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PubMed2002

Angiogenesis in hematologic malignancies and its clinical implications.

Angiogenesis is defined as a neoformation of blood vessels of capillary origin. Hematopoiesis is closely linked with angiogenesis, for they share a common ancestor, the hemangioblast. Although it is well established that growth in solid tumors is dependent on angiogenesis, its role in hematologic malignancies has not yet been clarified. In this review, the direct evidence, ie, increased microvessel density, and the indirect evidence, ie, elevated level of angiogenic factors or overexpression of messenger RNA or protein of angiogenic factors, for and against the role of angiogenesis in the development and progression of hematologic malignancies are presented.

Angiogenesis Inhibitors↗

PubMed1992

[Abnormalities of the retinoblastoma susceptibility gene (RB) in hematologic malignancies].

The retinoblastoma susceptibility gene (RB) is expressed in all lineages of normal hematopoietic cells and plays an important role in controlling cell cycle progression at G1/S. Abnormalities of the RB gene may, therefore, predispose to the development of hematologic malignancies. DNA rearrangement was reported to be present in 1.5-12.1% of cases with primary leukemias and the absence of the RB gene product was also observed in 6.3-23.2%. The abnormalities were frequently observed in blastic crisis of CML, especially of the megakaryoblastic phenotype, AML with monocytic differentiation and Ph1-positive leukemias. These results indicate that abnormalities of RB are relatively common in hematologic malignancies and loss of RB function may contribute to the altered growth of these cells.

Blast Crisis↗

PubMedDate not supplied

Cardiac troponin I in patients with hematologic malignancies.

BACKGROUND: The cardiac isoform of troponin I (cTnI) is a myofibrillar protein highly specific for myocardial injury. We used a recently developed new-generation immunoassay with high analytical sensitivity to measure cTnI in patients diagnosed with hematologic malignancies, before chemotherapy and after an intermediate cumulative dose of anthracyclines. We hypothesized that measurement of cTnI with this sensitive method would provide evidence of myocardial injury in these patients. METHODS: Sera from 115 individuals (60 healthy controls, 25 anthracycline-naive patients and 30 patients treated with intermediate cumulative doses of anthracyclines) were assessed for cTnI, creatine kinase MB (CKMB) mass and myoglobin. Radionuclide left ventricular ejection fraction (LVEF) was also determined. RESULTS: Using this sensitive assay, detectable concentrations of cTnl were measured in the healthy population [mean, 19.5 pg/ml, 95% confidence interval (CI) 13.5-25.5 pg/ml]. Anthracycline-naive patients had cTnI mean values (36.5 pg/ml, 95% CI 25.1-47.9 pg/ml) that were significantly (P < 0.01) greater than those in the control group. cTnI was significantly (P < 0.00001) increased in anthracycline-treated patients (76.4 pg/ml, 95% CI 67.0-85.8 pg/ml) compared with both the anthracycline-naive patients and the controls. CKMB, myoglobin and LVEF were within the normal range in all patients. CONCLUSIONS: These data provide evidence for cardiac involvement in patients with hematological malignancies before and during the course of anthracycline chemotherapy. They suggest that detection of myocardial injury may be facilitated by measurement of cTnI with a highly sensitive assay.

Adult↗

PubMed1998

Analysis of the Smad2 gene in hematological malignancies.

A total of 34 leukemia and lymphoma samples (17 clinical samples and 17 cell lines) were analyzed for mutations of the Smad2 gene by reverse transcriptase-polymerase chain reaction single strand conformation polymorphism (RT-PCR-SSCP) analysis. Nine of the 34 samples had 18q chromosomal abnormalities. No shifted bands were detected in any of the hematological malignancies. Our results suggest that resistance to cell growth inhibitory effects of TGF-beta in hematological malignancies is not due to alterations of the Smad2 gene.

Adolescent↗

PubMed1999

Bacteremia by gram-negative bacilli in patients with hematologic malignancies. Comparison of the clinical presentation and outcome of infections by enterobacteria and non-glucose-fermenting gram-negative bacilli.

