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At least 613 records · Page 34Linked to original sources
PubMed1989

Phosphotyrosine phosphatase activity prevents the detection of P210bcr/abl protein in mature cells in chronic myelogenous leukemia even by an immunoblotting technique.

P210bcr/abl protein with tyrosine protein kinase has been implicated in the proliferation and differentiation of chronic myelogenous leukemia cells. Using an immunoblotting technique with antiphosphotyrosine (anti-P-Tyr) antibodies, we examined whether P210bcr/abl protein was expressed in chronic phase cells in patients with chronic myelogenous leukemia (CML). We could detect P210bcr/abl protein in blast cells regardless of myeloid or lymphoid lineage but not in chronic phase cells from patients. However, in a patient with both blast cells and chronic phase cells, we could identify the protein only after the enrichment of the blast crisis cells by Percoll gradient centrifugation. When K562 cells were mixed with mature granuloid cells, the P210bcr/abl in K562 cells detected by immunoblotting was decreased. Using phosphotyrosyl proteins in K562 cells as substrates, high phosphotyrosyl (P-Tyr) phosphatase activity was observed, not only in the lysate of chronic phase cells from CML patients but also in the lysate of neutrophils from normal subjects. These findings suggest the possibility that high P-Tyr phosphatase activity prevents the detection of P210bcr/abl in CML cells in the chronic phase. The activity may be characteristic of mature cells and may regulate cellular events through dephosphorylation of P210bcr/abl.

Blast Crisis↗
PubMed1992

The effect of granulocyte-macrophage colony-stimulating factor on undifferentiated and mature acute myelogenous leukemia blast progenitors.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used recently to recruit undifferentiated acute myelogenous leukemia (AML) blasts into the S-phase of the cell cycle and increase the fraction of cells killed by cell cycle-specific drugs. Using three AML blast colony assays combined with a suspension culture (delta assay), we determined the in vitro effect of GM-CSF on mature and undifferentiated AML blast progenitors obtained from bone marrow aspirates of six AML patients. GM-CSF stimulated AML blast colony proliferation at a concentration of 5 ng/ml in the methylcellulose and the agar clonogenic assays in six of six AML marrow samples. However, in the delta assay, which selects for immature AML progenitors, GM-CSF did not affect AML blast colony-forming cells in five of six AML marrow samples at concentrations ranging from 5 to 300 ng/ml. Our data imply that GM-CSF stimulates mature but not undifferentiated AML blast progenitors. It is therefore possible that GM-CSF may not be beneficial as a recruiting agent in most AML patients.

Adult↗
PubMed1989

No correlation between locations of bcr breakpoints and clinical states in Ph1-positive CML patients.

The majority of patients with chronic myelogenous leukemia (CML) have a characteristic reciprocal translocation between chromosome 9 and 22, resulting in the Philadelphia (Ph1) chromosome. During this translocation, the c-abl oncogene on chromosome 9 is transferred to the Ph1 chromosome and linked to a breakpoint cluster region (bcr), which is part of a large bcr gene. This phenomenon results in the formation of a bcr-c-abl fusion gene, which is transcribed into an 8.5 kb chimeric mRNA encoding a 210 kd bcr-c-abl fusion protein. The fusion protein has tyrosine kinase activity implicated in the pathogenesis of CML. The breakpoint near the c-abl locus on chromosome 9 can occur within a large area. In contrast, the breakpoints on chromosome 22 cluster within the bcr region of 5.8 kb. A chronic phase lasts for an average of 2 to 3 years; and, subsequently, most patients enter blast crisis. In the present study, we examined 15 Ph1-positive CML patients (eight in chronic phase, one in accelerated phase, and six in blast crises) as to whether the identifiable difference in the locations of the bcr breakpoints exist between CML patients in chronic phase and those in blast crisis. In seven of eight CML patients in chronic phase, in one in accelerated phase, and in four out of six CML patients in blast crisis, the bcr breakpoints clustered in the 3' portion of the bcr. Thus, we could not find out the correlation between the locations of the bcr breakpoints and the clinical stage of the CML patients. This might imply that blastic transformation in Ph1-positive CML was caused by other mechanisms than the transition of the bcr breakpoints.

