Journal articles on the topic 'Board of directors dynamics'

Abstract We develop a dynamic model of board decision-making akin to dynamic voting models in the political economy literature. We show a board could retain a policy all directors agree is worse than an available alternative. Thus, directors may retain a CEO they agree is bad—deadlocked boards lead to entrenched CEOs. We explore how to compose boards and appoint directors to mitigate deadlock. We find board diversity and long director tenure can exacerbate deadlock. We rationalize why CEOs and incumbent directors have power to appoint new directors: to avoid deadlock. Our model speaks to short-termism, staggered boards, and proxy access.

Purpose – The purpose of this paper is to understand the influence of information and knowledge exchange and sharing between managers and non-executive directors is important in assessing the dynamic processes of accountability in boardrooms. By analysing information/knowledge at multiple levels, invoking the literature on implicit/tacit and explicit information/knowledge, the authors show that information asymmetry is a necessary condition for effective boards. The authors introduce a conceptual model of manager-non-executive director information asymmetry as an outcome of the interpretation of information/knowledge-sharing processes amongst board members. The model provides a more nuanced agenda of the management-board information asymmetry problem to enable a better understanding of the role of different types of information in practice. Design/methodology/approach – The analysis of information/knowledge exchange, sharing and creation and the resultant conceptual model are based on the following elements: manager-non-executive director information/knowledge, management-board information/knowledge and board dynamics and reciprocal processes converting implicit/tacit into explicit information/knowledge. Findings – The paper provides new insights into the dynamics of information/knowledge exchange, sharing and creation between managers and non-executive directors (individual level)/between management and boards (group level). The authors characterise this as a two-way process, back-and-forth between managers/executive directors and non-executive directors. The importance of relative/experienced “ignorance” of non-executive directors is revealed, which the authors term the “information asymmetry paradox”. Research limitations/implications – The authors set out key opportunities for developing a research agenda from the model based on prior research of knowledge conversion processes and how these may be applied in a boardroom setting. Practical implications – The model may assist directors in better understanding their roles and the division of labour between managers and non-executive directors from an information/knowledge perspective. Originality/value – The authors apply Ikujiro Nonaka’s knowledge conversion framework to consider the transitioning from individual implicit personal to explicit shared information/knowledge, to understand the subtle processes at play in boardrooms influencing information/knowledge exchange, sharing and creation between managers and non-executive directors.

Considering the complexities and dynamics that firms are facing in a digital era, it is no exaggeration to argue that the way boards of directors contribute to strategy needs some new perspectives. In this article, we reconsider some of the commonly used notions and assumptions of board strategizing. We conceptualize a framework for board strategizing by revisiting and providing new elements to the work introduced by McNulty and Pettigrew in 1999 (Strategists on the board. Organization Studies, 20(1): 47-74. http://doi.org/10.1177/0170840699201003). Our framework highlights a number of timely board practices that have the potential to improve the way boards strategize under conditions of increasing digitalization. Further, the findings suggest that valuable strategic actions and priorities can be made by boards that use and develop dynamic capabilities as they strategize. Implications for theory and practice as well as future research directions are discussed.

When the boards of family firms are active, their properties as groups shape the authority of the chief executive and the quality of advice that directors provide to management. An understanding of the group dynamics of the board and the board-management relationship helps to reach a satisfactory balance between family concerns and company interests. Boards of directors can improve their value to firms and to individual directors by developing a capacity for self-reflection.

Purpose The purpose of this paper is to document that religious adherence in the county of the corporate headquarter and educational attainment of the female director pool near the firm headquarters are influential to the likely addition of female corporate board directors. Design/methodology/approach The sample covers 1,630 unique firms and 30,369 unique directors covering a ten-year period to investigate the effects of religiosity and educational attainment. Findings The analysis reveals that while the number of women has increased in general terms, this change is mostly limited to boards that are increasing in size. Women do not tend to replace exiting male board members but are appointed when the board size grows. Therefore, while the number of women is increasing in absolute terms, they are not increasing in relative terms. In areas where religiosity is high, as measured by church affiliation and attendance, female participation in the boardroom is lower and a more educated and qualified female population leads to higher board participation. These effects supersede any regional effects. Originality/value The study adds insights into corporate board dynamic, providing new evidence concerning the impact of local conditions on board composition as well as additional information concerning the interplay of board dynamics and female board representation.

The boards of large corporations sharing some of their directors are connected in complex networks. Boards are responsible for corporations' long-term strategy and are often involved in decisions about a common topic related to the belief in economical growth or recession. We are interested in understanding under which conditions a large majority of boards making the same decision can emerge in the network. We present a model where board directors are engaged in a decision-making dynamics based on "herd behavior." Boards influence each other through shared directors. We find that imitation of colleagues and opinion bias due to the interlock do not trigger an avalanche of identical decisions over the board network, whereas the information about interlocked boards' decisions does. There is no need to invoke global public information, nor external driving forces. This model provides a simple endogenous mechanism to explain the fact that boards of the largest corporations of a country can, in the span of a few months, make the same decisions about general topics.

This article argues that chief human resource officers (CHROs) as directors on the board are strategically best placed to lead conversations pertaining to board processes due to their extensive expertise in talent management. Board composition and managing board processes and dynamics are important aspects of board effectiveness. Using the behavioural perspective to corporate governance, the article holds that the key differentiator in value creating boards are the members, the roles they play and the dynamics that allows them to create value for the firm. CHROs can play a decisive role in the board skill evaluation and incorporation of new and diverse members into boards.

This study focuses on the role of the corporate board of directors and the relationship between the dynamics of board structure and the financial performance of listed South African companies. The research results found that the proportion of independent non-executive directors had a significant positive effect on firm performance as measured by earnings per share and enterprise value, but had no significant effect on Tobin’s Q ratio. Board ownership had a significant negative correlation with firm performance as measured by earnings per share, enterprise value and Tobin’s Q ratio. The number of directors serving on the corporate board had a significant positive effect on firm performance as measured by earnings per share, enterprise value and Tobin’s Q ratio. The study suggests that greater independent non-executive director representation, lower board share-ownership and larger board sizes should be encouraged to enhance firm performance.

Abstract Background : Infectious disease plays a central role in malignancy, with up to one in six cancers having a microbial association (Parkin Int. J. Cancer 2006). Lymphomas in particular are associated with multiple viral pathogens, including Epstein Barr virus (EBV), Kaposi Sarcoma herpesvirus (KSHV), and HIV. Sequencing of cell-free DNA (cfDNA) is an emerging technique in the diagnosis and surveillance of cancer. While studies to date have focused primarily on tumor-associated somatic variants, cfDNA may also provide insight into the infectious and immune state of cancer patients. We examined cfDNA from lymphoma patients of multiple histologic subtypes to characterize viral detection and dynamics. Methods: Plasma from 360 pre-treatment patients with various lymphoma histologies was analyzed along with that of 69 healthy adults. Multiple samples per patient were included when available. All samples underwent deep sequencing with error correction by CAPP-Seq (Newman Nat Biotech 2016). Reads were filtered for homology to the human genome and endogenous retroviruses, mapped to NCBI consensus genomes for human-hosted viral species, and filtered by breadth of genomic coverage. Viral read count was normalized by total sequencing depth to determine viral read fraction (VRF). EBV fragment size was assessed via single-read BLAST alignment length considering reads with expect value < 1E-5. Integration sites were assessed with the VirusClip package (Ho Oncotarget 2015). Results: Patients with most lymphoma histologic subtypes had viral loads not significantly different from those of healthy adults. However, post-transplant lymphoproliferative disorder (PTLD) patients receiving immunosuppression for solid organ transplants had significantly increased total viremia (Fig 1A) and EBV levels (Fig 1B) when compared to healthy adults and non-transplant DLBCL patients. EBER+ classical Hodgkin lymphoma (cHL) displayed no difference in total viremia but had significantly elevated EBV. In an EBV-positive PTLD patient, cfDNA viral levels tracked both clinical viral qPCR and circulating tumor DNA (ctDNA) levels in serial samples leading to diagnosis (Fig 1C). Elevated EBV levels were also present in a subset of non-transplant DLBCL. In a cohort of DLBCL patients treated with frontline R-CHOP-like chemotherapy (n=152), individuals with pre-treatment EBV frequency greater than VRF 1E-7 had significantly higher risk of disease progression at three years (HR 1.8, CI 1.0-3.4, p=0.013) (Fig 1D). Immunosuppression in transplant patients is associated with the expansion of the endogenous anellovirus family (De Vlaminck Cell 2013). Accordingly, anellovirus was detected significantly more often in PTLD patients (91% of samples) compared to DLBCL NOS (2.8%) and controls (1.4%) (Fig 1E, p < 0.0001). As the standard-of-care R-CHOP regimen for DLBCL has activity against both B- and T- lymphocytes, we hypothesized that an immunosuppressive effect might be observed. In non-transplant DLBCL patients receiving R-CHOP (n=31), we detected anellovirus in 6% of samples at the time of first chemotherapy infusion, 16% immediately before cycle 2, but in no samples from post-treatment patients in complete response (Fig 1F). Viral integration into the host genome is associated with malignant transformation. We profiled a cohort of EBER+ cHL (n=8) and found circulating EBV/human chimeric reads suggesting integration in all cases. Viral fragment size distribution also distinguishes integrated DNA from shorter free episomes and may increase cancer screening performance (Lam PNAS 2018). We profiled EBV fragment sizes in cHL and PTLD patients grouped by EBER positivity. Plasma from EBER+ cHL and PTLD patients was significantly enriched in longer fragments (Fig 1G), suggesting nucleosomal protection of EBV integrated within tumor genomes but not their benign episomal counterparts. Conclusions: Viral infection in lymphoma has diagnostic and prognostic significance: elevated circulating EBV levels are associated with active PTLD (Kanakry Blood 2016) and poor outcomes in advanced HL (Kanakry Blood 2013) and DLBCL (Tisi Leuk & Lymph 2015). Our work demonstrates the utility of cfDNA sequencing for simultaneous characterization of malignancy, infection, and immunosuppression. The integration of viral dynamics into cfDNA analysis may assist in risk stratification and treatment monitoring in lymphoma patients. Disclosures Dührsen: Amgen: Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Janssen: Honoraria. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Meignan:F. Hoffman-La Roche Ltd: Honoraria. Casasnovas:Janssen: Consultancy; Takeda: Honoraria; Janssen: Honoraria; MSD: Honoraria; Merck: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Roche: Consultancy; Roche: Research Funding; takeda: Consultancy; Gilead Sciences: Consultancy; Roche: Honoraria; Gilead Sciences: Research Funding; merck: Consultancy; MSD: Consultancy. Westin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees. Gaidano:Amgen: Consultancy, Honoraria; Morphosys: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Advani:Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Agensys: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Merck: Research Funding; Janssen: Research Funding; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; Kura: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Regeneron: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven Inc.: Research Funding; Celgene: Research Funding.

