Dual Erb B Inhibition in Oesophago-gastric Cancer (DEBIOC): A phase I dose escalating safety study and randomised dose expansion of AZD8931 in combination with oxaliplatin and capecitabine chemotherapy in patients with oesophagogastric adenocarcinoma

Background: AZD8931 has equipotent activity against epidermal growth factor receptor, erbB2, and erbB3. Primary objectives were to determine the recommended phase II dose (RP2D) of AZD8931 + chemotherapy, and subsequently assess safety/preliminary clinical activity in patients with operable oesophagogastric cancer (OGC). Methods: AZD8931 (20 mg, 40 mg or 60 mg bd) was given with Xelox (oxaliplatin + capecitabine) for eight 21-day cycles, continuously or with intermittent schedule (4 days on/3 off every week; 14 days on/7 off, per cycle) in a rolling-six design. Subsequently, patients with OGC were randomised 2:1 to AZD8931 + Xelox at RP2D or Xelox only for two cycles, followed by radical oesophagogastric surgery. Secondary outcomes were safety, complete resection (R0) rate, six-month progression-free survival (PFS) and overall survival. Results: During escalation, four dose-limiting toxicities were observed among 24 patients: skin rash (1) and failure to deliver 100% of Xelox because of treatment-associated grade III-IV adverse events (AEs) (3: diarrhoea and vomiting; vomiting; fatigue). Serious adverse events (SAE) occurred in 15 of 24 (63%) patients. RP2D was 20-mg bd with the 4/3 schedule. In the expansion phase, 2 of 20 (10%) patients in the Xelox + AZD8931 group and 5/10 (50%) patients in the Xelox group had grade III–IV AEs. Six-month PFS was 85% (90% CI: 66%–94%) in Xelox + AZD8931 and 100% in Xelox alone. Seven deaths (35%) occurred with Xelox + AZD8931 and one (10%) with Xelox. R0 rate was 45% (9/20) with Xelox + AZD8931 and 90% (9/10) with Xelox-alone (P = 0.024). Conclusion: Xelox + AZD8931 (20 mg bd 4/3 days) has an acceptable safety profile administered as neoadjuvant therapy in operable patients with OGC. (Trial registration: EudraCT 2011-003169-13, ISRCTN-68093791)

Strain elastography for noninvasive assessment of liver fibrosis: A prospective study with histological comparison

The aim of this study was to prospectively evaluate the diagnostic performance of strain elastography for the assessment of liver fibrosis in patients with chronic liver disease using Ishak (0–6) histology stage as a reference standard. Ninety-eight consecutive patients with suspected chronic liver disease scheduled for liver biopsy (n = 78) or histologically confirmed cirrhosis (n = 20) were enrolled. Liver fibrosis Index (LF Index) calculated by strain elastography, liver stiffness by transient elastography and serum fibrosis markers (aspartate aminotransferase-to-platelet ratio index and King’s Score) were measured. Spearman’s correlation coefficient between the LF Index, liver stiffness, serum fibrosis markers and fibrosis stage were calculated and compared using areas under the receiver-operating characteristics (AUROCs) curves. Among 73 patients who underwent strain elastography, there was weak correlation between fibrosis stage and the LF Index (Spearman’s: ρ = 0.385 for Ishak score; P = 0.001). Among 52 patients who underwent strain elastography and transient elastography, the AUROC values using LF Index, transient elastography, aspartate aminotransferase-to-platelet ratio index and King’s Score for diagnosing significant fibrosis (Ishak score ≥ 3) were 0.79, 0.87, 0.86 and 0.85, respectively (P < 0.0001) and for diagnosing severe fibrosis/cirrhosis (Ishak score ≥ 5) were 0.83, 0.94, 0.92 and 0.92, respectively (P < 0.0001). When comparing the diagnostic performance using LF Index, transient elastography, aspartate aminotransferase-to-platelet ratio index and King’s Score, transient elastography shows a significantly higher AUROC value than LF Index in detecting severe fibrosis (P = 0.0149). The diagnostic performance of LF Index calculated by strain elastography was not statistically significantly different to the other noninvasive tests for the assessment of significant liver fibrosis but inferior to transient elastography for the assessment of severe fibrosis/cirrhosis

Hepatic Resection Following Selective Internal Radiation Therapy for Colorectal Cancer Metastases in the FOXFIRE Clinical Trial: Clinical Outcomes and Distribution of Microspheres