Blast Crisis↗
PubMed1999

Medical consequences of terrorism. The conventional weapon threat.

As long as gunpowder and explosives are used to solve disagreements between nations, ethnic groups, and individuals, victims of blast injury continue to arrive occasionally at trauma centers around the world. Bombs planted in crowded urban locations or suicide bombings continue to stress civilian EMS and urban medical systems. Although the clinical presentation depends on whether the blast occurs in open or confined quarters, open air, or water, the pattern of injury inflicted on the body is relatively consistent. The proximity to the detonating device is probably much more important than the size of the bomb. If not injured by secondary, tertiary, or other miscellaneous mechanisms of most conventional bombs with 1 to 20 kg of TNT, people at distances exceeding 6 m will probably not experience substantial blast-induced injury. Three systems are prone to injury. The first is the auditory system, with damage to the eardrum in milder cases and inner-ear injury in more severe cases. The alimentary tract with contusions, hematoma, and occasional perforation of a hollow viscus is the second system involved. Solid organs are rarely damaged in survivors of blast injury. Close proximity to the blast can impose traumatic amputation of limbs (i.e., arms and legs) and ear lobes. Most of these victims succumb to their injuries in the immediate post-injury phase, but the hallmark of blast injury is the involvement of the respiratory system. With expeditious evacuation performed by efficiently coordinated and highly skilled EMS personnel, more patients with blast injuries arrive with signs of life to the medical facility. At the medical facility, the staff need to triage many victims into urgent and nonurgent groups. Only lifesaving procedures should be performed during the initial phase. Later, medical care is directed at patients moved to ICUs. Prompt evacuation after necessary lifesaving procedures in the field; proper triage and distribution; prudent hospital triage and surgical care; and, last but not least, expert critical care provide the best possible outcome in such circumstances.

Amputation, Traumatic↗
PubMed2003

Diagnostic significance of detecting dysgranulopoiesis in chronic myeloid leukemia.

We examined whether the detection of dysgranulopoiesis in blood or bone marrow would predict chronic myeloid leukemia (CML) in transformation in 31 cases that fulfilled World Health Organization criteria for disease transformation, including 14 in accelerated phase (AP), 10 in myeloid blast crisis (MBC), and 7 in lymphoid blast crisis (LBC). Dysgranulopoiesis was detected in 7 cases, 6 in AP and 1 in MBC, but not in LBC or chronic phase cases. In 3 AP cases, dysgranulopoiesis was identified 2 to 5 months before the morphologic diagnosis of transformation. Two AP cases showed no dysgranulopoiesis in previous blood or marrow smears. For 2 cases (1 AP and 1 MBC), no previous blood or marrow specimens were available. Cytogenetic information was available for 6 of 7 cases with and 22 of 24 cases without dysgranulopoiesis. All cases with dysgranulopoiesis had secondary chromosome abnormalities in addition to t(9;22). In 5 (83%) of 6 cases with dysgranulopoiesis, the secondary chromosome abnormalities included abnormalities of 17p. In contrast, none of the 22 cases of CML in AP or BC but without dysgranulopoiesis showed 17p abnormalities (P = .001). Our findings demonstrated that dysgranulopoiesis was associated strongly with chromosome 17p abnormalities and may indicate the onset of or impending disease transformation.

Adult↗
PubMedDate not supplied

Rearrangements of immunoglobulin- and BCR-genes in chronic myeloid leukemia.

Clonal rearrangements of immunoglobulin (Ig) and T cell receptor (TCR) genes have been demonstrated in malignant lymphoid tumors of B and T cell origin. In Philadelphia chromosome (Ph1) positive chronic myeloid leukemia (CML) the bcr and c-abl genes are reorganized and a new transcript, composed of both genes is expressed. Immunoglobulin gene rearrangements were also detected in lymphoid blast crisis but not in myeloid blast crisis of CML. We analyzed in Southern blot experiments whether Ig and TCR rearrangements could also occur in the chronic or accelerated phase of the disease. Our results indicate that immunoglobulin but not TCR delta or TCR gamma gene rearrangements also occurred in some patients with CML in chronic and accelerated phase but not in myeloid blast crisis, together with rearrangements of the bcr gene.

