Remission induction therapy: the more intensive the better?

Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity.

Female Fertility and Single Nucleotide Polymorphism Comparisons in Cylindrocladium pauciramosum.

Cylindrocladium pauciramosum is well established in South America, and has recently been collected from nurseries in South Africa, Italy, and the United States. Isolates were compared with respect to the percentages of hermaphrodites and the respective mating types in the different samples. Based on these data, the effective population size could be determined for the different areas studied.

Species concepts in the Cylindrocladium floridanum and Cy. spathiphylli complexes (Hypocreaceae) based on multi-allelic sequence data, sexual compatibility and morphology.

Much attention has recently been devoted to the delimitation of species units in Cylindrocladium (Cy.). In this regard the present study focuses on the taxa within the unresolved Cy.

Proliferative activity of leukaemic blasts and cytosine arabinoside pharmacodynamics are associated with cytogenetically defined prognostic subgroups in acute myeloid leukaemia.

The biological mechanisms responsible for the association of specific karyotypes with prognosis in acute myeloid leukaemia (AML) remain largely unclear. A prospective study was performed to evaluate how far cytogenetically defined prognostic subgroups of AML differ in their proliferative activity as a potential mechanism for differential sensitivities to S-phase-specific induction chemotherapy comprising cytosine arabinoside (AraC). One hundred and eighty-seven patients with de novo AML were included in the study; 25 patients with a favourable [inv(16), t(8;21), t(15;17)] karyotype, 99 with a normal karyotype, 29 with an unfavourable karyotype (-5, 5q-, -7, 7q-, complex aberrations) and 34 with cytogenetic aberrations of unknown prognostic significance (all others).

Acute myeloid leukaemia M0: haematological, immunophenotypic and cytogenetic characteristics and their prognostic significance: an analysis in 241 patients.

Haematological, immunophenotypic and cytogenetic characteristics were analysed in 241 patients with acute myeloid leukaemia (AML) M0, including 58 children. Children < 3 years and adults between 60 and 70 years of age were most frequently affected. Immunophenotyping showed a heterogeneous phenotype.

Gain of an isochromosome 5p: a new recurrent chromosome abnormality in acute monoblastic leukemia.

In acute myeloid leukemia (AML) close associations are known between cytomorphology and cytogenetics such as in AML M3/M3v showing a t(15;17) and in AML M4eo associated with inv(16)/t(16;16). In AML M5 a heterogenous cytogenetic pattern is observed. We describe the gain of an isochromosome of the short arm of chromosome 5 together with the gain of chromosome 8 as the sole abnormalities in two cases of acute monoblastic leukemia.

Comparison of the vasoactive effects of the docosanoid unoprostone and selected prostanoids on isolated perfused retinal arterioles.

Purpose: To compare the vasoactive properties of the docosanoid unoprostone, its free acid, and different members of the prostanoid family on isolated perfused pig retinal arterioles to assess their potential to modulate retinal blood flow.

Methods: Segments of porcine retinal arterioles were dissected, cannulated, and perfused, and their diameter monitored during either intraluminal or extraluminal application of increasing doses (10(-10)-10(-4) M) of either the docosanoid unoprostone isopropyl and its free acid or of selected prostanoids: prostaglandin (PG) F(2alpha) and thromboxane A(2) analogue (U46619). Studies were performed on arterioles in their uncontracted state, and also during precontraction with endothelin-1 (10(-9) M).

Acute myeloid leukaemia (AML): treatment of the older patient.

Undertreatment of the older patients with acute myeloid leukaemia (AML) can explain, in part, their inferior outcome when compared with that of younger patients. Corresponding to the benefit to patients under the age of 60 from high-dose Ara-C there are also dose effects in those over 60 years old, in particular for daunorubicin in the induction treatment, and for the quantity in terms of duration of postremission treatment. The use of these effects can partly overcome the mostly unfavourable disease biology seen in older age AML patients, which is expressed by the absence of favourable and the over-representation of adverse chromosomal abnormalities as well as by the expression of drug resistance.

