Neoadjuvant chemotherapy improves survival in patients with oesophageal mucinous adenocarcinoma: Post-hoc analysis of the UK MRC OE02 and OE05 trials

Background: Adenocarcinoma with more than 50% extracellular mucin is a relatively rare histological subtype of gastrointestinal adenocarcinomas. The clinical impact of extracellular mucin in oesophageal adenocarcinoma (OeAC) has not been investigated in detail. We hypothesised that patients with mucinous OeAC (OeACmucin) do not benefit from neoadjuvant chemotherapy. Methods: OeAC patients either treated by surgery alone in the OE02 trial (S-patients) or by neoadjuvant chemotherapy followed by surgery (CS-patients) in OE02 or OE05 trials were included. Cancers from 1055 resection specimens (OE02 [test cohort]: 187 CS, 185 S; OE05 [validation cohort]: 683 CS) were classified as either mucinous (more than 50% of the tumour area consists of extracellular mucin, OeACmucin) or non-mucinous adenocarcinoma (OeACnon-mucin). The relationship between histological phenotype, clinicopathological characteristics, survival and treatment was analysed. Results: Overall, 7.3% and 9.6% OeAC were classified as OeACmucin in OE02 and OE05, respectively. In OE02, the frequency of OeACmucin was similar in S and CS-patients. Patients with OeACmucin treated with surgery alone had a poorer overall survival compared with OeACnon-mucin patients (hazard ratio: 2.222, 95% confidence interval: 1.08–4.56, P = 0.025). Patients with OeACmucin treated with neoadjuvant chemotherapy and surgery had similar survival as OeACnon-mucin patients in test and validation cohort. Conclusions: This is the first study to suggest in a post-hoc analysis of material from two independent phase III clinical trials that the poor survival of patients with mucinous OeAC can be improved by neoadjuvant chemotherapy. Future studies are warranted to identify potential underlying biological, biochemical or pharmacokinetic interactions between extracellular mucin and chemotherapy

The Anatomy of Asilisaurus kongwe, a Dinosauriform from the Lifua Member of the Manda Beds (~Middle Triassic) of Africa

The diagnosis of Dinosauria and interrelationships of the earliest dinosaurs relies on careful documentation of the anatomy of their closest relatives. These close relatives, or dinosaur “precursors,” are typically only documented by a handful of fossils from across Pangea and nearly all specimens are typically missing important regions (e.g., forelimbs, pelves, skulls) that appear to be important to help resolving the relationships of dinosaurs. Here, we fully describe the known skeletal elements of Asilisaurus kongwe, a dinosauriform from the Middle Triassic Manda Beds of the Ruhuhu Basin of Tanzania. The taxon is known from many disarticulated and partially articulated remains and, most importantly, from a spectacularly preserved associated skeleton of an individual containing much of the skull, pectoral and pelvic girdles, forelimb and hindlimb, and parts of the vertebral column including much of the tail. The unprecedented detail of the anatomy indicates that Asilisaurus kongwe had a unique skull that was short and had both a premaxillary and dentary edentulous margin, but retained a number of character states plesiomorphic for Archosauria, including a crocodylian-like ankle configuration and a rather short foot with well-developed metatarsals I and V. Additionally, character states present across the skeleton of Asilisaurus kongwe suggest it is more closely related to Silesaurus opolensis than to dinosaurs; thus suggesting high homoplasy and parallel trends within Silesauridae and within lineages of early dinosaurs. The anatomy of Asilisaurus kongwe and detailed description of early members of clades found outside Dinosauria are clearly needed to untangle the seemingly complex character evolution of the skeleton within avemetatarsalians.Fil: Nesbitt, Sterling J.. Virginia Polytechnic Institute; Estados UnidosFil: Langer, Max C.. Universidade de Sao Paulo; BrasilFil: Ezcurra, Martin Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales "Bernardino Rivadavia"; Argentin

