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Background Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti-programmed death 1 (anti-PD-1) immunotherapy, pembrolizumab, in programmed death ligand 1 (PD-L1)-positive, recurrent glioblastoma. Methods Adult patients with PD-L1-positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator-assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD-L1 expression levels (prospectively) and T-cell-inflamed gene expression profile score (retrospectively). Results After a median follow-up of 14 months (range, 2-55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%-26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progression-free survival (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD-L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment-related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune-mediated adverse events and infusion reactions occurred in 7 patients (27%). Conclusions Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal-finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.

International audience; Metallotropism of the M[N(SiMe3)2]2 metal fragment in the tautomeric system IAR⇌ACR involving imidazolium salts/N‐heterocyclic carbenes with remote aminide/amine substituents, respectively, is manifested by its CNHC carbophilicity (R=tBu, M=Co, Fe) or NRaminido nitrogenophilicity (R=Cy, M=Co, Fe; R=Mes, M=Fe) and has been rationalized on the basis of steric and electronic effects. The thermolysis products of the [M{N(SiMe3)2}2]/ IAR⇌ACR system are also substituent‐dependent, leading to a rearranged aminide‐functionalized aNHC Co2 complex of an unprecedented type or to ring‐opened metallaketenimines; they are postulated to originate from different metalloisomers. The results are interpreted on the basis of the X‐ray diffraction analysis of 11 new compounds.

Lymph node metastasis is an important prognosis factor in non-small cell lung cancer (NSCLC) patients. The aim of this study was to investigate the role of epithelial to mesenchymal transition (EMT) in lymph node progression in the early stages of NSCLC. We studied a retrospective cohort of 160 consecutive surgically treated NSCLC patients with available frozen tumor samples for expression of EMT markers (CDH1, CTNNB1, CDH2, and VIMENTIN), inducers (TGFB1, c-MET, and CAIX), and transcription factors (EMT-TF: SNAI1, SNAI2, ZEB1, TWIST1, and TWIST2). Partial EMT was more frequent in N1-2 (N+) vs N0 patients (P < .01). TGFB1 (P = .02) as well as SNAI2 (P < .01) and TWIST1 (P = .04) were the most differentially expressed genes in N+ tumors. In this group, ZEB1 was correlated with all EMT inducers and other EMT-TFs were overexpressed depending on the inducers. CAIX was an independent prognostic factor for overall survival (IC 95% HR: 1.10-5.14, P = .03). Partial EMT is involved in lymph node progression of NSCLC patients and depends on the TGFβ pathway. EMT-TFs are differentially expressed depending on EMT inducers. CAIX might be a relevant prognostic marker in early stage NSCLC.

Background & aims Early TIPS placement must be considered in patients with Child-Pugh B and active bleeding at endoscopy or in patients with Child-Pugh C 10-13 and variceal bleeding. However, active bleeding at endoscopy is a subjective criterion. Moreover, a previous study has shown that a MELD-based score accurately predicted 6-week mortality and helped to stratify patients. Using a prospective series of patients included in a multicentre study before the era of early TIPS, we aimed (i) to identify factors associated with 6-week mortality, focusing on the prognostic value of active bleeding; and (ii) to assess whether a recalibrated MELD-based score accurately predicted 6-week mortality. Methods Ancillary study of the prospective multicentre Baveno IV study, including patients with acute variceal bleeding. Results Two hundred and nineteen patients were analysed (Child-Pugh A/B/C = 18/45/37%). The overall actuarial likelihood of survival on day 42 was 84%. The variability for the diagnosis of active bleeding at endoscopy was high (range, 41.4% to 84.6% among the centres). Active bleeding at endoscopy was not associated with 6-week mortality in the entire population or in Child-Pugh B patients. In a multivariate analysis, independent factors associated with mortality were liver function, infection, HE and HCC. The recalibrated MELD-based score was accurate in predicting 6-week mortality (AUROC = 0.787). The recalibrated MELD-based score demonstrated better performance compared to the MELD score. Conclusion The recalibrated MELD-based score accurately predicted mortality in our prospective cohort. Active bleeding at endoscopy had no prognostic value in cirrhotic patients presenting with acute variceal bleeding. Standardizing active bleeding assessment at endoscopy is warranted.