Adult↗
PubMed1994

Combinations of stem cell factor with other hematopoietic growth factors enhance growth and sensitivity to cytosine arabinoside of blast progenitors in acute myelogenous leukemia.

The blast progenitors in acute myelogenous leukemia grow in response to hematopoietic growth factors (HGFs), and their sensitivity to antileukemic drugs is influenced by HGFs. We report the effects of stem cell factor (SCF) on the growth and sensitivity to 1-beta-D-arabinofuranosylcytosine (Ara-C) of blast progenitors in acute myelogenous leukemia. SCF stimulated both colony formation and self-renewal of blast progenitors and, when used in combination with other HGFs, synergistic enhancement of colony formation was noted in 8 of the 15 patients examined. Cell fractionation studies demonstrated no unique growth dependency on SCF in either CD34+ or CD34- populations. Blast cells of patients that displayed synergistic growth enhancement with SCF displayed the highest Ara-C sensitivity when HGFs were used in combination with SCF. The tritiated thymidine suicide test (20-min exposure) revealed that the proportion of blast progenitors in the S phase of the cell cycle was highest when SCF and another HGF were simultaneously present, although 24-h exposure killed most or all of the blast progenitors. These data indicate that SCF enhances growth and sensitivity to Ara-C of acute myelogenous leukemia blast progenitors in a closely correlated fashion and that the cell cycle changes as well as other mechanisms are involved in the Ara-C sensitivity modulation by SCF.

Adolescent↗
PubMed2007

Paraplegia as the presenting manifestation of extramedullary megakaryoblastic transformation of previously undiagnosed chronic myelogenous leukemia.

Extramedullary tumors, also known as granulocytic sarcomas (GS), occur most frequently in acute myelogenous leukemia (AML). They may signal the onset of the accelerated phase of chronic myelogenous leukemia (CML) or the blastic transformation of a myeloproliferative disorder. Occasionally, a GS may be the presenting sign of undiagnosed AML, and rarely the presenting sign of undiagnosed CML or aleukemic leukemia. Paraplegia due to a spinal cord GS is an extremely rare presentation of undiagnosed leukemia. This is the first case report of paraplegia as the presenting manifestation of extramedullary megakaryoblastic transformation of previously undiagnosed CML. A 53-year-old woman reported back pain for 6 days, rapidly progressing to paraplegia. Physical examination noted a large abdominal mass and flaccid paralysis in both lower extremities. Spinal MRI revealed a T4-T6 vertebral mass causing spinal stenosis and cord compression. Tumor debulking and laminectomy were performed emergently. The tumor consisted of noncohesive blast cells. The CBC revealed a leukocyte count of 238,300/microl and a differential consistent with CML. Reexamination of the patient found that the abdominal mass was a giant spleen. Further immunohistochemical studies of the tumor were consistent with extramedullary acute megakaryoblastic blast transformation of CML. Although extramedullary blast crises herald the accelerated phases in approximately 10% of CML cases, megakaryoblastic blast transformation of CML accounts for less than 3% of these cases. The combination of acute paraplegia and megakaryoblastic transformation in a previously undiagnosed patient with CML is extremely rare and may pose a diagnostic dilemma.

Combined Modality Therapy↗
PubMedDate not supplied

[Prognosis of children with chronic myeloid leukemia: a retrospective analysis of 75 patients].

