Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs\u27 therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy

A Confirmatory Factor Analysis Of The Attitude Towards Computers Instrument (ATCI)

A confirmatory factoranalysis was performed on the ATCI to test if it has a unidimensional structure. Data from 176 students was used to investigate the hypotheses. The results indicate that the instrument is a good fit with a single factor mode

Ownership, Activism and Engagement: Institutional Investors as Active Owners

Research Question We research two questions: First, why do some institutional investors operate at a distance from organizations seemingly acting only to “exit” and “trade” shares while others actively engage through various means of “voice”? Second, what processes and behaviour are associated with active ownership? Research Findings/Insights We develop the concept of active ownership by drawing on contrasting theories and images of ownership, identifying antecedents of active ownership and distinguishing between alternative processes of active ownership. Theoretical/Academic Implications Alternative pathways to active ownership contrast the distant, sometimes adversarial nature of shareholder activism with an engaged, collaborative relationship between investors and corporations. Few studies examine active ownership as a process of engagement and mutual exchange between parties taking a generally longer-term perspective towards investment in the firm and its affairs. After modelling active ownership, we develop a research agenda of substantive issues ranging from market and institutional conditions, through investment organization and practice, to board and investor relations. Practitioner/Policy Implications Opening up the multidimensionality of engagement and relations between investors and corporations is crucial to promoting good corporate governance. Policymakers and practitioners require such knowledge when anticipating and developing adjustments to institutions of corporate governance. This article is protected by copyright. All rights reserved

Corporate ethical identity as a determinant of firm performance : a test of the mediating role of stakeholder satisfaction

In this article, we empirically assess the impact of corporate ethical identity (CEI) on a firm’s financial performance. Drawing on formulations of normative and instrumental stakeholder theory, we argue that firms with a strong ethical identity achieve a greater degree of stakeholder satisfaction (SS), which, in turn, positively influences a firm’s financial performance. We analyze two dimensions of the CEI of firms: corporate revealed ethics and corporate applied ethics. Our results indicate that revealed ethics has informational worth and enhances shareholder value, whereas applied ethics has a positive impact through the improvement of SS. However, revealed ethics by itself (i.e. decoupled from ethical initiatives) is not sufficient to boost economic performance.Publicad

Edging toward ‘reasonably’ good corporate governance

Over four decades, research and policy have created layers of understandings in the quest for “good” corporate governance. The corporate excesses of the 1970s sparked a search for market mechanisms and disclosure to empower shareholders. The UK-focused problems of the 1990s prompted board-centric, structural approaches, while the fall of Enron and many other companies in the early 2000s heightened emphasis on director independence and professionalism. With the financial crisis of 2007-09, however, came a turn in some policy approaches and in academic literature seeking a different way forward. This paper explores those four phases and the discourse each develops and then links each to assumptions about accountability and cognition. After the financial crisis came pointers n policy and practice away from narrow, rationalist prescriptions and toward what the philosopher Stephen Toulmin calls “reasonableness”. Acknowledging that heightens awareness of complexity and interdependence in corporate governance practice. The paper then articulates a research agenda concerning what “reasonable” corporate governance might entail

Risk propensity in the foreign direct investment location decision of emerging multinationals

A distinguishing feature of emerging economy multinationals is their apparent tolerance for host country institutional risk. Employing behavioral decision theory and quasi-experimental data, we find that managers’ domestic experience satisfaction increases their relative risk propensity regarding controllable risk (legally protectable loss), but decreases their tendency to accept non-controllable risk (e.g., political instability). In contrast, firms’ potential slack reduces relative risk propensity regarding controllable risk, yet amplifies the tendency to take non-controllable risk. We suggest that these counterbalancing effects might help explain observation that risk-taking in FDI location decisions is influenced by firm experience and context. The study provides a new understanding of why firms exhibit heterogeneous responses to host country risks, and the varying effects of institutions

A Model of the Global and Institutional Antecedents of High-Level Corporate Environmental Performance

Stories of firms that exceed local compliance requirements in their environmental performance appear routinely. However, we have limited theoretical explanations of what propels these firms to exceed compliance. Our theory suggests that global competitive and institutional pressures lead multinational firms to develop highlevel, environmental management systems (EMS) that make them more competitive. For economic and other reasons, select firms make the choice to rationalize their collective environmental performance to the highest common denominator rather than the lowest. Regulations around the world differ widely and are a moving target in many settings. The need to comply with such myriad, shifting rules leads to firms creating EMS to help stay ahead of regulations worldwide. Using institutional and internationalization theories as our basis, we offer a propositional model concerning global competitive/institutional pressures and their effects on corporate environmental performance. We conclude the paper with a discussion of the implications of the model.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Chronic alcohol withdrawal-associated increases in VTA Hcrtr1 expression are associated with heightened nociception and anxiety-like behavior in female rats