Brazil was the first low- and middle-income country to provide universal treatment access to people living with the acquired immunodeficiency syndrome (AIDS), becoming a widely acclaimed model for best practice to managing this epidemic. However, we know little about important challenges to the key pillars of Brazil's response. This article discusses how the evolution of the country's health system institutions and international advancements in AIDS treatment and prevention affected the national response. Decentralization of health system resources and policy making brought fresh challenges to the centralized governance of the national AIDS program and to civil society, weakening their coordination and advocacy capacity. Regardless, AIDS treatment and prevention strategies in Brazil remain aligned with the current international protocols, but unfortunately have been restricted in some geographic areas and/or populations.

Although a third of all cancers are diagnosed after the age of 75, only 9% of elderly people are recruited in clinical trials, because of fear of the risk of toxicity. The aim of this study was to compare the tolerance and efficacy observed in Phase I trials among patients aged over 75 years with that observed in younger patients. Patients treated from 2007 to 2012 at Institut Gustave Roussy in Phase I trials were included. The conditional Cox proportional hazards model was used to compare the occurrence of AE and overall survival in a subpopulation of elderly people (EP, aged >75 years) matched with patients aged

Two p-cymene-ruthenium complexes 1 and 2 were isolated in high yields by treating the [RuCl2(p-cymene)]2 dimer with new hybrid phosphane- or NHC-linked diene ligands. Both complexes were fully characterized by NMR spectroscopy, and the molecular structure of the ruthenium–p-cymene complex 1, containing the phosphane–diene ligand system, was determined by X-ray diffraction analysis. The catalytic activities of both compounds were probed in atom-transfer radical addition (ATRA) and polymerization (ATRP), in the cyclopropanation of olefins, in the ring-opening metathesis polymerization (ROMP) of norbornene, and in the synthesis of enol esters from hex-1-yne and 4-acetoxybenzoic acid.

This study addresses the socio-cognitive determinants of traffic offences, in particular of speeding and drinking and driving. It has two aims: (1) to test the hypothesis of a direct effect of habits on offences (i.e., independent of intentions) by employing a specific measure of habits (i.e., the SRIH) and (2) to analyse the offences by taking account of three distinct parameters: Frequency, usual magnitude (i.e., the most frequent deviation from the law) and maximal magnitude (i.e., the greatest deviation occasionally adopted) in order to represent more accurately the variability of the offending behaviours. A total of 642 drivers replied to a questionnaire. The results corroborate the idea that intention and habit are distinct and direct determinants of offences. The use of the SRIH dismisses the criticisms made with regard to the measure of past behaviour. The distinction between the three behavioural parameters proves to be relevant, as their determinants are not exactly similar. Finally, attitude and subjective norm had direct effects on the maximal magnitude and/or on the frequency of the offence. The discussion concerns the contribution of this study to the analysis of offences as well as its limitations and addresses the theoretical plausibility of the direct effects of attitude and the subjective norm.

Many economists have long held that market failures create a gap between social and private returns to research and development (R&D), thereby limiting private incentives to invest in R&D. However, this common belief that firms significantly underinvest in R&D is increasingly being challenged, leading the rationale behind public support for private R&D to be questioned. In this paper, we attempt to clarify the perspectives of two sources: the theoretical literature on endogenous growth, and its recent developments in integrating a geographical dimension, and the empirical literature that measures the social returns to R&D in relation to the private returns. Ultimately, we are able to clearly distinguish among different types of market failures and compare their relative impact on the gap between the private and social returns to R&D. Two main conclusions are reached. First, systematic firm underinvestment in R&D is not demonstrated. Second, even though instances of underinvestment do occur, they are mainly explained by surplus appropriability problems rather than by knowledge externalities. This suggests the need for a new policy mix that employs more demand-oriented instruments and is more concentrated on identifying efficient allocations among activities rather than merely increasing global private R&D investment.

