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PubMed2004

Epigenetic inactivation of tumor suppressor genes in hematologic malignancies.

A number of genetic alterations are involved in the development of hematologic malignancies. These alterations include the activation of oncogenes by chromosomal translocation or gene amplification and the inactivation of tumor suppressor genes by gene deletion or mutations. Recently, epigenetic change has been proven to be another important means of inactivating tumor suppressor genes in tumor cells, and hypermethylation of promoter DNA is one of the most important mechanisms. In hematologic malignancies, many kinds of tumor suppressor genes and candidate suppressor genes are epigenetically inactivated. Inactivation of tumor suppressor genes usually occurs in a disease-specific manner and plays important roles in the development and progression of the disease. Some of these alterations have clinical effects on treatment results or the prognoses of the patients.

Animals↗

PubMed2001

The vascular endothelial growth factor (VEGF) signaling pathway: a therapeutic target in patients with hematologic malignancies.

Angiogenesis is an important component in the progression and metastasis of solid tumors. We now appreciate that angiogenesis is also critically involved in the pathogenesis of hematologic malignancies. Current data suggest important prognostic and therapeutic implications of angiogenesis in a variety of malignancies of the hematopoietic system, including acute and chronic leukemias, myeloproliferative diseases, multiple myeloma, non-Hodgkin's lymphomas, and Hodgkin's disease. Vascular endothelial growth factor (VEGF) is a major angiogenic factor that regulates multiple endothelial cell functions, including mitogenesis. Cellular and circulating levels of VEGF are elevated in hematologic malignancies and are adversely associated with prognosis. Angiogenesis is a very complex, tightly regulated, multistep process, the targeting of which may well prove useful in the creation of novel therapeutic agents. Current approaches being investigated include the inhibition of angiogenesis stimulants (e.g., VEGF), or their receptors, blockade of endothelial cell activation, inhibition of matrix metalloproteinases, and inhibition of tumor vasculature. Preclinical, phase I, and phase II studies of both monoclonal antibodies to VEGF and blockers of the VEGF receptor tyrosine kinase pathway indicate that these agents are safe and offer potential clinical utility in patients with hematologic malignancies.

Angiogenesis Inhibitors↗

PubMed1999

Treatment with interleukin-2 (IL-2) and interferon (IFN(alpha 2b)) after autologous bone marrow or peripheral blood stem cell transplantation in onco-hematological malignancies with a high risk of relapse.

Nine patients with onco-hematological malignancies with a poor prognosis due to high risk of relapse received immunotherapy with interleukin-2 (IL-2) and interferon (IFN(alpha 2b)) s.c. as maintenance therapy after receiving autologous bone marrow or peripheral blood stem cell transplantation (ABMT/PBSCT). All the patients were considered at very high risk of relapse. We attempted to assess the efficiency, toxicity and clinical effects of these cytokines in these patients. Five patients were treated with high-dose of IL-2 and the other four patients with escalating doses every month. Side-effects in the first group of patients consisted of fever, chills, weakness, nausea, anorexia, loss of weight and local dermatitis in the injection site. Toxicity on the WHO scale was grade II in three patients and grade IV in the other two patients. In the second group of patients, the same clinical signs of toxicity appeared, but these were grade I on the WHO scale in all patients. None of the patients had infections or died in relation to administration of IL-2. Four patients died of relapse or progression of their hematological malignancies. The other five patients are alive, one in chronic phase of CML and the other four patients are in complete remission of their malignancies.

Adult↗

PubMed2002

Low-dose total body irradiation followed by allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy.

