Neuroblastoma is a malignant paediatric tumour of the sympathetic nervous system1. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive2–4. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type1,2,5. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.

Transpedicular screws in the cervical spine and cervicothoracic junction can be applied safely and with high accuracy in a conventional technique. Cannulated screws and the use of separate stab incisions from C3-C6 with a trocar system allow for reduced screw misplacement rates. The CAS system leads to significantly reduced screw misplacement rates. Therefore, because of the potential risk of injury to the vertebral artery and neural elements, the use of a CAS system seems to be beneficial, especially for pedicle instrumentation C3-C6.

BackgroundThe use of chemotherapy to manage newly diagnosed low grade glioma (LGG) was first introduced in the 1980s. One randomised trial has studied two- versus four-drug regimens with a duration of 12 months of treatment after resection.MethodsWithin the European comprehensive treatment strategy for childhood LGG, the International Society of Paediatric Oncology–Low Grade Glioma (SIOP LGG) Committee launched a randomised trial involving 118 institutions and 11 countries to investigate the addition of etoposide (100 mg/m2, days 1, 2 & 3) to a four-course induction of vincristine (1.5 mg/m2 × 10 wkly) and carboplatin (550 mg/m2 q 3 weekly) as part of 18-month continuing treatment programme. Patients were recruited after imaging diagnosis, resection or biopsy with progressive disease/symptoms. Some 497 newly diagnosed patients (M/F 231/266; median age 4.26 years (interquartile range (IQR) 2.02–7.06)) were randomised to receive vincristine carboplatin (VC) (n = 249) or VC plus etoposide (VCE) during induction (n = 248), stratified by age and tumour site.FindingsNo differences between the two arms were found in term of survival and radiological response. Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS. 5-year OS for patients in early progression at week 24 were 46% (StDev 13.8) and 49% (StDev 16.5) in the two arms, respectively.InterpretationThe addition of etoposide to VC did not improve PFS or OS. High non-progression rates at 24 weeks justify retaining VC as standard first-line therapy. Infants with diencephalic syndrome and early progression need new treatments to be tested. Future trials should use neurological/visual and toxicity outcomes and be designed to discriminate between the impact on disease outcomes of ‘duration of therapy’ and ‘age at stopping therapy’.

Overall, vertebroplasty has a low complication rate. Nevertheless, severe complications can occur. The majority of these are related to cement extrusion. The rate of cement leakage is often obtained by X-ray, with only a single leak registration per vertebra. Detection rate of leaks in comparison with CT and inter-observer reliability for X-ray is, in large parts, unknown. We conducted this study to determine the value of fluoroscopy and X-ray used to detect cement leakage as compared to CT scans. Intraoperative findings in lateral fluoroscopy by the surgeon, and postoperative findings in X-rays by two orthopaedic surgeons, were compared with CT scans for the same study group. Multiple cement leakage was considered, and agreement rate was determined. The detection rate for leaks was 34% for lateral X-ray and 48% for lateral and AP view. Additional AP views only enhanced the detection of leaks in the segmental veins. The agreement rate between fluoroscopy/X-ray and CT scans ranged between 66% and 74%, while inter-observer reliability showed only fair agreement. The rate of cement leaks in vertebroplasty is high if multiple leaks are considered in CT scans. Detection rates using X-rays are low and complicated by only fair inter-observer agreement. Leaks in the basivertebral veins are frequently misinterpreted and can lead to severe complications. Therefore, CT scans should be obtained to calculate the exact leakage rate and to assess persistent or new pain occurring postoperatively.

Sevoflurane and isoflurane induce apoptosis in T lymphocytes via increased mitochondrial membrane permeability and caspase-3 activation, but independently of death receptor signaling.

Rationale: Ventilator-induced lung injury (VILI) leads to an unacceptably high mortality. In this regard, the antiinflammatory properties of inhaled carbon monoxide (CO) may provide a therapeutic option. Objectives: This study explores the mechanisms of CO-dependent protection in a mouse model of VILI. Methods: Mice were ventilated (12 ml/kg, 1-8 h) with air in the absence or presence of CO (250 ppm). Airway pressures, blood pressure, and blood gases were monitored. Lung tissue was analyzed for inflammation, injury, and gene expression. Bronchoalveolar lavage fluid was analyzed for protein, cell and neutrophil counts, and cytokines. Measurements and Main Results: Mechanical ventilation caused significant lung injury reflected by increases in protein concentration, total cell and neutrophil counts in the bronchoalveolar lavage fluid, as well as the induction of heme oxygenase-1 and heat shock protein-70 in lung tissue. In contrast, CO application prevented lung injury during ventilation, inhibited stress-gene up-regulation, and decreased lung neutrophil infiltration. These effects were preceded by the inhibition of ventilation-induced cytokine and chemokine production. Furthermore, CO prevented the early ventilationdependent up-regulation of early growth response-1 (Egr-1). Egr-1-deficient mice did not sustain lung injury after ventilation, relative to wild-type mice, suggesting that Egr-1 acts as a key proinflammatory regulator in VILI. Moreover, inhibition of peroxysome proliferatoractivated receptor (PPAR)-g, an antiinflammatory nuclear regulator, by GW9662 abolished the protective effects of CO. Conclusions: Mechanical ventilation causes profound lung injury and inflammatory responses. CO treatment conferred protection in this model dependent on PPAR-g and inhibition of Egr-1.

Inhalation of hydrogen sulfide during mechanical ventilation protects against VILI by the inhibition of inflammatory and apoptotic responses. Hydrogen sulfide confers lung protection independently of its ability to induce mild hypothermia during ventilation.

Objective: To determine predisposing or prognostic factors and mortality rates of patients with Fournier’s gangrene compared to other necrotizing soft tissue infections (NSTI). Material and Methods: Data of 55 intensive care patients (1981–2010) with NSTI were evaluated. Data were collected prospectively. Results: 43.4% of the patients were in septic condition and 27.3% were hemodynamically unstable. Half of the patients showed predisposing factors (52.7%). The lower extremity (63.2%), abdomen (30.9%), and perineum (14.5%) were most affected. Polymicrobial infections were frequent (65.5%, mean 2.8, range: 1–4). The mortality rate was 16.4% (n = 9). An increase was shown for diabetes mellitus (20%), cardiac insufficiency (22.3%), septic condition at presentation (33.3%), abdominal affection (47.1%), and hemodynamic instability (46.7%). Comparing survivors and nonsurvivors, statistical significance was seen with age (p < 0.001), septic condition at admission (p < 0.001), hemodynamic instability (p < 0.001), low blood pressure (p < 0.001), and abdominal affection (p < 0.001). In laboratory findings, an increase of creatine kinase (p < 0.001) and lactate (p < 0.001) and a decrease of antithrombin III (p < 0.007) and the Quick value (p < 0.01) proved to be significant. Conclusion: Patients with Fournier’s gangrene do not differ in all aspects from those with other NSTI. Successful treatment consists of immediate surgical debridement, broad-spectrum antibiotic treatment, and critical care management. Supportive hyperbaric oxygen therapy should be considered.