Background Pulmonary metastasectomy of renal cell carcinomas (RCC) remains controversial. Thoracic lymph node involvement (LNI) is a known prognostic factor. The aim of our analysis is to evaluate whether patients with LNI, and particularly N2 patients, should be excluded from surgical treatment. Methods We retrospectively reviewed data from 122 patients who underwent operations at two French thoracic surgery departments between 1993 and 2011 for RCC lung metastases. Results The population consisted of 38 women and 84 men; the average age at time of metastasectomy was 63.3 years (min: 43, max: 82). LNI was identified as a prognostic factor using univariate and multivariate analysis (median survival: 107 months vs. 37 months, P = 0.003; HR = 0.384 (0.179; 0.825), P = 0.01, respectively). Although differences in survival between metastases at the hilar and mediastinal locations were not significant (median survival: 74 months vs. 32 months, respectively, P = 0.75), length of survival time was associated with disease-free interval less than 12 months (median survival: 23 months vs. 94 months, P

Background The aim of our study was to describe the lung cancer characteristics in lung transplant recipients at our institution. Methods Between January 1, 1992, and August 15, 2017, 463 patients underwent lung transplantation. Results We found a total of 19 lung cancers (4.10%). Eight patients had lung cancer in the explanted lung, 8 in the native remaining lung, and 3 in the transplanted lung. Histopathological findings were: adenocarcinoma in 10, SCC in 8 patients, and 1 was undetermined. Among lung cancers in the explanted lungs, there were 6 stage I, 1 stage III, 1 stage IV. Among patients with a lung cancer in the remaining native lung, 3 had early stage disease and 5 had stage IV disease. Among lung cancers in the transplanted lung, there were: 1 stage I, 1 stage II and 1 stage IV. Overall median survival in lung transplant recipients without lung cancer was 8.77 ± 0.74 years compared to 6.19 ± 1.4 years in recipients with lung cancer. Conclusion Lung cancer following lung transplantation was uncommon. Early stage lung cancer discovered in the explanted lungs had no impact on survival. Lung cancer occurring in the transplanted or in the native remaining lung had a poor prognosis.

A molecularly defined new phosphine–diolefin cubane copper pre-catalyst used at 1.25 mol % under mild conditions promotes the coupling of pyrazoles to functionalised aryl and heteroaryl bromides, which hold a variety of functional groups. This versatile phosphorus-based system was thus successfully used, under identical conditions, for the coupling of a large scope of heteroaromatics to selectively produce pyridinyl- and pyrimidinyl-pyrazoles, as well as several novel furyl-, thienyl- and thiazolyl-substituted pyrazoles. The careful investigation of coupling with the analogous aryl and heteroaryl chlorides clearly indicated that for specifically activated chloroarenes a direct nucleophilic aromatic substitution (SNAr) is easily achieved in the absence of any copper and ligand. These results are pertinent with regards to the reported protocols in which copper–ligand systems have been claimed as useful for coupling activated chloroarenes.

Summary Background Physiopathology and prognosis of peptic ulcer bleeding (PUB) have never been described in cirrhotic patients. Aim To assess risk factors and outcome of PUB in two groups of patients with PUB with or without cirrhosis. Methods We included prospectively all patients with PUB referred to our ICU of Hepatology and Gastroenterology between January 2008 and March 2011. All patients were treated according to international recommendations. Diagnosis of cirrhosis was based on clinical, biological and morphological exams. Aetiologies, characteristics and outcomes of PUB were compared in cirrhotic vs. noncirrhotic patients. Results A total of 203 patients with PUB were included prospectively. Twenty-nine patients had cirrhosis (group Cirr+), and 174 patients had no cirrhosis (group Cirr−). Demographic data were similar between the two groups except for age and alcohol consumption. Aetiology of cirrhosis was alcohol in 97% of cirrhotic patients. Characteristics of PUB were not different between the two groups. Ninety-three per cent of patients with cirrhosis had endoscopic portal hypertension. Aetiology of PUB was different between the group Cirr+ and Cirr− (Helicobacter pylori = 10.3% vs. 48.8%, P