Allogeneic stem cell transplantation is curative for certain cancers, but the high doses of chemotherapy/radiotherapy lead to toxicity. Here, we treat patients with refractory cancer with 100 cGy total body irradiation (TBI) followed by infusion of nonmobilized pheresed allogeneic peripheral blood cells. Twenty-five patients, with a median age of 47 years, with refractory cancers were enrolled. Eighteen patients received sibling and 7 received unrelated cord blood cells. Donor chimerism was assessed at weeks 1, 2, 3, 4, and 8 after transplantation. Seven patients with solid tumors received a sibling transplant and 6 received a cord blood transplant; none achieved donor chimerism, but 1 treated at the higher dose level of 1 x 10(8) CD3+ cells/kg had a transient nodal response. Twelve patients with hematologic malignancies were treated; 1 received a cord blood transplant and 11 received sibling donor cells. Nine of these 11 patients achieved donor chimerism, ranging from 5% to 100%. Four patients had sustained complete remission of their cancers, including one patient with transient 5% donor chimerism. The development of chimerism correlated with hematologic malignancy (P <.001), total previous myelotoxic chemotherapy (P <.001), T-cell dose (P =.03), and graft-versus-host disease (P =.01). Tumor response correlated with donor chimerism (P =.01). Engraftment was achieved in patients with hematologic malignancies who had been heavily pretreated, suggesting the degree of immunosuppression may be a determinant of engraftment. Low-dose TBI and allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy.

Adult↗

PubMed1989

Effect of chemotherapy on dental maturity in children with hematological malignancies.

Dental maturity or dental age was determined in 44 children with hematological malignancies treated with chemotherapy. No significant difference was observed between the chronological and dental age in children treated with chemotherapy compared to healthy controls. With regard to the number of erupted permanent teeth, no significant differences could be found between the two groups. The results indicate that chemotherapy given to children with hematological malignancies did not interfere with dental maturity or eruption of permanent teeth.

Adolescent↗

PubMed2005

Prevention of hepatitis B reactivation with lamivudine in hepatitis B virus carriers with hematologic malignancies treated with chemotherapy--a prospective case series.

Administration of immunosuppressive treatment in hepatitis B virus carriers with malignancies is associated with the risk of hepatitis B reactivation. This complication is more frequent in patients with hematologic malignancies because administration of corticosteroids, the mainstay of treatment of these patients, is an independent risk factor for hepatitis B reactivation. When lamivudine is given prior to chemotherapy, it prevents the viral replication during the immunosuppression period; therefore, it might reduce the risk of hepatitis B exacerbation. We performed a prospective study to assess the efficacy of prophylactic administration of lamivudine in this setting. Ten hepatitis B virus carriers with hematologic malignancies were included in this study; seven were HBsAg positive, and three had isolated antiHBc and detectable HBV-DNA levels. Nine patients were given corticosteroids after the administration of lamivudine. Lamivudine was given per os at a dose of 100 mg once daily. In four patients that had not been previously treated with chemotherapy, lamivudine was started 19 days (median) (range, 0-35 days) prior to the onset of chemotherapy. The administration of lamivudine has not stopped since in any of our patients. After a median follow-up of 15 months (range 6-38 months), no hepatitis B reactivation was observed. HBV-DNA levels were decreased in all 6 patients who had detectable HBV-DNA at baseline. Lamivudine was well tolerated. Chemotherapy regimens were administered as planned, and their effectiveness was not compromised by lamivudine. In conclusion, prophylactic administration of lamivudine should be considered as a means of reducing the frequency of hepatitis B reactivation in hepatitis B virus carriers with hematologic malignancies who are being treated with chemotherapy.

Adrenal Cortex Hormones↗

PubMed1994

Incidence and clinical significance of positive blood cultures in febrile episodes of patients with hematological malignancies.

The characteristics of 554 febrile episodes in 126 patients with a hematological malignancy over a 6-year period (1985-90) were reviewed in order to study the current incidence and clinical significance of blood culture positivity. An infection was documented microbiologically in 28% and clinically in 30% of the episodes. Blood cultures were positive in 19% of the febrile episodes. The rate of blood culture positivity was unrelated to the type of hematological malignancy, to neutropenia and to the presence of infection foci. 21% (26/126) of the patients died of sepsis-related causes. Sepsis-related death occurred in 23% of the blood culture positive febrile episodes, with a median survival time of 2 days. Infection prophylaxis did not reduce either the rate of blood culture positivity or the rate of sepsis-related deaths. Thus, the small proportion of febrile episodes whose fever etiology could be established by blood culture represented 'the tip of the iceberg', i.e. rapidly lethal septic infections with a high mortality rate. This fatality could neither be predicted by a search for infection foci nor prevented by infection prophylaxis.