Purpose This paper aims to offers suggested practices for dealing with the challenge of providing relevant and reliable information to boards. Design/methodology/approach Notes and reports from formal governance reviews have been considered from five organizations where board information was flagged as a key area for improvement. The cases were chosen from dozens of organizations the author worked with over a 10-year period. Findings The paper explains that boards struggle to process information because of challenges such as group dynamics and cognitive biases. Key themes identified reveal that both the type of information and how it is presented matters to boards. Most significantly, giving more information to boards is not always better. Research limitations/implications This is not an empirical study but instead seeks to use themes identified in practice as the base for suggestions for boards to consider when seeking relevant and reliable information to make decisions. Practical implications This paper makes practical suggestions on how boards and managers can ensure boards receive appropriate information from managers. These include having a clear philosophy for presenting information to the board, being clear on the story that is told, using knowledge visualization when appropriate, explaining how information is relevant to decision items and information items and appointing a steward to oversee the process if needed. Originality/value The struggle around board information has been noted in both research and practice. This paper empowers boards and managers with proactive strategies to steward processes and procedures related to board information.

PurposeThe fundamental role of corporate boards is to monitor and advise top management on strategic issues. It is therefore of the utmost importance that corporate directors are effective as a decision-making group to ensure corporate performance (Zattoni et al., 2015; Minichilli et al., 2012). But, what do we know about what is really going on inside the boardroom? This study aims to shed light on this important question.Design/methodology/approachThe authors undertake a targeted review of the literature to take account of all publications regarding board dynamics in relation to board effectiveness.FindingsThis study shows that we know very little about what is going on inside the “black box” of board dynamics and its relation to how effective directors are at doing their job, namely, monitoring and advising top management and establishing and expanding the firm’s network, to gain access to the resources it needs. The authors propose several avenues of research to better understand board dynamics.Originality/valueIn this study, the authors show how and why the present body of knowledge on team effectiveness should be harnessed to better understand corporate board dynamics in relation to board effectiveness.

Purpose Corporate accountability is a complex chain of reporting that reaches from external stakeholders into the organization’s management structure. The transition from external to internal accountability mechanisms primarily occurs at the board of directors. Yet outside of incentive mechanisms, we know surprisingly little about how internal actors (management) are held to account by the representatives of external shareholders (the board). The purpose of this paper is to explore the process of accountability at this transition point by documenting the routines used by boards to hold the firm’s management to account. In doing so, we develop the understanding of the important transition between internal and external firm accountability. Design/methodology/approach An inductive, case-based approach identifies recurrent behaviour patterns in two matched boards over three video-taped meetings. Sequential analysis of coded group and individual behaviours provides insight into boards’ accountability routines. Findings The boards engaged in clear, recurrent accountability routines. Individuals on the boards play different roles in these routines depending on the issue before the board, allowing both directors and managers to hold each other to account. The outsiders (directors) both challenge and support the insiders (managers) during board discussions, switching their behaviours with different agenda items but maintaining a consistent group level of support and scepticism across the meeting. This allows for the simultaneous development of trust and verification at the group level, a necessary condition for effective accountability. Research limitations/implications As board relationships and organisational context are highly variable, future research should concentrate on testing the generalizability of the results across different board and shareholder structures. Practical implications The results call into question the current governance focus on the independence of the individual director, as the authors identify that all directors appear to act as agents at one time or another in a meeting. Accountability at the boardroom level requires an effective group process not usually addressed in governance recommendations or regulation. Originality/value This study provides unique insights into board dynamics, documenting the accountability implications of group behaviours. By focussing on the group process, the authors highlight the potential mismatch of monotonic, individual-level approaches to governance and accountability prevalent in current agency approaches.

Abstract Background: Imetelstat, a first in class specific telomerase inhibitor, induced hematologic responses in all patients (pts) with essential thrombocythemia (ET) in a recent phase-2 study, and molecular responses were seen within 1-12 months in the majority of pts carrying JAK2 V617F (JAK2m) and CALR mutations (CALRm) (Baerlocher et al., ASH 2014). It has been reported that the treatment response to imetelstat in pts with myelofibrosis (Tefferi et al., ASH 2014) was negatively influenced by mutations in ASXL1 and favorably impacted by mutations in SF3B1 and U2AF1. In pts with CALRm ET treated with Interferon-alpha (INFa) the response rate was lower if the patient carried more than one mutation in ASXL1, TET2, IDH2, CSF3R and SH2B3 (Kiladjian et al., ASH 2014). In addition, in JAK2m pts with polycythemia vera, TET2-mutated clones have been demonstrated to be resistant to IFNa therapy (Kiladjian et al., Leukemia 2010). Aims: Our aim was to assess the dynamics of additional mutations besides JAK2 V617F, CALR and MPL mutations in pts with ET treated with imetelstat, and to investigate their association with hematologic and molecular response. Methods: The study enrolled 18 pts with ET who had failed or were intolerant to ≥1 prior therapy, or refused standard therapy. Pts were treated with imetelstat 7.5 mg/kg or 9.4 mg/kg IV weekly until attainment of platelet count ~250-300x109/L followed by a maintenance phase with dosing titrated according to platelet count. DNA was extracted from granulocytes or leukocytes. Mutation analysis was performed by high-throughput sequencing of selectively amplified target sequences on a PGM Ion Torrent instrument covering the coding and adjacent intronic sequences of 15 genes known for mutations in MPN (ASXL1, CBL, DNMT3A, EZH2, IDH1, IDH2, JAK2, MPL, SF3B1, SRSF2, SOCS1, TET2, TP53, U2AF1 and ZRSR2). Samples were taken at baseline and up to 8 time points during treatment through cycle 26, with approximately 3 cycles between samples. Results: As a driver mutation, at baseline, 9 pts had JAK2V617F, 5 pts had CALR and 2 pts had MPL mutations (MPLm; one L and one K). Two pts were triple negative. A partial molecular response (according to Barosi et al., Blood 2009) was seen in 7/8 JAK2m pts and reductions in CALRm allele burden were between 15% and 55%. At baseline, 19 additional somatic mutations (11 missense, 4 frameshift, 3 nonsense, 1 splice site) were detected in 6/9 JAK2m and 2/5 CALRm pts, affecting the genes ASXL1 (n=3), DNMT3A (n=5), EZH2(n=1), SF3B1 (n=1), SOCS1 (n=2), TET2 (n=4) and TP53 (n=3). Two mutations in DNMT3A and ZRSR2 were detected in 1/2 MPLm pts and none were found in the triple negative pts. Of note, all but one mutated pts carried at least 2 mutations in addition to their driver mutation (up to 5 additional mutations). ASXL1 and SOCS1 mutations were only present in JAK2m pts, and these pts reached hematologic and partial molecular response. At time of best molecular response, a reduction of mutant allele burden corresponding to the reduction of the driver mutations was observed for mutations in ASXL1, EZH2, SOCS1 and some DNMT3A, TET2 and TP53 mutations, but not for SF3B1 and ZRSR2 mutations. Sequential analysis in a JAK2m patient with 4 additional mutations showed that all 4 mutated clones were sensitive to imetelstat treatment and followed the dynamics of the JAK2 mutation, and in a patient with 5 mutations in addition to the CALR mutation, 3/5 mutated clones were responsive. Three pts with a weaker molecular response had TP53 mutations which persisted over time, and 2 were accompanied by additional mutations. Conclusions: 9/18 (50%) pts in this study carried no additional mutations at baseline, and 50% carried 1-5 mutations in addition to the driver mutation, suggesting genetic instability in a subset of pts. Genetic instability might be enhanced in this pretreated patient cohort with a median time since diagnosis of 7.2 years (range 0.3-24.9). Clones with ASXL1 mutations, a known poor prognostic marker in MPN, appear to be sensitive to imetelstat treatment, and pts with 2-5 additional mutations had both hematologic and molecular responses. TP53 mutations were an exception, being associated with weaker molecular responses to imetelstat treatment. Additional analyses of associations between mutations, disease characteristics and response will be presented. . Disclosures Oppliger Leibundgut: Novartis: Research Funding; Geron: Research Funding. Burington:Geron Corporation: Employment. Ottmann:Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Spitzer:Moldx Palmetto GBA: Consultancy; Incyte: Consultancy; Trovagene Inc: Consultancy. Odenike:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding. McDevitt:Salamandra Inc: Consultancy; Alexion: Membership on an entity's Board of Directors or advisory committees. Roeth:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Research Funding. Snyder:Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Baerlocher:Geron: Research Funding; Janssen: Research Funding; Novartis: Research Funding.

The board of directors’ role is evolving and becoming more important in the wake of corporate scandals resulting in the collapse of large corporations and losses to shareholders. Poor governance can lead to wrong decision-making, which might destroy organizations, particularly during times of environmental turbulence. The 2008 Global Financial Crises followed by the 2011 Arab Spring throughout the MENA region and then the 2019 pandemic situation are few of many factors that created a turbulent economic and political environment for organizations, highlighting the importance of excellent decision-making skills. However, there is limited research on boards’ decision-making during difficult times in the MENA region. The authors interviewed 26 board members of 21 companies operated under duress to examine the effects on boardroom level decision making of the magnified levels of duress and stress experienced during turbulent times. Key findings from the research include trends in emotional responses in relation to decision-making, changes in the decision-making process after crises, leadership positions, and board behavior. The authors recommend that boards incorporate diversity training and awareness into all levels of their decision-making process and to the board members’ selection process. Future research should expand to different regions and industries and examine the effects of board members’ personal traits and backgrounds on their quality of choices and decision-making

Purpose – This study aims to open up the black box of the boardroom by directly observing directors’ interactions during meetings to better understand board processes. Design/methodology/approach – We analyze videotaped observations of board meetings at two Australian companies to develop insights into what directors do in meetings and how they participate in decision-making processes. The direct observations are triangulated with semi-structured interviews, mini-surveys and document reviews. Findings – Our analyses lead to two key findings: while board meetings appear similar at a surface level, boardroom interactions vary significantly at a deeper level (i.e. board members participate differently during different stages of discussions), and factors at multiple levels of analysis explain differences in interaction patterns, revealing the complex and nested nature of boardroom discussions. Research implications – By documenting significant intra- and inter-board meeting differences, our study challenges the widespread notion of board meetings as rather homogeneous and monolithic, points towards agenda items as a new unit of analysis and highlights the need for more multi-level analyses in a board setting. Practical implications – While policymakers have been largely occupied with the “right” board composition, our findings suggest that decision outcomes or roles’ execution could be potentially affected by interactions at a board level. Differences in board meeting styles might explain prior ambiguous board structure-performance results, enhancing the need for greater normative consideration of how boards do their work. Originality/value – This study complements existing research on boardroom dynamics and provides a systematic account of director interactions during board meetings.