Alterations induced during the first step of fossilization are examined. Molars and premolars of a modern large mammal were crushed to expose fresh dentine. Fragments were placed in solutions of acids present in humus for 2 months. Changes in composition of the solutions were analysed. Micro- and nanostructural changes of fresh and etched dentine were observed with scanning electron and atomic force microscopes. The ion contents of the acetic acid solution are higher than those of oxalic and oxalic plus acetic acid solutions. Oxalic acid etching results in secondary deposits of oxalates on the exposed dentine. The composition of the soil in natural fossilization processes is a main factor in fossil preservation.

Standards are needed to control the quality of the lungs from nonheart-beating donors as potential grafts. This was here assessed using the metabolomics 1H high-resolution magic angle spinning NMR spectroscopy. Selective perfusion of the porcine bilung block was set up 30 min after cardiac arrest with cold Perfadex®. Lung alterations were analyzed at 3, 6, and 8 h of cold ischemia as compared to baseline and to nonperfused lung. Metabolomics analysis of lung biopsies allowed identification of 35 metabolites. Levels of the majority of the metabolites increased over time at 4°C without perfusion, indicating cellular degradation, whereas levels of glutathione decreased. When lung was perfused at 4°C, levels of the majority of the metabolites remained stable, including levels of glutathione. Levels of uracil by contrast showed a reverse profile, as its signal increased over time in the absence of perfusion while being totally absent in perfused samples. Our results showed glutathione and uracil as potential biomarkers for the quality of the lung. The metabolomics 1H high-resolution magic angle spinning NMR spectroscopy can be efficiently applied for the assessment of the quality of the lung as an original technique characterized by a rapid assessment of intact biopsy samples without extraction and can be implemented in hospital environment.

Portable multi-media devices with electrowetting-based displays take advantage of the supreme optical performances and of the video capabilities of the screen. As described in this paper these displays benefit from the implementation of dynamic adaptive frame rate driving schemes, resulting in ultra-low power consumption and extended battery life while maintaining the high level of image quality.

Anticancer agents targeting circulating vascular endothelial growth factor (VEGF) (e.g., bevacizumab and aflibercept) are strong angiogenesis inhibitors. As such, they may hamper the healing process, notably in the early postoperative period. Whether antiangiogenic agents may be associated with late postoperative healing complications is less known. We reviewed three cases of patients with anastomotic complications under antiangiogenic treatment occurring more than 1 year after initial surgery and we conducted a review of the literature. We report the first case of delayed anastomotic leakage which occurred under aflibercept therapy 13 months after a bilioenteric anastomosis and two cases of delayed rectal anastomotic complications associated with bevacizumab treatment 18 and 78 months after surgery. Fifteen similar cases of late gastrointestinal anastomotic complications were found in the English literature. Antiangiogenic agents are probably not deleterious to a healed wound. However, they appear to be associated with an increased risk of complications in a subgroup of patients. According to the 18 cases reported, the main risk factors appear to be low anterior resection for rectal cancer, perioperative radiotherapy, and early postoperative leak which heals through the formation of abundant and hypervascularized granulation tissue.

