Royal National Orthopaedic Hospital NHS Trust

Somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in gliomas and acute myeloid leukaemia (AML). Since patients with multiple enchondromas have occasionally been reported to have these conditions, we hypothesized that the same mutations would occur in cartilaginous neoplasms. Approximately 1200 mesenchymal tumours, including 220 cartilaginous tumours, 222 osteosarcomas and another ∼750 bone and soft tissue tumours, were screened for IDH1 R132 mutations, using Sequenom(®) mass spectrometry. Cartilaginous tumours and chondroblastic osteosarcomas, wild-type for IDH1 R132, were analysed for IDH2 (R172, R140) mutations. Validation was performed by capillary sequencing and restriction enzyme digestion. Heterozygous somatic IDH1/IDH2 mutations, which result in the production of a potential oncometabolite, 2-hydroxyglutarate, were only detected in central and periosteal cartilaginous tumours, and were found in at least 56% of these, ∼40% of which were represented by R132C. IDH1 R132H mutations were confirmed by immunoreactivity for this mutant allele. The ratio of IDH1:IDH2 mutation was 10.6 : 1. No IDH2 R140 mutations were detected. Mutations were detected in enchondromas through to conventional central and dedifferentiated chondrosarcomas, in patients with both solitary and multiple neoplasms. No germline mutations were detected. No mutations were detected in peripheral chondrosarcomas and osteochondromas. In conclusion, IDH1 and IDH2 mutations represent the first common genetic abnormalities to be identified in conventional central and periosteal cartilaginous tumours. As in gliomas and AML, the mutations appear to occur early in tumourigenesis. We speculate that a mosaic pattern of IDH-mutation-bearing cells explains the reports of diverse tumours (gliomas, AML, multiple cartilaginous neoplasms, haemangiomas) occurring in the same patient.

BACKGROUND: The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. METHODS: We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. RESULTS: Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of -1.4 percentage points (90% confidence interval [CI], -4.9 to 2.2; 95% CI, -5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). CONCLUSIONS: Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927 .).

Abstract Objective To compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation. Design Systematic review, network meta-analysis, and cost effectiveness analysis. Data sources Medline, PreMedline, Embase, and The Cochrane Library. Eligibility criteria for selecting studies Published randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation. Results 23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin. Conclusions The network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis. Systematic review registration PROSPERO CRD 42013005324.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.

X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care.

Abstract Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage–fusion–bridge cycles, among others, which may lead to chromosomal instability and aneuploidy 1,2 . These copy number alterations contribute to cancer initiation, progression and therapeutic resistance 3–5 . Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas 6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2 . In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations.

STUDY DESIGN: Retrospective review of a prospectively collected database. OBJECTIVE: Our objective was to assess the rates of postoperative wound infection associated with spine surgery. SUMMARY OF BACKGROUND DATA: Although wound infection after spine surgery remains a common source of morbidity, estimates of its rates of occurrence remain relatively limited. The Scoliosis Research Society prospectively collects morbidity and mortality data from its members, including the occurrence of wound infection. METHODS: The Scoliosis Research Society morbidity and mortality database was queried for all reported spine surgery cases from 2004 to 2007. Cases were stratified based on factors including diagnosis, adult (≥ 21 years) versus pediatric (<21 years), primary versus revision, use of implants, and whether a minimally invasive approach was used. Superficial, deep, and total infection rates were calculated. RESULTS.: In total, 108,419 cases were identified, with an overall total infection rate of 2.1% (superficial = 0.8%, deep = 1.3%). Based on primary diagnosis, total postoperative wound infection rate for adults ranged from 1.4% for degenerative disease to 4.2% for kyphosis. Postoperative wound infection rates for pediatric patients ranged from 0.9% for degenerative disease to 5.4% for kyphosis. Rate of infection was further stratified based on subtype of degenerative disease, type of scoliosis, and type of kyphosis for both adult and pediatric patients. Factors associated with increased rate of infection included revision surgery (P < 0.001), performance of spinal fusion (P < 0.001), and use of implants (P < 0.001). Compared with a traditional open approach, use of a minimally invasive approach was associated with a lower rate of infection for lumbar discectomy (0.4% vs. 1.1%; P < 0.001) and for transforaminal lumbar interbody fusion (1.3% vs. 2.9%; P = 0.005). CONCLUSION: Our data suggest that postsurgical infection, even among skilled spine surgeons, is an inherent potential complication. These data provide general benchmarks of infection rates as a basis for ongoing efforts to improve safety of care.

extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues.