PurposeThe emergence of Governance practices in the non-governmental organisation (NGO) sector has become associated with increasingly high levels of organisational complexity. In the light of an expanding civil society sector in Chile and the emergence of formalised governance practices, this paper explores the construction of the Executive Director role in Chilean NGOs with reference to organisational functions, organisational dynamics, and external influences.Design/methodology/approachGrounded theory is used to explore qualitative data derived from a set of N = 39 interviews conducted in Chile These interviews involve NGO founders, funders, Executive Directors, scholars, consultants, and team members.FindingsThe findings reveal the pivotal role played by Executive Directors in conducting organisational activities which, in other types of organisations, are often distributed across various organisational functions. The data also highlight complex dynamics involving overt compliance with external regulatory requirements, uncertainties about financial sustainability, the recruitment of Executive Board members, the exercise of power by Executive Directors, and the influence of founders in leadership configurations.Research limitations/implicationsThe implications of the study are discussed in relation to the governance and accountability of NGOs, the nature of the Executive Director role, the purpose of Executive Boards in the NGO sector, and the recruitment and training of Board members. It is noted that the study was conducted in the NGO sector in Chile; further research is necessary to establish the generalisability of the findings to other contexts.Originality/valueThis paper addresses the shortage of organisational research on NGOs. It contributes by offering analytical perspectives on organisational processes of Leadership and Governance. This paper highlights the relationship between, and interdependency of, those processes.

Our paper seeks to further understand the influence of gender board diversity on firms’ corporate social performance (CPS) in the context of publicly held family firms. Grounded on corporate governance and family firm literature, we argue that the influence of women directors on CSP will be contingent on their relative power and legitimacy within the board, and that such dynamics are particularly important in family firm boardrooms. Our empirical results show that increases in CSP associated with the presence of women in the boards of family firms are due mainly to the presence of outsider nonfamily and insider family women directors. Implications for the theory of family firms are discussed.

Purpose The purpose of this paper is to use the dynamic capabilities framework to explain the effect of board networks, as a source of intellectual capital, on firm performance. The authors propose that the influence of board interlocks depends on their ability to contribute to strategic decision making. As a result, their effect is subject to the business context in which they occur and the different role of the interconnected directors involved. Design/methodology/approach The authors use social network analysis to make board connections and to calculate centrality measures. The authors also identify busy boards to analyze whether their effect differs from centrality. The authors estimate the theoretical model using the Generalized Method of Moments in order to take advantage of the panel database. Findings For a sample of Spanish firms from 1999 to 2015, the results show there is no direct significant effect of directors’ networks on firm performance. However, the authors find a positive and significant influence of intra-industry board connections, particularly when they are established among outsiders. Research limitations/implications The Spanish context of the study can limit the generalization of the papers’ results. Practical implications The results can be useful both for practitioners – since they can serve as a guide for companies to reformulate their boards in search of the optimal structure-, and when implementing good governance codes – establishing limits for director interlocking. Originality/value This study helps to offer a better understanding of how directors’ networks can add value to the firm depending on the kind of resources they provide (context) and the role of the director who is connected.

PurposeThe purpose of this paper is to identify how board recruitment processes have been impacted by the Australian Securities Exchange (ASX) governance changes requiring listed boards to report annually on their gender diversity policy and profile.Design/methodology/approachEmploying a social constructivist approach, the research analyses interviews conducted with matched samples of board directors and stakeholders in 2010 and 2017 about board recruitment in ASX50 companies.FindingsThe introduction of ASX guidelines requiring gender reporting disrupted traditional board appointment processes. Women's gender capital gained currency, adding an additional dimension to the high levels of human and social capital seen as desirable for board appointments. The politics of women's presence is bringing about changes to the discourse and practice about who should/can be a director. The authors identify highly strategic ways in which women's gender capital has been used to agitate for more women to be appointed to boards.Research limitations/implicationsWhile sample sizes are small, data within the themes cohered meaningfully across the time periods, making visible how women's presence in the board room has been reframed. Future research could consider what this may mean for board dynamics and how enduring are these changes.Practical implicationsThis study highlights the forms that human and social capital take in board appointments, which can be instructive for potential directors, and how these intersect with gender capital. The insights from the study are relevant to board recruitment committees seeking to reflect their commitment to a more gender equitable environment.Originality/valueThere has been a recalibration of men's and women's gender capital in board appointments, and there is now a currency in femaleness disrupting the historical privilege afforded “maleness”.

A common intervention to address women’s underrepresentation in governance has been the introduction of gender quotas. This study examined the impact of gender quotas on gender equality in governance among boards of National Sport Organizations (NSOs) in Australia. Central to the study was the theoretical concept of a gender regime. Part of a larger study, the research design comprised a comparative case study of five NSOs with data collected mainly through semistructured interviews with directors and CEOs. The findings suggest that a quota of a minimum of three women was a first condition to advance gender equality in governance. It needed to operate, however, in conjunction with other gender dynamics to move toward equal participation by men and women in board decision making. These included women in influential board positions, solidaristic emotional relations between men and women directors, and directors’ adoption of gender equality as an organizational value.

It is increasingly evident that the composition of the tumor microenvironment (TME) and the interplay between malignant and immune cells determine the efficacy of antitumor immune responses, whether pre-existing or induced by therapy. To profile the complexity and plasticity of the TME and track antitumor immunity, we performed single cell RNA sequencing on tumor fine needle aspirates and peripheral blood of lymphoma patients undergoing immunotherapy on a clinical trial (NCT02927964). In this in situ vaccination study motivated by compelling preclinical data (Sagiv-Barfi et al., Blood 2015), patients with low-grade lymphoma receive local low-dose radiation and a TLR9 agonist (CpG) intratumorally to one site of disease. In the second week, after the second of 5 intratumoral CpG injections, they begin taking oral ibrutinib. Tumor fine needle aspirates (FNAs)and peripheral blood samples are obtained prior to treatment, and at 1 week and 6 weeks after treatment start. Single cell preparations of FNA and blood samples are processed using the 10X Genomics platform (based on Zheng et al., Nat Commun 2017). Libraries are sequenced to an average targeted depth of 50,000 reads/cell. Identification of variable genes, principal component and graph-based clustering, and differential expression analysis of single-cell gene expression data is performed using the Seurat algorithm (Butler et al., Nat Biotech, 2018). We have prepared sequencing libraries from 58 tumor FNA and peripheral blood samples from 7 patients thus far. For the first 6 patients, approximately 3,000-10,000 cells per sample have been sequenced, with excellent sequencing quality metrics. Evaluating treatment-induced changes at the CpG-injected site across patients, we found a loss of tumor B cells and T follicular helper cells (Tfh) along with increases in CD8 and CD4 effector cells. Genes associated with cell death, DNA damage response, interferon response, and antigen presentation were induced in tumor B cells after treatment, while genes associated with several signaling pathways, including Myc, Wnt/beta-catenin, and MTOR were down-regulated. In contrast, treatment-induced changes in the tumor-resident T-cells were dominated by a strong interferon response (to both interferon-alpha and -gamma), strongest in CD4 effector and memory populations and weakest in T follicular helper cells and exhausted T cells. T-cells also showed induction of genes associated with TNF-alpha signaling, IL6 signaling, and inflammatory chemokines and cytokines. Interestingly, at the distal, non-injected site, similar changes occurred with smaller magnitude and more so at the week 6 timepoint. Further expression analysis, sequencing and analysis of single cell TCR clonotypes, and relation of results to clinical data is ongoing. Deep profiling of serial biopsies offers a comprehensive view of the evolving immune microenvironment during immunotherapy. By sampling multiple tumors over time in patients undergoing in situ vaccination, we identify significant and distinct transcriptional shifts in different tumor microenvironmental subpopulations at both the injected and un-injected sites, including activation of T-cells both sites with different dynamics. Our approach represents successful application of single-cell genomics to a clinical trial, illuminating cellular dynamics induced by treatment. Disclosures Levy: Apexigen: Membership on an entity's Board of Directors or advisory committees; Nohla: Membership on an entity's Board of Directors or advisory committees; Spotlight: Membership on an entity's Board of Directors or advisory committees; 47 Inc: Membership on an entity's Board of Directors or advisory committees; XCella: Membership on an entity's Board of Directors or advisory committees; Immunocore: Membership on an entity's Board of Directors or advisory committees; Walking Fish: Membership on an entity's Board of Directors or advisory committees; Five Prime: Membership on an entity's Board of Directors or advisory committees; Corvus: Membership on an entity's Board of Directors or advisory committees; Quadriga: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; GigaGen: Membership on an entity's Board of Directors or advisory committees; Teneobio: Membership on an entity's Board of Directors or advisory committees; Sutro: Membership on an entity's Board of Directors or advisory committees; Checkmate: Membership on an entity's Board of Directors or advisory committees; Nurix: Membership on an entity's Board of Directors or advisory committees; Dragonfly: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Abpro: Membership on an entity's Board of Directors or advisory committees.

Audit procedures are considered to be an external governance mechanism tool used by shareholders from an agency theory perspective. The empirical model is constructed to assess the theoretical and statistical relationship between audit lag and corporate governance characteristics over a period of four years (for FTSE 350 companies excluding financial institutions between 2007 and 2010). This paper studies the effect of corporate governance mechanisms, board of directors and audit committee, on audit report lag. The importance of this research comes from the few studies conducted regarding the relationship between corporate governance and audit report lag. It is crucial to understand the determinants of audit lag in order to minimize it as much as possible and accordingly generate timely information.