Adult↗

PubMed2002

Report of the fifteenth international symposium of the foundation for promotion of cancer research: new horizons in the diagnosis and treatment of hematological malignancies based on molecular genetic features.

The Fifteenth International Symposium of the Foundation for Promotion of Cancer Research entitled 'New Horizons in the Diagnosis and Treatment of Hematological Malignancies Based on Molecular Genetic Features' was held in Tokyo on January 15-17, 2002. Twenty-nine invited speakers, including 12 from abroad and 17 from Japan, presented the updated results of their research. After an overview of the classification of hematological malignancies, new findings on some disease entities based on novel immunophenotypic and molecular genetic features were presented. The results of gene expression profiling and BCL6 and C-MYC gene rearrangement in diffuse large B-cell lymphoma were presented and oncogenic mechanism of acute myeloid leukemia was discussed. In the treatment of non-Hodgkin's lymphoma and acute leukemia, the present consensus and future directions were discussed based on the results of multicenter trials in the USA and Japan. As a molecular targeting therapy, the remarkable effect of a BCR-ABL tyrosine kinase inhibitor, STI571, in chronic myeloid leukemia and gastrointestinal stromal tumor was presented. Thereafter, promising results of active immunotherapy, chimeric anti-CD20 monoclonal antibody, anti-CD20 radioimmunoconjugate and anti-CD22 immunotoxin for B-cell lymphoma were presented. Finally, recent advances in allogeneic hematopoietic stem cell transplantation were discussed, focusing on reduced-intensity preparative regimens. The recent advances in basic and clinical research on hematological malignancies would lead to further improvement in the prognosis and quality of life of patients suffering from leukemia or lymphoma.

Biomedical Research↗

PubMed2006

Concurrent FSGS and Hodgkin's lymphoma: case report and literature review on the link between nephrotic glomerulopathies and hematological malignancies.

BACKGROUND: The link between the nephrotic syndrome (NS) and malignancy was first described in 1922. In solid tumors, the NS is most often due to membranous glomerulonephropathy, whereas in common hematological malignancies, minimal-change disease predominates. Focal segmental glomerulosclerosis (FSGS) is among the least frequently reported renal lesion associated with malignancy. METHODS: We report a case of the simultaneous diagnoses of FSGS and Hodgkin's lymphoma, and review the literature on various nephrotic glomerulonephropathies associated with common leukemia and lymphoma. RESULTS: Although nephrotic glomerulonephropathies rarely occur in association with acute leukemia, they have often been described in chronic lymphocytic leukemia (CLL). Membranoproliferative glomerulonephropathy and membranous glomerulonephropathy are the most common lesions observed in CLL. Nephrotic glomerulonephropathies have also been well documented among patients with lymphomas, in particular, Hodgkin's lymphoma. While minimal-change disease is most commonly found in association with Hodgkin's lymphoma, more diverse and complex renal lesions are associated with non-Hodgkin's lymphoma. FSGS remains a rare association with hematological malignancies. CONCLUSIONS: Nephrotic glomerulonephropathies are not only linked to solid-organ tumors, but also to hematological malignancies. A thorough evaluation, including a physical examination for lymphadenopathy and organomegaly, as well as a hematological evaluation, must be performed in all patients presenting with nephrotic glomerulonephropathies.

Adult↗

PubMed2006

Changes in severity and organ failure scores as prognostic factors in onco-hematological malignancy patients admitted to the ICU.