The FOXFIRE (5-Fluorouracil, OXaliplatin and Folinic acid ± Interventional Radio-Embolisation) clinical trial combined systemic chemotherapy (OxMdG: Oxaliplatin, 5-fluorouracil and folic acid) with Selective Internal Radiation Therapy (SIRT or radio-embolisation) using yttrium-90 resin microspheres in the first-line management for liver-dominant metastatic colorectal cancer (CRC). We report clinical outcomes for patients having hepatic resection after this novel combination therapy and an exploratory analysis of histopathology. Multi-Disciplinary Teams deemed all patients inoperable before trial registration and reassessed them during protocol therapy. Proportions were compared using Chi-squared tests and survival using Cox models. FOXFIRE randomised 182 participants to chemotherapy alone and 182 to chemotherapy with SIRT. There was no statistically significant difference in the resection rate between groups: Chemotherapy alone was 18%, (n = 33); SIRT combination was 21% (n = 38) (p = 0.508). There was no statistically significant difference between groups in the rate of liver surgery, nor in survival from time of resection (hazard ratio (HR) = 1.55; 95% confidence interval (CI) = 0.83-2.89). In the subgroup studied for histopathology, microsphere density was highest at the tumour periphery. Patients treated with SIRT plus chemotherapy displayed lower values of viable tumour in comparison to those treated with chemotherapy alone (p < 0.05). This study promotes the feasibility of hepatic resection following SIRT. Resin microspheres appear to preferentially distribute at the tumour periphery and may enhance tumour regression

PET/MRI technique role in Alzheimer disease

Abstract Background Group-sequential testing is widely used in pivotal therapeutic, but rarely in diagnostic research, although it may save studies, time, and costs. The purpose of this paper was to demonstrate a group-sequential analysis strategy in an intra-observer study on quantitative FDG-PET/CT measurements, illuminating the possibility of early trial termination which implicates significant potential time and resource savings. Methods Primary lesion maximum standardised uptake value (SUVmax) was determined twice from preoperative FDG-PET/CTs in 45 ovarian cancer patients. Differences in SUVmax were assumed to be normally distributed, and sequential one-sided hypothesis tests on the population standard deviation of the differences against a hypothesised value of 1.5 were performed, employing an alpha spending function. The fixed-sample analysis (N = 45) was compared with the group-sequential analysis strategies comprising one (at N = 23), two (at N = 15, 30), or three interim analyses (at N = 11, 23, 34), respectively, which were defined post hoc. Results When performing interim analyses with one third and two thirds of patients, sufficient agreement could be concluded after the first interim analysis and the final analysis. Other partitions did not suggest early stopping after adjustment for multiple testing due to one influential outlier and our small sample size. Conclusions Group-sequential testing may enable early stopping of a trial, allowing for potential time and resource savings. The testing strategy must, though, be defined at the planning stage, and sample sizes must be reasonably large at interim analysis to ensure robustness against single outliers. Group-sequential testing may have a place in accuracy and agreement studies

Counteractive effects of antenatal glucocorticoid treatment on D1 receptor modulation of spatial working memory

RATIONALE: Antenatal exposure to the glucocorticoid dexamethasone dramatically increases the number of mesencephalic dopaminergic neurons in rat offspring. However, the consequences of this expansion in midbrain dopamine (DA) neurons for behavioural processes in adulthood are poorly understood, including working memory that depends on DA transmission in the prefrontal cortex (PFC). OBJECTIVES: We therefore investigated the influence of antenatal glucocorticoid treatment (AGT) on the modulation of spatial working memory by a D1 receptor agonist and on D1 receptor binding and DA content in the PFC and striatum. METHODS: Pregnant rats received AGT on gestational days 16-19 by adding dexamethasone to their drinking water. Male offspring reared to adulthood were trained on a delayed alternation spatial working memory task and administered the partial D1 agonist SKF38393 (0.3-3 mg/kg) by systemic injection. In separate groups of control and AGT animals, D1 receptor binding and DA content were measured post-mortem in the PFC and striatum. RESULTS: SKF38393 impaired spatial working memory performance in control rats but had no effect in AGT rats. D1 binding was significantly reduced in the anterior cingulate cortex, prelimbic cortex, dorsal striatum and ventral pallidum of AGT rats compared with control animals. However, AGT had no significant effect on brain monoamine levels. CONCLUSIONS: These findings demonstrate that D1 receptors in corticostriatal circuitry down-regulate in response to AGT. This compensatory effect in D1 receptors may result from increased DA-ergic tone in AGT rats and underlie the resilience of these animals to the disruptive effects of D1 receptor activation on spatial working memory

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Measurement of single top-quark production in association with a W boson in the single-lepton channel at \sqrt{s} = 8\,\text {TeV} with the ATLAS detector