Cutaneous T cell lymphoma (CTCL) is a CD4+ T cell malignancy of the skin with heterogeneous outcomes and limited treatment options. Monoclonal antibodies directed against PD-1, such as pembrolizumab, have shown impressive efficacy in multiple advanced malignancies, and are currently tested in clinical trials in patients with CTCL. Initial data indicate that about half of the patients experience treatment response, whereas the other half are non-responders. Non-responders can be further divided into patients with stable disease versus rapid progressors. It is currently unknown why some CTCL patients respond to pembrolizumab while others rapidly progress, and no predictive biomarkers are available. Single-cell analysis approaches to identify biomarkers of response, for example quantifying the expression of PD-1 on tumor cells vs. reactive immune cells, have not enabled stratification of patients. We therefore hypothesized that more complex spatial cellular interactions within the immune tumor microenvironment (iTME) of CTCL could provide insight into the mechanisms of pembrolizumab response and enable prediction. We applied CODEX (CO-Detection by indEXing) highly multiplexed tissue imaging to study the CTCL iTME in matched biopsies before and after pembrolizumab therapy in 7 responders and 7 non-responders (see the Figure). Using 54 markers simultaneously allowed discriminating malignant CD4+ tumor cells from reactive CD4+ T cells and identified 30 different cell clusters with spatial information, including an M2 macrophage cluster that was enriched in non-responders before therapy. Unexpectedly, in pembrolizumab responders compared to non-responders, PD-1 expression levels were higher in multiple clusters of tumor cells and reactive T cells. Computational spatial analysis revealed ten distinct, conserved cellular neighborhoods in the CTCL iTME that changed in composition and frequency during therapy. Interestingly, one cellular neighborhood to be presented dramatically increased after therapy only in responders. Therefore, highly multiplexed spatial analysis of the CTCL iTME allows discovering novel, predictive biomarkers of immunotherapy response and will pave the way for future studies that functionally address the identified cell types and cellular interactions. Disclosures Khodadoust: Corvus Pharmaceuticals: Research Funding. Kim:miRagen: Research Funding; Merck: Research Funding; Medivir: Honoraria, Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Soligenix: Research Funding; Forty Seven Inc: Research Funding; Neumedicine: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Elorac: Research Funding; Galderma: Research Funding; Corvus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding. Nolan:Akoya Biosciences Inc.: Consultancy, Equity Ownership, Patents & Royalties.

The purpose of this paper is to identify key indicators of corporate governance that affect the market value of Russian companies. To this end, we examine the possibility of modifying the Ohlson model of evaluating stock price dynamics in public companies, by adding corporate governance variables that may affect market value. The study consists of the following stages: the key points of the Ohlson economic model are described, empirical works that demonstrate corporate governance as a factor in assessing the value of companies are presented, and the significance of the modified Ohlson model for the Russian market is evaluated. The novelty of our methodology is represented in the prioritisation of our “other information” parameter, which is a combination of forecast analytical data and corporate governance indicators. Through analysis of panel data, we estimate differences in the predicted net profit indicator, calculated as the average of analyst forecasts for an individual company for a financial year, and the actual net profit. Corporate governance is represented by the percentage of board members holding professional certificates and licenses, the average term of board of directors members, the share of independent members on the board of directors, the share of independent members in the audit committee, the proportion of women on the board of directors, and the size of the board of directors. Our results indicate dependence of share prices on the dynamics of the book value of equity, abnormal profits, the share of board members holding professional qualifications, the difference between the actual net profit and the forecast net profit of companies, and the level of gender diversification in the board of directors. The results of our analysis of deviations in average stock prices are comparable to the findings of existing literature examining the markets of Europe, Latin America and Africa.

This paper uses a sample of 76 family businesses in Tunisia to investigate the impact of the family firm dynamic on the composition of their boards of directors. We argue that whether or not a transition in ownership is planned, firms have different governance needs and characteristics depending on the generational phase. The empirical results show that board composition is positively influenced by both generational evolution and succession planning. This study provides evidence of an increase in the appointment of outside directors to boards of family firms from the third generation of ownership. This result implies that it is important to consider the generational phase and succession process of the family firm in order to better understand its governance system.

Introduction: Acute myeloid leukemia (AML), a hematologic malignancy characterized by clonal expansion of abnormal myeloid progenitors, is a complex disease exhibiting a dynamic mutational landscape over time. Somatic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~20% of patients with AML, resulting in production of the oncometabolite D-2-hydroxyglutarate (2-HG). Ivosidenib (IVO), a mutant IDH1 (mIDH1) inhibitor, is approved in the US for mIDH1 relapsed or refractory (R/R) AML and newly diagnosed mIDH1 AML in patients ≥75 years old or with comorbidities precluding intensive induction chemotherapy. Durable remissions in mIDH1 R/R AML were achieved with IVO in a phase 1 study (NCT02074839), with a complete remission (CR) plus complete remission with partial hematologic recovery (CRh) rate of &gt;30%, and a median duration of CR+CRh response of &gt;8 months. In these patients, bulk next-generation sequencing (NGS) identified the most frequent baseline co-mutations as DNMT3A (34%), NPM1 (23%), and SRSF2 (20%), with mIDH2 detected in 2 of 101 (~2%) patients (DiNardo et al. N Engl J Med 2018). Though a recent case study (Harding et al. Cancer Discov 2018) described the appearance of mIDH2 in patients who relapsed to IVO (isoform switching), the frequency of this phenomenon is unknown. In addition, it is unclear whether mIDH2 and other co-occurring mutations exist within the same clone as mIDH1 at baseline and relapse, as dynamic clonal architecture cannot be precisely imputed by bulk NGS. Aim: To define clonal architecture heterogeneity and pattern of mechanism of relapse at single-cell resolution in a subset of patients with mIDH2 detectable by bulk NGS following IVO treatment. Methods: Single-cell targeted DNA sequencing (scDNA-seq) was performed on matched patient peripheral blood mononuclear cell (PBMC) samples at baseline and relapse, using a microfluidic platform (Tapestri®) with a 19-gene AML panel (Pellegrino et al. Genome Res 2018) capable of detecting rare subclones to a level of 0.1%. Data were processed and analyzed using Tapestri® Insights software and the timescape R package. Results: Of 129 patients with available longitudinal genomic profiling data, 15 (12%) patients had detectable mIDH2 on treatment. Here we report findings from 9 of 15 patients with available scDNA-seq data. Seven of 9 patients had no detectable mIDH2 at baseline. Six of these 7 acquired mIDH2 at relapse within the same clone as the original mIDH1, whereas mIDH2 was identified in a separate clone to mIDH1 in 1 patient. In the 2 of 9 cases in which mIDH2 was detected at baseline, mIDH2 was present in a separate clone to mIDH1. AML-related gene mutations (e.g. PTPN11, NRAS, ASXL1) were also identified upon relapse following IVO treatment. Figure 1 demonstrates the emergence of mIDH2 in the same cell as mIDH1, concurrent with the expansion of a separate mIDH1 clone harboring a PTPN11 mutation at relapse. Figure 2 demonstrates two distinct mIDH1 clones at baseline, one harboring NPM1/NRAS co-mutations and the other harboring NPM1/FLT3-TKD co-mutations. Following IVO treatment, the IDH1/NPM1/NRAS clone was no longer detected. Reduction in the IDH1/NPM1/FLT3-TKD clone was observed at Cycle 2 Day 1, but it ultimately expanded at relapse with the acquisition of mIDH2. In both cases, plasma 2-HG was first inhibited by &gt;95% but increased at relapse. Furthermore, phylogenetic tree reconstruction from clonotypes indicated patterns of both branching and linear clonal evolution. Conclusions: In a subset of patients with mIDH2 detectable at relapse, mIDH2 was mostly not detectable at baseline but emerged within the same clone as mIDH1, highlighting 2-HG restoration as an important mechanism of resistance to IVO. Moreover, these data provide unique insights into the clonal dynamics in patients with mIDH1 R/R AML harboring mutations in the receptor tyrosine kinase (RTK) pathway, notably that the presence of RTK mutations at baseline does not universally preclude a clinical response. scDNA-seq proved to be a powerful tool in delineating molecular outcomes for patients with mIDH1 R/R AML. These findings, a part of emerging data highlighting the interplay between baseline mutation profiles and response and clonal evolution on treatment, support combinations or sequential treatment modifications at early relapse before overt clinical progression. Disclosures Wang: Agios: Employment, Equity Ownership. Choe:Agios: Employment, Equity Ownership. DiNardo:jazz: Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; medimmune: Honoraria; agios: Consultancy, Honoraria; syros: Honoraria. Stein:Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees. de Botton:Agios: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Pierre Fabre: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Forma: Consultancy, Research Funding; Syros: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy. Fathi:Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy; Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria. Tallman:Biosight: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; ADC Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; UpToDate: Patents & Royalties; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellerant: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Cellerant: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellerant: Research Funding; Cellerant: Research Funding. Kantarjian:Ariad: Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding. Quek:Agios: Research Funding; Celgene: Research Funding, Speakers Bureau. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Attar:Aprea Therapeutics: Employment; Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership.

Introduction: In situ vaccination aims to induce an immune response locally at one tumor site, that propagates systemically to all tumor sites. Prior clinical studies have demonstrated that this strategy can be effective in indolent lymphoma (Brody et al., JCO 2010, Frank et al., Cancer Discov 2018, Hammerich et al., Nat Med 2019). The underlying mechanisms, however, remain unclear, as immune recognition and destruction of cancer cells occurs at the level of the tumor microenvironment (TME), and the human TME has been difficult to study due to challenges in acquiring adequate tissue samples. Here, we directly investigate changes induced in the TME by in situ vaccination, applying single cell methods to serial samples from patients on a clinical trial, and relate these changes to clinical tumor response. Methods: We profiled serial specimens from 2 sites of disease in 10 indolent lymphoma patients enrolled in an in situ vaccination trial (NCT02927964). Motivated by compelling preclinical data demonstrating the efficacy of intratumoral CpG, a TLR9 agonist, and systemic ibrutinib, a BTK inhibitor (Sagiv-Barfi et al., Blood 2015), patients receive local low-dose radiation and CpG intratumorally to one site of disease and begin oral ibrutinib in the second week of treatment. Tumor fine needle aspirates (FNAs) from the injected and a distant uninjected tumor site as well as peripheral blood samples are obtained prior to, and at 1 and 6 weeks after treatment start. Single cells from the FNAs and blood samples are then subject to droplet-based single cell RNA sequencing, with approximately 3,000-10,000 cells sequenced per sample. Results: In total, we analyzed 314,827 cells from 52 tumor samples and 30 peripheral blood samples (Fig. 1A). At both the local injected and the distant uninjected tumor sites, we found significant changes in proportions and transcriptional phenotypes of tumor and immune cells, several of which tracked with clinical response. Upon treatment, the proportions of tumor cells decreased significantly at the treated site, even within the 6-week time frame (p=0.003). Increased expression of inflammation related genes at both the injected and uninjected sites (Fig. 1B) and of TGFb pathway genes at the uninjected site (Fig. 1C) were negatively associated with clinical response. Conversely, high expression of antigen presentation genes by week 6 at the injected site correlated with greater shrinkage of distant uninjected tumors (Fig. 1D). Among T and NK cells (Fig. 1E), we observed treatment-induced increases in naïve and cytotoxic CD4 and CD8 T cells, and reductions in T follicular helper and exhausted T cells (Fig. 1F). While all patients exhibited strong interferon responses in their T and NK cells, the degree of interferon response was not associated with overall clinical response (Fig. 1G). Instead, higher cytotoxic CD4 T cells at the injected site and fewer exhausted T cells at the uninjected site after treatment correlated with clinical response. Conclusions: By sampling multiple tumors over time in patients undergoing in situ vaccination, we identify significant changes in tumor and microenvironmental cells at both the injected and uninjected sites, several of which associate with clinical tumor regression. Our approach represents successful application of single-cell genomics to a clinical trial, illuminating treatment-induced cellular dynamics, and implicating tumor cell antigen presentation and CD4 T cell responses as possible determinants of clinical response. Disclosures Levy: Immunocore: Membership on an entity's Board of Directors or advisory committees; Walking Fish: Membership on an entity's Board of Directors or advisory committees; Viracta: Membership on an entity's Board of Directors or advisory committees; Quadriga: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; GigaGen: Membership on an entity's Board of Directors or advisory committees; Teneobio: Membership on an entity's Board of Directors or advisory committees; Sutro: Membership on an entity's Board of Directors or advisory committees; Checkmate: Membership on an entity's Board of Directors or advisory committees; Nurix: Membership on an entity's Board of Directors or advisory committees; Dragonfly: Membership on an entity's Board of Directors or advisory committees; Abpro: Membership on an entity's Board of Directors or advisory committees; Apexigen: Membership on an entity's Board of Directors or advisory committees; Spotlight: Membership on an entity's Board of Directors or advisory committees; 47 Inc.: Membership on an entity's Board of Directors or advisory committees; XCella: Membership on an entity's Board of Directors or advisory committees.