OBJECTIVE: To determine whether severity and organ failure scores over the first 3 days in an ICU predict in-hospital mortality in onco-hematological malignancy patients. DESIGN AND SETTING: Retrospective study in a 22-bed medical ICU. PATIENTS: 92 consecutive patients with onco-hematological malignancies including 20 hematopoietic stem cell transplantation (HSCT) patients (11 with allogenic HSCT). MEASUREMENTS: Simplified Acute Physiology Score (SAPS) II, Organ Dysfunction and/or Infection (ODIN) score, Logistic Organ Dysfunction System (LODS), and Sequential Organ Failure Assessment (SOFA) score were recorded on admission. The change in each score (Delta score) during the first 3 days in the ICU was calculated as follows: severity or organ failure score on day 3 minus severity or organ failure score on day 1, divided by severity or organ failure score on day 1. RESULTS: In-hospital mortality was 58%. Using multivariate analysis in-hospital mortality was predicted by all scores on day 1 and all Delta scores. Areas under the receiver operating characteristics curves were similar for SAPS II (0.78), ODIN (0.78), LODS (0.83), and SOFA (0.78) scores at day 1. They were also similar for DeltaSAPS II, DeltaODIN, DeltaLODS, and DeltaSOFA. Similar results were observed when excluding patients with allogenic HSCT. CONCLUSION: Severity and three organ failure scores on day 1 and Delta scores perform similarly in predicting in-hospital mortality in ICU onco-hematological malignancy patients but do not predict individual outcome. Decision to admit such patients to the ICU or to forgo life-sustaining therapies should not be based on these scores.

Female↗

PubMed2004

Risk assessment of patients with hematologic malignancies who develop fever accompanied by pulmonary infiltrates: a historical cohort study.

BACKGROUND: The mortality rate associated with fever accompanied by pulmonary infiltrates after chemotherapy for hematologic malignancies remains higher than the corresponding rate associated with febrile neutropenia without pulmonary infiltrates. Nonetheless, few studies have focused on the factors that predict outcome for patients with lung infiltrates. The purpose of the current study was to construct a risk model for clinical use by assessing the factors that affect outcome for patients with fever and pulmonary infiltrates. METHODS: A historical cohort of 110 patients with hematologic malignancies who developed fever and pulmonary infiltrates was examined. Using parameters for which data were available at the onset of lung infiltrates, univariate and multivariate analyses were performed to assess factors affecting outcome. After a value of one point was assigned to each significant variable, a prediction score was calculated for each patient; scores were used to generate a system for identifying patients with a low risk of death due to fever accompanied by pulmonary infiltrates. RESULTS: The crude mortality rate associated with pulmonary infiltrates was 23%; factors associated with cure included a favorable change in white blood cell counts (odds ratio [OR], 5.6; 95% confidence interval [CI], 1.7-18.9; P = 0.001), C-reactive protein levels < 10 mg/dL (OR, 4.6; 95% CI, 1.6-13.8; P = 0.001), and serum albumin levels > or = 3 g/dL (OR, 3.2; 95% CI, 1.4-7.3; P = 0.004). Low-risk patients (risk score, 2-3) and high-risk patients (risk score, 0-1) had survival rates of 95% and 46%, respectively (P < 0.0001). The risk model had a specificity of 88% and a positive predictive value of 95%. CONCLUSIONS: The risk model tested in the current study accurately predicted the survival of patients with hematologic malignancies who developed fever with pulmonary infiltrates. Once prospectively validated, the model could be used to select patients for trials involving novel diagnostic and therapeutic strategies.

Age Distribution↗

PubMed2006

[Unrelated donor peripheral blood stem cell transplantation for hematologic malignancies].

This study was aimed to explore feasibility and efficacy of unrelated donor peripheral blood stem cell transplantation (UD-PBSCT) in treatment of hematologic malignancies. Ten patients with hematologic malignancies underwent high resolution DNA based typing HLA-matched or 1 locus mismatched UD-PBSCT. Busulfan, cyclophosphamide, Ara-C, MeCCNU and antithymocyte globulin (ATG) were used for preconditioning regimen in all cases. All patients received mycophenolate mofetile, cyclosporin A and short-term methotrexate with CD25 antibody as the graft-versus-host disease (GVHD) prophylaxis. The results showed that rapid engraftment was observed in all cases who presented full donor chimerism at 28 days post transplantation by STR-PCR. The median time of neutrophil recovery > 0.5 x 10(9)/L, platelet recovery > 20 x 10(9)/L was 13, 17.5 days respectively after transplantation. The incidence of acute GVHD was 3 cases (one case with grade I was recovered from GVHD by himself, one case with grade III was cured, one case with grade VI was died). It is concluded that above-mentioned preconditioning regimen and GVHD prophylaxis are effective approaches for unrelated donor peripheral blood stem cell transplantation in hematopoietic malignancies.