UNLABELLED: As the probability of survival of patients with chronic myelocytic leukemia (CML) gradually decreases over a period of 10 years, long-term follow-up is mandatory. Between 1977 and 1994, 68 children and adolescents between 1.0 and 18 years of age with CML in chronic phase and 7 presenting with blast crisis at diagnosis were reported to the study center in Münster. The Philadelphia-chromosome and/or BCR/ABL rearrangement could be detected in 66 children. The 4 Philadelphia-negative patients and 5 patients without karyotyping fulfilled the morphological criteria of CML. Clinical symptoms and hematological findings at presentations were similar to adult patients. THERAPY: Until 1985 chemotherapy consisted predominantly in busulfan (BU), later in hydroxyurea (HU) or a combination of both and since 1987 increasingly in HU plus interferon-alpha. 47 patients (6 in blast crisis) were allografted once or twice (n = 4) (27 HLA-identical, 16 unrelated, 4 haplo-identical) within 2.3-135 months (median 12 months) after diagnosis. RESULTS: 38 of 75 patients (3 in blast crisis at diagnosis) were alive after a median follow-up of 5.5 years. The probability of 12 years survival was 27%, SE 9% for patients in chronic phase. All deaths (n = 19) were leukemia-related in the 27 non-transplanted children. A comparison of survival for patients with or without bone-marrow transplantation (BMT) showed a significant difference in favour of the BMT-group (42%, SE 13% vs. 10%, SE 8%, p log-rank 0.003). The probability of survival increased to 62%, SE 10%, if patients transplanted later than 3 years after diagnosis were excluded. Only few patients (4/39 with information about the cause of death = 10%) died due to recurrent CML after BMT. CONCLUSION: Our data confirm the unfavourable outcome of CML in pediatric patients if treated with chemotherapy alone. With early BMT high cure rates can be achieved. If transplant-related mortality which in our patient group was 21% (8/39) can be reduced, even a higher cure rate appear realistic for the future.

Adolescent↗
PubMed1979

Selective sensitivity of chronic myelogenous leukemia cell populations to alkyl-lysophospholipids.

In order to evaluate the specificity of alkyl-lysophospholipid-induced cell destruction, peripheral blood leukocytes from chronic myelogenous leukemia (CML) patients in chronic phase of the disease as well as in blastic crisis have been separated by density centrifugation. These subpopulations, enriched for the different maturation stages, were tested for their sensitivity to alkyl-lysophospholipids. It is shown that myelocytes in chronic phase CML are resistant, but blast cells from both clinical stages as well as maturational defective myelocytes from blastic crisis CML are highly sensitive to these antimetabolites. In contrast to chronic phase CML myelocytes, these sensitive cells show a high lysophospholipid adsorption rate and lack an O-alkyl-cleavage enzyme.

Chronic Disease↗
PubMed2006

Mutations of the myeloid transcription factor CEBPA are not associated with the blast crisis of chronic myeloid leukaemia.

The transcription factor CEBPA is crucial for normal myeloid differentiation. CEBPA gene mutations have been reported in patients with acute myeloid leukaemia. The inevitable evolution of chronic myeloid leukaemia (CML) in chronic phase (CP) to a fatal blast crisis (BC) is assumed to result from the acquisition of additional genetic changes in the leukaemic clone. Gain of CEBPA mutations might represent a key event causing the differentiation block observed in myeloid CML-BC, but not in CML-CP. Here, no CEBPA mutation in 95 CML-BC patients was found, suggesting a limited role, if any, of CEBPA mutations in this disorder.

Blast Crisis↗
PubMed1979

Alpha-naphthyl acetate esterase activity in human lymphocytes: distribution in lymphocyte subpopulations and in mitogen-activated cells.

The cytochemical demonstration of nonspecific alpha-naphthyl acetate esterase (ANAE) activity in human peripheral blood mononuclear cells was studied. Different staining patterns were found, allowing differentiation of mononuclear cells into macrophages (strong granular cytoplasmic activity), B lymphocytes (negative reaction), Tgamma lymphocytes, i.e. bearing IgG Fc receptors (granular scattered reaction), and T non-gamma lymphocytes, i.e. devoid of IgG Fc receptors (single cytoplasmic ANAE spot). During the early phases of phytohaemagglutinin (PHA)- and concanavalin A (Con A)-induced activation, the reactivity of most lymphocytes became granular and scattered, similar to that found in Tgamma cells. Blast cells generating in successive phases appeared devoid of detectable enzymatic activity. The hypothesis is put forth that T cells showing granular, scattered reactivity represent a population of activated cells and that the redistribution of enzymatic activity could represent a preliminary step leading to secretion (lymphokine-like?) of enzyme from cytoplasm in the course of cell activation.