The production cross-section of a top quark in association with a W boson is measured using proton–proton collisions at \sqrt{s} = 8\,\text {TeV}. The dataset corresponds to an integrated luminosity of 20.2\,\text {fb}^{-1}, and was collected in 2012 by the ATLAS detector at the Large Hadron Collider at CERN. The analysis is performed in the single-lepton channel. Events are selected by requiring one isolated lepton (electron or muon) and at least three jets. A neural network is trained to separate the tW signal from the dominant t{\bar{t}} background. The cross-section is extracted from a binned profile maximum-likelihood fit to a two-dimensional discriminant built from the neural-network output and the invariant mass of the hadronically decaying W boson. The measured cross-section is \sigma _{tW} = 26 \pm 7\,\text {pb}, in good agreement with the Standard Model expectation

Measurement of the top-quark mass in tt¯ events with dilepton final states in pp collisions at √s = 7 TeV

Open Access: This article is distributed under the terms of the Creative Commons Attribution License.-- Chatrchyan, S. et al.The top-quark mass is measured in proton-proton collisions at s√=7 TeV using a data sample corresponding to an integrated luminosity of 5.0 fb−1 collected by the CMS experiment at the LHC. The measurement is performed in the dilepton decay channel tt¯→(ℓ+νℓb)(ℓ−ν¯¯ℓb¯), where ℓ=e,μ. Candidate top-quark decays are selected by requiring two leptons, at least two jets, and imbalance in transverse momentum. The mass is reconstructed with an analytical matrix weighting technique using distributions derived from simulated samples. Using a maximum-likelihood fit, the top-quark mass is determined to be 172.5±0.4 (stat.)±1.5 (syst.) GeV.Acknowledge support from BMWF and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS (Colombia); MSES (Croatia); RPF (Cyprus); MoER, SF0690030s09 and ERDF (Estonia); Academy of Finland, MEC, and HIP (Finland); CEA and CNRS/IN2P3 (France);BMBF, DFG, and HGF (Germany); GSRT (Greece); OTKA and NKTH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); NRF and WCU (Korea); LAS (Lithuania); CINVESTAV, CONACYT, SEP, and UASLP-FAI (Mexico); MSI (New Zealand); PAEC (Pakistan); MSHE and NSC (Poland); FCT (Portugal); JINR (Armenia, Belarus, Georgia, Ukraine, Uzbekistan); MON, RosAtom, RAS and RFBR (Russia); MSTD (Serbia); SEIDI and CPAN (Spain); Swiss Funding Agencies (Switzerland); NSC (Taipei); ThEP, IPST and NECTEC (Thailand); TUBITAK and TAEK (Turkey); NASU (Ukraine); STFC (United Kingdom); DOE and NSF (USA). Individuals have received support from the Marie-Curie program and the European Research Council (European Union); the Leventis Foundation; the A. P. Sloan Foundation; the Alexander von Humboldt Foundation; the Austrian Science Fund (FWF); the Belgian Federal Science Policy Office; the Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture (FRIA-Belgium); the Agentschap voor Innovatie door Wetenschap en Technologie (IWTBelgium); the Ministry of Education, Youth and Sports (MEYS) of Czech Republic; the Council of Science and Industrial Research, India; the Compagnia di San Paolo (Torino); and the HOMING PLUS program of Foundation for Polish Science, cofinanced from European Union, Regional Development Fund.Peer Reviewe

Measurement of the tt¯tt¯ production cross section in pp collisions at √s=13 TeV with the ATLAS detector

A measurement of four-top-quark production using proton-proton collision data at a centre-of-mass energy of 13 TeV collected by the ATLAS detector at the Large Hadron Collider corresponding to an integrated luminosity of 139 fb−1 is presented. Events are selected if they contain a single lepton (electron or muon) or an opposite-sign lepton pair, in association with multiple jets. The events are categorised according to the number of jets and how likely these are to contain b-hadrons. A multivariate technique is then used to discriminate between signal and background events. The measured four-top-quark production cross section is found to be 26+17−15 fb, with a corresponding observed (expected) significance of 1.9 (1.0) standard deviations over the background-only hypothesis. The result is combined with the previous measurement performed by the ATLAS Collaboration in the multilepton final state. The combined four-top-quark production cross section is measured to be 24+7−6 fb, with a corresponding observed (expected) signal significance of 4.7 (2.6) standard deviations over the background-only predictions. It is consistent within 2.0 standard deviations with the Standard Model expectation of 12.0 ± 2.4 fb