Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Bone-tendon and bone-ligament interface

Reconstruction or repair of ligaments and tendons to bone, following injury, to improve joint function is a very common surgical procedure in orthopedics. The most common surgical ligament reconstruction in humans is anterior cruciate ligament (ACL) reconstruction. Because ACL is not amenable to repair after tear, replacement of the ligament using autograft or allograft tissue is currently the treatment of choice for young and active patients. On the other hand, surgical reattachment to bone is the most reliable treatment in case of rotator cuff tendon tears. Tendon grafting or repair to bone is performed during hand, foot, and ankle surgery. Nowadays, ACL reconstruction and repair of rotator cuff tendon tears are the most commonly performed surgical procedures for soft tissue injuries in orthopedics. © 2014 Springer-Verlag London. All rights are reserved

Complex elbow Instability: treatment and rehabilitation

Complex elbow instability represent a challenging injury even for expert elbow surgeons. Chronic instability, posttraumatic osteo-arthritis, stiffness and poor functional outcomes are frequent if these injuries are not adequately treated. A correct preoperative evaluation includes X-rays, CT scan with 2D and 3D reconstruction and stability tests under fluoroscopy in order to recognize all osseous and ligamentous lesions. The most common patterns of complex elbow instability includes: (1) radial head fractures associated with lateral and medial collateral ligaments lesions; (2) coronoid fractures and lateral collateral ligament lesion; (3) Terrible Triad; (4) fracture-dislocations of the proximal ulna and radius, also referred to as transolecranon fracture-dislocations and Monteggia-like lesions; and (5) humeral shear fractures associated with lateral and medial collateral ligament lesions. The main goals of the treatment are (1) to perform a stable osteosynthesis of all fractures, (2) to obtain concentric and stable reduction of the elbow throught the repair of soft tissue constraint lesions and (3) to allow early motion. All the patterns of complex elbow instability share the same therapeutic algorithm based on seven main principles: 1) the proximal ulna must be anatomically reduced and fixed; 2) the radial head or humeral shear fracture must be repaired or replaced, 3) bone length, alignment and rotation of ulnar and radial shaft fractures must be recovered; 4) the lateral collateral ligament complex must be repaired to obtain elbow stability; 5) the medial collateral ligament must be repaired if persistent instability is observed after lateral collateral ligament repair; 6) an hinged external fixator must be considered if the elbow remains unstable or the protection of the joint reconstruction is required; 7) re-evaluation of the surgical steps if congruent ulno-humeral and radio-humeral joints have not been achieved. Following the surgical treatment an adequate rehabilitation programme should be started promptly and continued for at least 6 months since a significant improvement of the range of motion occurs prevalently in this period, which should be considered the critical time period to obtain a functional elbow

Mortality after surgery in Europe: a 7 day cohort study

Background: Clinical outcomes after major surgery are poorly described at the national level. Evidence of heterogeneity between hospitals and health-care systems suggests potential to improve care for patients but this potential remains unconfirmed. The European Surgical Outcomes Study was an international study designed to assess outcomes after non-cardiac surgery in Europe.Methods: We did this 7 day cohort study between April 4 and April 11, 2011. We collected data describing consecutive patients aged 16 years and older undergoing inpatient non-cardiac surgery in 498 hospitals across 28 European nations. Patients were followed up for a maximum of 60 days. The primary endpoint was in-hospital mortality. Secondary outcome measures were duration of hospital stay and admission to critical care. We used χ² and Fisher’s exact tests to compare categorical variables and the t test or the Mann-Whitney U test to compare continuous variables. Significance was set at p<0·05. We constructed multilevel logistic regression models to adjust for the differences in mortality rates between countries.Findings: We included 46 539 patients, of whom 1855 (4%) died before hospital discharge. 3599 (8%) patients were admitted to critical care after surgery with a median length of stay of 1·2 days (IQR 0·9–3·6). 1358 (73%) patients who died were not admitted to critical care at any stage after surgery. Crude mortality rates varied widely between countries (from 1·2% [95% CI 0·0–3·0] for Iceland to 21·5% [16·9–26·2] for Latvia). After adjustment for confounding variables, important differences remained between countries when compared with the UK, the country with the largest dataset (OR range from 0·44 [95% CI 0·19 1·05; p=0·06] for Finland to 6·92 [2·37–20·27; p=0·0004] for Poland).Interpretation: The mortality rate for patients undergoing inpatient non-cardiac surgery was higher than anticipated. Variations in mortality between countries suggest the need for national and international strategies to improve care for this group of patients.Funding: European Society of Intensive Care Medicine, European Society of Anaesthesiology