In Brief Study Design. Retrospective analysis of patients treated with single and dual growing rods who had completed their course of treatment, had definitive fusion, and had a minimum of 2 years follow-up. Objectives. To determine which technique was the most effective in the management of severe spinal deformity in young children: control of the spinal deformity, spinal growth, and the incidence of complications. Summary of Background Data. Growing rod techniques provide proximal and distal segmental “claw” foundations, but their overall results through definitive fusion have not been clearly determined. Methods. A total of 28 consecutive patients who had growing rod procedures followed through definitive spinal fusions were analyzed. There were three patient groups: Group 1 (N = 5), single submuscular rod and short apical fusion; Group 2 (N = 16), single growing rod alone; and Group 3 (N = 7), dual growing rods. Results. The interval between initial rod insertion and definitive spinal fusion was similar in all three groups. The best overall results occurred in Group 3, whereas the patients in Group 1 had the worse results. Both Groups 2 and 3 provided good initial correction of the spinal deformity and allowed spinal growth. Group 2 had better frontal and sagittal plane balance and the lowest complication rate. Conclusion. The use of growing rods is effective in controlling severe spinal deformities and allowing spinal growth. Dual rods are stronger than single rods and, therefore, provide better initial correction and maintenance of correction. The use of an apical fusion does not appear to be effective over the course of treatment. A total of 28 children with growing rods through definitive fusion were evaluated. There were three groups: Group 1 (N = 5), single rod and short apical fusion; Group 2 (N = 16), single rod; and Group 3 (N = 7), dual rods. Group 3 had the best results with respect to correction and spinal growth. Group 1 had the worst results.

Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.

BACKGROUND: The COVID-19 outbreak has placed the National Health Service under significant strain. Social distancing measures were introduced in the UK in March 2020 and virtual consultations (via telephone or video call) were identified as a potential alternative to face-to-face consultations at this time. LOCAL PROBLEM: The Royal National Orthopaedic Hospital (RNOH) sees on average 11 200 face-to-face consultations a month. On average 7% of these are delivered virtually via telephone. In response to the COVID-19 crisis, the RNOH set a target of reducing face-to-face consultations to 20% of all outpatient attendances. This report outlines a quality improvement initiative to rapidly implement virtual consultations at the RNOH. METHODS: The COVID-19 Action Team, a multidisciplinary group of healthcare professionals, was assembled to support the implementation of virtual clinics. The Institute for Healthcare Improvement approach to quality improvement was followed using the Plan-Do-Study-Act (PDSA) cycle. A process of enablement, process redesign, delivery support and evaluation were carried out, underpinned by Improvement principles. RESULTS: Following the target of 80% virtual consultations being set, 87% of consultations were delivered virtually during the first 6 weeks. Satisfaction scores were high for virtual consultations (90/100 for patients and 78/100 for clinicians); however, outside of the COVID-19 pandemic, video consultations would be preferred less than 50% of the time. Information to support the future redesign of outpatient services was collected. CONCLUSIONS: This report demonstrates that virtual consultations can be rapidly implemented in response to COVID-19 and that they are largely acceptable. Further initiatives are required to support clinically appropriate and acceptable virtual consultations beyond COVID-19. REGISTRATION: This project was submitted to the RNOH's Project Evaluation Panel and was classified as a service evaluation on 12 March 2020 (ref: SE20.09).

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.

Importance: Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear. Objective: To investigate the germline genetic architecture of 1244 patients with osteosarcoma. Design, Setting, and Participants: Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27 173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019. Main Outcomes and Measures: The frequency of rare pathogenic or likely pathogenic genetic variants. Results: Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 × 10-18). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27 173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-associated gene, TP53. Conclusions and Relevance: In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.

