Background: Mutations of the stem cell factor receptor C-KIT play a major pathogenetic role in the development of different malignant diseases like human mastocytosis, myeloproliferative disorders, gastrointestinal stromal tumors, acute myelogenous leukemia, and sinonasal lymphomas. Furthermore, the expression of C-KIT has been described in Hodgkin’s disease and nodal CD30(+) anaplastic large cell lymphomas (ALCLs). As it is possible to inhibit C-KIT by innovative kinase inhibitors like STI571, it may be an attractive target for new therapeutical approaches. Therefore, we screened more than 50 different types of cutaneous T-cell lymphomas (TCLs) for the presence of C-KIT. Immunohistochemical stainings were performed on paraffin-embedded tissue sections using a polyclonal rabbit anti-human C-KIT antibody. Naphtol-ASD-chloroacetate esterase (NASDCE)-control stainings were performed on every positive sample to distinguish C-KIT-positive lymphoma cells from C-KIT-positive mast cells. Results: We found weak expression of C-KIT in seven of 18 patients with primary cutaneous CD30(+) ALCL, two of eight patients with primary cutaneous pleomorphic TCL, six of 18 patients suffering from mycosis fungoides, and three of five patients with Sezary’s syndrome. Generally, only a very small population of the lymphoma cells expressed C-KIT. This finding indicates a difference to the systemic variant of CD30(+) ALCL. The potential use of C-KIT targeting new therapeutical approaches is therefore discussed critically, because C-KIT expression is very rare in all investigated types of primary cutaneous lymphoma. Brauns TC, Schultewolter T, Dissemond J, Maschke J, Goos M. C-KIT expression in primary cutaneous T-cell lymphomas.

With the current standard chemotherapy regimens only approximately 25% of acute myelogenous leukaemia (AML) patients survive > 5 years. Aurora kinases are overexpressed in many human cancers. VX-680 inhibited Aurora-A, -B, -C and the FMS-like tyrosine kinase-3 with apparent inhibitory constants of 0.6, 18, 4.6 and 30 nM, respectively. In primary leukaemia cells from patients with AML, which were refractory to standard therapies, VX-680 inhibited colony formation. In nude mice, VX-680 markedly reduced human AML tumours. The development of VX-680 for use in AML should continue.

The differentiation induction of K562 chronic myelogenous leukemia (CML) cells by crambescidin 800, a pentacyclic guanidine alkaloid isolated from a marine sponge, was examined. Crambescidin 800 increased hemoglobin production in K562 cells at concentrations of 0.15-1 microM and arrested the cell cycle of K562 cells at the S-phase. The expression of p21 was detected after 24-h treatment with crambescidin 800, and an increase of the expression was observed after 48-h treatment, but there was no remarkable change in the expression level of p27. This evidence indicates that crambescidin 800 induced the differentiation of K562 cells into erythroblasts accompanied by cell cycle arrest at the S-phase. Furthermore, crambescidin 800 induced a morphological change with neurite outgrowth in Neuro 2A cells at a 0.03-0.1 microM concentration.

BACKGROUND: The objective of the current study was to verify the ability to predict response to imatinib therapy using in vitro assays to evaluate the inhibition of Wilms tumor gene (WT1) expression and colony growth after samples obtained from patients with chronic myelogenous leukemia (CML) before the start of treatment were subjected to short-term incubation with imatinib. METHODS: WT1 transcript levels and colony growth in bone marrow (BM) samples from 23 patients with CML that was later identified as being responsive to imatinib and from 13 patients with CML that was later identified as not being responsive to imatinib were evaluated after incubation of these samples with imatinib at a concentration of 1 microM for 18 hours. In addition, real-time quantitative polymerase chain reaction (RQ-PCR) analysis of WT1 expression was performed during follow-up, and the results were analyzed for associations with cytogenetic response and with BCR/ABL transcript levels as determined using RQ-PCR analysis. RESULTS: Before treatment, it was found that WT1 expression was elevated in BM samples obtained from all patients with CML. WT1 expression and colony growth were reduced significantly after an 18-hour incubation with imatinib in samples obtained from patients who were later identified as responders to treatment, but not in samples obtained from patients who did not experience responses to treatment. Inhibition of WT1 expression in vitro was associated with inhibition of imatinib-induced BCR-ABL tyrosine kinase activity, a finding that also has been made in studies involving certain Philadelphia chromosome (Ph)-positive and Ph-negative cell lines. CONCLUSIONS: Inhibition of WT1 transcript levels after a short period of in vitro exposure of pretherapy BM samples to imatinib was correlated with inhibition of colony growth and may represent the basis for an easy test that is capable of predicting the sensitivity of CML to treatment with imatinib for individual patients. Cancer 2004. Copyright 2004 American Cancer Society.

Anthracycline derivatives often induce cardiomyopathy. Patients with seriously decreased cardiac function due to chemotherapeutic drugs cannot usually receive allogeneic hematopoietic stem cell transplantation (SCT) for hematologic disorders. We successfully performed allogeneic bone marrow transplantation (BMT) in a patient with severe cardiomyopathy. An 18-year-old woman with relapsed acute myelogenous leukemia had cardiomyopathy due to previous anthracycline administration. She underwent allogeneic BMT from her HLA-identical brother. Her preconditioning regimen was cytosine arabinoside, etoposide, total body irradiation, and high-dose cyclophosphamide. Congestive heart failure (CHF) was not present before BMT. Right heart pressures were monitored by a pulmonary arterial balloon catheter system (Swan-Ganz catheter). After BMT, she had severe CHF, which was controlled using pimobendan and amrinone. Patients with cardiomyopathy can receive allogeneic SCT under strict hemodynamic management.

Gastrointestinal stromal tumor is a mesenchymal tumor of the digestive tract. Although there used to be no effective therapy for the tumor, there have been many recent reports on the efficacy of imatinib. We report on a 53-year-old female patient with a primary tumor of the jejunum who underwent 3 operations. As the tumor could not be removed at the 3rd operation, she was given imatinib orally. Results showed significant reduction ratios of the tumor area (83.0%) and volume (92.2%) at 18 months after starting imatinib administration. Also, the mean reduction ratios of the tumor area and volume per month (%/M) after starting imatinib treatment showed remarkable results, especially during the initial 3 weeks: 53.9%/M and 49.5%/M, respectively. Whether imatinib is the first choice of treatment for GIST or not, and what is the appropriate dose and period should be resolved.