To compare the characteristics of bacteremic infections by different aerobic gram-negative bacilli (GNB) in patients with hematologic malignancies, we studied 54 consecutive monomicrobial bacteremias by Enterobacteriaceae (EB), 15 by Pseudomonas aeruginosa, 43 by other non-glucose-fermenting GNB (NGFGNB) and 11 by other GNB. Patients with EB and P. aeruginosa bacteremia usually developed the infection after intensive chemotherapy for leukemia or during a hematopoietic stem cell transplantation, while most infections in outpatients off therapy were due to NGFGNB. A significant proportion of bacteremias by EB (37%) and P. aeruginosa (40%) were accompanied by severe morbidity (septic shock, pneumonia or deep-seated organ infections) vs. only 7% of other NGFGNB (p < 0.01). Most infections by these latter bacteria were catheter-related bacteremias (80 vs. 2% of EB, p < 0.005), while most EB infections (61%) were uncomplicated bacteremias of unknown source (vs. 14% of other NGFGNB, p < 0.005). Appropriate antibiotics alone cured 98% of EB and 73% of P. aeruginosa bacteremias but only 26% of other NGFGNB (p < 0.005 for both differences), which were cured by catheter removal in 70%, usually after failure of antibiotic treatment. In conclusion, our results suggest that there are significant differences in the patient populations and clinical characteristics of bacteremic infections by the classic GNB (EB and P. aeruginosa) and the new NGFGNB in adults with hematologic malignancies.

Adolescent↗

PubMed2000

Splenic rupture in children with hematologic malignancies.

BACKGROUND: Splenic rupture is an uncommon but life-threatening complication of leukemias and lymphomas, and is reported mostly in adults. The authors investigated the frequency with which splenic rupture is diagnosed in pediatric patients with hematologic malignancies and reviewed its clinical profile and outcome. METHODS: The data base of St. Jude Children's Research Hospital was searched for cases coded as splenic laceration or rupture, splenic infarction, or splenectomy in patients diagnosed with lymphoma or leukemia between January 1962 and December 1997. The medical records of patients with histopathologic or radiologic evidence of splenic rupture were reviewed. The time spanned by the study was divided into early (1962-1990) and recent (1991-1997) eras to reflect the availability of modern diagnostic imaging techniques. RESULTS: Seven children experienced splenic rupture. They were between ages 5-17 years. There were four males and three females. Primary diagnoses included acute myeloid leukemia (four patients), acute lymphoblastic leukemia (two patients), and Hodgkin lymphoma (one patient). Five patients were diagnosed in the recent era and two in the early era. Four patients had radiologic or bacteriologic evidence of fungal infection concomitant with the splenic event. Of five deaths, only two were related causally to splenic rupture; these occurred in the early era. All seven acute episodes of splenic rupture were managed conservatively without surgery. CONCLUSIONS: The overall frequency with which splenic rupture was detected in children with hematologic malignancy at the study institution was 0.18%. In the recent era, the frequency of detection was 9-fold higher (0.55%) than that of the early era (0.06%). Improved imaging techniques and increased utilization of imaging studies may account for the increased incidental detection of "preclinical" splenic rupture. Adolescent age group, acute myeloid leukemia (especially acute promyelocytic leukemia), a high leukocyte count, thrombocytopenia, and coagulopathy may predispose children with leukemia to pathologic splenic rupture. Fungal infection frequently was associated with splenic rupture and may play a role in its pathogenesis.

Adolescent↗

PubMed2002

Microsatellite instability in hematological malignancies.

The replication error (RER+) phenotype, characterized by microsatellite instability (MSI) has been recently related to mutations of genes involved in DNA mismatch repair pathway. These genetic alterations were first described in hereditary non polyposis colorectal cancer (HNPCC). We examined 44 patients with hematological malignancies (27 AML, 9 MDS, 2 CML-BP and 6 T-ALL) for evidence of MSI. Twenty seven percent of our patients showed differences for only one marker. In four cases (9.1%) MSI was observed in multiple markers and these cases were described as RER+ phenotype. Presented data suggest that this phenomenon may play a role in at least a subset of patients with hematological malignancies.