STUDY DESIGN: Prospective nonrandomized study. OBJECTIVE: To report the preliminary results of magnetically controlled growing rod (MCGR) technique in children with progressive early-onset scoliosis. SUMMARY OF BACKGROUND DATA: The growing rod (GR) technique is a viable alternative for treatment of early-onset scoliosis. High complication rate is attributed to frequent surgical lengthening. The safety and efficacy of MCGR were recently reported in a porcine model. METHODS: Multicenter study of clinical and radiographical data of patients who underwent MCGR surgery and at least 3 distractions. Distractions were performed in clinic without anesthesia/analgesics. T1-T12 and T1-S1 heights and the distraction distance inside the actuator were measured after lengthening. RESULTS: Fourteen patients (7 girls, 7 boys) with a mean age of 8 years, 10 months (3 yr, 6 mo to 12 yr, 7 mo) had 14 index surgical procedures. Of the 14, 5 had single-rod (SR) surgery and 9 had dual-rod (DR) surgery, with overall 68 distractions. Diagnoses were idiopathic (N = 5), neuromuscular (N = 4), congenital (N = 2), syndromic (N = 2), and neurofibromatosis (N = 1). Mean follow-up was 10 months (5.8-18.2). The Cobb angle changed from 60° to 34° after initial surgery and 31° at latest follow-up. During distraction period, T1-T12 height increased by 7.6 mm for SR (1.09 mm/mo) and 12.12 mm for DR (1.97 mm/mo). T1-S1 height gain was 9.1 mm for SR (1.27 mm/mo) and 20.3 mm for DR (3.09 mm/mo). Complications included superficial infection in 1 SR, prominent implant in 1 DR, and minimal loss of initial distraction in 3 SR after index. Partial distraction loss observed after 14 of the 68 distractions (1 DR and 13 SR) but regained in subsequent distractions. There was no neurological deficit or implant failure. CONCLUSION: Preliminary results indicated MCGR was safe and provided adequate distraction similar to standard GR. DR achieved better initial curve correction and greater spinal height during distraction compared with SR. No major complications were observed during the follow-up.

Giant cell tumor of bone (GCTB) is a locally aggressive subarticular tumor. Having recently reported that H3.3 G34W mutations are characteristic of this tumor type, we have now investigated the sensitivity and specificity of the anti-histone H3.3 G34W rabbit monoclonal antibody in a wide variety of tumors including histologic mimics of GCTB to assess its value as a diagnostic marker. We also determined the incidence of H3.3 G34 mutations in primary malignant bone tumors as assessed by genotype and H3.3 G34W immunostaining. A total of 3163 tumors were tested. Totally, 213/235 GCTB (90.6%) showed nuclear H3.3 p.G34W immunoreactivity. This was not the case for the rare variants, p.G34L, M, and V, which occurred most commonly in the small bones of the hands, patella, and the axial skeleton. If these sites were excluded from the analysis, H3.3 G34W expression was found in 97.8% of GCTB. Malignant bone tumors initially classified as osteosarcomas were the only other lesions (n=11) that showed G34W expression. Notably an additional 2 previously reported osteosarcomas with a p.G34R mutation were not immunoreactive for the antibody. A total of 11/13 of these malignant H3.3-mutant tumors exhibited an osteoclast-rich component: when imaging was available all but one presented at a subarticular site. We propose that subarticular primary malignant bone sarcoma with H3.3 mutations represent true malignant GCTB, even in the absence of a benign GCTB component.

BACKGROUND: Hip fracture is the most common serious injury of older people. The UK National Hip Fracture Database (NHFD) was launched in 2007 as a national collaborative, clinician-led audit initiative to improve the quality of hip fracture care, but has not yet been externally evaluated. METHODS: We used routinely collected data on 471,590 older people (aged 60 years and older) admitted with a hip fracture to National Health Service (NHS) hospitals in England between 2003 and 2011. The main variables of interest were the use of early surgery (on day of admission, or day after) and mortality at 30 days from admission. We compared time trends in the periods 2003-2007 and 2007-2011 (before and after the launch of the NHFD), using Poisson regression models to adjust for demographic changes. FINDINGS: The number of hospitals participating in the NHFD increased from 11 in 2007 to 175 in 2011. From 2007 to 2011, the rate of early surgery increased from 54.5% to 71.3%, whereas the rate had remained stable over the period 2003-2007. Thirty-day mortality fell from 10.9% to 8.5%, compared with a small reduction from 11.5% to 10.9% previously. The annual relative reduction in adjusted 30-day mortality was 1.8% per year in the period 2003-2007, compared with 7.6% per year over 2007-2011 (P<0.001 for the difference). INTERPRETATION: The launch of a national clinician-led audit initiative was associated with substantial improvements in care and survival of older people with hip fracture in England.