Evaluation of range of motion restriction within the hip joint

In Total Hip Arthroplasty, determining the impingement free range of motion requirement is a complex task. This is because in the native hip, motion is restricted by both impingement as well as soft tissue restraint. The aim of this study is to determine a range of motion benchmark which can identify motions which are at risk from impingement and those which are constrained due to soft tissue. Two experimental methodologies were used to determine motions which were limited by impingement and those motions which were limited by both impingement and soft tissue restraint. By comparing these two experimental results, motions which were limited by impingement were able to be separated from those motions which were limited by soft tissue restraint. The results show motions in extension as well as flexion combined with adduction are limited by soft tissue restraint. Motions in flexion, flexion combined with abduction and adduction are at risk from osseous impingement. Consequently, these motions represent where the maximum likely damage will occur in femoroacetabular impingement or at most risk of prosthetic impingement in Total Hip Arthroplasty

Systematic review of studies generating individual participant data on the efficacy of drugs for treating soil-transmitted helminthiases and the case for data-sharing

Preventive chemotherapy and transmission control (PCT) by mass drug administration is the cornerstone of the World Health Organization (WHO)’s policy to control soil-transmitted helminthiases (STHs) caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm) and hookworm species (Necator americanus and Ancylostama duodenale) which affect over 1 billion people globally. Despite consensus that drug efficacies should be monitored for signs of decline that could jeopardise the effectiveness of PCT, systematic monitoring and evaluation is seldom implemented. Drug trials mostly report aggregate efficacies in groups of participants, but heterogeneities in design complicate classical meta-analyses of these data. Individual participant data (IPD) permit more detailed analysis of drug efficacies, offering increased sensitivity to identify atypical responses potentially caused by emerging drug resistance

Pain outcomes in patients with bone metastases from advanced cancer: assessment and management with bone-targeting agents

Bone metastases in advanced cancer frequently cause painful complications that impair patient physical activity and negatively affect quality of life. Pain is often underreported and poorly managed in these patients. The most commonly used pain assessment instruments are visual analogue scales, a single-item measure, and the Brief Pain Inventory Questionnaire-Short Form. The World Health Organization analgesic ladder and the Analgesic Quantification Algorithm are used to evaluate analgesic use. Bone-targeting agents, such as denosumab or bisphosphonates, prevent skeletal complications (i.e., radiation to bone, pathologic fractures, surgery to bone, and spinal cord compression) and can also improve pain outcomes in patients with metastatic bone disease. We have reviewed pain outcomes and analgesic use and reported pain data from an integrated analysis of randomized controlled studies of denosumab versus the bisphosphonate zoledronic acid (ZA) in patients with bone metastases from advanced solid tumors. Intravenous bisphosphonates improved pain outcomes in patients with bone metastases from solid tumors. Compared with ZA, denosumab further prevented pain worsening and delayed the need for treatment with strong opioids. In patients with no or mild pain at baseline, denosumab reduced the risk of increasing pain severity and delayed pain worsening along with the time to increased pain interference compared with ZA, suggesting that use of denosumab (with appropriate calcium and vitamin D supplementation) before patients develop bone pain may improve outcomes. These data also support the use of validated pain assessments to optimize treatment and reduce the burden of pain associated with metastatic bone disease

Treatment of non-small-cell lung cancer: a perspective on the recent advances and the experience with gefitinib