Adolescent↗

PubMed1999

Use of amifostine in hematologic malignancies, myelodysplastic syndrome, and acute leukemia.

The phosphorylated thiol amine, amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA), is a cytoprotective agent for cisplatin-based chemotherapy. Recent investigations have given rise to new potential applications of amifostine in hematologic malignancies. Amifostine appears to exert a sustained mitogenic effect in primitive hematopoietic progenitors that results in a significant increase in colony-forming capacity. Amifostine also retards cell loss and delays commitment to apoptosis initiated by cytokine deprivation, suggesting that amifostine has trophic effects similar to the hematopoietic cytokines. The abilities to prolong progenitor survival and to delay apoptosis under conditions of cellular stress make amifostine an attractive agent for investigation in bone marrow failure states. Amifostine promotes more effective hematopoiesis in patients with myelodysplastic syndrome, although additional investigation is needed to further define the optimal dose and schedule of administration. Furthermore, amifostine may selectively enhance the cytotoxicity of chemotherapeutic agents in leukemia progenitors. When the sensitivity of leukemic and normal progenitors to mafosfamide was evaluated with and without amifostine pretreatment, amifostine effectively protected normal myeloid and erythroid progenitors while increasing leukemic cell kill. Thus, amifostine represents a unique agent with promising potential for therapeutic application in hematologic malignancies. Further investigation is needed to define its role in clinical practice.

Acute Disease↗

PubMed2000

Prospective randomized comparison of single-dose versus hyperfractionated total-body irradiation in patients with hematologic malignancies.

PURPOSE: Fractionated total-body irradiation (HTBI) is considered to induce less toxicity to normal tissues and probably has the same efficacy as single-dose total-body irradiation (STBI) in patients with acute myeloid leukemia. We decided to determine whether this concept can be applied to a large number of patients with various hematologic malignancies using two dissimilar fractionation schedules. PATIENTS AND METHODS: Between December 1986 and October 1994, 160 patients with various hematologic malignancies were randomized to receive either a 10-Gy dose of STBI or 14.85-Gy dose of HTBI. RESULTS: One hundred forty-seven patients were assessable. The 8-year overall survival rate and cause-specific survival rate in the STBI group was 38% and 63.5%, respectively. Overall survival rate and cause-specific survival rate in the HTBI group was 45% and 77%, respectively. The incidence of interstitial pneumonitis was similar in both groups. However, the incidence of veno-occlusive disease (VOD) of the liver was significantly higher in the STBI group. In the multivariate analysis with overall survival as the end point, the female sex was an independent favorable prognostic factor. On the other hand, when cause-specific survival was considered as the end point, the multivariate analysis demonstrated that sex and TBI were independent prognostic factors. CONCLUSION: The efficacy of HTBI is probably higher than that of STBI. Both regimens induce similar toxicity with the exception of VOD of the liver, the incidence of which is significantly more pronounced in the STBI group.

Adolescent↗

PubMed2003

Pulmonary side effects of interferon-alpha therapy in patients with hematological malignancies.

Several side effects of interferon-alpha-2b (IFN-alpha) therapy have been described. Pulmonary side effects have seldom been reported. The four patients we describe all developed respiratory disorders while being treated with IFN-alpha for hematological malignancies. We point out the similarities and differences noticed concerning the clinical course, pathological findings, and prognosis in the four different cases. Also, in addition to our review of the literature, we discuss the possible mechanisms involved in development of lung symptoms. In three patients the pulmonary disorder seems to have been caused by a cell-mediated immunological side effect in the form of interstitial pneumonitis. In one patient the symptoms were most likely caused by an autoimmunologic reaction, primarily engaging the vascular system, initially in the lungs. The single pathological finding existing in all four cases was the marked decrease in carbon monoxide diffusion capacity when performing spirometry. This was not necessarily associated with the existence of radiological findings. The decrease in diffusion capacity and the clinical symptoms were completely reversible in three of the patients, either spontaneously after the withdrawal of IFN-alpha or after treatment with corticosteroids. Our conclusion is that IFN-alpha, on rare occasions, can cause serious pulmonary side effects when used to treat both lympho- and myeloproliferative hematological malignancies. When pulmonary symptoms are evaluated during IFN-alpha therapy, spirometry, including estimation of carbon monoxide diffusion capacity, high-resolution computerized tomography, and ultracardiography should be used.