Because of the recent approval of several drugs for the treatment of renal cell carcinoma (including sorafenib, sunitinib, temsirolimus, and, in Europe, bevacizumab plus interferon), the use of sequential therapy has become routine practice. There is now evidence that administering these targeted agents sequentially provides clinical benefit by inducing tumor shrinkage and prolonged progression-free survival (PFS) in a large number of patients. However, data regarding overall survival (OS) are still pending. By adding these drugs in an adequate order, one can expect an increase in overall PFS of up to 27 months and a subsequent improvement in the OS of patients with renal cell carcinoma. It has been recently reported that the OS of patients treated with sunitinib in the first-line setting was 26 months. Expecting a survival of 40 months does appear possible based on currently available data, although this assumption will have to be proven in the future.

Spurred on by the theory of network formation, and by the geography of innovation, traditional analyses on R&D cooperation face a deep renewal. This paper assesses the extent to which these renewals find an empirical validation. Based on the research projects submitted to the 6th Framework Program of the European Union, a binary choice model is used in order to highlight the existence of network and spatial effects alongside other microeconomic determinants of cooperation. Our findings suggest that network effects are present, so that probability of collaboration is influenced by each individual's position within the network. Social distance thus seems to matter more than geographical distance. Abstract. Los analisis tradicionales de cooperacion I+D se enfrentan a una renovacion profunda, estimulada por la teoria de formacion de redes, y la geografia de la innovacion. Este articulo evalua el alcance con que esta renovacion logra obtener una validacion empirica. Basado en proyectos de investigacion presentados al Sexto Programa Marco de la Union Europea, se emplea un modelo de eleccion binaria para poner de relieve la existencia de efectos de red y espaciales junto con otros determinantes macroeconomicos de cooperacion. Nuestros hallazgos sugieren que los efectos de red estan presentes, de modo que la probabilidad de colaboracion se ve influida por la posicion de cada individuo dentro de la red. La distancia social parece por tanto importar mas que la distancia geografica.

International audience; The theory of endogenous growth and the geography and growth synthesis both consider that local growth and spatial concentration of economic activities emanate from localised knowledge spillovers (Lucas 1988; Martin and Ottaviano 1999). Since the end of the 1980's, the spatial dimension of knowledge diffusion has been investigated from an empirical point of view, and the existence and role of local spillovers has been generally confirmed (see among others Jaffe 1989; Audretsch and Feldman 1996). The concern that now arises is to unravel the mechanisms underlying and explaining the geographical knowledge spillovers. The aim of this special issue is to present the latest new findings on such questions and to identify some new lines of research for future work. Before presenting the content of this special issue, we very briefly review the main results of the empirical literature on the geography of innovation. We also explain the context of this special issue by pointing out some of the limitations faced by this literature and, by stressing the complex dynamic and network dimensions of the observed processes of production and diffusion of knowledge.

SUMMARY High-dose omeprazole reduces the rate of recurrent bleeding after endoscopic treatment of peptic ulcer bleeding. However, the effectiveness of high-dose vs. standard-dose omeprazole in peptic ulcer bleeding has never been shown. Aim To compare the benefits of high-dose vs. standard-dose omeprazole in peptic ulcer bleeding. Methods We reviewed the medical files of patients admitted between 1997 and 2004 for high-risk peptic ulcer bleeding who had undergone successful endoscopic treatment. We distinguished 2 periods: before 2001, standarddose omeprazole (40 mg ⁄ day intravenously until alimentation was possible, then 40 mg ⁄ day orally for 1 week); after 2001, high-dose omeprazole (80 mg bolus injection, then 8 mg ⁄ h continuous infusion for 72 h, then 40 mg ⁄ day orally for 1 week). During both periods, patients subsequently received omeprazole, 20 mg ⁄ day, orally for 3 weeks. Results We enrolled 114 patients (period 1, n = 45, period 2, n = 69). Therapy with high-dose omeprazole significantly decreased the occurrence of poor outcome (27 vs. 12%, P = 0.04), rebleeding (24 vs. 7%, P = 0.01), mortality due to haemorrhagic shock (11 vs. 0%, P < 0.001) and need for surgery (9 vs. 1%, P = 0.05). Conclusions In this retrospective study, high-dose omeprazole reduced the occurrence of rebleeding, need for surgery and mortality due to hemorrhagic shock in patients with high-risk peptic ulcer bleeding, as compared with standard-dose omeprazole.

Background and aim. About 35% of iron deficiency anemia cases remain unexplained after a gastrointestinal evaluation. An association between Helicobacter pylori and iron malabsorption has been suggested. The aim of this study was to determine whether H. pylori-associated chronic gastritis is linked to unexplained iron deficiency anemia in adults. Methods. From 1996 to 2001, we identified 105 patients with unexplained iron deficiency anemia after upper endoscopy, colonoscopy, small bowel radiographic examination and duodenal biopsies. Two biopsies were obtained from the gastric antrum and two from the corpus of each patient. Gastritis status was described according to the Sydney System and H. pylori infection was assessed by an immunohistochemical test on biopsy specimens. This group was compared to a control group matched for sex and age. Results. There were 76 women and 29 men (mean age 57.4 ± 21.4 years) examined in the study. A H. pylori-associated chronic gastritis was identified in 63 cases (60%) vs. 45 cases (43%) cases in the control group (p

The majority of lung cancer patients have tumor-derived genetic alterations in circulating plasma DNA that could be exploited as a diagnostic tool. We used fluorescent microsatellite analysis to detect alterations in plasma and tumor DNA in 34 patients who underwent bronchoscopy for lung cancer, including 11 small cell lung cancer (SCLC) and 23 nonsmall cell lung cancer (NSCLC) (12 adenocarcinomas, 11 squamous cell carcinomas) and 20 controls. Allelotyping was performed with a selected panel of 12 microsatellites from 9 chromosomal regions 3p21, 3p24, 5q, 9p, 9q, 13q, 17p, 17q and 20q. Plasma DNA allelic imbalance (AI) was found in 88% (30 of 34 patients), with a similar sensitivity in SCLC and NSCLC. In the 24 paired available tumor tissues, 83% (20 of 24) presented at least 1 AI. Among these patients, 85% (17 of 20) presented also at least 1 AI in paired plasma DNA, but the location of the allelic alterations in paired plasma and tumor DNA could differ, suggesting the presence of heterogeneous tumor clones. None of the 20 controls displayed plasma or bronchial DNA alteration. A reduced panel of six markers (at 3p, 5q, 9p, 9q) showed a sensitivity of 85%. Moreover, a different panel of microsatellites at 3p and 17p13 in SCLC and at 5q, 9p, 9q and 20q in NSCLC patients could be specifically used. Analysis of plasma DNA using this targeted panel could be a valuable noninvasive test and a useful tool to monitor disease progression without assessing the tumor.

Background The vascular side effects of angiogenesis inhibitors are well known, but laryngeal effects are not widely reported. We report the first 5 cases, to our knowledge, of objective vocal fold lesions attributable to these therapies. Methods Four patients treated with bevacizumab-paclitaxel or bevacizumab for metastatic breast or lung cancer and 1 patient treated with a pan-fibroblast growth factor receptor (FGFR) inhibitor presented with spontaneous dysphonia without other etiologic factors. Results In all cases, we observed a well-limited mucosal lesion on the superior surface of the anterior portion both vocal folds, symmetrical, sparing the anterior commissure and the vocal process. Histopathology showed necrosis and inflammation. After discontinuation of treatment in 3 patients, their voices improved, but with persistent inflammation in 2 patients and vocal fold scarring in 1 patient. Conclusion Clinicians should systematically perform laryngoscopy in case of dysphonia in patients treated with angiogenesis inhibitors in order to diagnose laryngeal lesions and rule out differential diagnoses. © 2014 Wiley Periodicals, Inc. Head Neck 36: E81–E85, 2014

The combination of cubane (I)/PPH is found to catalyze the coupling of aryl and heteroaryl bromides with pyrazole (II) and its derivatives (V) under mild conditions.