Redes sociales y rendimiento dinámico de la empresa: Evidencia de la industria de semiconductores de Taiwán. Este estudio examina la relación entre la interconexión del consejo directivo y el rendimiento de la empresa. Utilizando datos de la industria de semiconductores de Taiwán de 2013 a 2015, este estudio utiliza la centralidad, los agujeros de la estructura y el número de interconexiones entre consejos directivos como proxies de la interconexión de los consejos directivos. Este estudio también evalúa el rendimiento de la empresa a largo plazo mediante un modelo de análisis envolvente de datos dinámicos. donde se concluye que la interconexión de los directivos mejora la eficiencia dinámica. Utilizando un análisis de la red social de los directivos, también identificamos las cinco mejores empresas con mejor interconexión del consejo directivo en términos de centralidad, agujeros estructurales, y el número de directores interconectados. En general, este trabajo es novedoso en la vinculación de la interconexión de los directivos con la eficiencia dinámica. El estudio enriquece la literatura contable existente sobre el papel de los directivos para influir en el rendimiento de la empresa y evaluar éste desde una perspectiva de eficiencia multidimensional. This study examines the relationship between board interlock and firm performance. Using the Taiwanese semiconductor industry’s dataset from 2013 to 2015, this study uses centrality, structure holes, and the number of interlocking boards as proxies of board interlock. This study also evaluates firm performance over a long-term period through a dynamic data envelopment analysis model. which concluded that board interlock improves dynamic efficiency. Using a directors’ social network analysis, we also identified the top five companies with the best board interlock in terms of centrality, structural holes, and the number of interlocking directors. Overall, this paper is novel in linking board interlock to dynamic efficiency. The study enriches the extant accounting literature regarding the role of directors in influencing firm performance and evaluate firm performance from a multidimensional efficiency perspective.

Purpose This study aims to understand the antecedents of export performance at the firm level. Building on agency theory but taking into account emerging market settings and institutional differences, the authors investigate how the board composition determines the export competitiveness of the firms operating in an emerging country from the point of view of corporate governance mechanisms. Design/methodology/approach Using data from 221 exporting firms for four years (2007-2010), the authors find that there is a significantly positive relationship between board size and all measures of export performance, while a higher presence of outside directors on the board is negatively associated with export performance, consistently with expectations. The separation of chairman of board of directors and chief executive officer (CEO) positions has significantly positive impact on export performance. On the other hand, the authors find no support for the position that inside director professional representation neither reduce nor increase all measures of export performance of firms. In other words, the convergence with Western practices and consistently with agency theory’s claims is evident for both board size and CEO duality. However, the effects of inside professional and outside directors are no consistent with agency theorists’ expectations. Findings Using data from 221 exporting firms for four years (2007-2010), the authors find that there is a significantly positive relationship between board size and all measures of export performance, while a higher presence of outside directors on the board is a negatively associated with export performance, consistently with expectations. The separation of chairman of board of directors and CEO positions has significantly positive impact on export performance. On the other hand, the authors find no support for the position that inside director professional representation neither reduce nor increase all measures of export performance of firms. In other words, the convergence with Western practices and consistently with agency theory’s claims is evident for both board size and CEO duality. However, the effects of inside professional and outside directors are no consistent with agency theorists’ expectations. Research limitations/implications Export performance is one of the most widely researched areas within international marketing research but least reached topic of management. However, exporting continues to be an important mode of internationalization for multinational companies, especially operating an emerging economy. This study is one of the first studies on the impact of governance factors such as board structure on only export performance rather than overall (firm) performance in light of international management. In other words, the study of the determinants of exports in the context of an emerging economy is an important contribution to the literature, given that our understanding of how the board composition determines the export competitiveness from the point of view of firms operating in an emerging country such as Turkey. Moreover, this research investigates this relationship at objective export performance dimensions using primary data set from listed and non-listed export firms. Practical implications The current study offered in-depth information to multinational companies that aim to gain a competitive exporting advantage in Turkey. Further, the results of this study give managers an opportunity to see the reasons behind the success of the exporting firms from the point of view of corporate governance mechanism. Originality/value In this paper, the authors contribute to this recent stream of research providing evidence on the effects of governance mechanism on the export performance from the point of view of emerging countries. Building on agency theory but taking into account emerging market settings and institutional differences, and international management, the authors provide a new framework that models the linkages between board composition and export performance. This work helps us to gain a deeper understanding of how board dynamics contribute to the internalization of firms. Research in this area has been sparse, although some studies have linked governance with export intensity. In this effort, the authors differentiate from previous studies in several ways.

PurposeThis study examines whether female directorship on board is related to firm's risk-taking behavior in India.Design/methodology/approachThe study considers the top 500 listed companies in India during the period 2013 to 2018 for the analysis. The paper employs fixed effects as well as a dynamic panel data model to address the bias in the fixed effects model when the lagged risk outcome is included as an explanatory variable.FindingsThe study finds that the presence of female directors on board is unrelated to the firm's risk-outcomes and the risk-adjusted return earned by the shareholders. The results are in line with the tokenism theory of board diversity. Having a higher share of female independent directors is also unrelated to the risk-taking behavior of firms. The findings are in contrast to the critical mass theory and the agency theory of gender diversity. The study does not rule out the possibility of female directors' risk-preferences being similar to those of male directors.Practical implicationsThe findings suggest that regulations related to having independent female directors may not add value for the shareholders in the short run. The business case for such stringent regulations in India on the gender diversity of boards remains unclear.Originality/valueThis is the first study to analyze the relationship between gender diversity of boards and firm-level risk in India. Most of the studies have focused on gender diversity and firm performance in India. However, modern portfolio theory suggests that both risk and return are important as shareholders care about risk-adjusted returns.

Purpose – This paper aims to provide insights on the gender-performance relationship, this paper studies the impact of board gender diversity on firm performance, by taking into account the “critical mass” of women directors and their educational level. Design/methodology/approach – The hypotheses are tested on a unique dataset of 211 European Union publicly listed companies in 2012 belonging to the construction industry from 28 different countries through a set of ordinary least squares regressions. Findings – The evidence shows that the “critical mass” rather than the simple presence of women has an incremental benefit on firm performance. In addition, results show that the educational level of women directors negatively affects firm performance, as it might impact the dynamics within the boardroom. Research limitations/implications – The quantitative nature of the study does not allow drawing strong inferences on behavioral processes and dynamics in and around the boardroom. Nevertheless, this study will open new research insights on exploring the educational level on board. Practical implications – Regulators and policymakers that should be aware of the influence of women as a group on firm performance and that this role is differential across industries. Originality/value – The novelty of this paper is that it investigates the role of women in a high masculine gender-specific industry and explores a still poorly understood demographic variable (i.e. the educational level) of women directors.

Past studies on CEO hubris has found that board vigilance is effective in managing the negative outcome of hubris. Some studies found CEO non-duality and independent director representation are effective in decreasing the damage of hubris. However, these studies have only explored the causal relationship of hubris and firm performance in the one-tier corporate governance setting. This study analyzed the influence of CEO hubris on firm performance in Indonesia by taking into account the CEO-board power dynamics. Indonesia adopts the two-tier corporate system where the board is divided into the board of directors and commissioners. Through 99 public listed companies, this study found that hubris in Indonesian CEOs contributes well to firm performance. Moreover, a bigger commissioner board is effective in strengthening the positive influence of hubris on firm performance in Indonesia. Furthermore, this study hints that two-tier corporate governance is more efficient in controlling hubris than the one-tier system.