In vitro corneal permeation of unoprostone isopropyl (UI) and its metabolism in the isolated pig eye.

The corneal permeability, hydrolysis, and metabolism of unoprostone isopropyl (UI), a docosanoid, were examined in isolated porcine ocular tissues. The apparent permeability coefficient (Papp) of the esterified prodrug and of the acid metabolite were determined in a modified Valia-Chien permeation chamber and quantified by high performance liquid chromatography. Enzymatic hydrolysis and subsequent metabolism were examined in isolated tissue homogenates.

AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia.

The transcription factor CCAAT/enhancer binding protein alpha, or C/EBPalpha, encoded by the CEBPA gene, is crucial for the differentiation of granulocytes. Conditional expression of C/EBPalpha triggers neutrophilic differentiation, and Cebpa knockout mice exhibit an early block in maturation. Dominant-negative mutations of CEBPA have been found in some patients with acute myeloid leukemia (AML), but not in AML with the t(8;21) translocation which gives rise to the fusion gene RUNX1-CBF2T1 (also known as AML1-ETO) encoding the AML1-ETO fusion protein.

Cytogenetic subgroups in acute myeloid leukemia differ in proliferative activity and response to GM-CSF.

The current study was undertaken to search for differences in the biology of cytogenetic subgroups in patients with de novo acute myeloid leukemia (AML). In addition, factors influencing the metabolism of cytosine arabinoside (araC) as the key agent of antileukemic activity were assessed. Bone marrow aspirates from 91 patients with newly diagnosed AML in whom karyotypes were successfully obtained were analyzed: (1) for spontaneous proliferative activity by 3H-thymidine (3H-TdR) incorporation; (2) proliferative response to GM-CSF by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4-h exposure to 3H-TdR (0.

Impact of CD133 (AC133) and CD90 expression analysis for acute leukemia immunophenotyping.

Background And Objectives: AC133 is a novel monoclonal antibody (Moab) reacting with a population of immature/primitive or granulo-monocytic committed CD34+ve cells. Up to now, only few studies with small numbers of cases have examined AC133 (recently designated CD133) expression in acute leukemia. To determine the value of this Moab for acute leukemia immunophenotyping, we investigated a large series of leukemic cell samples for their reactivity with Moab AC133.

Acute myeloid leukemia in adults: is postconsolidation maintenance therapy necessary?

Maintenance treatment for patients with acute myeloid leukemia (AML) in remission has recently been controversially discussed and even abandoned by several groups. An analysis of 14 recently published multicenter trials, however, revealed the highest probabilities of relapse-free survival (RFS), in the range of 35% to 42% at 4 to 5 years, only in patients assigned to maintenance treatment as far as adult age and intent-to-treat conditions were considered. After having demonstrated a superior RFS rate from 3 years of maintenance after standard-dose consolidation compared with that from consolidation alone (P = .

Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: a study of 90 patients.

The clinical significance of complex chromosome aberrations for adults with acute myeloid leukaemia (AML) was assessed in 920 patients with de novo AML who were karyotyped and treated within the German AML Cooperative Group (AMLCG) trials. Complex chromosome aberrations were defined as three or more numerical and/or structural chromosome aberrations excluding translocations t(8;21)(q22;q22), t(15;17)(q22;q11-q12) and inv(16)(p13q22). Complex chromosome anomalies were detected in 10% of all cases with a significantly higher incidence in patients > or = 60 years of age (17.

Chromosomal organization and localization of the human histone deacetylase 5 gene (HDAC5).

Histone deacetylases (HDACs) are important participants in the remodeling of chromatin structure and in the regulation of eukaryotic proliferation and differentiation. We have isolated and characterized the human HDAC5 genomic sequence, which spans a region of 39,138 bp and which has one single chromosomal locus. Determination of the exon-intron splice junctions established that HDAC5 is encoded by 26 exons ranging in size from 22 bp (exon 1) to 285 bp (exon 12).

Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. German AML Cooperative Group.

A prospective multicenter study was performed to investigate the clinical and molecular results of intensified double induction therapy including high-dose cytarabine (ara-C) in combination with ATRA in newly diagnosed acute promyelocytic leukemia (APL), followed by consolidation and 3 years maintenance therapy. Fifty-one patients, diagnosed and monitored from December 1994 to June 1999, were evaluated. The median age was 43 (16-60) years.

The pharmacodynamic basis for the increased antileukaemic efficacy of cytosine arabinoside-based treatment regimens in acute myeloid leukaemia with a high proliferative activity.

The current study was initiated to explore the mechanisms underlying the previously demonstrated association between the proliferative activity of leukaemic blasts and the response to cytosine arabinoside (AraC)-based therapy in de novo acute myeloid leukaemia (AML). The activity of key enzymes of AraC metabolism-deoxycytidine kinase (DCK), cytidine deaminase (DCD) and polymerase alpha (PolyA) were determined in blast cells from 33 patients. In addition, formation and retention of intracellular levels of AraC triphosphate (AraCTP) and DNA incorporation of AraC were measured, as was the proliferative activity of leukaemic blasts by [3H]-TdR incorporation before and after stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte CSF (G-CSF) for 48 h.

Genetic instability in myelodysplastic syndrome: detection of microsatellite instability and loss of heterozygosity in bone marrow samples with karyotype alterations.

Using a polymerase chain reaction (PCR)-based approach, we examined the prevalence of loss of heterozygosity (LOH) and microsatellite instability (MSI) in relation to chromosomal imbalances in myelodysplastic syndrome (MDS). Two of 26 patients displayed MSI (8%), one of them at five loci. LOH was detected in six out of 26 cases (23%), predominantly involving markers IRF1 [5q31] and WT1 [11p].

Detection of acute leukemia cells with mixed lineage leukemia (MLL) gene rearrangements by flow cytometry using monoclonal antibody 7.1.

Translocations involving 11q23 are among the most common genetic abnormalities in hematologic malignancies, occurring in approximately 5-10% of acute lymphoblastic leukemia (ALL) and 5% of acute myeloblastic leukemia (AML). In 11q23 translocations, the mixed lineage leukemia (MLL) gene on chromosome 11, band q23, is usually disrupted. The human homologue of the rat NG2 chondroitin sulfate proteoglycan molecule, as detected by the monoclonal antibody (moab) 7.

Clinical significance of P-glycoprotein expression and function for response to induction chemotherapy, relapse rate and overall survival in acute leukemia.

Background And Objectives: A multidrug-resistance (MDR) phenotype mediated by P-glycoprotein (P-gp) contributes to chemotherapy failure in acute leukemia. However, the exact prognostic significance of this resistance mechanism is still unclear, mostly due to methodologic problems in P-gp detection. We therefore investigated, whether P-gp expression levels or functional P-gp activity better predict response to induction chemotherapy, relapse rate and overall survival in acute leukemia.

Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML.

Partial tandem duplications of the MLL gene have been associated with trisomy 11 in acute myeloid leukemia (AML) and recently, have also been reported for karyotypically normal AML. In order to test the incidence and prognostic importance of this molecular marker, we have analyzed eight cases of AML with trisomy 11 and 387 unselected consecutive cases with AML for partial duplications of the MLL gene. Patients with normal karyotypes and those with various chromosome aberrations were included.

Cytostatic sensitivity and MDR in bladder carcinoma cells: implications for tumor therapy.

The clinical success generally seen in chemotherapy of advanced bladder carcinoma is far from optimal. The mechanism of resistance development is unclear and the expression of P-170 glycoprotein is generally low. The aim of this study, carried out in vitro in sensitive and cisplatin-resistant cell lines, was to examine sensitivity modulation using R-verapamil and cell membrane perturbing agents.