Constitutive activation of the MAPkinase p38 is critical for MMP-9 production and survival of B-CLL cells on bone marrow stromal cells.

In the present work we investigated the role and biological significance of mitogen activated protein kinases (MAPK) in B-cell chronic lymphocytic leukaemia (B-CLL). The MAPK p38 was constitutively activated in B-CLL, but not in normal peripheral B cells. In addition, we demonstrated that the upstream kinases of p38, MKK3/6 were also constitutively activated in B-CLL cells.

A cell-based screen for resistance of Bcr-Abl-positive leukemia identifies the mutation pattern for PD166326, an alternative Abl kinase inhibitor.

In Philadelphia-positive (Ph(+)) leukemia, point mutations within the Bcr-Abl kinase domain emerged as a major mechanism of resistance to imatinib mesylate. We established a cell-based screening strategy for detection of clinically relevant point mutations using Bcr-Abl-transformed Ba/F3 cells. We identified 32 different single-point mutations within the kinase domain of Bcr-Abl.

[An alternative Abl-kinase inhibitor overcomes imatinib resistance mutations of Bcr-Abl oncogenes].

Background And Objective: The tyrosinkinase inhibitor Imatinib is active in Philadelphia-positive (Ph+) leukemia. Mutations within the Bcr-Abl kinase domain represent the major cause for clinical resistance toward imatinib. We aimed to examine, whether the alternative Abl Kinaseinhibitor SKI-DV 2 - 43 may be capable of suppressing the growth of cells expressing mutant forms of Bcr-Abl.

Incidence of anemia in patients receiving neoadjuvant chemotherapy for locally advanced esophagogastric cancer.

Background: There is rising evidence that anemia and blood transfusion increase perioperative mortality in cancer patients. Patients who are treated with neoadjuvant chemotherapy with a curative intent are exposed to toxicity that may negatively affect their future outcome.

Methods: The charts of 29 patients (21 males; median age, 59.

Neoadjuvant therapy for oesophagogastric cancer.

Background: The prognosis after surgery for oesophagogastric cancer remains poor.

Methods: This review clarifies current indications for neoadjuvant therapy for oesophageal and gastric cancer. A systematic literature research and evaluation of data from international cancer meetings were carried out.

Expression of cyclin E in resting and activated B-chronic lymphocytic leukaemia cells: cyclin E/cdk2 as a potential therapeutic target.

Disease progression in B-cell chronic lymphocytic leukaemia (B-CLL) is determined by the interplay between proliferation kinetics in the proliferating compartment and cell death in the accumulating compartment. Improving our knowledge of cell cycle regulation in B-CLL cells might therefore be important for identifying therapeutic targets. Cyclin E was detected by Western blotting in purified B-CLL cells from peripheral blood samples of all 12 patient tested but not in normal peripheral blood B cells.

The impact of delayed chemotherapy-induced nausea and vomiting on patients, health resource utilization and costs in German cancer centers.

Background: Delayed chemotherapy-induced nausea and vomiting (CINV) remains a major adverse effect of cancer chemotherapy. We assessed, under current practice patterns, the occurrence and impact on healthcare resource utilization of CINV in patients receiving emetogenic chemotherapy. An additional aim of this study was to estimate costs imputable to CINV in the German healthcare environment.

Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells.

A new class of cell cycle inhibitors is currently entering clinical trials. These drugs exert their activity by inhibition of cyclin-dependent kinases (cdk) and induce cell cycle arrest and apoptosis in cancer cells. Roscovitine, a cdk2-inhibitor that is in preclinical evaluation, induced apoptosis in B-CLL cells at doses that were not cytotoxic for normal human B cells.

Efficacy and safety of imatinib in adult patients with c-kit-positive acute myeloid leukemia.

This phase 2 pilot study was conducted to determine the efficacy and safety of imatinib mesylate in patients with c-kit-positive acute myeloid leukemia (AML) refractory to or not eligible for chemotherapy. Twenty-one patients were enrolled and received imatinib 600 mg orally once daily. Five responses were seen primarily in patients, starting with relatively low blast counts in bone marrow (BM) and peripheral blood (PB): 2 patients who were considered refractory on chemotherapy on the basis of persistence of blasts in PB and BM met the criteria for complete hematologic remission, 1 patient had no evidence of leukemia, and 2 patients achieved a minor response.

Melanoma-reactive class I-restricted cytotoxic T cell clones are stimulated by dendritic cells loaded with synthetic peptides, but fail to respond to dendritic cells pulsed with melanoma-derived heat shock proteins in vitro.

Immunization with heat shock proteins (hsp) isolated from cancer cells has been shown to induce a protective antitumor response. The mechanism of hsp-dependent cellular immunity has been attributed to a variety of immunological activities mediated by hsp. Hsp have been shown to bind antigenic peptides, trim the bound peptides by intrinsic enzymatic activity, improve endocytosis of the chaperoned peptides by APCs, and enhance the ability of APCs to stimulate peptide-specific T cells.

Report of a male patient with brain metastases from breast cancer.

As in female patients, the clinical course in male patients with breast cancer is determined mainly by tumor stage. The literature contains very limited data on either the occurrence or the treatment of CNS metastases. This paper presents the case report of a 69-year-old man with multiple brain metastases 7 years after a diagnosis of lymph-node positive breast cancer, which had earlier already spread to the bones and liver.

Inhibition of wild-type and mutant Bcr-Abl by pyrido-pyrimidine-type small molecule kinase inhibitors.

Imatinib mesylate (STI571, Glivec), a 2-phenylaminopyrimidine small-molecule ATP competitor-type kinase inhibitor, proved to be active in Philadelphia-positive leukemias. Resistance toward imatinib develops frequently in advanced-stage Philadelphia-positive leukemia, and is even observed in chronic-phase chronic myelogenous leukemia. Point mutations within the BCR-ABL kinase domain emerged as a major mechanism of resistance toward imatinib.