Adult↗

PubMed2006

The JAK-STAT pathway: a therapeutic target in hematological malignancies.

The development and function of hematopoietic cells depends on complex signaling pathways that are mediated by numerous cytokines and their receptors. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is prominent both in normal hematopoiesis and in hematological malignancies. STATs are phosphorylated on tyrosine residues via JAK kinases and on serine residues by a variety of serine/threonine kinases. STATs then dimerize, translocate to the nucleus and bind DNA, initiating the transcription of target genes. STAT proteins mediate cell growth, differentiation, apoptosis, transformation, and other fundamental cell functions. Recently, mutations in the JAK2 gene driving the proliferation of the neoplastic clone have been identified in myeloproliferative disorders. In addition constitutive activation of the JAK-STAT pathway has been reported in various types of leukemias such as acute myelogenous leukemia, T-LGL leukemia, and multiple myeloma. This review describes the pathophysiological role of this pathway in hematological malignancies and the potential benefits of JAK-STAT inhibition.

Animals↗

PubMed2005

Control of bleeding caused by thrombocytopenia associated with hematologic malignancy: an audit of the clinical use of recombinant activated factor VII.

This paper presents an analysis of 24 cases in which recombinant factor VIIa (rFVIIa) was used in the management of hemorrhage in patients with thrombocytopenia associated with hematologic malignancies. This is the largest case aggregation to date and focuses on preliminary experience in the off-label use of this hemostatic agent. Data were extracted from the international, Internet-based registry, www.haemostasis.com, accessed in September 2003. The search results were manually cross-checked against monthly summary reports. The physicians providing the cases were contacted individually to approve the use of their cases, supply any information missing from the database, and validate the data already held. Patients with acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, Burkitt's lymphoma, B-cell or T-cell lymphoma, or aplastic anemia received rFVIIa at total doses of between 18 and 1040 mug/kg body weight. Bleeding stopped in 11 of 24 (46%) patients, markedly decreased in 8 of 24 (33%) patients, and decreased in 4 of 24 (17%) patients. In most patients, the response was achieved within 2.5 hours of administration of rFVIIa. The use of rFVIIa was generally well tolerated -- 1 case of ischemic stroke was considered to be possibly related to rFVIIa administration, but this has yet to be confirmed. A review of these 24 cases submitted to the www.haemostasis.com database suggests that rFVIIa is beneficial in the management of hemorrhage in patients with thrombocytopenia and hematologic malignancies. This warrants further investigation in rigorously controlled clinical trials.

Adolescent↗

PubMed2002

[A pilot study of G-CSF mobilized allogeneic bone marrow cells plus peripheral blood stem cells transplantation for malignant hematological diseases].

OBJECTIVE: To study the feasibility and clinical outcome of granulocyte-colony stimulating factor (G-CSF) mobilized allogeneic bone marrow (G-BM) plus G-CSF mobilized peripheral blood stem cells (G-PBSC) transplantation for malignant hematological disease. METHODS: G-BM plus G-PBSC transplantation was conducted between siblings or between parent and child. G-CSF was injected hypodermically into 14 stem cell donors 5 micro g x kg(-1) x d(-1) for 4 approximately 6 days. On the 3rd day after beginning of G-CSF injection bone marrow blood was extracted from the posterior superior iliac spine of the donors; on the 4th day G-PBSCs were collected. The collected stem cells were transplanted immediately into the bodies of the 14 patients with hematological disease, including acute myelocytic leukemia, acute lymphocytic leukemia, multiple myeloma, myelodysplastic syndrome and severe aplastic anemia. The clinical outcomes, including the rate of engraftment, speed of engraftment, and the occurrence of acute graft versus host disease (aGVHD) and chronic graft versus host disease (cGVHD) were investigated. RESULTS: All patients got endurable engraftment. The median time of recovery of neutrophil count to >or= 1 x 10(9)/L was 14 days (range 12 approximately 18 days). The median time to achieve a platelet count >or= 20 x 10(9)/L without transfusion was 13 days (range 11 approximately 65 days). Seven of the 14 patients developed aGVHD, 4 being in the grade I and 3 being in grade II. Three of the evaluable 9 patients developed extensive chronic GVHD. Two patients died of relapsed leukemia. One patient received secondary PBSCT from hte same donor because of ill engraftment and developed grade IV GVHD and died. The other 11 patients were still alive and event-free with a median follow-up duration of 455 days (range 84 approximately 715 days). CONCLUSION: An effective treatment for malignant hematological disease, G-CSF mobilized allogeneic bone marrow plus peripheral blood stem cells transplantation provides rapid and sustained engraftment without increase in incidence of aGVHD and cGVHD.

