A sketch of known and novel MYCN-associated miRNA networks in neuroblastoma

Neuroblastoma (NB) originates from neural crest-derived precursors and represents the most common childhood extracranial solid tumour. MicroRNAs (miRNAs), a class of small non-coding RNAs that participate in a wide variety of biological processes by regulating gene expression, appear to play an essential role within the NB context. High-throughput next generation sequencing (NGS) was applied to study the miRNA transcriptome in a cohort of NB tumours with and without MYCN-amplification (MNA and MNnA, respectively) and in dorsal root ganglia (DRG), as a control. Out of the 128 miRNAs differentially expressed in the NB vs. DRG comparison, 47 were expressed at higher levels, while 81 were expressed at lower levels in the NB tumours. We also found that 23 miRNAs were differentially expressed in NB with or without MYCN-amplification, with 17 miRNAs being upregulated and 6 being downregulated in the MNA subtypes. Functional annotation analysis of the target genes of these differentially expressed miRNAs demonstrated that many mRNAs were involved in cancer-related pathways, such as DNA-repair and apoptosis as well as FGFR and EGFR signalling. In particular, we found that miR-628-3p negatively affects MYCN gene expression. Furthermore, we identified a novel miRNA candidate with variable expression in MNA vs. MNnA tumours, whose putative target genes are implicated in the mTOR pathway. The present study provides further insight into the molecular mechanisms that correlate miRNA dysregulation to NB development and progression

Gefitinib in combination with oral topotecan and cyclophosphamide in relapsed neuroblastoma: Pharmacological rationale and clinical response

Aim. Activity and toxiciy of gefitinib in combination with topotecan and cyclophosphamide (CPA) were evaluated in a case-series of relapsed neuroblastoma (NB) patients. The in vitro activity of the combination was also assessed. Procedure. Gefitinib (250 mg/ day), topotecan (0.8 mg/m2/day), and CPA (50 mg/m2/day) (GTC) were administered orally for 14 consecutive days out of 28 days. Antitumor activity of gefitinib as single agent and in combination with either topotecan or CPA was assessed in a panel of NB cell lines. Results. Ninety-two courses were given in 10 patients. Grade 4 neutropenia was observed in 7/92 courses (8%) and grade 4 thrombocytopenia in 8/92 (9%). Two patients had a grade 2 liver toxicity, four a grade 1/2 skin toxicity, and two a grade 1/2 diarrhea. Dose reduction of topotecan and/or CPA was required in eight patients. After four courses, three patients were in partial response (PR) and four with a stable disease (SD), while three experienced a progressive disease (PD). Time to progression (TTP) was 9 months (range, 1-27). After a median follow-up of 16 months (range 5-54), seven patients are died of disease (DOD) and three alive with disease (AWD). All but one patient discontinued oral chemotherapy because of a PD, whilst one patient stopped chemotherapy after 27 months with a SD. In vitro, gefitinib was synergistic with topotecan and additive with CPA. Conclusion. The GTC combination was well tolerated and the TTP was encouraging. These promising results, also supported by in vitro evidence, should be further confirmed in a phase II study. © 2009 Wiley-Liss, Inc

Infective Endocarditis in People Who Inject Drugs: Report from the Italian Registry of Infective Endocarditis

Intravenous drug use is a predisposing condition for infective endocarditis (IE). We report the clinical features of IE, taken from the Italian Registry of IE, in people who inject drugs (PWIDs). The registry prospectively collected epidemiological, clinical, in-hospital, and follow-up data on patients with IE from 17 Italian centers. A total of 677 patients were enrolled, and 61 (9%) were intravenous drug users (IDUs). Most PWIDs were male (78.6%), and aged between 41 and 50 years old (50%). The most frequent comorbidities were HIV (34.4%) and chronic liver disease (32%). Predisposing factors for IE were present in 6.5% of the patients, and 10% had minor valvular abnormalities. IE had occurred previously in 16.4% of the patients, and 50% of them had undergone heart surgery. Overall mortality was 9.8% in IDUs and 20% in patients with recurrent IE. IE in PWIDs mostly affected the native valves (90%). The echocardiographic diagnosis of IE was based on the detection of vegetation in 91.82% of cases. Staphylococcus aureus was the main microorganism isolated (70%) from blood cultures. Thirty patients (49%) underwent heart surgery: thirteen had aortic valves, eleven had mitral valves, and six had tricuspid valve interventions. IE in PWIDs was relatively common, and patients with native valve right-sided IE had a better prognosis, with a low rate of surgical interventions