B-Lymphocytes↗
PubMed2003

Phase II trial of CPT-11 in myelodysplastic syndromes with excess of marrow blasts.

CPT-11 is an antineoplastic agent which acts as a specific inhibitor of DNA topisomerase 1 and has a broad spectrum of activity in solid tumors. Very few studies have evaluated the activity of CPT-11 in hematological malignancies. We conducted a phase II trial of CPT-11 in 26 patients with high-risk MDS (RAEB 1: n = 4; RAEB 2: n = 9; MDS having progressed to AML: n = 10; CMML: n = 3) who could not receive anthracycline/cytarabine intensive chemotherapy. Induction therapy consisted of four courses of CPT-11 given intravenously at 200 mg/m(2) every 2 weeks. Patient characteristics were: median age, 71 (range 51-77); sex, (M/F), 21/5, median % marrow blasts cells, 13.5 (range 7-52). Cytogenetics according to IPSS were: low-risk n = 13, intermediate-risk n = 6, high-risk n = 3, failure or not done n = 4. Six patients stopped treatment after only one or two courses of CPT-11 due to severe infection (n = 2), progressive disease (n = 3), acute lysis syndrome with renal failure (n = 1). In the 20 patients who received at least three cycles of CPT-11, complete remission was achieved in one case, partial remission in four cases, and hematological improvement in three cases with an overall response rate of 33% in the 26 patients. Duration of response was short (median 4 months, range 1-6 months) and median survival was 8 months (range 1-23 months). Digestive toxicity (diarrhea) occurred in 26/89 (29%) courses, but was mild (grade 1, 20% courses; grade 2 or 3, 9% courses). Hematological toxicity was difficult to assess in non-responders because of initial pancytopenia, but all the patients who responded had grade 3/4 hematological toxicity associated with grade >/=2 infection requiring hospitalization in 18% of the courses. No other major toxicity was observed. Thus CPT-11 has an interesting activity in MDS with excess of blasts; toxicity is easily managed and most patients can be treated in the out-clinic setting. These results suggest that further evaluation of CPT-11 in MDS is warranted.

Aged↗
PubMed1982

Flow cytometric analysis of cellular DNA in human acute nonlymphatic leukemias and dysmyelopoietic syndromes.

The proliferation patterns of bone marrow cells from 16 cases of acute nonlymphatic leukemia (ANLL) and 13 of dysmyelopoietic syndromes were analyzed with DNA-flow cytometry. In order to reduce the contamination by nonproliferating peripheral blood cells, all aspirates were submitted to a density centrifugation step. DNA content measurements were performed with a PHYWEICP 22 flow system apparatus. The distribution of cells in te cell cycle phases was calculated by means of an automated fitting procedure. No significant difference between the cell cycle distribution in ANLL and dysmyelopoietic syndromes was detectable. No relationship was observed between the size of the S phase compartment and the percentage of blasts in the original samples. Aspirates from ANLL were also cultured in vitro in liquid phase on dialysis membranes. A clear relationship was observed between the size of the phase compartment and in vitro cell growth since, with the exception of one case, all samples with less than 11% cells in S phase failed to proliferate in vitro. The proliferation profile of ANLL cells after 10 days in culture was similar to that of the original samples.

Anemia, Aplastic↗
PubMed2005

p210BCR-ABL inhibits SDF-1 chemotactic response via alteration of CXCR4 signaling and down-regulation of CXCR4 expression.

It has been shown that p210(BCR-ABL) significantly impairs CXCR4 signaling. We report here that the migratory response to SDF-1 was profoundly altered in blast crisis, whereas chronic-phase CD34(+) cells migrated normally to this chemokine. This migratory defect was associated with a low CXCR4 membrane expression. In vitro STI-571 treatment of CD34(+) cells from patients in blast crisis markedly increased the CXCR4 transcript and CXCR4 membrane expression. Because p210(BCR-ABL) frequently increases with disease progression, we determined the effects of high and low p210(BCR-ABL) expression on CXCR4 protein in the granulocyte macrophage colony-stimulating factor-dependent human cell line MO7e. p210(BCR-ABL) expression distinctly alters CXCR4 protein through two different mechanisms depending on its expression level. At low expression, a signaling defect was detected with no modification of CXCR4 expression. However, higher p210(BCR-ABL) expression induced a marked down-regulation of CXCR4 that is related to its decreased transcription. The effect of p210(BCR-ABL) required its tyrosine kinase activity. Collectively, these data indicate that p210(BCR-ABL) could affect CXCR4 by more than one mechanism and suggest that down-regulation of CXCR4 may have important implications in chronic myelogenous leukemia pathogenesis.