Abstract Background/Aims: Myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF), are clonal disorders characterized by unlimited proliferation of hematopoietic cells. Besides the dominant clone, in the majority of cases defined by a driver mutation (JAK2V617F, CALR or MPL mutation), sub-clones carrying additional mutations (e. g. in the genes ASXL1, CBL, DNMT3A, EZH2, IDH1, U2AF1, SF3B1, TET2, TP53) and/or normal polyclonal hematopoiesis coexist. Due to the loss of telomere sequences with each cell division, the length of telomeres can be used to describe clonal dynamics of hematopoietic cells. In neoplastic cells with a high mitotic rate shorter telomeres are typically found compared to the telomere length (TL) in normal counterparts. In the ET phase 2 study with the telomerase inhibitor imetelstat we demonstrated rapid and durable hematologic and molecular responses (Baerlocher et al. N Engl J Med 2015) and suppression of clones with non-driver mutations (Oppliger Leibundgut et al, ASH 2015). Here, our aims were 1) to evaluate the TL in subsets of leukocytes from patients (pts) with MPN compared to healthy individuals and 2) to study the TL dynamics in ET pts treated with imetelstat and to correlate those with hematologic and molecular responses. Patients and Methods: Blood samples from 63 standard of care (SOC)-treated or untreated pts with MPN (15 ET, 36 PV, 12 MF) diagnosed according to WHO 2008 criteria as well as from 14 ET pts treated with imetelstat after failure or intolerance to ≥1 prior therapy were analyzed for TL. TL percentiles from over 400 healthy individuals served as reference. Leukocytes were extracted from the peripheral blood and TL was measured in subsets of leukocytes by automated multicolor flow-FISH (Baerlocher et al, Nat Protoc. 2006). Results: 81% of the 62 MPN pts (11/15 ET, 32/35 PV, 7/12 MF) carried a JAK2 mutation, 6 (1 ET, 5 MF) a CALR mutation, 1 ET pt had a MPL mutation, 2 ET pts were triple negative and 3 PV pts were JAK2 wild type. 23 pts were treated with phlebotomy, 32 with hydroxyurea, 3 with anagrelide and 3 with IFN-alpha. The median age at study entry was 62 yrs (23-89, ET/PV/MF 64/58/66 yrs) and the median time since diagnosis was 2.7 yrs (0.3-14.2) in the ET SOC cohort. In the imetelstat cohort, 9/14 ET pts carried a JAK2V617F mutation and 5 a CALR mutation. The median age at study entry was 60.5 yrs (21-80) and the median time since diagnosis was 6.7 yrs (0.3-21). The telomere length values (TLV) in granulocytes from the 63 MPN pts on SOC were around the 10th percentile for pts with ET and PV and below the 1st percentile for most pts with MF. In the imetelstat cohort, 8 of 14 ET pts with a median of 2 prior therapies demonstrated TLV in granulocytes <1st percentile before the imetelstat treatment, which is significantly lower than in ET pts on SOC (p < 0.01). In 6 of 9 ET pts on imetelstat the TLV were higher after 9 months. In addition, this difference in TL correlated significantly with the maximum reduction of the JAK2V617F mutational burden (p = 0.0137). Of interest, the 3 pts with lower or steady TLV after 9 months of treatment had the highest number of additional mutations before imetelstat treatment and despite a good suppression of the clone with the driver mutation these sub-clones were only partially responsive to imetelstat (i.e. 3 to 5 additional mutations in ASXL1, CBL, DNMT3A, EZH2, TET2, TP53, SF3B1 and U2AF1). Overall, pts with high level additional mutational burden had shorter TLV (age-adjusted mean difference from 50th percentile ±STD -3.6 ± 0.5 kb) at baseline than pts with no or low level additional mutational burden (age-adjusted mean difference from 50th percentile ±STD -2.9 ± 1 kb), and in both sets of pts mean TLV were higher after 9 months of imetelstat treatment. Conclusions: The lower TLV found in granulocytes of pts with MPN and especially with MF compared to healthy individuals reflect the higher mitotic history of malignant clones. In the ET imetelstat cohort, the very low TLV found at baseline might result from longer disease duration and resistance and/or intolerance to prior therapies. The higher TLV observed after 9 months of treatment with imetelstat and correlation with the reduction in the driver mutational burden suggests that imetelstat treatment in ET pts may suppress neoplastic clones and, in the absence of a high additional mutational burden, favor recovery of normal hematopoiesis. Disclosures Oppliger Leibundgut: Geron: Research Funding; Novartis: Research Funding. Burington:Geron Corporation: Employment. Ottmann:Fusion Pharma: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Spitzer:Trovagene Inc: Consultancy; Moldx Palmetto GBA: Consultancy; Incyte: Consultancy. Odenike:CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding. McDevitt:Salamandra Inc: Consultancy; Alexion: Membership on an entity's Board of Directors or advisory committees. Röth:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Research Funding. Snyder:Ariad: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Baerlocher:Geron: Research Funding; Janssen: Research Funding; Novartis: Research Funding.

Abstract Introduction: Monoclonal B cell lymphocytosis (MBL) is an asymptomatic expansion of clonal CD19+/CD5+ B cells with less than 5x109/L cells in the peripheral blood and without other manifestations of chronic lymphocytic leukemia (CLL). Approximately 1% of MBL evolves to CLL requiring therapy per year; thus it is critical to develop more precise tools to identify which MBL will progress to CLL and require treatment. Patients and Methods: In this study, we performed targeted deep sequencing (TDS) on 49 high-count MBL individuals (median B-cell count 3.7x109/L; range 0.8-4.9x109/L) and explored the mutation status of 20 driver genes recurrently mutated in CLL. We analyzed the clonal evolution in 45 of these 49 MBLs by screening 2-4 sequential samples (average time between samples 56 months, range 10-119 months). At last follow-up, 19 cases (39%) had progressed to Rai>0, and 10 cases (20%) required treatment. Tumor and germ line DNAs were isolated from sorted CD5+/CD19+ and CD5-/CD19- cell populations, respectively. Overall, 154 samples from 49 MBL cases (105 tumor and 49 germ line) were screened using semiconductor sequencing technology. The latter genetic information was integrated with relevant clinical and biological parameters, and we evaluated the effect of driver mutations and clonal expansion on time to CLL progression and time to treatment (TTT). Results and Discussion: Our cohort consisted in 17 women and 32 men, with a median age of 66 years (range: 44-80). Five cases presented secondary diseases, including melanoma, lung and bladder cancer. Clinical and biological parameters were collected, including IGHV mutation status (mutated 66%, unmutated 34%), ZAP70 and CD49 expression (25% each). At presentation, 46% of cases had del(13q), 27% trisomy 12, 6% del(11q), and 4% del(17p). Overall, we found somatic non-synonymous mutations in 23 of 49 MBLs (47%) at the initial time point including 22% of cases with more than one mutated driver gene. The average depth of coverage was 730x, thus allowing the identification of small subclonal mutations. Recurrent mutations were found in most of the drivers: CHD2, DDX3X (8% of cases), FBXW7, NOTCH1, SF3B1 (6% each), ATM, BCOR, BIRC3, BRAF, KRAS, MED12, MYD88 and ZMYM3 (4% each). Furthermore, ITPKB, POT1, SAMHD1 and XPO1 were mutated in only one case, whereas no mutations were found in HIST1H1E, RIPK1 and TP53. In 4 individuals, we found two mutations in the same gene (BRAF, DDX3X, KRAS and SAMHD1). Genes that are known to be associated with disease progression in CLL were either mutated with significantly lower incidence (NOTCH1, SF3B1) or not mutated (TP53). Mutations were detected on average 45 months (range 9-73) prior to progression to CLL Rai>0 indicating the early origin of most driver gene mutations in the MBL/CLL continuum. The presence of driver mutations in MBL was associated with shorter TTT (median TTT: present: 96 months vs. not present: not reached, HR: 5.52, 95% CI: 1.2-26.2, P =0.015). Next, we looked at clonal expansion of driver mutations over time (defined as >2-fold change in the allelic frequency of driver mutations between time points). Of 20 MBLs with mutations at baseline who had sequential samples available, 10 cases showed clonal expansion. Seven out of 10 MBLs who required therapy showed clonal expansion, which was detected on average 15 months (range 6-30 month) prior to treatment. Finally, the detection of clonal expansion was significantly associated with reduced TTT (median TTT: clonal expansion: 21 months vs. no clonal expansion: 84 months, HR: 7.79, 95% CI: 1.94-31.3, P <0.001). Conclusion: We have confirmed the existence of recurrent mutations in most CLL putative driver genes at the premalignant MBL stage many years before progression to CLL. Furthermore, the early identification of driver mutations and its clonal expansion predicts a shorter TTT. Of note, clonal evolution under selective pressure has recently been linked to the onset of CLL progression after therapy. In this study, we characterized the clonal dynamics in the pre-malignant stages of the disease and underlined its impact on clinical outcome. Despite the relatively small size of the cohort, these findings suggest that the sequential monitoring of MBL individuals with a simple and reliable technique, such as TDS, will be at least of prognostic use and thus its incorporation in the disease stratification and clinical management should be further tested. Disclosures Fonseca: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Kay:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Tolero Pharma: Research Funding; Genentech: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding.

Abstract Background We previously found that the combination of ibrutinib (IBR) or duvelisib (DUV) with FCR leads to a high rate of MRD undetectability when given as frontline therapy for younger, fit CLL patients (Davids et al., ASH 2017 and EHA 2018), a strategy we call KI+FCR. However, not all patients achieve deep response, and identifying predictive biomarkers may further improve efficacy rates while not exposing patients unlikely to benefit from FCR to the risks of this therapy. Dynamic BH3 profiling (DBP) is a functional assay that measures the net pro-apoptotic signaling induced in a cell in response to a drug treatment (delta priming). Here, we evaluated whether DBP could predict the likelihood of achieving MRD undetectability on two KI+FCR trials. Methods Mononuclear cells were isolated by Ficoll separation from peripheral blood (PB) and bone marrow (BM) of CLL patients in two different investigator-initiated trials of frontline therapy in patients age ≤ 65: IBR+FCR (iFCR, n=30) or DUV+FCR (dFCR, n=25). Samples were isolated pre-treatment and after one week of KI monotherapy (just prior to the first cycle of KI+FCR). BH3 profiling was performed on untreated cells by measuring %cytochrome C release in cells exposed to BH3-only peptides or small molecules targeting pro-survival BCL-2 family proteins. Untreated CLL cells were also co-cultured with NK.TERT stromal cells (1:10 ratio) with 1 µM drug treatments, and DBP was performed as previously described (Montero et al., Cell, 2015) to measure the net pro-apoptotic signaling induced by each drug. Venetoclax (VEN) was used to measure BCL-2 dependence, and the BH3-only peptides HRK, MS1, and FS1 were used to measure BCL-xL, MCL-1, and BFL-1 dependence, respectively. BIM BH3 peptide was used to measure overall mitochondrial priming for apoptosis. Clinical response was assessed by 2008 IW-CLL criteria. Results In ex vivo experiments, pre-treatment PB-derived CLL cells showed similar increased BCL-2 dependence after 24 hrs of treatment with IBR or DUV (IBR, n=22, delta priming= +11.6%, CI=5.5-17.7, p= 0.0007 and DUV, n=13, delta priming= +8.4%, CI=1.1-15.7, p=0.0274). Similarly, pre-treatment BM-derived CLL cells treated ex vivo with IBR or DUV for 24 hrs. had increased BCL-2 dependence (IBR, n=13, delta priming= +15.4%, CI= 9.1-21.7, p=0.0002 and DUV, n=13, delta priming= +9.3%, CI =1.5-17.2, p=0.0235). No significant changes were observed in overall priming for apoptosis, nor in BCL-XL, MCL-1, or BFL-1 dependence. In in vivo experiments performed on CLL cells from patients treated with one week of IBR or DUV monotherapy prior to combination with FCR, no significant change in BCL-2 dependence was observed in aggregate comparing the pre-treatment and one week post-treatment PB-derived CLL cells. However, PB-derived CLL cells from patients in both trials who later went on to achieve complete response (CR) had significantly higher delta priming for BCL-2 than those achieving a partial response (PR) as best response. (Fig. 1: iFCR, CR, n=20, mean delta priming= +9.9%, PR, n=10, mean delta priming= -6.2%, CI= -27.6 to -4.55 and p = 0.0084, dFCR, CR, n=10, mean delta priming=+12.1%, PR, n=9, mean delta priming= -1.7%, CI= -26.6 to -1.02, p = 0.0359). As in the ex vivo experiments, no significant alteration in overall priming or in dependence on other anti-apoptotic proteins was observed. Pre-treatment PB-derived CLL cells from patients treated with dFCR who reached BM-MRD undetectability (MRD-) also had significantly higher baseline BCL-2 dependence than those who were BM-MRD detectable (MRD+) as best response (MRD-, n=11, priming=+36.9%, MRD+, n=5, priming=21.7%, p=0.0377). Similar trends were observed with iFCR, though these results did not reach statistical significance, possibly due to the small number of MRD+ patients (n=5). Conclusions Ex vivo treatment of CLL cells with IBR or DUV leads to increased BCL-2 dependence, and the level of in vivo delta-priming for BCL-2 dependence predicts depth of response to KI+FCR based frontline therapy in CLL. Additional experiments are ongoing to better define the mechanism underlying the altered anti-apoptotic dependencies seen with KI therapy in CLL cells. DBP should be further evaluated for its potential as a clinical decision-making tool to identify those young, fit CLL patients who are the best candidates for frontline KI+FCR therapy and who may have a more favorable risk/benefit ratio from a novel agent only regimen. Disclosures Valentin: Roche: Other: Travel reimbursement; AbbVie: Other: Travel reimbursement. Brown:Verastem: Consultancy, Research Funding; Loxo: Consultancy; Roche/Genentech: Consultancy; Sunesis: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Gilead: Consultancy, Research Funding; Genentech: Consultancy; Celgene: Consultancy; Boehringer: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Sun Pharmaceutical Industries: Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy. Davids:Sunesis: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Merck: Consultancy; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Surface Oncology: Research Funding; Roche: Consultancy; Merck: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Sunesis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; BMS: Research Funding.

