order to avoid disrupting the structure of the p53 monomer. Consistent with this notion, structural mutations are more conservative than the binding mutations. Finally, molecular mechanisms that lead to p53 mutations, etiological factors that play a role in their formation, and the pathophysiological significance of consequent p53 protein alterations are discussed.

Amino Acid Substitution↗

PubMed1985

Superinfections during antimicrobial treatment with betalactam-aminoglycoside combinations in neutropenic patients with hematologic malignancies.

The frequency, etiology and risk factors of superinfections during and/or within one week after antibiotic therapy with betalactam-aminoglycoside combinations were evaluated in 631 patients with hematologic malignancies admitted to the Institute of Hematology of Rome from January 1982 to December 1984. 356 patients (56%) developed 402 episodes of proven or presumed infection. Of these patients, 78 developed 102 superinfections. Overall, superinfections responded less satisfactorily to antibiotic therapy than the primary febrile episodes (63% vs. 85%). The distribution of etiologic agents of superinfections differed from those responsible for primary infections, since fungi and anaerobes (especially Clostridium difficile) were mostly isolated after antibiotic therapy had begun. Moreover, among aerobic bacteria, frequently antibiotic-resistant species, such as Pseudomonas aeruginosa, Streptococcus faecalis and Staphylococcus epidermidis were the leading etiologic agents of superinfection. The risk of superinfection appeared to increase with the depth and persistence of granulocytopenia. On the other hand, the length of hospitalization, length of previous antibiotic therapy, previous chemoprophylaxis and presence of indwelling venous catheter did not affect the risk of superinfection.

Adolescent↗

PubMed1984

Study of blood lipids in 30 children with a malignant hematological disease or carcinoma.

Levels of total lipids, cholesterol and triglycerides were followed in 30 children with malignant hematological diseases, or solid tumors; in addition, chylomicrons, VLDL, LDL and HDL were separated by electrophoresis on polyacrylamide gel. Nine of the 13 children with acute lymphoblastic leukaemia presented an increase of triglycerides and VLDL at time of diagnosis; all other parameters (cholesterol, HDL, LDL, chylomicrons) were normal. The lipid profile went back quickly to normal when hematological remission was obtained and remained stable throughout the course of the disease whatever the evolution might be. Five more patients in relapse were studied and did not present abnormalities. Similar results were obtained in 1/2 patients with acute myeloblastic leukaemia and in 3/5 patients with lymphoma. No lipid profile abnormality was observed in four patients with solid tumor and in one patient with histiocytosis X. The values of triglycerides and VLDL in pathological cases will be given. The endogenous nature of this disturbance is discussed as well as its relation with the rate of malignant lymphoid proliferation.

Apolipoproteins↗

PubMed2001

Genomic approaches to the pathogenesis of hematologic malignancy.

Recent advances in genome technologies and computational biology have facilitated genome-wide views of hematologic malignancy. In particular, comparative gene expression methods using DNA microarrays have allowed for the analysis of gene expression patterns in both primary patient material and model systems of hematopoietic development. This review provides an overview of the basic technologies underlying these approaches and provides a summary of recent progress in the genome-wide molecular classification of human acute leukemias and lymphomas and of initial attempts to define oncogene-mediated transcriptional programs using DNA microarrays.

Acute Disease↗

PubMed2001

Returning home after specialist treatment for hematological malignancies: an Australian study.

The technologically advanced and specialist nature of the treatments for patients with hematological malignancies necessitate that they are carried out in major metropolitan treating hospitals. Consequently, patients from regional, rural, and remote areas in Queensland, Australia, must relocate, often for lengthy periods of time, for treatment. To date, there has been scant research carried out on what happens to these patients and their families when they return home after such intensive treatments in the metropolitan centers. This article documents recent, seminal work in this area. The findings indicate that these families have many emotional, medical, and practical needs. These needs change over time, depending on the trajectory of the illness.

Aftercare↗

PubMed2005

[Study on DNA methylation status of WT1 gene in its promoter region in hematologic malignancy cell lines].

OBJECTIVE: To study the DNA methylation status of WT1 gene promoter region in hematologic malignancy cell lines and its correlation with WT1 gene expression. METHODS: 1. RT-PCR and methylation-specific PCR were performed for detecting WT1 gene expression and DNA methylation status in its promoter region in 8226, HL-60, Jurkat, K562, KG-1, NB4, Raji, SHI-1, U266 and U937 cell lines. 2. Treatment of U937 cells with 5-aza-CdR, a demethylation inducing agent and the changes in WT1 gene expression level and its promoter region methylation status were determined. RESULTS: 1. HL-60, K562, KG-1, NB4 and SHI-1 cells showed higher levels while 8226, Jurkat, Raji, U266 and U937 cells showed extremely low levels of WT1 expression. DNA hypermethylation in WT1 gene promoter region was identified in 8226, Jurkat, Raji, U266 and U937 cells. 2. The WT1 gene expression in U937 was enhanced after treatment with 5-aza-CdR accompanied with the decrease of methylated and the increase of unmethylated levels in its promoter region. CONCLUSION: Modulation of the DNA methylation status in WT1 promoter region is one of the epigenetic mechanisms for regulating its expression.

Cell Line, Tumor↗