Adolescent↗

PubMed1999

Fluconazole versus amphotericin B for the prevention of fungal infection in neutropenic patients with hematologic malignancy.

Effective prophylaxis against fungal infection is important in neutropenic patients with hematologic malignancies, but the best method remains unclear. We investigated the effectiveness of fungal prophylaxis with amphotericin B or fluconazole. We reviewed the data on fungal isolates, plasma (1-->3)-beta-D glucan (beta-D glucan) levels, febrile periods (the number of days with an axillary temperature > 38 degrees C), and the duration of an axillary temperature > 38 degrees C when the neutrophil count was < 500/microliter. Of the 124 patients studied, 57 had acute myelogenous leukemia, 19 had acute lymphoblastic leukemia, 18 had non-Hodgkin's lymphoma, six had chronic myeloid leukemia, three had adult T-cell leukemia, and five had chronic lymphocytic leukemia. There were no significant differences in clinical characteristics between the 70 patients treated with amphotericin B and the 54 patients given fluconazole. There was a significant decrease of fungal isolates (chi 2-test, p < 0.001), the plasma beta-D glucan level (Wilcoxon test, p = 0.0001), and the febrile period (t-test, p < 0.05) in the patients given fluconazole compared with those given amphotericin B. In neutropenic patients with hematologic malignancies, prophylaxis with fluconazole significantly decreased fungal isolation and other indicators of fungal infection when compared with amphotericin B. Fluconazole may therefore be more effective for fungal prophylaxis in these patients.

Adolescent↗

PubMed2006

Is there a role for inhaled nitric oxide as a rescue therapy in respiratory failure associated with hematologic malignancies?

Inhaled nitric oxide has been demonstrated to improve oxygenation in critically ill patients requiring mechanical ventilation. We therefore performed a retrospective review to determine the outcome of patients with hematological malignancies and acute respiratory failure who received inhaled nitric oxide (INO) in a multidisciplinary intensive care unit of a single tertiary referral medical center. Thirteen patients with hematological malignancies who required endotracheal intubation and mechanical ventilation and received INO for acute respiratory failure between January 1998 and December 2002 were identified. Mean +/- standard deviation (SD) age was 47.6 (+/-13.2) years. The mean +/- SD Acute Physiology and Chronic Health Evaluation (APACHE) III score on the day of ICU admission was 94.1 +/- 33.7 with a mean (SD) predicted probability of ICU death of 42.4% (+/-28.6). Mean APACHE III score on the day of initiating INO was 107.6 (+/-34.4) with a predicted mortality in the intensive care unit of 72.7% (+/-23.3). Mean PaO(2) to FiO(2) (PF) ratios (+/-SD) prior to, and immediately after, the initiation of INO were 62.6 (+/-28.2) and 111 (+/-65.1), respectively (P < 0.001). The median duration of INO therapy was 41.8 h (interquartile range, 6.3-98.2). Patients with hematological malignancies and acute respiratory failure to whom INO was administered had clinical deterioration since ICU admission. Despite a marked initial improvement in arterial oxygen tension, all patients ultimately died in the intensive care unit, 8 of them within 48 h of initiating INO. Therefore, despite initial improvement in oxygenation, we did not observe any survival benefit to INO in this setting.

APACHE↗

PubMed2005

Coccidioidomycosis in patients with hematologic malignancies.