Adolescent↗

PubMedDate not supplied

Prospective study on humoral immune response induced by fungal infection in patients with hematologic malignancies.

To evaluate the immune response in an immunosuppressed population, antibodies against commercially available Candida albicans antigens were prospectively studied during 37 episodes of acute stomatitis caused by C. albicans and 36 episodes complicated by deep-seated mycoses in 62 adult patients with hematologic malignancies. During uncomplicated stomatitis in patients with acute leukemia, the mean peak IgM, IgG and IgA class enzyme-linked immunosorbent assay (ELISA) units differed significantly from the basic level preceding fungal infection. Mean time until peak values was 2.7-3.8 weeks after diagnosis of stomatitis. During systemic mycoses the antibody response was similar. Among patients with other hematologic malignancies, predominantly lymphomas, several were terminally ill and responded infrequently by antibody production. Similar results were given by Ouchterlony immunodiffusion and counterimmunoelectrophoresis. Thus, patients with acute leukemia showed an antibody response to fungal infection; the peak values, however, were somewhat delayed.

Adolescent↗

PubMed2000

Idarubicin intensified BUCY2 regimen in allogeneic unmanipulated transplant for high-risk hematological malignancies.

Twenty-nine consecutive patients with high-risk hematological malignancy aged from 3 to 58 years underwent an unmanipulated graft from an HLA-identical sibling after an irradiation-free preparative regimen consisting of idarubicin (IDA), 21 mg/m2/day administered by continuous infusion on days -12 and -11, followed by busulphan (BU), 4 mg/kg/day orally from day -7 to -4, and cyclophosphamide (CY), 60 mg/kg/day intravenously on days -3 and -2 (IDA-BUCY2). Most clinically relevant extra-hematological regimen-related toxicities consisted of stomatitis observed in all subjects and hemorrhagic cystitis occurred in five cases (17%) within 100 days after transplant. Six patients (21%) developed a grade 2 acute graft-versus-host disease (GVHD) and three (10%) a grade 3 or 4; extensive chronic GVHD was assessed in nine of 22 (41%) evaluable patients. So far, 12 patients have died and 17 are alive, 16 of whom disease-free, 5-41 months after transplant (median, 15 months). The causes of death were related to GVHD in three patients, to sepsis in one and to disease recurrence in the remaining eight. At present, only one of nine relapsed patients is alive. For all patients the actuarial probability of survival (OS) at 1 and 2 years +/- standard error (s.e.) was 63 +/- 9% and 52 +/- 10%, respectively. The actuarial probabilities of disease-free survival (DFS), relapse and transplant-related mortality (TRM) at both 1 and 2 years +/- s.e. were 53 +/- 9%, 35 +/- 9% and 16 +/- 7%, respectively. These results are encouraging but not substantially different from those obtained in 28 patients with malignancy in advanced phase transplanted after the standard BUCY2 regimen, who had an actuarial probability of OS, DFS, relapse and TRM projected at 10 years +/- s.e. of 54 +/- 10%, 57 +/- 9%, 36 +/- 9% and 11 +/- 6%, respectively. Although the retrospective comparison between the two groups does not seem to show any advantage in the use of the IDA intensified regimen, only a prospective randomized trial could answer this question.