INTRODUCTION: CXCR4 chemokine receptor inhibitors such as BL-8040 (BioLineRx) have been investigated by us and others as possible anti-leukemic drugs due to their ability to "mobilize" leukemia cells out of the BM and into the circulation, where they are more sensitive to chemotherapy. However, the exact mode of cell relocation remains unclear. CXCR4/CXCL12 signaling pathway also participates in BM homing of immune cells, including both central memory T cells and immunosuppressive CD4+FoxP3+ T-regulatory cells (T-reg). Therefore, CXCR4 inhibition has the potential to either counteract or enhance the process of AML immune surveillance. Therefore, we sought to develop a syngeneic AML model for intravital 2-photon microscopy (TPM) compatible with existing immune reporter mouse strains, which typically occupy the green, yellow and red fluorescence channels. HYPOTHESIS: CXCR4 inhibition decreases AML and T cell BM cellularity by increasing the rate of intravascular cell entry and/or decreasing the rate of circulating cell homing back to BM. MODEL: The cyan-colored fluorescent protein mTurquoise2 was lentivirally introduced into C57BL6-origin AML cells containing the MLL, ENL-FLT3, ITD, and p53-/- mutations, termed AML1-mTurq2. Syngeneic FoxP3-GFP/CD11c-YFP/hCD2-DsRed reporter mice were generated by inter-breeding of the corresponding strains, respectively highlighting T-reg, myeloid antigen presenting cells, and all T cells. After intravenous infusion of 1E5 AML1-mTurq2 cells, 1-2% blasts appeared in peripheral blood on day 9, increasing to 70% on day 15-20 when animals had to be euthanized. TREATMENT: Mice with >1% blasts were given BL-8040 I.P. in two daily 400 µg doses followed by imaging 24 h later, or intravenously during imaging 10 µg and 50 µg one hour later. ANALYSIS: Disease progression was characterized by blood flow cytometry, symptom scoring and thick-mount organ tissue fluorescence microscopy. Intravital TPM of the calvarial bone marrow (BM) was performed through intact bone under general anesthesia. By interline multiplexing dual femtosecond lasers with four-sensor detection for 8 distinct channels, mTurquoise2 and SHG were recorded by the same sensor at, respectively, 860 and 990 nm excitation, along with GFP, YFP, DsRed and dextran-TRITC (blood tracer). AML and T cell subsets were 3-D tracked using Imaris software. RESULTS: AML1-mTurq2 cells stably and uniformly expressed bright cyan fluorescence, suitable for intravital TPM with low incident laser powers and fast imaging rates in deep tissue locations. In C57BL6 mice, sparse AML cell clusters were found in BM perivascular spaces on day 1 after cell infusion. AML cells were slowly motile (~4 um/min) and highly proliferative, gradually filling BM spaces and emerging in other organs. T cells and CD11c dendritic cells were present in leukemic BM, and the vasculature appeared largely intact and well perfused. T cells interacted with AML cells and the stroma, migrating with high average velocities (~10 µm/min) and slowing down to ~3 µm/min in late-stage disease. After 2 days of BL-8040 treatment, disease symptom scores improved from 3 to 1 while the untreated controls progressed from 3 to 4 (range 0-6). TPM revealed a 4-fold reduction of AML cellularity in BM. Cellular velocities of both AML and T cells were unchanged by BL-8040 treatment. After acute drug administration, a fraction of stromal AML cells begun entering capillary vessel lumens by amoeboid movement. The intravasated AML cells adhered to vessel wall for 1-2 minutes before rapid detachment. Some cells remained tethered while already loose in the blood stream. CONCLUSIONS: A novel, brightly cyan-fluorescent syngeneic AML1-mTurq2 AML model is advantageous for 6-color intravital microscopy of cell trafficking and immune surveillance in optimal compatibility with green, yellow and red reporters of cell lineages and tissue architecture. Using this model, we show that CXCR4 inhibitor BL-8040 decreases AML BM cellularity by increasing the frequency of intravasation without increasing AML migratory velocity. Disclosures Zal: Daiichi-Sankyo: Research Funding; NIH-CTEP: Research Funding; BioLineRx: Research Funding; VueBio.com: Equity Ownership; NIH/NCI: Research Funding; CPRIT: Research Funding; Moleculin Biotech, Inc.: Research Funding. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; AstaZeneca: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy.

There has been scant research exploring the implications of board heterogeneity for board's functioning and subsequent corporate outcome of stability in firm performance. A number of hypotheses are developed based on a multi-theoretic approach incorporating board resources, board dynamics, and board independence. Results of testing the hypotheses reveal that board heterogeneity in organizational tenure, functional experience, and educational specialty is related to the stability of returns. Furthermore, increased ownership position by directors and institutional investors strengthens the relationship between board heterogeneity and stability of returns. The results of this study suggest that board heterogeneity increases organizational rationality and further the stability in firm performance through its more effective control and counsel functions to management.

The purpose of the paper is to explore the impact of firm risk on board independence, typically the proportion of non-executive directors. Our sample is based on a panel data of publicly listed firms on Vietnamese stock markets over a ten-year period (2007-2016). By applying dynamic generalized method of moments estimators, the results are robust to endogeneity issues and highlight the U-shaped nonlinear impact of firm risk on non-executive director ratio. In addition, because the lack of information transparency in Vietnamese enterprises caused many risks for investors, the government issued the Circular 121/2012/TT-BTC dated July 26, 2012 on corporate governance applicable to public companies, which enhanced changes in the board structure of listed companies. Under the pressure of this regulation, high-risk companies increased the proportion of non-executive directors.

Abstract Introduction The combination of tyrosine kinase inhibitors (TKI) with intensive therapy has improved survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The survival with the combination of hyper-CVAD (HCVAD) with ponatinib has now reached 3-year overall survival of 75%. Allogeneic stem cell transplant (ASCT) is indicated for patients with Ph+ALL in first complete response (CR) as standard recommendation. Given observed improved survival with effective frontline therapy and the risk of treatment-related mortality associated with ASCT, personalized assessment of the indication of ASCT is needed with the consideration of longitudinal data of BCR-ABL1 transcript levels after therapy. Conventional statistical models cannot incorporate dependencies between longitudinal and time-to-event data. Therefore, joint models can combine these two types of data to assess the effect of treatment as well as the impact of longitudinal biomarkers such as BCR-ABL1 transcript levels. The aim of this study is to develop a multivariate joint model for dynamic personalized assessment of outcome in patients with Ph+ALL with or without ASCT. Methods From April 2001 to June 2017, 223 patients enrolled in frontline trials of the combination of intensive therapy with TKI were analyzed (HCVAD [hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] + imatinib, 54 patients; HCVAD + dasatinib, 72 patients; HCMAD [hyper-fractionated cyclophosphamide, liposomal vincristine, doxorubicin, and dexamethasone] + TKI, 21 patients; HCVAD + ponatinib, 68 patients), including 2445 measurements of BCR-ABL1 transcripts by reverse transcriptase polymerase chain reaction. Multivariate joint modeling with multiple longitudinal measurements was performed for dynamic personalized assessment with the combination of multivariate Cox proportional hazard model with generalized linear mixed models. For the estimation of parameters of the joint model, a Bayesian approach was used with Markov Chain Monte Carlo methods. The BCR-ABL1/ABL1 ratio and time from diagnosis to ASCT were considered as time-dependent covariates in the generalized linear mixed model. Results Overall, the median follow-up was 72 months (range, 0.2-199.4); HCVAD + imatinib, 168 months; HCVAD + dasatinib, 97 months; HCVAD + ponatinib, 45 months; H (Table 1). The median overall survival (OS) duration was 27.7 months, 67.0 months, not reached, not reached, and 87.2 months in the HCVAD + imatinib, HCVAD + dasatinib, HCVAD + ponatinib, and HCMAD + TKI, respectively (p= 0.027). Of the 48 patients (22%) who received ASCT, the median time to SCT was 5 months (range, 0.89-21.26). The trajectories of BCR-ABL1 transcript levels of P190 and P210 were shown in Figure 1 and Figure 2, respectively. Multivariate joint model identified age at the start of therapy (p <0.001; post-mean, 0.0167; 95% credible interval [CI], 0.0150 - 0.0175), type of transcript (P210 or P190) (p=0.030; post-mean, 2.5375; 95% CI, 1.3568 - 3.9252), BCR-ABL1 transcripts levels at diagnosis (p< 0.001; post-mean, 0.0083; 95% CI, 0.0072 - 0.0097), TKI therapy (imatinib, dasatinib, or ponatinib) (p <0.001; post-mean, -0.4929; 95% CI, -0.5543 - -0.4532), time-dependent logarithmic P190 levels (p= 0.006; post-mean, 0.0407; 95% CI, 0.0300 - 0.0605), time-dependent logarithmic P210 levels (p<0.001; post-mean, 0.0599; 95% CI, 0.0423 - 0.0812), and the use of ASCT (p= 0.020; post-mean, 0.1276; 95% CI, 0.0869 - 0.2371) as prognostic factors for OS. An example of dynamic personalized assessment for the guidance of the ASCT indication was shown in Figure 3. Patient #1 was a 47-year-old male with newly diagnosed Ph+ALL who was treated with front-line HCVAD + ponatinib. At diagnosis, the patient had P190 transcript type with a BCR-ABL level of 100% by reverse transcriptase polymerase chain reaction. At 2.89 months of therapy, his BCR-ABL level was undetectable. Dynamic personalized assessment by multivariate joint model estimated 5-year OS rates were 84.6% (95% CI, 69.4-94.1) without ASCT, and 81.9% (95% CI, 49.8-93.4) with ASCT. Conclusion Dynamic personalized assessment of outcome in patients with Ph+ALL is feasible to optimize treatment decision in patients with Ph+ALL. Through the personalized recommendation, the assessment can identify patients who may benefit from ASCT. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Jabbour:Abbvie: Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding. Ravandi:Orsenix: Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Xencor: Research Funding; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria. Short:Takeda Oncology: Consultancy. Daver:Daiichi-Sankyo: Research Funding; ImmunoGen: Consultancy; Novartis: Research Funding; Karyopharm: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding; Sunesis: Research Funding; BMS: Research Funding; Incyte: Research Funding; Kiromic: Research Funding; Otsuka: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Alexion: Consultancy. Kadia:Abbvie: Consultancy; BMS: Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Celgene: Research Funding; Takeda: Consultancy; BMS: Research Funding; Jazz: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding. Jain:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Verastem: Research Funding; Celgene: Research Funding; Adaptive Biotechnologioes: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Verastem: Research Funding; Pfizer: Research Funding; Servier: Research Funding; Astra Zeneca: Research Funding; BMS: Research Funding; Celgene: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding. Thompson:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pemmaraju:celgene: Consultancy, Honoraria; cellectis: Research Funding; samus: Research Funding; novartis: Research Funding; plexxikon: Research Funding; stemline: Consultancy, Honoraria, Research Funding; Affymetrix: Research Funding; abbvie: Research Funding; daiichi sankyo: Research Funding; SagerStrong Foundation: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. O'Brien:Janssen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Astellas: Consultancy; Alexion: Consultancy; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Regeneron: Research Funding; Gilead: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; GlaxoSmithKline: Consultancy; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Amgen: Consultancy; Aptose Biosciences Inc.: Consultancy; Acerta: Research Funding; TG Therapeutics: Consultancy, Research Funding; Kite Pharma: Research Funding.

