Expression profiling of extramedullary acute myeloid leukemia suggests involvement of epithelial-mesenchymal transition pathways.

Extramedullary (EM) colonization is a rare complication of acute myeloid leukemia (AML), occurring in about 10% of patients, but the processes underlying tissue invasion are not entirely characterized. Through the application of RNAseq technology, we examined the transcriptome profile of 13 AMLs, 9 of whom presented an EM localization. Our analysis revealed significant deregulation within the extracellular matrix (ECM)-receptor interaction and focal-adhesion pathways, specifically in the EM sites. The transcription factor TWIST1, which is known to impact on cancer invasion by dysregulating epithelial-mesenchymal-transition (EMT) processes, was significantly upregulated in EM-AML. To test the functional impact of TWIST1 overexpression, we treated OCI-AML3s with TWIST1-siRNA or metformin, a drug known to inhibit tumor progression in cancer models. After 48 h, we showed downregulation of TWIST1, and of the EMT-related genes FN1 and SNAI2. This was associated with significant impairment of migration and invasion processes by Boyden chamber assays. Our study shed light on the molecular mechanisms associated with EM tissue invasion in AML, and on the ability of metformin to interfere with key players of this process. TWIST1 may configure as candidate marker of EM-AML progression, and inhibition of EMT-pathways may represent an innovative therapeutic intervention to prevent or treat this complication.

Bacteriological and clinical evaluation of cefotetan in the treatment of severe infections in hospitalized patients.

The authors studied 302 hospitalized patients, 164 males and 138 females aged 15-88 years (average 66 years), with severe infections. Cefotetan was administered to 278 of them at the dose of 1 or 2 g, b.i.d. or a single daily dose i.m. Other patients [24] were treated with a continuous intravenous infusion of cefotetan (3 g daily in 5% dextrose). Of these patients 121 were treated for urinary tract infections (UTI); 114 for respiratory tract infections (RTI); 41 for liver biliary duct infections (BDI); 17 for skin or skin structure infections (SKI); 6 for fever of unknown origin and 3 for sepsis. The following Gram-positive organisms [156] were isolated: Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus group D; and the following Gram-negative organisms [122]: Escherichia coli, Proteus vulgaris, Proteus mirabilis, Serratia spp., Klebsiella spp., Haemophilus influenzae and Pseudomonas aeruginosa. The overall eradication rate for Gram-positive organisms was 74% and for Gram-negative organisms it was 88%. The clinical response was satisfactory in 87.7% of patients (specifically, cefotetan was effective in 90% of UTI, 84.2% of RTI, 97.5% of BDI and 82.3% of SKI). The drug was well tolerated and side-effects (such as skin rash, diarrhoea, purpura and pain at the site of injection) occurred in only 4% of patients treated with cefotetan. In conclusion, cefotetan appears to be safe and highly effective for the treatment of severe infections in hospitalized patients.