Animals↗
PubMed1986

Additional c-abl/bcr rearrangements in a CML patient exhibiting two ph1 chromosomes during blast crisis.

Recent data suggest that two human genes, c-abl on chromosome 9 and bcr on chromosome 22, are involved in the generation of Ph1-positive CML. To examine a possible role of these sequences in transition from chronic towards blastic phase, rearrangements within bcr were analysed in 4 patients with Ph1-positive CML during chronic and acute phase. In 3 patients bcr rearrangements were identical in both phases, while in a fourth patient with duplicated Ph1 an amplified additional bcr fragment was detected in acute phase. Northern blot analysis of blast cells of the latter patient showed a novel 10.3 kb RNA species that replaced the altered 8 kb RNA transcript usually found in Ph1-positive CML.

Adolescent↗
PubMed1988

Attempted prevention of blast crisis in chronic myeloid leukemia by the use of pulsed doses of cytosine arabinoside and cis-chloronitrosurea during the course of busulfan-maintained remission.

We performed this chemotherapeutic trial to try to delay the onset of the blast crisis of chronic myeloid leukemia (CML) by pulsing doses of drugs most likely to be effective against emerging "blast" cells characteristic of acute phase disease. A randomized trial in patients with CML comparing busulfan maintenance to busulfan maintenance plus pulsed doses of cytarabine and lomustine did not yield any differences in either time to blast crisis or death.

Adult↗
PubMedDate not supplied

Safety and efficacy of an indigenous recombinant interferon-alpha-2b in patients with chronic myelogenous leukaemia: results of a multicentre trial from India.

BACKGROUND: Compared to hydroxyurea, treatment with interferon-alpha (IFN-alpha) is known to prolong survival in patients with chronic phase of chronic myelogenous leukaemia (CML) and was considered as first-line therapy till recently. We conducted a multicentre trial using an indigenous recombinant IFN-alpha-2b to evaluate its efficacy and toxicity in chronic phase CML. METHODS: Between September 2000 and August 2001, patients with chronic phase CML were recruited within 8 weeks of diagnosis at 7 centres in India. The study was approved by the Ethics Committee of each participating Institute and Informed, written consent was obtained from all patients. All patients were given the study drug in a dose of 5 million units daily subcutaneously. Response and survival analyses were done with intent-to-treat analysis. RESULTS: One hundred and fourteen patients (75 men and 39 women) were included in the study. Their ages ranged from 18 to 62 years (median 37 years). Fifty-seven per cent of patients had a haematological response; complete response in 31.6% and partial response in 25.4%. The median time to achieve complete haematological response was 6 months (range 3-12 months). Cytogenetic response was seen in 39.4% of patients; complete in 1.8%, partial in 28% and minimal in 9.6%. The median time to achieve partial and complete cytogenetic response was 6 and 12 months, respectively. Nineteen patients had progression (blast crisis n=15, accelerated phase n=4) while on treatment. Two patients refused further treatment after the initial 4 weeks due to IFN-a toxicity, mainly bone pains and fever. The major toxic effects of treatment were fever (78%), fatigue (25.4%) and myalgia (52%). No patient died of toxicity. Currently, 95 patients are alive, 91 in the chronic phase and 4 in the accelerated phase. Four patients were lost to follow up and all 15 patients with blast crisis died of progressive disease at a median Interval of 6.5 months (range 1-15 months). The Kaplan-Meier probability of survival at 36 months was 76%. CONCLUSION: This study confirms the efficacy of the indigenous recombinant IFN-alpha-2b in chronic phase CML. The drug has a toxicity profile similar to that of other preparations.

Adolescent↗