Adolescent↗

PubMed2004

Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies.

Unrelated cord blood transplantation (CBT) has now become more common, but as yet there have been only a few reports on its outcome compared with bone marrow transplantation (BMT), especially for adults. We studied the clinical outcomes of 113 adult patients with hematologic malignancies who received unrelated BM transplants (n = 45) or unrelated CB transplants (n = 68). We analyzed the hematopoietic recovery, rates of graft-versus-host disease (GVHD), risks of transplantation-related mortality (TRM) and relapse, and disease-free survival (DFS) using Cox proportional hazards models. The time from donor search to transplantation was significantly shorter among CB transplant recipients (median, 2 months) than BM transplant recipients (median, 11 months; P < .01). Multivariate analysis demonstrated slow neutrophil (P < .01) and platelet (P < .01) recoveries in CBT patients compared with BMT patients. Despite rapid tapering of immunosuppressants after transplantation and infrequent use of steroids to treat severe acute GVHD, there were no GVHD-related deaths among CB transplant recipients compared with 10 deaths of 24 among BM transplant recipients. Unrelated CBT showed better TRM and DFS results compared with BMT (P = .02 and P < .01, respectively), despite the higher human leukocyte antigen mismatching rate and lower number of infused cells. These data strongly suggest that CBT could be safely and effectively used for adult patients with hematologic malignancies.

Adolescent↗

PubMed1998

[Serum levels of carboxyterminal propeptide of type I procollagen (PICP), cross-linked carboxyterminal telopeptide region of type I collagen (ICTP) and carboxyterminal parathyroid hormone-related protein (C-PTHrP) in hematological malignancies with bone lesions and hypercalcemia].

We measured the levels of carboxyterminal propeptide of type I procollagen (PICP), cross-linked carboxyterminal telopeptide region of type I collagen (ICTP) and carboxyterminal parothyroid hormone-related protein (C-PTHrP) in serum of patients with hematological malignancies. ICTP and C-PTHrP levels in serum of multiple myeloma (MM), non-Hodgkin's lymphoma (NHL) and adult T-cell leukemia (ATL) patients with bone lesions and hypercalcemia were significantly higher than those of patients without bone lesions and hypercalcemia. ICTP and C-PTHrP levels in ATL were significantly higher than in MM and NHL. There was a correlation between ICTP and C-PTHrP in serum of ATL patients, but no correlation in MM and NHL. Serum ICTP levels tended to correlate with serum beta 2-microglobulin and survival in patients with MM. Therefore, ICTP and C-PTHrP levels in serum may be useful in the diagnosis of bone lesions and hypercalcemia in hematological malignancies. In particular, ICTP may be a useful bone resorption marker in MM.

Adult↗

PubMed2005

[Itraconazole capsules as antifungal prophylaxis for neutropenic patients with hematological malignancies from a single institution].

We have previously reported that itraconazole (ITCZ) at a dose of 200 mg/day is more effective than ITCZ at a dose of 100 mg/day and is safe for prophylaxis of mycosis. In this prospective study, 37 patients with hematological malignancies were administered 200 mg/day of ITCZ for prophylaxis of mycosis during neutropenia. Although none of the patients developed mycosis, 31 patients (83.8%) of the ITCZ administered patients developed neutropenia (neutrophil < 1000/microL), and 12 patients of them showed the possibility of fugitive fungal infection. The prolonged neutropenia and low neutrophil level were observed in the patients with malignant lymphoma at stage III-IV, which suggested the necessity of prophylactic antifungal drugs. Four patients showed the adverse events which might be caused by drug interactions between ITCZ and vinca alkaloid. However adequately modified administration of ITCZ prevented these effect. There were no other obvious side effects which were supposed to be caused by prophylactic ITCZ administration. Twenty-eight patients were measured plasma concentration of ITCZ about 10 days after the beginning of administration and mean trough ITCZ level was expected to be above the effective level (250 ng/ml). These results suggested that ITCZ is effective and safe for prophylaxis of mycosis during neutropenia in patients with hematological malignancies.

Adolescent↗