Genetic landscape of ultra-stable chronic lymphocytic leukemia patients.

Background: Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course. Beside patients requiring immediate treatment, others show an initial indolent phase followed by progression and others do not progress for decades. The latter two subgroups usually display mutated IGHV genes and a favorable FISH profile. Patients and methods: Patients with absence of disease progression for over 10 years (10-34) from diagnosis were defined as ultra-stable CLL (US-CLL). Forty US-CLL underwent extensive characterization including whole exome sequencing (WES), ultra-deep sequencing and copy number aberration (CNA) analysis to define their unexplored genetic landscape. Microarray analysis, comparing US-CLL with non-US-CLL with similar immunogenetic features (mutated IGHV/favorable FISH), was also carried out to recognize US-CLL at diagnosis. Results: WES was carried out in 20 US-CLL and 84 non-silent somatic mutations in 78 genes were found. When re-tested in a validation cohort of 20 further US-CLL, no recurrent lesion was identified. No clonal mutations of NOTCH1, BIRC3, SF3B1 and TP53 were found, including ATM and other potential progression driving mutations. CNA analysis identified 31 lesions, none with known poor prognostic impact. No novel recurrent lesion was identified: most cases showed no lesions (38%) or an isolated del(13q) (31%). The expression of 6 genes, selected from a gene expression profile analysis by microarray and quantified by droplet digital PCR on a cohort of 79 CLL (58 US-CLL and 21 non-US-CLL), allowed to build a decision-tree capable of recognizing at diagnosis US-CLL patients. Conclusions: The genetic landscape of US-CLL is characterized by the absence of known unfavorable driver mutations/CNA and of novel recurrent genetic lesions. Among CLL patients with favorable immunogenetics, a decision-tree based on the expression of 6 genes may identify at diagnosis patients who are likely to maintain an indolent disease for decades.

[Closure of Botallo's ductus arteriosus with indomethacin. Considerations on 4 cases]. / Chiusura del dotto arterioso di Botallo con indometacina. Considerazioni su quattro casi.

Persistence of Patent Ductus Arteriosus (PDA) frequently occurs in preterm infants. In a remarkable number of cases, PDA may undergo spontaneous closure. In other cases, especially in patients with respiratory problems, a ductal left-to-right shunt may compromise the cardiac-respiratory function. Until a few years ago, surgery was the only possible therapy. Recently, pharmacological closure of the duct by means of Indomethacin, a powerful inhibitor of prostaglandin synthesis, was successfully carried out. The medical treatment, however, appears to be less effective if it is carried out on patients older than 2 weeks. It has also been reported that in patient with a very low birthweight and with lack of muscular tissue in the duct wall, closure of the duct may be transient. It is the purpose of this communication to report observations made on 4 preterm infants of 24-33 weeks gestational age, and with a weight range of 660 to 2.280 g. They received Indomethacin via naso-gastric tube, in a single dose of 0,3 mg/Kg, within 8 days of age. Successful closure of the PDA was obtained in all cases. The pharmacological treatment resulted also in reductions in ventilatory support requirements, reduced respiratory component of acidosis, reduced pCO2, increased pO2. A second administrations of Indo was necessary only in one case, and it was followed by permanent closure of the duct. Collateral effects, such as reduced diuresis and reduced number of platelets, were transient. Indo therapy was successful regardless of very low birthweight: in three cases, birthweight was under 1.000 g.(ABSTRACT TRUNCATED AT 250 WORDS)