Worldwide, non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related mortality and, until screening detects early disease, treatment for the majority of patients will consist of radiation therapy, chemotherapy or combinations thereof. Modern mono and doublet chemotherapy regimens have translated into modest increases in life expectancy and improved quality of life, but at the expense of systemic and pulmonary adverse events (AEs). There is a great unmet need to provide effective therapy for advanced NSCLC that does not have the toxicity burden of conventional chemotherapy and radiotherapy. Novel drugs that inhibit a range of growth factor receptors, such as the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib (‘Iressa’) and erlotinib (‘Tarceva’) or the monoclonal antibody cetuximab (‘Erbitux’), have recently been evaluated. Having demonstrated antitumour activity and rapid symptom improvement in pretreated patients with advanced NSCLC, gefitinib was approved in the USA, Japan and other countries. Gefitinib is well tolerated with a low incidence of grade 3/4 AEs. Interstitial lung disease has been reported in a small number of patients receiving gefitinib, although this may be attributed to other treatments and conditions. Nevertheless, although the use of novel treatments requires vigilance for unexpected AEs such as pulmonary toxicity, in this area of high unmet clinical need, the benefits outweigh the risks in patients for whom no other proven effective treatment exists

Untangling the dinosaur family tree

For over a century, the standard classification scheme has split dinosaurs into two fundamental groups: ‘lizard-hipped’ saurischians (including meat-eating theropods and long-necked sauropodomorphs) and ‘bird-hipped’ ornithischians (including a variety of herbivorous species).In a recent paper, Baron et al. challenged this paradigm with a new phylogenetic analysis that places theropods and ornithischians together in a group called Ornithoscelida, to the exclusion of sauropodomorphs, and used their phylogeny to argue that dinosaurs may have originated in northern Pangaea, not in the southern part of the supercontinent, as has more commonly been considered. Here we evaluate and reanalyse the morphological dataset underpinning the proposal by Baron et al. and provide quantitative biogeographic analyses, which challenge the key results of their study by recovering a classical monophyletic Saurischia and a Gondwanan origin for dinosaurs. This shows that the Ornithoscelida hypothesis is not the final word, and that there is still great uncertainty around the basic structure of the dinosaur family tree.Fil: Langer, Max C.. Universidade de Sao Paulo; BrasilFil: Ezcurra, Martin Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales “Bernardino Rivadavia”; ArgentinaFil: Rauhut, Oliver Walter Mischa. Ludwig Maximilians Universitat; AlemaniaFil: Benton, Michael J.. University of Bristol; Reino UnidoFil: Knoll, Fabien. University of Manchester; Reino UnidoFil: McPhee, Blair W.. Universidade de Sao Paulo; BrasilFil: Novas, Fernando Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales “Bernardino Rivadavia”; ArgentinaFil: Pol, Diego. Museo Paleontológico Egidio Feruglio; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Brusatte, Stephen L.. University of Edinburgh; Reino Unid

A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency

Receptor agonism remains poorly understood at the molecular and mechanistic level. In this study, we identified a fully human anti-Fas antibody that could efficiently trigger apoptosis and therefore function as a potent agonist. Protein engineering and crystallography were used to mechanistically understand the agonistic activity of the antibody. The crystal structure of the complex was determined at 1.9 Å resolution and provided insights into epitope recognition and comparisons with the natural ligand FasL (Fas ligand). When we affinity-matured the agonist antibody, we observed that, surprisingly, the higher-affinity antibodies demonstrated a significant reduction, rather than an increase, in agonist activity at the Fas receptor. We propose and experimentally demonstrate a model to explain this non-intuitive impact of affinity on agonist antibody signalling and explore the implications for the discovery of therapeutic agonists in general

Measurement of the branching fraction and CP content for the decay B(0) -> D(*+)D(*-)

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APS.We report a measurement of the branching fraction of the decay B0→D*+D*- and of the CP-odd component of its final state using the BABAR detector. With data corresponding to an integrated luminosity of 20.4  fb-1 collected at the Υ(4S) resonance during 1999–2000, we have reconstructed 38 candidate signal events in the mode B0→D*+D*- with an estimated background of 6.2±0.5 events. From these events, we determine the branching fraction to be B(B0→D*+D*-)=[8.3±1.6(stat)±1.2(syst)]×10-4. The measured CP-odd fraction of the final state is 0.22±0.18(stat)±0.03(syst).This work is supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the A.P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation