Randomised, multicentre, phase III, open-label study of alectinib vs crizotinib in treatment-naïve anaplastic lymphoma kinase (ALK)-positive advanced NSCLC (ALEX study).

Background: In ∼5% of advanced NSCLC tumours, ALK tyrosine kinase is constitutively activated after translocation of ALK. ALK+ NSCLC was shown to be highly sensitive to the first approved ALK inhibitor, crizotinib. However, all pts eventually relapse on crizotinib mainly due to secondary ALK mutations/amplification or CNS metastases. Alectinib is a highly selective, potent, oral next-generation ALK inhibitor. Clinical phase II alectinib data in 46 crizotinib-naïve pts with ALK+ NSCLC reported an objective response rate (ORR) of 93.5% and a 1-year progression-free rate of 83% (95% CI: 68-92) (Inoue et al. J Thorac Oncol 2013). CNS activity was seen: of 14 pts with baseline brain metastasis, 11 had prior CNS radiation, 9 of these experienced CNS and systemic PFS of >12 months; of the 3 pts without prior CNS radiation, 2 were >15 months progression free. Trial design: Randomised, multicentre, phase III, open-label study in pts with treatment-naïve ALK+ advanced, recurrent, or metastatic NSCLC. All pts must provide pretreatment tumour tissue to confirm ALK rearrangement (by IHC). Pts (∼286 from ∼180 centres, ∼30 countries worldwide) will be randomised to alectinib (600mg oral bid, with food) or crizotinib (250mg oral bid, with/without food) until disease progression (PD), unacceptable toxicity, withdrawal of consent, or death. Stratification factors are: ECOG PS (0/1 vs 2), race (Asian vs non-Asian), baseline CNS metastases (yes vs no). Primary endpoint: PFS by investigators (RECIST v1.1). Secondary endpoints: PFS by Independent Review Committee (IRC); ORR; duration of response; OS; safety; pharmacokinetics; quality of life. Additionally, time to CNS progression will be evaluated (MRI) for the first time in a prospective randomised NSCLC trial as a secondary endpoint. Pts with isolated asymptomatic CNS progression will be allowed to continue treatment beyond documented progression until systemic PD and/or symptomatic CNS progression, according to investigator opinion. Time to CNS progression will be retrospectively assessed by the IRC using two separate criteria, RECIST and RANO. Further details: ClinicalTrials.gov (NCT02075840). Disclosure: T.S.K. Mok: Advisory boards: AZ, Roche, Eli Lilly, Merck Serono, Eisai, BMS, AVEO, Pfizer, Taiho, Boehringer Ingelheim, Novartis, GSK Biologicals, Clovis Oncology, Amgen, Janssen, BioMarin; board of directors: IASLC; corporate sponsored research: AZ; M. Perol: Advisory boards: Roche; S.I. Ou: Consulting: Pfizer, Chugai, Genentech Speaker Bureau: Pfizer, Genentech, Boehringer Ingelheim; I. Bara: Employee: F. Hoffmann-La Roche Ltd; V. Henschel: Employee and stock: F. Hoffmann-La Roche Ltd.; D.R. Camidge: Honoraria: Roche/Genentech. All other authors have declared no conflicts of interest.

Evidence on the role of ownership structure on firms' innovative performance

Based on the Knowledge Production Function framework given by Griliches -1979-, we slightly modify it so that the innovative output depends upon a set of factors related to the firm internal characteristics and are influenced by the environment. Specifically, regarding the firm internal determinants the effect of the concentration of the ownership, the composition of the boards of directors and the effect of the nature of the ownership (foreign and public) are analyzed. Additionally, in order to capture the determinants of the environment in which the firm operates other variables concerning the internationalization of market, the agglomeration economies and the regional knowledge externalities are also considered. In order to assess the impact of these determinants on the number of patents and models of use awarded by the firm, the discreteness of the latter variable has to be taken into account. We apply Poisson and Negative Binomial models for a more comprehensive evaluation of the hypothesis in a panel of Spanish manufacturing firms. The results show patenting activity is positively favoured by being located in an environment with a high innovative activity, due to the existence of knowledge spillovers and agglomeration economies.

Distribution and role of macrophytes in coastal lagoons : implications of critical shifts

Crossroads, crucibles and refuges are three words that may describe natural coastal lagoon environments. The words refer to the complex mix of marine and terrestrial influences, prolonged dilution due to the semi-enclosed nature and the function of a habitat for highly diverse plant and animal communities, some of which are endangered. To attain a realistic picture of the present situation, high vulnerability to anthropogenic impact should be added to the description. As the sea floor in coastal lagoons is usually entirely photic, macrophyte primary production is accentuated compared with open sea environments. There is, however, a lack of proper knowledge on the importance of vegetation for the general functioning of coastal lagoon ecosystems. The aim of this thesis is to assess the role of macrophyte diversity, cover and species identity over temporal and spatial scales for lagoon functions, and to determine which steering factors primarily restrict the qualitative and quantitative composition of vegetation in coastal lagoons. The results are linked to patterns of related trophic levels and the indicative potential of vegetation for assessment of general conditions in coastal lagoons is evaluated. This thesis includes five field studies conducted in flads and glo-flads in the brackish water northern Baltic Sea. Flads and glo-flads are defined as a Baltic variety of coastal lagoons, which due to an inlet threshold and post-glacial landuplift slowly will be isolated from the open sea. This process shrinks inlet size, increases exposure and water retention, and is called habitat isolation. The studied coastal lagoons are situated in the archipelago areas of the eastern coast of Sweden, the Åland Islands and the south-west mainland of Finland, where land-uplift amounts to ca. 5 mm/ per year. Out of 400 evaluated sites, a total of 70 lagoons varying in inlet size, archipelago position and anthropogenic influence to cover for essential environmental variation were chosen for further inventory. Vegetation composition, cover and richness were measured together with several hydrographic and morphometric variables in the lagoons both seasonally and inter-annually to cover for general regional, local and temporal patterns influencing lagoon and vegetation development. On smaller species-level scale, the effects of macrophyte species identity and richness for the fish habitat function were studied by examining the influence of plant interaction on juvenile fish diversity. Thus, the active election of plant monoand polycultures by fish and the diversity of fish in the respective culture were examined and related to plant height and water depth. The lagoons and vegetation composition were found to experience a regime shift initiated by increased habitat isolation along with land-uplift. Vegetation composition altered, richness decreased and cover increased forming a less isolated and more isolated regime, named the vascular plant regime and charophyte regime, respectively according to the dominant vegetation. As total phosphorus in the water, turbidity and the impact of regional influences decreased in parallel, the dominance of charophytes and increasing cover seemed to buffer and stabilize conditions in the charophyte regime and indicated an increased functional role of vegetation for the lagoon ecosystem. The regime pattern was unaffected by geographical differences, while strong anthropogenic impact seemed to distort the pattern due to loss of especially Chara tomentosa L. in the charophyte regime. The regimes were further found unperturbed by short-time temporal fluctuations. In fact the seasonal and inter-annual dynamics reinforced the functional difference between the regimes by the increasing role of vegetation along habitat isolation and the resemblance to lake environments for the charophyte regime. For instance, greater total phosphorus and chlorophyll a concentrations in the water in the beginning of the season in the charophyte regime compared with the vascular plant regime presented a steeper reduction to even lower values than in the vascular plant regime along the season. Despite a regional importance and positive relationship of macrophyte diversity in relation to trophic diversity, species identity was underlined in the results of this thesis, especially with decreasing spatial scale. This result was supported partly by the increased role of charophytes in the functioning of the charophyte regime, but even more explicitly by the species-specific preference of juvenile fish for tall macrophyte monocultures. On a smaller species-level scale, tall plant species in monoculture seemed to be able to increase their length, indicating that negative selection forms preferred habitat structures, which increase fish diversity. This negative relationship between plant and fish diversity suggest a shift in diversity patterns among trohic levels on smaller scale. Thus, as diversity patterns seem complex and diverge among spatial scales, it might be ambiguous to extend the understanding of diversity relationships from one trophic level to the other. All together, the regime shift described here presents similarities to the regime development in marine lagoon environments and shallow lakes subjected to nutrient enrichment. However, due to nutrient buffering by vegetation with increased isolation and water retention as a consequence of the inlet threshold, the development seems opposite to the course along an eutrophication gradient described in marine lagoons lacking an inlet threshold, where the role of vegetation decreases. Thus, the results imply devastating consequences of inlet dredging (decreasing isolation) in terms of vegetation loss and nutrient release, and call for increased conservational supervision. Especially the red listed charophytes would suffer negatively from such interference and the consequences are likely to also deteriorate juvenile fish production. The fact that a new species to Finland, Chara connivens Salzm. Ex. Braun 1835 was discovered during this study further indicates a potential of the lagoons serving as refuges for rare species.

Reforestation feasibility in area formerly used for cattle rasing in the state of Rondônia, Northwest Brazilian Amazon

Little knowledge on initial behavior of native tree species in recovering landscapes in the Amazon is a current concern for expanding reforestation in the region. Thus, the aim of this study was to evaluate the establishment of native tree species that could be used for reforestation in area previously covered by a pasture of brachiaria grass (Brachiaria brizantha) destined for intensive cattle rasing in the State of Rondônia. For this, there were performed previous diagnostic of landscape changes and the election of tree species based on the ecological group information. Some of the critical macronutrients for plant growth were supplied in the holes to alleviate nutrient deficiencies. In addition, growth and survival parameters were taken to evaluate the initial behavior of species. Six native tree species planted with different combinations (10mx10m, 5mx5m and 3mx3m) had survival rate and growth (total height, girth stem and crown projection area) measured in different intervals: 6-month, 12-month and 24-month after planting. All the species presented survival rate over 90% at 24 months and comparable growth indices to other native species under similar situation and in the region. Overall, Schizolobium amazonicum (bandarra), the non-identified legume tree 1 (acácia grande) and Colubrina glandulosa (sóbrasil) averaged over 90% the highest girth stem growth all over the area. S. amazonicum and the non-identified legume tree 1 (acácia grande) presented the best results for height and canopy area growth parameters, respectively. The combination among native tree species from initial successional ecological groups and fertilizer was favorable to promote reforestation in the conditions of the study area in Rondônia.

Effects of low-level laser therapy on wound healing

OBJECTIVE: To gather and clarify the actual effects of low-level laser therapy on wound healing and its most effective ways of application in human and veterinary medicine.METHODS: We searched original articles published in journals between the years 2000 and 2011, in Spanish, English, French and Portuguese languages, belonging to the following databases: Lilacs, Medline, PubMed and Bireme; Tey should contain the methodological description of the experimental design and parameters used.RESULTS: doses ranging from 3 to 6 J/cm2 appear to be more effective and doses 10 above J/cm2 are associated with deleterious effects. The wavelengths ranging from 632.8 to 1000 nm remain as those that provide more satisfactory results in the wound healing process.CONCLUSION: Low-level laser can be safely applied to accelerate the resolution of cutaneous wounds, although this fact is closely related to the election of parameters such as dose, time of exposure and wavelength.

The effect of governance mechanism and structure on fees and performance of Mutual Funds in Canada

Taking advantage of the unique Canadian setting, this study empirically analyzes the impact of presence of the board of directors, as an internal governance mechanism, on fees and performance of mutual funds. Further, the impact of the board structure on fees and performance of corporate class funds is analyzed. We find that corporate class funds, which have a separate board of directors for the fund, charge higher fees; however, they also provide superior performance than trust funds. Furthermore, we find that for corporate class funds, smaller board, with higher percentage of independent directors, and with the fund CEO acting as the chairman of the board is likely to charge lower fees. Also, more independent boards are strongly associated with superior fee-adjusted performance.

Memo Re: The 70th General Assembly of O.I.V., 1990

A memo from Donald Ziraldo to the Board of Directors of the VQA and C.W.I. in regards to the 70th General Assembly of O.I.V. The memo is dated 24 September, 1990 and discusses conversations with the Director of O.I.V. and Canada (and Quebec's) possible membership. The memo also remarks "there was a noticeable absence of EEC delegates". One delegate was part of the O.I.V. Assembly and there were informal discussions with him in regards to Canada's request for recognition.

Barnes Wines, Limited By-Law no. 82

A by-law "to fix the remuneration and expense allowances of directors". It reads "Be it enacted as a By-law of Barnes Wines Limited: 1. That each Director of the Company be paid the sum of Seventy-five ($75,00) Dollars annually in respect of general services rendered by the Director in his capacity as Director, such remuneration to accrue from the date of his election or appointment as a Director. 2. That each Director shall be paid and allowed travelling and other expenses properly incurred in connection with the affairs of the Company. 3. That this provision shall be and remain in force and effect in the fiscal years of the Company, 1971 to 1973 both inclusive. Enacted this 8th day of February, 1971."

Report from the annual meeting of the shareholders held on June 1, 1886 regarding shares

Report from the annual meeting of the shareholders held on June 1, 1886 regarding shares (copy of 1 handwritten page). The board of directors also met and new directors were named. This is signed by Louis N. Hayne, secretary, June 7, 1886.

Convergence of corporate governance : comparative study in Canada and in China

"Mémoire présenté à la Faculté des études supérieures En vue de l'obtention du grade de Maître en droit (LL.M.)"

A study of the co-operative banking system in kerala

The co-operative credit structure in a state set up consists of 3 tiers — Primary Societies at the base, District Co-operative Banks at the middle and State Cooperative Bank at the top. But, some societies at the primary level are governed by, in addition to Co-operative Societies Act, the Banking Regulation Act. Thus they are under dual control. In addition, they are working under the direct purview of Reserve Bank of India. The scope of this study is restricted to such Primary Societies, District Co-operative Banks and State Co-operative Bank. For the evaluation of the working of Co-operative Banks, the board of directors and staff were interviewed with the help of pre-constructed and pre-tested interview schedules. However, the share holders and customers were not interviewed mainly because almost all respondents were reluctant to provide copies of an exhaustive list of share holders and non-share holder customers, for the purpose of maintaining secrecy. This being an individual work, it was found physically and financially very difficult to extend the study so as to cover the share holders and non-share holder customers. Limitations of time were also responsible for restricting this study. The period of study was restricted to 1980-'81 to 1983-'84 as the data relating to earlier periods were firstly not available from all banks and secondly the prior data was considered out of date for the purpose of the study.

Experience of the Flexible Internship in University of Rosario-Medical School

Objective: To evaluate the flexible program implemented for the medical internship at School of Medicine, Universidad del Rosario during the period 1997-2002. Methodology: A descriptive study was performed to summarize the choices of medical clerkships made by the interns during the whole studied period. The coincidence with the further choice of a determined medical specialty was assessed. Conclusions: Most of the last year’s students remain preferring a conservative approach to their career, by choosing clerkships in a basic area, such as internal medicine, pediatrics, gynecology and obstetrics or general surgery. The coincidence between the type of internship or clerkships a student performs and the future election of a specialty is high.

The President above parties: a founding illusion of the Fifth Republic

De Gaulle, founder of the Fifth French Republic, cherished the notion that the president of the Republic could somehow stand above party politics. In many ways this belief shaped the early institutional configuration of the new Republic. Party politics, however, rapidly reached the presidency, especially with the move, under the constitutional reform of 1962, to direct election of the president. This article charts the development of France's 'political constitution' and the relationship between president and parties over the first decade of the Fifth Republic. It finds that although the presidency became the prime goal of party political competition, the (often dysfunctional) illusion of a head of state above politics continues to shape the behaviour and perceptions of French presidents.

Investigation of institutional investors’ responsible investment practices in UK

The focus of Corporate Governance is shifting from the role of directors to active ownership. Based on their fiduciary duty to other shareholders, it is believed that institutional investors have an important role to play in this regard. However, the Pension Funds and the Sovereign Wealth Organisations are not driven by the same set of objectives. In addition, Environmental Social and Governance (ESG) issues in investment decision-making are now becoming more important and they are capable of becoming the mainstream in the future. However, there are widespread variations in perception of fiduciary responsibilities, ESG issues appraisal, as well as the strategies adopted by institutional investors on shareholder engagement as responsible investors. Responsible Investment market is largely driven by institutional investors and they are expected to continue to lead the way. This research work investigates the role of the main asset owners and their advisors in responsible investment practices in the UK. It adopts a qualitative approach using semi-structured interviews, questionnaire and meetings observations. Gathered data is analysed using grounded theory and the findings highlight the perception of the various investor groups to corporate governance. The research work contributes to the body of knowledge by assessing the corporate governance perspectives of the various classes of institutional investors which may have practical implications for other countries.

Brazil's election: as polarized as can be

What you see above is a graphic representation of something anyone who followed the campaign that led to the re-election of Dilma Rousseff as Brazil’s president on October 26 already knows: the election was the most polarised in the country’s history. Brasil was split down the middle, not only numerically (Dilma got 52 per cent, Aécio Neves 48) and geographically (Dilma won in the less developed north, Aécio in the more prosperous south). The twitterspere, too, was divided into two camps. Not only that; they hardly talked to each other at all.