Alcohol withdrawal is characterized by various symptoms that include pain and negative affect in the absence of the drug. The neural underpinnings of these behaviors are not entirely understood, but orexin has emerged as a candidate target for the treatment of substance use disorders. Here, we explored changes in orexin system-related gene expression in brain regions important for mediating reward and stress, including the ventral tegmental area (VTA) and extended amygdala (including the central amygdala, nucleus accumbens shell, and bed nucleus of the stria terminalis), in adolescent and adult female Wistar rats following chronic alcohol exposure. We observed higher numbers of Hcrtr1- (orexin receptor 1)-expressing neurons in the VTA of adolescent and adult female rats during withdrawal from chronic alcohol exposure. The number of Hcrt1+ VTA neurons was negatively correlated with thermal sensitivity in adolescent female rats and anxiety-like behavior in adult female rats. These data suggest that chronic alcohol effects on orexin receptor expression in the VTA are related to specific behaviors that manifest during withdrawal, highlighting potential avenues for targeting alcohol withdrawal-associated behaviors across development

Downregulation Of Neurofilament Light Chain Expression In Human Neuronal-glial Cell Co-cultures By A Microbiome-derived Lipopolysaccharide-induced Mirna-30b-5p

Microbiome-derived Gram-negative bacterial lipopolysaccharide (LPS) has been shown by multiple laboratories to reside within Alzheimer\u27s disease (AD)-affected neocortical and hippocampal neurons. LPS and other pro-inflammatory stressors strongly induce a defined set of NF-kB (p50/p65)-sensitive human microRNAs, including a brain-enriched Homo sapien microRNA-30b-5p (hsa-miRNA-30b-5p; miRNA-30b). Here we provide evidence that this neuropathology-associated miRNA, known to be upregulated in AD brain and LPS-stressed human neuronal-glial (HNG) cells in primary culture targets the neurofilament light (NF-L) chain mRNA 3\u27-untranslated region (3\u27-UTR), which is conducive to the post-transcriptional downregulation of NF-L expression observed within both AD and LPS-treated HNG cells. A deficiency of NF-L is associated with consequent atrophy of the neuronal cytoskeleton and the disruption of synaptic organization. Interestingly, miRNA-30b has previously been shown to be highly expressed in amyloid-beta (Aβ) peptide-treated animal and cell models, and Aβ peptides promote LPS entry into neurons. Increased miRNA-30b expression induces neuronal injury, neuron loss, neuronal inflammation, impairment of synaptic transmission, and synaptic failure in neurodegenerative disease and transgenic murine models. This gut microbiota-derived LPS-NF-kB-miRNA-30b-NF-L pathological signaling network: (i) underscores a positive pathological link between the LPS of gastrointestinal (GI)-tract microbes and the inflammatory neuropathology, disordered cytoskeleton, and disrupted synaptic signaling of the AD brain and stressed brain cells; and (ii) is the first example of a microbiome-derived neurotoxic glycolipid having significant detrimental miRNA-30b-mediated actions on the expression of NF-L, an abundant neuron-specific filament protein known to be important in the maintenance of neuronal cell shape, axonal caliber, and synaptic homeostasis

Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis

BackgroundDespite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune‐related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life‐threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment‐related encephalitis, and provide practical guidance on diagnosis and management.MethodsWe searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8‐year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol‐Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned.ResultsIn our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy (n = 22), noninfective meningitis (n = 5), encephalitis (n = 6), neuromuscular disorders (n = 3), and nonspecific adverse events (n = 7). Study drug was discontinued (n = 20), interrupted (n = 8), or unchanged (n = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1–170) and to resolution was 32 days (2–809+). Median time to onset of encephalitis was 55.5 days (range 18–297); four cases resolved and one was fatal.ConclusionBoth oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs.Implications for PracticeWith increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune‐related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.Melanoma is a particularly immunogenic cancer, and immune checkpoint inhibitors have been extensively studied in this tumor type. This review focuses on the incidence of serious neurologic immune‐related adverse events, specifically encephalitis, in patients with advanced melanoma treated with nivolumab alone or in sequence or combination with ipilimumab. Practical guidance is provided for the diagnosis and management of treatment‐related encephalitis associated with nivolumab and ipilimumab.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139998/1/onco12130.pd