PurposeThe prime objective of this study is to investigate the moderating influence of executive and independent female directors on the relationship between remuneration packages (CEO and executive director) and socially responsible practices (marketplace, environment, community, workplace and money spent on CSR) of 483 Malaysian listed firms during 2006–2017.Design/methodology/approachThe dynamic estimator, namely, system generalized method of moments (GMM) given by Blundell and Bond (1998) has been employed on the dataset to control dynamic endogeneity, unobserved heterogeneity and simultaneity problems.FindingsFindings indicate that there is a significant relationship between remuneration patterns of CEOs and executive directors and socially responsible activities. In the same way, executive board gender diversity significantly, whereas independent board gender diversity insignificantly moderates the remuneration and CSR nexus.Practical implicationsThis study is particularly significant for regulatory bodies of Malaysia, e.g. Securities Commission Malaysia, Bursa Malaysia, policy makers, investors and managers. For academia, this study fetches support from agency theory, stakeholder theory and upper echelons theory and presents integrated theoretical approach to be considered for future research.Originality/valueThis paper is unique in providing empirical evidence on the moderating effect of both executive and independent women directors on the relationship between remuneration patterns of CEOs and executive directors and independent CSR activities for the first time. Moreover, this study has sourced several theoretical and practical implications. And, the study employs dynamic estimator for precise and concrete results.

The board characteristics are an important factor affecting the growth of the company. This paper selects the data of A-share listed companies in the Shanghai and Shenzhen Stock Exchanges during the five-year period from 2014 to 2019, and analyzes whether the board characteristics will affect the growth of the company from a dynamic perspective. The research found that: ① the scale of the board of a listed company has an inverted U-shaped relationship with the company’s growth; ② the proportion of independent directors has a positive correlation with the company’s growth; ③ the director’s salary has a positive correlation with the company’s growth.

ABSTRACT:Corporate governance and finance are dynamic academic fields that offer myriad opportunities for business ethics analysis. Within the corporate governance triad in recent years, shareholders have increased their power over boards of directors and executives through both regulation and movements to change corporate by-laws. The impact of board characteristics on firm performance has proven elusive, leading to questions concerning board processes and individual director beliefs and behaviors. At the same time, CEOs have lost considerable power, leaving many struggling to regain their control and maintain their compensation levels, while others adopt a stewardship approach to their posts. In the field of finance, the recent financial debacle has led to a reexamination of financial regulation and of the fundamental nature and purpose of the industry. All of these issues provide business ethicists fodder for investigation and analysis.

Purpose – This paper aims to understand the determinants of board structure of listed firms at institutional, industry and firm levels within an emerging economy. At the institutional level, the paper explores laws, managerial culture and the role of state in instituting and endorsing corporate governance practices. At the firm level, ownership patterns (family and non-family), experience in the capital markets, age and size of the firms are studied to find out the relation between these variables and the board structure. Design/methodology/approach – The research domain of the study is listed firms operating on the Istanbul Stock Exchange. The data for the study are collected at two phases; at the first phase, compliance reports, annual reports, articles of association and annual shareholders’ meeting reports of each firm in the sample are analyzed. At the second stage, secondary data are used for understanding the dynamics of Turkish institutional context. Findings – The results of this study reveal that boards of directors of listed Turkish firms comply with the governance practices instituted by state agencies, except on issues as independent members and committees that will influence the majority owners’ control domain and private benefits. Originality/value – This paper draws attention on institutional context and argues that “good governance” instruments developed for Anglo-Saxon stock market-controlled business systems provide limited explanation for an emerging economy that is characterized by close cooperation between the state, family-owned businesses and financial markets. The study offers insight to policy makers at a national level, interested in developing corporate governance principles regarding boards of directors of listed firms.

Introduction: 5'-Azacitidine (AZA), a DNA demethylating agent, is the primary drug for the treatment of high-risk Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukaemia (CMML). Response is associated with improved survival. However, only half of patients respond, and these responses are rarely durable. We recently reported that primary AZA resistance is associated with a molecular signature of cell cycle quiescence within bone marrow (BM) hematopoietic progenitor cells (Unnikrishnan et al, Cell Reports, 20:572-585 (2017)). As DNA incorporation of the deoxyribonucleic form of AZA (5-aza-2′-deoxycytidine, DAC) occurs during DNA replication, cell cycle quiescence is predicted to lead to less DAC in DNA and concomitantly less DNA demethylation. We recently developed a quantitative multi-parameter assay, AZA-MS (Unnikrishnan, Vo et al, Leukemia 32:900-910 (2018)), to measure the intracellular dynamics of AZA in patients. Using AZA-MS, we reported data supporting the predicted resistance model. CC486 is an oral formulation of AZA. A 28-day cycle of CC486 involves 21 continuous days (21/28) versus the standard 7/28 subcutaneous (SC) injection AZA scheme. Whether levels of in vivo DAC incorporation into DNA during a cycle of CC486 are comparable with that of SC AZA is unknown. AZA-MS provides us with a unique opportunity to empirically assess the in vivo intracellular dynamics of SC versus oral AZA. Study Design and Methods: To directly assess in vivo DAC incorporation and concomitant DNA demethylation with SC AZA and CC486 in the same patient, we initiated a phase II clinical trial (NCT03493646; Fig A). MDS (IPSS; intermediate-2 or high-risk), CMML (bone marrow [BM] blasts 10-29%) and AML (20-30%) patients were recruited for six cycles of SC AZA (75mg/m^2/day for 7/28 days) followed by six cycles of CC486 (100mg bid for 21/28 days in C7-C8 and 150mg bid for 21/28 in C9-C12). Clinical response was assessed at the end of C6 and C12 using International Working Group criteria. Clinical responders and non-responders to SC AZA at C6 received CC486 from C7 onwards. From each patient, 36 peripheral blood (PB) samples and five BM samples were collected over the study period. DNA, RNA and intracellular fractions were isolated from the PB MNCs, for intracellular DAC/AZA measurements by AZA-MS (primary endpoint; Fig A). BM MNCs were utilised for AZA-MS as well as flow cytometry-based cell cycle measurements (secondary endpoint). Results: 31 of 42 consented patients have commenced treatment since trial opening (Fig B-C). We applied the AZA-MS assay on the longitudinal PB and BM samples collected from the seven patients who had completed six months AZA and commenced CC486 as at 26th June 2019 (Fig D). DAC incorporation into DNA and DNA methylation levels were quantified within the same cells, in addition to measuring other parameters (Fig E). As represented by patient 61213-005 (Fig F) who had a complete response (CR) at cycle 6, after 7 days of injection AZA we observed robust incorporation of DAC within PB MNCs (left panel, Fig F) together with concomitant DNA demethylation (right panel, Fig F). DAC levels diminished upon cessation of AZA within a cycle, with corresponding increases in DNA methylation. There were quantitatively higher levels of DAC incorporated in DNA during SC AZA cycles versus CC486. The trend observed is also appreciated from 2.3x higher area under the curve (AUC) measurements in 61213-005 during the SC AZA cycle. DAC incorporation was higher at C9/10 (CC486 150mg bid 21/28) than at C7/8 (CC486 100mg bid 21/28) without appreciable changes in DNA demethylation. During SC AZA cycles, higher DAC levels (top panel, Fig G) and greater DNA methylation (lower panel, Fig G) were seen in the BM MNCs. In a non-responding patient at cycle 6 (61290-002, SD), we saw less DAC incorporation and DNA demethylation (Fig H). We also observed a positive correlation between baseline proportions of cycling BM cells (LIN-CD34+CD38+) and the amount of DAC incorporated in BM MNCs at C1 day 8 (Fig I). Conclusion: AZA-MS can be used to reliably measure in vivo DAC incorporation and concomitant DNA demethylation in PB MNCs and inform appropriate CC486 dosing. Figure Disclosures Unnikrishnan: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fong:Astellas: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Roncolato:St. George Hospital: Employment. Enjeti:Roche: Honoraria, Speakers Bureau; Bayer and Sanofi: Honoraria, Speakers Bureau; Astellas: Consultancy; Novartis: Consultancy; Abbvie: Consultancy. Hertzberg:BMS: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Polizzotto:Janssen: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; ViiV: Research Funding. Pimanda:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.