BACKGROUND: An endemic fungal infection of the desert southwestern United States, coccidioidomycosis is generally a self-limited illness in healthy persons. Immunosuppressed persons who contract coccidioidomycosis, however, are at increased risk for disseminated infection. METHODS: We conducted a retrospective review of patients with coccidioidomycosis and hematologic malignancy or bone marrow disease. RESULTS: Fifty-five patients were identified. The most common underlying malignancies were non-Hodgkin lymphoma and chronic lymphocytic leukemia. Extrathoracic (or disseminated) infection was observed in 12 patients (22%). Fifteen patients (27%) died with active coccidioidomycosis. Treatment of the hematologic disease with corticosteroids or antineoplastic chemotherapy increased the risk of death. CONCLUSION: To date, this is the largest case series of patients with hematologic malignancy and coccidioidomycosis. In persons with hematologic malignancy, coccidioidomycosis can be a severe illness with a high risk for disseminated infection and death.

Adrenal Cortex Hormones↗

PubMed1995

Ten-year survey of incidence of infection as a cause of death in hematologic malignancies: study of 90 autopsied cases.

We investigated 90 autopsied cases with hematologic malignancy, including malignant lymphoma (ML), acute leukemia (AL), and adult T-cell leukemia (ATL) peculiar to our district, during the 10-year period 1982-1991 to determine the change in incidence of infection as a cause of death. We divided the cases into two groups representing the first half decade (1982-1986) and the second half decade (1987-1991) and compared the findings made in the two groups. Although infection was the major cause of death in those autopsied cases, the incidence of fatal infections decreased during the latter period. The incidence of fatal bacterial infections decreased, while fungal infections showed a relative increase. Pneumocystis carinii pneumonia and cytomegalovirus (CMV) infection occurred more frequently in patients with ATL than in those with ML or AL. Combined infection by more than three pathogens was observed in 2 cases of ATL. Our study revealed the characteristics of ATL specific to our district, and indicated the need to apply new strategies to prevent and treat fungal and viral infections in patients with hematologic malignancies.

Acute Disease↗

PubMed1981

Splenic rupture in patients with hematologic malignancies.

Five cases of pathologic rupture of the spleen in patients with hematologic malignancy are presented along with a review of the 48 cases previously described in the English literature. Pathologic splenic rupture occurred most commonly in patients with acute leukemia but has been well documented in chronic leukemias and in lymphoma as well. Nearly all patients experience abdominal pain at the time of rupture; however, this pain was frequently confused clinically with that of biliary tract obstruction, aortic aneurysm, perforated viscus, pancreatitis, and angina pectoris. Pain referred to the left shoulder (Kehr's sign) was present in only 17% of patients. Hypotension was documented in 66%, fever in 74%, and tachycardia in 75%. The most effective diagnostic procedure was paracentesis, which confirmed intraabdominal hemorrhage in each of the nine cases in which the procedure was used. A correct preoperative diagnosis of splenic rupture was reported in only 10 of the 53 cases reviewed. Fifty-two percent of the patients underwent laparotomy; 48% died without operation. Of those that underwent surgery, 78% survived the procedure and the immediate postoperative period. The survival rate of all patients was 38%. There was no correlation of the type of hematologic malignancy, occurrence or type of treatment, peripheral blood counts, or spleen size to survival. The most important factor in predicting survival was appropriate surgery.

Adult↗

PubMed1990

[Second neoplasms in malignant hematologic disorders. Experience from 1978 to 1987].

Neoplasia may develop in patients with malignant hematologic disorders, during remission after radio and/or chemotherapy. A multifactorial origin related to therapy may be postulated. From 1978 to 1987, among 142 patients with malignant hematologic disorders (Hodgkin lymphoma 33, non-Hodgkin lymphoma 51, Multiple Myeloma 35 and Chronic Myeloid Leukemia 31) we observed 3 patients developing another neoplasia. An additional patient with acute non-lymphatic leukemia had been submitted to chemotherapy for gastric cancer. Four other patients with double neoplasia, one of them a hematologic one, had not been submitted to chemotherapy. The lack of national registries for neoplastic diseases precludes an estimation of the odd ratios involved in our findings.

Adolescent↗