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

Ising nematic phase in ultra-thin magnetic films: a Monte Carlo study

We study the critical properties of a two--dimensional Ising model with competing ferromagnetic exchange and dipolar interactions, which models an ultra-thin magnetic film with high out--of--plane anisotropy in the monolayer limit. We present numerical evidence showing that two different scenarios appear in the model for different values of the exchange to dipolar intensities ratio, namely, a single first order stripe - tetragonal phase transition or two phase transitions at different temperatures with an intermediate Ising nematic phase between the stripe and the tetragonal ones. Our results are very similar to those predicted by Abanov et al [Phys. Rev. B 51, 1023 (1995)], but suggest a much more complex critical behavior than the predicted by those authors for both the stripe-nematic and the nematic-tetragonal phase transitions. We also show that the presence of diverging free energy barriers at the stripe-nematic transition makes possible to obtain by slow cooling a metastable supercooled nematic state down to temperatures well below the transition one.Comment: 13 pages, 19 figure

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Interplay between coarsening and nucleation in an Ising model with dipolar interactions

We study the dynamical behavior of a square lattice Ising model with exchange and dipolar interactions by means of Monte Carlo simulations. After a sudden quench to low temperatures we find that the system may undergo a coarsening process where stripe phases with different orientations compete or alternatively it can relax initially to a metastable nematic phase and then decay to the equilibrium stripe phase through nucleation. We measure the distribution of equilibration times for both processes and compute their relative probability of occurrence as a function of temperature and system size. This peculiar relaxation mechanism is due to the strong metastability of the nematic phase, which goes deep in the low temperature stripe phase. We also measure quasi-equilibrium autocorrelations in a wide range of temperatures. They show a distinct decay to a plateau that we identify as due to a finite fraction of frozen spins in the nematic phase. We find indications that the plateau is a finite size effect. Relaxation times as a function of temperature in the metastable region show super-Arrhenius behavior, suggesting a possible glassy behavior of the system at low temperatures

Activity in Inferior Parietal and Medial Prefrontal Cortex Signals the Accumulation of Evidence in a Probability Learning Task

In an uncertain environment, probabilities are key to predicting future events and making adaptive choices. However, little is known about how humans learn such probabilities and where and how they are encoded in the brain, especially when they concern more than two outcomes. During functional magnetic resonance imaging (fMRI), young adults learned the probabilities of uncertain stimuli through repetitive sampling. Stimuli represented payoffs and participants had to predict their occurrence to maximize their earnings. Choices indicated loss and risk aversion but unbiased estimation of probabilities. BOLD response in medial prefrontal cortex and angular gyri increased linearly with the probability of the currently observed stimulus, untainted by its value. Connectivity analyses during rest and task revealed that these regions belonged to the default mode network. The activation of past outcomes in memory is evoked as a possible mechanism to explain the engagement of the default mode network in probability learning. A BOLD response relating to value was detected only at decision time, mainly in striatum. It is concluded that activity in inferior parietal and medial prefrontal cortex reflects the amount of evidence accumulated in favor of competing and uncertain outcomes

Sustainability disclosure and reputation: a comparative study

“This is a post-peer-review, pre-copyedit version of an article published in Corporate Reputation Review. The definitive publisher-authenticated version Corporate Reputation Review 14(2), pp.79-96 is available online at: http://www.palgrave-journals.com/crr/index.html”Drawing on legitimacy theory, we discuss that a company’s reputation is a determinant of sustainability disclosure. Specifically, we consider the concept of reputation into three dimensions for analysis: stakeholders’ commitment, financial performance and media exposure. This paper differs from previous social and environmental reporting studies in that it investigates both internal and external contextual factors that influence disclosure practice. We claim that companies with a good financial performance, that are adopting an active strategic position towards stakeholders and that are exposed to significant public pressure are more likely to use sustainability disclosure in order to communicate their legitimacy to operate to stakeholders. Moreover the paper analyses a wide range of corporate reports for their social and environmental content using an international sample that allows for a comparison of disclosure practices among Continental European, UK and USA companies. Our results show that stakeholder commitment and media exposure are positively associated with sustainability disclosure. Moreover, we find evidence that the drivers of disclosure vary by information type

Left Ventricular Ejection Fraction in Patients With Ovarian Cancer Treated With Avelumab, Pegylated Liposomal Doxorubicin, or Both

In the phase III JAVELIN Ovarian 200 trial, 566 patients with platinum-resistant/refractory ovarian cancer were randomized 1:1:1 to receive avelumab alone, avelumab plus pegylated liposomal doxorubicin (PLD), or PLD alone. Cardiac monitoring was included for all patients. We report left ventricular ejection fraction (LVEF) data from the trial. Grade ≥3 cardiac adverse events (AEs) occurred in 4 (2.1%), 1 (0.5%), and 0 patients in the avelumab, combination, and PLD arms, respectively. LVEF decreases of ≥10% to below institutional lower limit of normal at any time during treatment were observed in 1 (0.8%), 3 (1.9%), and 2 (1.5%) patients, respectively; 4 had subsequent assessments, and these showed transient decreases. No patient had a cardiovascular AE related to LVEF decrease. This analysis is, to our knowledge, the first analysis of LVEF in patients receiving immune checkpoint inhibitors. CLINICALTRIALS.GOV IDENTIFIER: NCT02580058