Sustained expansion and transgene expression of coagulation factor VIII-transduced cord blood-derived endothelial progenitor cells.

Objective: Although hemophilia A seems particularly suitable for gene therapy because even low amounts of plasma coagulation factor VIII (FVIII) provide a significant clinical benefit to the patients, the ideal target cell for recombinant FVIII expression and gene therapy approaches remains to be identified. In this study, we tested the capacity of cord blood-derived endothelial progenitor cells (CBECs) for FVIII expression on stable lentiviral transduction.

Methods And Results: CD34+ endothelial progenitor cells (EPCs) from cord blood were differentiated into CBECs.

Induction of caspase-dependent programmed cell death in B-cell chronic lymphocytic leukemia by anti-CD22 immunotoxins.

B cells of chronic lymphocytic leukemia (CLL) are long-lived in vivo, possibly because of defects in apoptosis. We investigated BL22, an immunotoxin composed of the Fv portion of an anti-CD22 antibody fused to a 38-kDa Pseudomonas exotoxin-A fragment. B cells from 22 patients with CLL were immunomagnetically enriched (96% purity) and were cultured with BL22 or an immunotoxin that does not recognize hematopoietic cells.

Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron.

Background: Although all first-generation 5-HT(3) receptor antagonists demonstrate efficacy in preventing acute chemotherapy-induced nausea and vomiting (CINV), effective prevention of delayed CINV has not yet been achieved. This study compared the efficacy and tolerability of palonosetron, a novel, second-generation 5-HT(3) receptor antagonist, with ondansetron.

Patients And Methods: In this multicenter, randomized, double-blind, stratified, phase III study, 570 adult cancer patients were randomized to receive a single i.

Phosphorylation of tyrosine 393 in the kinase domain of Bcr-Abl influences the sensitivity towards imatinib in vivo.

The Bcr-Abl fusion protein arising through the t(9;22)(q34;q11) reciprocal translocation is the causative agent in chronic myeloid leukemia and a subset of acute lymphocytic leukemia. Imatinib mesylate is a specific inhibitor of the Bcr-Abl kinase and has shown promising results in clinical studies. The structural relation between the Bcr-Abl oncogene and the tyrosine kinase inhibitor imatinib has recently been elucidated by an elegant crystal structure analysis, emphasizing the importance of dephosphorylated tyrosine 393 (Tyr393) in Bcr-Abl for access of the inhibitor to the kinase domain.

[Interdisciplinary psychoeducational intervention by oncologists proved helpful for cancer patients].

Objectives: We prospectively evaluated the effects of a six-session psychoeducational intervention held by medical doctors or psychologists in a German acute cancer center setting.

Methods: A cluster randomization was used to assign n=108 oncologic patients (55 female, 53 male; mean age=58.5) to the intervention or the control group.

Phase II trial of irinotecan plus docetaxel in cisplatin-pretreated relapsed or refractory oesophageal cancer.

This phase II trial assessed the toxicity and efficacy of irinotecan plus docetaxel in cisplatin-pretreated oesophageal cancer. Irinotecan 160 mg m(-2) plus docetaxel 65 mg m(-2) once every 3 weeks led to severe myelosuppression in four patients, all of whom experienced neutropenic fever. After amendment of this regimen, 24 patients (male/female=18/6; median age=58.

The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) induces two distinct malignant phenotypes in a murine retroviral transplantation model.

A t(2;5) (p23;q35) chromosomal translocation can be found in a high percentage of anaplastic large-cell lymphomas (ALCL). This genetic abnormality leads to the expression of the NPM-ALK fusion protein, which encodes a constitutively active tyrosine kinase that plays a causative role in lymphomagenesis. Employing a modified infection/transplantation protocol utilizing an MSCV-based vector, we were able to reproducibly induce two phenotypically different lymphoma-like diseases dependent on the retroviral titers used.

Positron emission tomography in non-small-cell lung cancer: prediction of response to chemotherapy by quantitative assessment of glucose use.

Purpose: To prospectively evaluate the use of positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) to predict response to chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC).

Patients And Methods: Patients with stage IIIB or IV NSCLC scheduled to undergo platinum-based chemotherapy were eligible for this study. Patients were studied by FDG-PET before and after the first cycle of therapy.

Inhibition of the proteasome induces cell cycle arrest and apoptosis in mantle cell lymphoma cells.

Mantle cell lymphoma (MCL) is a distinctive non-Hodgkin's lymphoma subtype, characterized by overexpression of cyclin D1 as a consequence of the chromosomal translocation t(11;14)(q13;q32). MCL remains an incurable disease, combining the unfavourable clinical features of aggressive and indolent lymphomas. The blastic variant of MCL, which is often associated with additional cytogenetic alterations, has an even worse prognosis and new treatment options are clearly needed.

Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back.

Cancer research within the last decades elucidated signaling pathways and identified genes and proteins that lead or contribute to malignant transformation of a cell. Discovery of the Bcr-Abl oncoprotein as the molecular abnormality causing chronic myeloid leukemia (CML) paved the way for the development of a targeted anticancer therapy. The substantial activity of imatinib mesylate (STI571, Glivec) in CML and Philadelphia (Ph)-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) changed the therapeutic approach to Ph+ leukemia and rang the bell for a new era of anticancer treatment.

Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA).

Anaplastic large-cell lymphoma is a subtype of non-Hodgkin lymphomas characterized by the expression of CD30. More than half of these lymphomas carry a chromosomal translocation t(2;5) leading to expression of the oncogenic tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). NPM-ALK is capable of transforming fibroblasts and lymphocytes in vitro and of causing lymphomas in mice.