[Increased response rate with rituximab in relapsed and refractory follicular and mantle cell lymphomas -- results of a prospective randomized study of the German Low-Grade Lymphoma Study Group].

Background And Objective: Rituximab has shown a high activity in relapsed follicular lymphomas when given alone. Further on, phase-II-studies indicate that its addition to chemotherapy may improve the response rate substantially. However, so far, prospective randomized studies have not been available.

Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial.

Risk assessment in acute myeloid leukemia (AML) using pretreatment characteristics may be improved by incorporating parameters of early response to therapy. In the 1992 trial of the German AML Cooperative Group (AMLCG), the amount of residual leukemic blasts in bone marrow was assessed one week after the first induction course (day 16 blasts). A total of 449 patients 16 to 76 years of age (median, 53 years) with de novo AML entered the trial and were evaluable.

The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia.

The transcription factor PU.1 plays a pivotal role in normal myeloid differentiation. PU.

Rapid diagnostic approach to PML-RARalpha-positive acute promyelocytic leukemia.

Introduction: Acute promyelocytic leukemia (APL) is a distinct entity characterized by a specific bone marrow morphology and a rearrangement of the PML- and the RARalpha-gene mostly due to a balanced translocation between the long arm of chromosome 15 with a breakpoint in 15q22 and the long arm of chromosome 17 with a breakpoint in 17q12-21. The introduction of all trans retinoic acid (ATRA) into treatment protocols has improved the outcome of APL dramatically. Therefore, it is essential to establish the diagnosis of APL as quickly and as reliably as possible.

A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia.

Activating length mutations in the juxtamembrane (JM) domain of the FLT3 gene (FLT3-LM) and mutations in the catalytic domain (FLT3D835/836) of this receptor tyrosine kinase represent the most frequent genetic alterations in acute myeloid leukemia (AML). Here, we describe a 6-bp insertion in the activation loop of FLT3 between codons 840 and 841 of FLT3 (FLT3-840GS) in 2 unrelated patients with AML. Screening for other activating mutations of FLT3, KIT, and NRAS showed no further genetic alterations in patients carrying the FLT3-840GS.

Karyotype instability between diagnosis and relapse in 117 patients with acute myeloid leukemia: implications for resistance against therapy.

The instability of the karyotype may play a role in the development of refractoriness of acute myeloid leukemia (AML) to anti-leukemic therapy. Therefore, in the current study cytogenetic analyses were performed in 117 patients with AML both at diagnosis and at relapse. Changes in karyotype were observed in 38% (36% of initially normal karyotypes, 39% of initially aberrant karyotypes).

Proteomic analysis of transcription factor interactions in myeloid stem cell development and leukaemia.

Recent results indicate that interactions of transcription factors with other nuclear proteins play an important role in stem cell development, lineage commitment and differentiation in the haematopoietic system, and the pathogenesis of myeloid leukaemias. High-throughput proteomics by mass spectrometric analysis of gel-separated proteins can identify multi-protein complexes and changes in the expression of multiple proteins simultaneously. This review describes an application of proteomic methods (2D gel electrophoresis (GE) and mass spectrometry (MS)), which can be used to identify regulated protein targets of transcription factors important in myeloid differentiation and leukaemia.

Loss of genetic material is more common than gain in acute myeloid leukemia with complex aberrant karyotype: a detailed analysis of 125 cases using conventional chromosome analysis and fluorescence in situ hybridization including 24-color FISH.

Patients with acute myeloid leukemia (AML) and a complex aberrant karyotype have a poor outcome despite intensive antileukemic treatment. The aim of this study was to analyze in detail the genetic abnormalities in this subgroup of AML. Therefore, 125 AML cases with complex aberrant karyotype detected by G-banding were examined in addition with 24-color FISH and FISH with locus-specific probes for EGR1 (5q31), D7S522 (7q31), and TP53 (17p13), given that these regions are known to be commonly deleted in AML with a complex aberrant karyotype.

CD40L stimulation enhances the ability of conventional metaphase cytogenetics to detect chromosome aberrations in B-cell chronic lymphocytic leukaemia cells.

Conventional metaphase cytogenetics underestimates the frequency of specific chromosome aberrations in B-cell chronic lymphocytic leukaemia (B-CLL) as a result of the very low proliferative activity of these cells in vitro. New molecular approaches, such as fluorescence in situ hybridization (FISH) or comparative genomic hybridization (CGH), may circumvent this problem, at least in part, but these techniques are either strongly dependent on the knowledge of candidate regions or detect only unbalanced aberrations. In the present study, we analysed 27 B-CLL peripheral blood samples by metaphase cytogenetics after CD40 ligand (CD40L)-induced cell cycle stimulation.

Soluble tumor necrosis factor receptor type II in the early diagnosis of fever in neutropenia.

Sepsis in chemotherapy-associated neutropenia is a major cause of mortality in the treatment of acute myeloid leukemia (AML). Early diagnosis of sepsis is crucial for patient survival. We analyzed the value of prospectively measuring serum concentrations of soluble tumor necrosis factor receptor type II (sTNF-RII) in patients with AML for early diagnosis of sepsis in neutropenia.

