Mast cell disorders are defined by an abnormal accumulation of tissue mast cells (MCs) in one or more organ systems. Symptoms in mastocytosis result from MC-derived mediators and, less frequently, from destructive infiltration of MCs. Cutaneous mastocytosis (CM) is a benign disease of the skin and may regress spontaneously. Systemic mastocytosis (SM) is a persistent disease in which a somatic c-kit mutation at codon 816 is usually detectable in MCs and their progenitors. The clinical course in these patients is variable ranging from asymptomatic for years to highly aggressive and rapidly devastating. The WHO discriminates five categories of SM: indolent SM (ISM), aggressive SM (ASM), SM with associated clonal hematological non-MC-lineage disease (AHNMD), and mast cell leukemia (MCL). The c-kit mutation D816V is quite common and may be found in all SM-categories. In SM-AHNMD, additional genetic abnormalities have been reported, whereas no additional defects are yet known for ASM or MCL. Patients with ISM and CM are treated with “mediator-targeting” drugs, whereas patients with ASM or MCL are candidates for cytoreductive therapy. The use of “Kit-targeting” tyrosine kinase inhibitors such as STI571 (Imatinib, Gleevec), has also been suggested. However, the D816V mutation of c-kit is associated with relative resistance against STI571. Therefore, these patients require alternative targeted drugs or new drug-combinations. In patients with SM-AHNMD, separate treatment plans for the SM-component and the AHNMD should be established. Examples include the use of STI571 in patients with SM plus hypereosinophilic syndrome (SM-HES) and the FIPL1/PDGFRA fusion gene target, or chemotherapy for eradication of AML in patients with SM-AML.

It is now widely recognized that the activated hepatic stellate cells (HSC) play a pivotal role in the liver fibrosis development. A platelet-derived growth factor (PDGF) is the most potent mitogen for the HSC. The aim of this study was to examine the effect of imatinib mesylate (STI571; Gleevec), which is a clinically used PDGF receptor (PDGFR) tyrosine kinase inhibitor, on the experimental liver fibrosis development. The rat model of pig serum-induced hepatic fibrosis was used to assess the effect of daily oral administration of STI571 on the indices of fibrosis. STI571 markedly attenuated the liver fibrosis development, hepatic hydroxyproline and serum fibrosis markers. The number of alpha-smooth muscle actin (alpha- SMA)-positive cells, and the mRNA expressions of alpha2-(I)-procollagen, tissue inhibitor of metalloproteinases-1 (TIMP-1), and transforming growth factor-beta (TGF-beta) were also significantly suppressed by STI571 treatment. Our in vitro study showed that STI571 markedly attenuated the PDGF-BB-induced proliferation, migration, and alpha-SMA, alpha2-(I)-procollagen mRNA of the activated HSC in a dose-dependent manner. STI571 also significantly attenuated the PDGF-BB-induced phosphorylation of PDGFR-beta, MEK1/2, and Akt in the activated HSC. Because STI571 is widely used in the clinical practice, this drug may provide an effective new strategy for anti-fibrosis therapy.

Over 60 years old, acute lymphoblastic leukemia (ALL) represents between 16 and 31% of all adult cases. Pre-B and common ALL are frequent, while T-cell lineage ALL is under-represented in elderly populations as compared with younger adults. The frequency of Philadelphia chromosome seems also to increase with age and adversely influences complete remission (CR) and survival rates. Poor performance status, co-morbidity factors and early mortality during intensive induction chemotherapy are the main reasons for poor outcome. Few reports on effectiveness and toxicity of therapeutic regimens involving exclusively elderly patients with ALL have been published and only some of them were prospective studies. Age-adapted approaches with less aggressive chemotherapy have been applied. The overall response ranged from 12 to 85%. Toxic death during induction chemotherapy was observed in 7 to 42% of the patients. Among the patients who received a curative approach, the median overall survival duration ranged from 3 to 14 months, while it ranged from 1 to 14 months for those treated palliatively. New therapeutic approaches are warranted to improve the outcome in this age group of ALL patients.

The use of imatinib mesylate (Gleevec), a selective tyrosine kinase inhibitor, has become the new gold standard for the treatment of chronic myeloid leukemia. Unfortunately, the medication has been commonly associated with mild to severe cutaneous reactions, which has limited its use for some patients. We describe a case of a successful progressive challenge of a patient with a drug-induced exanthem from imatinib mesylate and a review of the literature.

BACKGROUND: Cholangiocarcinoma is a highly malignant, usually fatal cancer with limited therapeutic options. Receptor tyrosine kinases contribute to the development and progression of this cancer. The relatively selective tyrosine kinase inhibitor imatinib mesylate (STI-571 or Gleevec(R)) has recently been licensed. However, the ability of this drug to inhibit signal transduction and induce apoptosis in human cholangiocarcinoma cells is incompletely studied. Thus, our goal was to examine the ability of STI-571 to induce apoptosis in KMCH-1 cells, a human cholangiocarcinoma cell line. METHODS: Apoptosis was assessed morphologically and also biochemically by measuring caspase activity and the mitochondrial membrane potential. STI-571 induced apoptosis and inhibited growth of KMCH-1 cells in a time- and concentration-dependent manner. The induction of apoptosis was accompanied by mitochondrial depolarization followed by a 4.5-fold increase in caspase activation and was abrogated by the pancaspase inhibitor z-VAD(OMe)-fmk. Interestingly, cholangiocarcinoma cells do not express detectable PDGFR, c-Abl or c-Kit, which are protein kinases known to be directly inhibited by STI-571. However, a significant decrease in epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK) phosphorylation was observed following treatment with STI-571. This decrease in EGFR and FAK phosphorylation was associated with a reduction in Akt activity resulting in loss of Mcl-1, a potent anti-apoptotic Bcl-2 family protein. CONCLUSIONS: These results indicate that STI-571 induces caspase-dependent apoptosis in a human cholangiocarcinoma cell line and suggest that STI-571 might warrant further investigation as a possible agent for treatment of human cholangiocarcinoma.