Activating c-KIT mutations confer oncogenic cooperativity and rescue RUNX1/ETO-induced DNA damage and apoptosis in human primary CD34+ hematopoietic progenitors.

The RUNX1/ETO (RE) fusion protein, which originates from the t(8;21) chromosomal rearrangement, is one of the most frequent translocation products found in de novo acute myeloid leukemia (AML). In RE leukemias, activated forms of the c-KIT tyrosine kinase receptor are frequently found, thereby suggesting oncogenic cooperativity between these oncoproteins in the development and maintenance of t(8;21) malignancies. In this report, we show that activated c-KIT cooperates with a C-terminal truncated variant of RE, REtr, to expand human CD34+ hematopoietic progenitors ex vivo. CD34+ cells expressing both oncogenes resemble the AML-M2 myeloblastic cell phenotype, in contrast to REtr-expressing cells which largely undergo granulocytic differentiation. Oncogenic c-KIT amplifies REtr-depended clonogenic growth and protects cells from exhaustion. Activated c-KIT reverts REtr-induced DNA damage and apoptosis. In the presence of activated c-KIT, REtr-downregulated DNA-repair genes are re-expressed leading to an enhancement of DNA-repair efficiency via homologous recombination. Together, our results provide new mechanistic insight into REtr and c-KIT oncogenic cooperativity and suggest that augmented DNA repair accounts for the increased chemoresistance observed in t(8;21)-positive AML patients with activated c-KIT mutations. This cell-protective mechanism might represent a new therapeutic target, as REtr cells with activated c-KIT are highly sensitive to pharmacological inhibitors of DNA repair.

Infections from CVC in the pediatric neoplastic patient. Single institution experience.

AIM: The present clinical study was carried out in order to evaluate in a perspective way the incidence of the infections caused by CVC, the micro-organisms mostly involved in the infectious process, the condition of aplasia in patients when blood cultures show positiveness and the incidence of removals expressed as number of performed removals/number of positive blood culture. METHODS: Between January 2003 and December 2009 452 blood cultures from CVC were carried out on 120 patients affected by acute lymphoblastyic and myelougenous leukemia (38), Hodgkin and non-Hodgkin lymphoma (17) and solid tumors (65), with an average of 65 blood cultures per year showing an average positiveness of 21 cases/year. The blood cultures were performed, in hyperpyrexia, when there was a clinical suspicion of infection from CVC. RESULTS: On 452 blood cultures from CVC carried out (31.4% positive per Gram +, 53.7% per Gram-, 14.9% per miceti) 128 (28.3%) resulted positive, excluding presumed contaminations. They were divided as follows: 21 of Staphylococcus epidermidis (16%), 10 of Escherichia coli (8%), 10 of Klebsiella pneumoniae (8%), 8 of Pseudomonas aeruginosa (6%), 8 of Staphylococcus aureus (6%), 6 of Enterobacter cloacae (5%), 4 of Candida parapsilosis (3%) and 61 of other micro-organisms (48%). It was necessary to perform 27 CVC removals. The micro-organisms most frequently involved in removals of the CVC were finally analyzed and the resulting frequency percentages are: - 85% for Gram- germs; -8% for Gram + germs; -7% for Mycete. CONCLUSION: Our clinical study has confirmed that in pediatric age neoplastic individuals there is a prevalence of CVC-correlated infections from Gram- and an elevated association of removals of the CVC caused by infections from Pseudomonas and Klebsiella, germs more frequently associated to clinical conditions of marked aplastic anemia.

Endovascular radiofrequency renal denervation in treating refractory arterial hypertension: a preliminary experience.

PURPOSE: This study was done to investigate the efficacy and safety of percutaneous renal denervation with the Symplicity catheter for reducing blood pressure in patients with essential hypertension resistant to medical therapy (systolic blood pressure >160 mmHg despite the use of three or more antihypertensive drugs, including a diuretic). MATERIALS AND METHODS: In September 2010, five patients affected by essential hypertension resistant to medical therapy were treated. All patients were studied by computed tomography angiography (CTA) of the renal arteries before the procedure and underwent follow-up at 30 and 60 days with colour Doppler ultrasound (CDUS) with evaluation of resistive index, glomerular filtration rate (GFR), 24-h blood pressure and serum catecholamine concentration. Student's t test was used to assess the effectiveness of the procedure in lowering blood pressure. RESULTS: In treated patients, mean blood pressure at baseline was 171/100 mmHg [standard deviation (SD) ± 8/10]; mean GFR was 91.6 ml/min/1.73 m(2) (SD ± 15). Blood pressure after the procedure was reduced by -18/-5 and -13/-10 mmHg at 30 and 60 days, respectively, with a mean medication reduction of 3.6. No complications occurred during the intra- or periprocedural period or during short-term follow-up. CONCLUSIONS: The Symplicity system proved to be efficacious and without serious adverse events in reducing blood pressure and antihypertensive medication use in patients affected by essential hypertension resistant to medical therapy. Although encouraging, our data are preliminary and need to be validated by larger prospective randomised studies.