Efficient gene transfer of CD40 ligand into primary B-CLL cells using recombinant adeno-associated virus (rAAV) vectors.

B cells of chronic lymphocytic leukemia (B-CLL) are resistant to transduction with most currently available vector systems. Using an optimized adenovirus-free packaging system, recombinant adeno-associated virus (rAAV) vectors coding for the enhanced green fluorescent protein (AAV/EGFP) and CD40 ligand (AAV/CD40L) were packaged and highly purified resulting in genomic titers up to 3 x 10(11)/mL. Cells obtained from 24 patients with B-CLL were infected with AAV/EGFP or AAV/CD40L at a multiplicity of infection (MOI) of 100 resulting in transgene expression in up to 97% of cells as detected by flow cytometry 48 hours after infection.

Fludarabine combination therapy for the treatment of chronic lymphocytic leukemia.

Fludarabine combination therapies have attained an increased popularity in the treatment of chronic lymphocytic leukemia (CLL). Among them, the combination of fludarabine/cyclophosphamide (FC) is by far the best regimen studied. Patients receiving FC at relapse show response rates (RRs) of 70%-94% with 11%-34% complete remission (CR) rates.

Distinct genetic patterns can be identified in acute monoblastic and acute monocytic leukaemia (FAB AML M5a and M5b): a study of 124 patients.

The French-American-British (FAB) classification and the new World Health Organization (WHO) classification distinguish acute monoblastic leukaemia (AML M5a) from acute monocytic leukaemia (AML M5b). Not much is known about the underlying genetic differences leading to these clearly different phenotypes. We analysed 58 patients with de novo AML M5a and 66 patients with de novo AML M5b in comparison with a whole group of 1603 de novo AML.

The protein tyrosine kinase inhibitor SU5614 inhibits VEGF-induced endothelial cell sprouting and induces growth arrest and apoptosis by inhibition of c-kit in AML cells.

Objective: Angiogenesis, the process of new blood vessel formation, is a critical process during growth and metastasis of solid tumors and might also represent a promising therapeutical target in patients with acute myeloid leukemia (AML).

Methods: In this study, we analyzed the expression of vascular endothelial growth factor receptors (VEGFR)-1/2 and its ligand VEGF in AML cell lines and characterized the inhibitory activity of the protein tyrosine kinase (PTK) inhibitor SU5614 on human endothelial and leukemic cells.

Results: Intracellular VEGF expression was detected in 9 of 10 leukemic cell lines.

Heterozygous PU.1 mutations are associated with acute myeloid leukemia.

The transcription factor PU.1 is required for normal blood cell development. PU.

Response to neoadjuvant chemotherapy combined with regional hyperthermia predicts long-term survival for adult patients with retroperitoneal and visceral high-risk soft tissue sarcomas.

Purpose: To determine the efficacy of neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for local tumor control and overall survival (OS) in adult patients with retroperitoneal or visceral (RP/V) high-risk soft tissue sarcomas (HR-STS).

Patients And Methods: From 1991 to 1997, 58 patients with HR-STS at RP/V sites were prospectively treated with four cycles of etoposide, ifosfamide, and doxorubicin combined with RHT followed by surgery, adjuvant chemotherapy, and radiation.

Results: Objective response rate assessable in 40 patients was 13% (five partial responses).

Acute myeloid leukemias with reciprocal rearrangements can be distinguished by specific gene expression profiles.

Acute myeloid leukemia (AML) is a heterogeneous group of genetically defined diseases. Their classification is important with regard to prognosis and treatment. We performed microarray analyses for gene expression profiling on bone marrow samples of 37 patients with newly diagnosed AML.

Granulocyte inducer C/EBPalpha inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions.

Several transcription factors have been implicated as playing a role in myelopoiesis. PU.1, an ets-family transcription factor, is required for the development of myeloid and lymphoid lineages, whereas the transcription factor CCAAT-enhancer binding protein family member C/EBPalpha is essential for granulocyte development.

Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease.

FLT3 length mutation (FLT3-LM) is a molecular marker potentially useful for the characterization of acute myeloid leukemia (AML). To evaluate the distribution of FLT3-LM within biologic subgroups, we screened 1003 patients with AML at diagnosis for this mutation. FLT3-LM was found in 234 (23.

Acute myeloid leukemia: treatment over 60.

Undertreatment of older patients with acute myeloid leukemia (AML) can explain, in part, their inferior outcome when compared to that of younger patients. In agreement with the benefit seen by patients under age 60 from high-dose cytosine arabinoside (Ara-C), there are dose effects in the over 60s, in particular for daunorubicin, in induction treatment and for the duration of postremission treatment. The use of these effects can partly overcome the mostly unfavorable disease biology in older age AML, as expressed by the absence of favorable and the over-representation of adverse chromosomal abnormalities as well as the expression of drug resistance.

Transcription of AML1 in hematopoietic subfractions of normal adults.

The transcription factor AML1 (CBFA2) is indispensable for early fetal hematopoiesis, but also transactivates target genes which are important for further downstream hematopoiesis. However, little is known about the impact of AML1 on lineage-committed stages. We investigated the transcription of AML1 in subfractions of four normal adult bone marrow aspirates isolated by fluorescence-activated cell sorting.