BACKGROUND: Warfarin is effective for stroke prevention in atrial fibrillation (AF), but anticoagulation is underused in clinical care. The risk of venous thromboembolic disease during hospitalisation can be reduced by low-molecular-weight heparin (LMWH): warfarin is the most frequently prescribed anticoagulant for treatment and secondary prevention of venous thromboembolism (VTE). Warfarin-related bleeding is a major reason for hospitalisation for adverse drug effects. Warfarin is cheap but therapeutic monitoring increases treatment costs. Novel oral anticoagulants (NOACs) have more rapid onset and offset of action than warfarin, and more predictable dosing requirements. OBJECTIVE: To determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention, treatment and secondary prevention of VTE. DESIGN: Four systematic reviews, network meta-analyses (NMAs) and cost-effectiveness analyses (CEAs) of randomised controlled trials. SETTING: Hospital (VTE primary prevention and acute treatment) and primary care/anticoagulation clinics (AF and VTE secondary prevention). PARTICIPANTS: Patients eligible for anticoagulation with warfarin (stroke prevention in AF, acute treatment or secondary prevention of VTE) or LMWH (primary prevention of VTE). INTERVENTIONS: NOACs, warfarin and LMWH, together with other interventions (antiplatelet therapy, placebo) evaluated in the evidence network. MAIN OUTCOME MEASURES: Major bleeding, clinically relevant bleeding and intracranial haemorrhage. We also considered myocardial infarction and all-cause mortality and evaluated cost-effectiveness. DATA SOURCES: MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library, reference lists of published NMAs and trial registries. We searched MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. The stroke prevention in AF review search was run on the 12 March 2014 and updated on 15 September 2014, and covered the period 2010 to September 2014. The search for the three reviews in VTE was run on the 19 March 2014, updated on 15 September 2014, and covered the period 2008 to September 2014. REVIEW METHODS: Two reviewers screened search results, extracted and checked data, and assessed risk of bias. For each outcome we conducted standard meta-analysis and NMA. We evaluated cost-effectiveness using discrete-time Markov models. RESULTS: , Daiichi Sankyo, Japan) [60 mg od (once daily)] was ranked second for major bleeding and all-cause mortality. Neither the clinical effectiveness analysis nor the CEA provided strong evidence that NOACs should replace postoperative LMWH in primary prevention of VTE. For acute treatment and secondary prevention of VTE, we found little evidence that NOACs offer an efficacy advantage over warfarin, but the risk of bleeding complications was lower for some NOACs than for warfarin. For a willingness-to-pay threshold of > £5000, apixaban (5 mg bd) had the highest expected net benefit for acute treatment of VTE. Aspirin or no pharmacotherapy were likely to be the most cost-effective interventions for secondary prevention of VTE: our results suggest that it is not cost-effective to prescribe NOACs or warfarin for this indication. CONCLUSIONS: NOACs have advantages over warfarin in patients with AF, but we found no strong evidence that they should replace warfarin or LMWH in primary prevention, treatment or secondary prevention of VTE. LIMITATIONS: These relate mainly to shortfalls in the primary data: in particular, there were no head-to-head comparisons between different NOAC drugs. FUTURE WORK: Calculating the expected value of sample information to clarify whether or not it would be justifiable to fund one or more head-to-head trials. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005324, CRD42013005331 and CRD42013005330. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma.Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.

Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS). For AML, low-grade glioma and CC, mutant IDH status is associated with a DNA hypermethylation phenotype, implicating altered epigenome dynamics in the aetiology of these cancers. Here we show that the IDH variants in CS are also associated with a hypermethylation phenotype and display increased production of the oncometabolite 2-hydroxyglutarate, supporting the role of mutant IDH-produced 2-hydroxyglutarate as an inhibitor of TET-mediated DNA demethylation. Meta-analysis of the acute myeloid leukaemia, low-grade glioma, cholangiocarcinoma and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets. By analysing sequence motifs surrounding hypermethylated sites across the four cancer types, and using chromatin immunoprecipitation and western blotting, we identify the transcription factor EBF1 (early B-cell factor 1) as an interaction partner for TET2, suggesting a sequence-specific mechanism for regulating DNA methylation.